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Sample records for autoimmune myasthenia gravis

  1. Insights in the autoimmunity of myasthenia gravis.

    PubMed

    De Baets, Marc H

    2010-08-01

    Myasthenia gravis is a prototype anti-receptor autoimmune disease. Antibodies against proteins at the neuromuscular junction cause a defect in the signal transmission from nerve terminal to the damaged postsynaptic membrane. This issue of Autoimmunity reviews the mechanisms that lead to the destruction of the neuromuscular junction and the role of the thymus in myasthenia gravis and its animal models. In addition, this issue explores recent advances in diagnosis and treatment of this disease.

  2. Myasthenia Gravis

    MedlinePlus

    Myasthenia gravis is a disease that causes weakness in your voluntary muscles. These are the muscles that you ... gets worse with activity, and better with rest. Myasthenia gravis is an autoimmune disease. Your body's immune system ...

  3. Therapeutic options in autoimmune myasthenia gravis.

    PubMed

    García-Carrasco, Mario; Escárcega, Ricardo O; Fuentes-Alexandro, Salvador; Riebeling, Carlos; Cervera, Ricard

    2007-06-01

    Autoimmune myasthenia gravis (MG) is associated with circulating antibodies to AChR, modification of the synaptic cleft, and destruction of the postsynaptic neuromuscular membrane. The hallmark is fluctuating muscular weakness and fatigability of muscles on sustained repeated activity. Various drugs and invasive procedures have been used in the treatment of MG including acetylcholinesterase inhibitors, corticosteroids, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, tacrolimus, etanercept, intravenous immunoglobulin, plasma exchange and thymectomy. We review the role of each of these drugs and invasive procedures in MG. Although current treatment is highly successful and mortality is almost nil, further trials are required to identify the most suitable treatments for different subgroups of MG patients. In addition, safer and more potent drugs are required as most current drugs have major side effects due to immunosuppression. Therefore, the goal of novel therapies should be increased specificity of the immune-directed agents.

  4. Myasthenia Gravis: paradox versus paradigm in autoimmunity.

    PubMed

    Berrih-Aknin, Sonia

    2014-08-01

    Myasthenia Gravis (MG) is a paradigm of organ-specific autoimmune disease (AID). It is mediated by antibodies that target the neuromuscular junction. The purpose of this review is to place MG in the general context of autoimmunity, to summarize the common mechanisms between MG and other AIDs, and to describe the specific mechanisms of MG. We have chosen the most common organ-specific AIDs to compare with MG: type 1 diabetes mellitus (T1DM), autoimmune thyroid diseases (AITD), multiple sclerosis (MS), some systemic AIDs (systemic lupus erythematous (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS)), as well as inflammatory diseases of the gut and liver (celiac disease (CeD), Crohn's disease (CD), and primary biliary cirrhosis (PBC)). Several features are similar between all AIDs, suggesting that common pathogenic mechanisms lead to their development. In this review, we address the predisposing factors (genetic, epigenetic, hormones, vitamin D, microbiota), the triggering components (infections, drugs) and their interactions with the immune system [1,2]. The dysregulation of the immune system is detailed and includes the role of B cells, Treg cells, Th17 and cytokines. We particularly focused on the role of TNF-α and interferon type I whose role in MG is very analogous to that in several other AIDS. The implication of AIRE, a key factor in central tolerance is also discussed. Finally, if MG is a prototype of AIDS, it has a clear specificity compared to the other AIDS, by the fact that the target organ, the muscle, is not the site of immune infiltration and B cell expansion, but exclusively that of antibody-mediated pathogenic mechanisms. By contrast, the thymus in the early onset subtype frequently undergoes tissue remodeling, resulting in the development of ectopic germinal centers surrounded by high endothelial venules (HEV), as observed in the target organs of many other AIDs.

  5. [Myasthenia gravis].

    PubMed

    Schodrowski, J; Seipelt, M; Adibi-Sedeh, I; Eienbröker, C; Tackenberg, B

    2016-04-01

    Myasthenia gravis is an autoimmune disease, which leads to load-dependent weakness of voluntary skeletal muscles with recovery of function after resting. The disease is caused by autoantibodies directed against the postsynaptic nicotinic acetylcholine receptors (AChR) leading to a reduction of neuromuscular transmission. Muscles and nerves are not affected. Disorders of the thymus play a role in the pathogenesis of AChR antibody-positive myasthenia. The clinical symptoms include exercise-induced fatigue either of the ocular muscles alone (ocular myasthenia) or striated skeletal muscle and the ocular, facial and bulbar musculature (generalized myasthenia). Treatment of myasthenia gravis involves administration of acetylcholine esterase inhibitors and immunosuppressive drugs. A myasthenic crisis is characterized by life-threatening complications with severe weakness, swallowing difficulties and respiratory failure, which requires intensive care treatment.

  6. Complicating autoimmune diseases in myasthenia gravis: a review.

    PubMed

    Nacu, Aliona; Andersen, Jintana Bunpan; Lisnic, Vitalie; Owe, Jone Furlund; Gilhus, Nils Erik

    2015-01-01

    Myasthenia gravis (MG) is a rare autoimmune disease of skeletal muscle endplates. MG subgroup is relevant for comorbidity, but usually not accounted for. MG patients have an increased risk for complicating autoimmune diseases, most commonly autoimmune thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. In this review, we present concomitant autoimmune disorders associated with the different MG subgroups, and show how this influences treatment and prognosis. Concomitant MG should always be considered in patients with an autoimmune disorder and developing new neuromuscular weakness, fatigue or respiratory failure. When a second autoimmune disorder is suspected, MG should be included as a differential diagnosis.

  7. The etiology of autoimmune diseases: the case of myasthenia gravis.

    PubMed

    Bach, Jean-François

    2012-12-01

    Autoimmune diseases comprise a wide variety of disorders, from those that are acute and spontaneously regressive to chronic diseases. Their occurrence is the sign of a loss of tolerance to self-antigens. With few exceptions, the etiology of autoimmune diseases has not been clearly established. In all cases, it is complex, involving genetic, epigenetic, and environmental factors. In this article I will attempt to analyze the various factors that have a triggering or protecting role, with particular reference to myasthenia gravis.

  8. The role of B cell-activating factor in autoimmune myasthenia gravis.

    PubMed

    Lisak, Robert P; Ragheb, Samia

    2012-12-01

    B cell-activating factor (BAFF) is important in the development and maturation of B cells and their progeny-plasma blasts and plasma cells. There is increasing evidence that BAFF is involved in the pathogenesis of several autoimmune diseases including myasthenia gravis. Increased expression of BAFF and receptors for BAFF have been demonstrated in thymus of patients with myasthenia gravis, and an increase in serum levels of BAFF have been reported in patients with myasthenia gravis. While the exact role of BAFF in the pathogenesis of myasthenia gravis is not clear, BAFF and its receptors may provide potential targets for therapy in patients with myasthenia gravis.

  9. Clinical and biological heterogeneity of autoimmune myasthenia gravis.

    PubMed

    Pal, Jozsef; Rozsa, Csilla; Komoly, Samuel; Illes, Zsolt

    2011-02-01

    Although myasthenia gravis (MG) has long been considered a well-established autoimmune disease associated with autoantibodies, which are convincingly pathogenic, accumulating data indicate both clinical and biological heterogeneity similar to many other putative autoimmune disorders. In a subset of patients, thymus plays a definite role: thymic autoimmunity results in generation of autoantibodies within the thymus, which cross-react with antigens at the neuromuscular junction, or thymoma leads to deficient central tolerance and impaired T cell selection. Heterogeneity on the autoantibody level may be associated with genetic heterogeneity and clinical phenotypes with different treatment responses.

  10. Myasthenia gravis - resources

    MedlinePlus

    Resources - myasthenia gravis ... The following organizations provide information on myasthenia gravis : Myasthenia Gravis Foundation of America -- www.myasthenia.org National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/disorders/myasthenia_gravis/ ...

  11. Diagnostic and clinical classification of autoimmune myasthenia gravis.

    PubMed

    Berrih-Aknin, Sonia; Frenkian-Cuvelier, Mélinée; Eymard, Bruno

    2014-01-01

    Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are against the acetylcholine receptor (AChR). Recently, other targets have been described such as the MuSK protein (muscle-specific kinase) or the LRP4 (lipoprotein related protein 4). Myasthenia gravis can be classified according to the profile of the autoantibodies, the location of the affected muscles (ocular versus generalized), the age of onset of symptoms and thymic abnormalities. The disease generally begins with ocular symptoms (ptosis and/or diplopia) and extends to other muscles in 80% of cases. Other features that characterize MG include the following: variability, effort induced worsening, successive periods of exacerbation during the course of the disease, severity dependent on respiratory and swallowing impairment (if rapid worsening occurs, a myasthenic crisis is suspected), and an association with thymoma in 20% of patients and with other autoimmune diseases such as hyperthyroidism and Hashimoto's disease. The diagnosis is based on the clinical features, the benefit of the cholinesterase inhibitors, the detection of specific autoantibodies (anti-AChR, anti-MuSK or anti-LRP4), and significant decrement evidenced by electrophysiological tests. In this review, we briefly describe the history and epidemiology of the disease and the diagnostic and clinical classification. The neonatal form of myasthenia is explained, and finally we discuss the main difficulties of diagnosis.

  12. [Pathogenesis of myasthenia gravis].

    PubMed

    Téllez Zenteno, J F; Morales Buenrostro, L E; Torre Delgadillo, A

    2000-01-01

    Myasthenia gravis is a neuromuscular, autoimmune, and acquired disturbance characterized by weakness and fatigue of skeletal muscles. During the past two decades, remarkable progress has been made in the understanding of myasthenia gravis, and the new knowledge has been applied directly to the clinical diagnosis and treatment of this formerly severe disease. Myasthenia gravis is undoubtedly the most thoroughly understood of all human autoimmune diseases and has served as a model for the elucidation of mechanisms underlying other autoimmune disorders. In this review we mention the most important physiopathological aspects and its application in the clinic practice.

  13. Treatment of passively transferred experimental autoimmune myasthenia gravis using papain

    PubMed Central

    Poulas, K; Tsouloufis, T; Tzartos, S J

    2000-01-01

    Antibody-mediated acetylcholine receptor (AChR) loss at the neuromuscular junction, the main cause of the symptoms of myasthenia gravis, is induced by bivalent or multivalent antibodies. Passive transfer of experimental autoimmune myasthenia gravis (EAMG) can be induced very efficiently in rats by administration of intact MoAbs directed against the main immunogenic region (MIR) of the AChR, but not by their monovalent Fab fragments. We tested whether papain, which has been used therapeutically in autoimmune and other diseases, is capable of preventing EAMG by in vivo cleavage of the circulating anti-AChR antibodies into Fab fragments. EAMG was induced in 4-week-old female Lewis rats by i.p. injection of anti-MIR mAb35. A total of 0·75 mg of papain was given as one or three injections 3–7 h after MoAb injection. The mAb35 + papain-treated animals developed mild weakness during the first 30 h and subsequently recovered, while all animals that received only mAb35 developed severe myasthenic symptoms and died within 24–30 h. Animals treated only with papain showed no apparent side effects for up to 2 months. Serum anti-AChR levels in mAb35 + papain-treated rats decreased within a few hours, whereas in non-papain-treated rats they remained high for at least 30 h. Muscle AChR in mAb35 + papain-treated animals was partially protected from antibody-mediated degradation. These results show that treatment of rats with papain can prevent passively transferred EAMG without any apparent harm to the animals, and suggest a potential therapeutic use for proteolytic enzymes in myasthenia gravis. PMID:10792389

  14. The thymus in myasthenia gravis: Site of "innate autoimmunity"?

    PubMed

    Cavalcante, Paola; Le Panse, Rozen; Berrih-Aknin, Sonia; Maggi, Lorenzo; Antozzi, Carlo; Baggi, Fulvio; Bernasconi, Pia; Mantegazza, Renato

    2011-10-01

    Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor. The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T cells, and autoantibody-secreting plasma cells). In this study we review early and more recent findings implicating the thymus as site of AChR autosensitization in MG and briefly discuss the therapeutic role of thymectomy. We also summarize data showing that the MG thymus is in a state of chronic inflammation, and we review emerging evidence of a viral contribution to the onset and maintenance of the thymic autoimmune response.

  15. Combined short-term immunotherapy for experimental autoimmune myasthenia gravis

    SciTech Connect

    Pestronk, A.; Drachman, D.B.; Teoh, R.; Adams, R.N.

    1983-08-01

    A therapeutic strategy was designed to eliminate the humoral immune response to acetylcholine receptor (AChR) in ongoing experimental autoimmune myasthenia gravis (EAMG). Rats with EAMG were treated with a protocol consisting of three components: (1) A single high dose of cyclophosphamide (200 mg/kg) was used to produce a rapid and sustained fall in the anti-AChR antibody levels by preferential destruction of antibody-producing B-lymphocytes. ''Memory'' lymphocytes were not eliminated by cyclophosphamide. (2) Irradiation (600 rads) was used to eliminate the ''memory'' cells. It eliminated the anamnestic response to a challenge with the antigen AChR. (3) Bone marrow transplantation was used to repopulate the hematopoietic system after the otherwise lethal dose of cyclophosphamide. We used bone marrow from syngeneic rats with active EAMG to simulate an autologous transplant. Rats with EAMG treated with this combined protocol showed a prompt and sustained fall in the anti-AChR antibody levels and had no anamnestic response to a challenge with AChR. Thus, an affected animal's own marrow could be stored and used later for repopulation after cyclophosphamide-irradiation treatment. This treatment eliminates the animal's ongoing immune responses and reconstitutes the immune system in its original state. The success of this approach suggests that, if their safety could be established, similar ''curative'' strategies might be developed for the treatment of patients with severe antibody-mediated autoimmune disorders, such as myasthenia gravis.

  16. Myasthenia gravis

    MedlinePlus

    ... receiving messages (neurotransmitters) from the nerve cells. The exact cause of myasthenia gravis is unknown. In some ... must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map FAQs Customer Support Get ...

  17. Alterations in the thymopoiesis in experimental autoimmune myasthenia gravis.

    PubMed

    Kosec, Dusko; Vidić-Danković, Biljana; Isaković, Katarina; Leposavić, Gordana

    2005-04-01

    Experimental autoimmune myasthenia gravis (EAGM) was induced in female AO rats, by a single immunization with Torpedo acetylcholine receptor (AChR). Animals injected with saline served as controls. The study showed substantial changes in EAMG rats in the thymopoiesis, causing an increase in the relative proportion of mature CD8+ and, particularly, CD4+ (possibly autoreactive) single positive (SP) cells expressing TCRalphabeta at high level (TCRalphabeta(high)), as well as in that of mature double negative (DN) TCRalphabeta(high) cells, which are believed to be the immunoregulatory cells that augment autoantibody (autoAb) production. These results indicate that an augmented production of autoreactive CD4+ cells, on one side, and an increase of the immunoregulatory T cells that augment autoAb production, on the other side (reflecting, most likely, an increased entry of activated autoreactive CD4+ T cells from the periphery into the thymus), may have a significant role in the sustention of immune response in EAMG, and may suggest a putative mechanism underlying the sustention of autoimmune response in acquired MG.

  18. Thymus, thymoma and myasthenia gravis.

    PubMed

    Fujii, Yoshitaka

    2013-05-01

    Myasthenia gravis is an autoimmune disease. An autoantibody directed toward acetylcholine receptor (AChR) causes the destruction of the postsynaptic membrane and a reduction of the number of AChRs at neuromuscular junctions. A very puzzling, but interesting characteristic of myasthenia gravis is that many of the patients have an abnormality in their thymus. Many have a hyperplastic thymus with germinal centers, while others have a thymic tumor. How is the abnormality of the thymus related to myasthenia gravis? This review will summarize the existing evidence and try to find the missing link between the thymus and myasthenia gravis. The review will also comment on two distinct populations of myasthenia gravis patients without thymoma. The autoimmunity found in elderly patients is nonspecific and initiated via a different mechanism from the initiation of myasthenia gravis in younger patients.

  19. Regulatory and pathogenic mechanisms in human autoimmune myasthenia gravis.

    PubMed

    Le Panse, Rozen; Cizeron-Clairac, Géraldine; Cuvelier, Mélinée; Truffault, Frédérique; Bismuth, Jacky; Nancy, Patrice; De Rosbo, Nicole Kerlero; Berrih-Aknin, Sonia

    2008-01-01

    The thymus is frequently hyperplastic in young female myasthenia gravis (MG) patients presenting with anti-acetylcholine receptor (AChR) antibodies. This thymic pathology is characterized by the presence of ectopic germinal centers (GCs) containing B cells involved at least partially in the production of pathogenic anti-AChR antibodies. Our recent studies have furthered our understanding of the mechanisms leading to GC formation in the hyperplastic thymus. First, we showed that CXCL13 and CCL21, chemokines involved in GC formation, are overexpressed in MG thymus. Second, we demonstrated an increase in pro-inflammatory activity in the thymus from MG patients and its partial normalization by glucocorticoids, as evidenced by gene expression profile. Third, we found that pro-inflammatory cytokines are able to upregulate the expression of AChR subunits in thymic epithelial and myoid cells. Fourth, we showed that the function of T regulatory (Treg) cells, whose role is to downregulate the immune response, is severely impaired in the thymus of MG patients; such a defect could explain the chronic immune activation observed consistently in MG thymic hyperplasia. Altogether, these new data suggest that CXCL13 and CCL21, which are produced in excess in MG thymus, attract peripheral B cells and activated T cells, which are maintained chronically activated in the inflammatory thymic environment because of the defect in suppressive activity of Treg cells. Presence of AChR in the thymus and upregulation of its expression by the pro-inflammatory environment contribute to the triggering and maintenance of the anti-AChR autoimmune response.

  20. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis.

    PubMed

    Piddlesden, S J; Jiang, S; Levin, J L; Vincent, A; Morgan, B P

    1996-12-01

    The loss of muscle function seen in myasthenia gravis and in the animal model of the disease, experimental autoimmune myasthenia gravis (EAMG) is in part due to the activation of complement by anti-acetylcholine receptor (AChR) antibodies at the motor end-plate. In this study we describe the effects of a soluble recombinant form of human complement receptor 1 (sCR1) on the development of clinical disease and receptor loss in EAMG induced passively by administration of anti-AChR antibodies. Daily intraperitoneal injection of sCR1 significantly reduced the weight loss and severity of clinical symptoms seen and allowed treated animals to recover normal muscle function. These data suggest that sCR1 could provide a useful additional therapeutic agent in myasthenia.

  1. Resolution of Autoimmune Oophoritis after Thymectomy in a Myasthenia Gravis Patient

    PubMed Central

    Özdemir, Özlem; Eren, Erdal; Sağlam, Halil; Okan, Mehmet; Tarım, Ömer Faruk

    2011-01-01

    Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against acetylcholine receptors. MG is generally an isolated disorder but may occur concomitantly with other autoimmune diseases. We describe an eighteen-year-old girl with MG who was admitted to our clinic with secondary amenorrhea and diagnosed as autoimmune oophoritis. Since her myasthenic symptoms did not resolve with anticholinesterase therapy, thymectomy was performed. After thymectomy, her menses have been regular without any hormonal replacement therapy. To our knowledge, this is the first report on a patient with autoimmune ovarian insufficiency and MG in whom premature ovarian insufficiency resolved after thymectomy, without hormonal therapy. Conflict of interest:None declared. PMID:22155465

  2. Vaccines against myasthenia gravis

    PubMed Central

    Berrih-Aknin, Sonia; Fuchs, Sara; Souroujon, Miriam C

    2007-01-01

    Myasthenia gravis (MG) is an autoimmune disease mediated by antibodies to nicotinic acetylcholine receptor (AChR) interfering with the neuromuscular transmission. Experimental autoimmune MG serves as an excellent animal model to study possible therapeutic modalities for MG. This review will focus on the different ways to turn off the autoimmune response to AChR, which results in suppression of myasthenia. This paper will describe the use of fragments or peptides derived from the AChR, antigen-presenting cells and anti-T cell receptor antibodies, and will discuss the underlying mechanisms of action. Finally, the authors propose new promising therapeutic prospects, including treatment based on the modulation of regulatory T cells, which have recently been found to be functionally defective in MG patients. PMID:16018742

  3. Genetics Home Reference: myasthenia gravis

    MedlinePlus

    ... Genetic basis of myasthenia gravis - a comprehensive review. J Autoimmun. 2014 Aug;52:146-53. doi: 10.1016/j.jaut.2013.12.001. Epub 2013 Dec 19. ... comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun. 2014 Aug;52:90-100. doi: 10. ...

  4. Prophylactic effect of probiotics on the development of experimental autoimmune myasthenia gravis.

    PubMed

    Chae, Chang-Suk; Kwon, Ho-Keun; Hwang, Ji-Sun; Kim, Jung-Eun; Im, Sin-Hyeog

    2012-01-01

    Probiotics are live bacteria that confer health benefits to the host physiology. Although protective role of probiotics have been reported in diverse diseases, no information is available whether probiotics can modulate neuromuscular immune disorders. We have recently demonstrated that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental disorders in mice model. In this study we further investigated whether IRT5 probiotics could modulate the progression of experimental autoimmune myasthenia gravis (EAMG). Myasthenia gravis (MG) is a T cell dependent antibody mediated autoimmune disorder in which acetylcholine receptor (AChR) at the neuromuscular junction is the major auto-antigen. Oral administration of IRT5 probiotics significantly reduced clinical symptoms of EAMG such as weight loss, body trembling and grip strength. Prophylactic effect of IRT5 probiotics on EMAG is mediated by down-regulation of effector function of AChR-reactive T cells and B cells. Administration of IRT5 probiotics decreased AChR-reactive lymphocyte proliferation, anti-AChR reactive IgG levels and inflammatory cytokine levels such as IFN-γ, TNF-α, IL-6 and IL-17. Down-regulation of inflammatory mediators in AChR-reactive lymphocytes by IRT5 probiotics is mediated by the generation of regulatory dendritic cells (rDCs) that express increased levels of IL-10, TGF-β, arginase 1 and aldh1a2. Furthermore, DCs isolated from IRT5 probiotics-fed group effectively converted CD4(+) T cells into CD4(+)Foxp3(+) regulatory T cells compared with control DCs. Our data suggest that IRT5 probiotics could be applicable to modulate antibody mediated autoimmune diseases including myasthenia gravis.

  5. Experimental Autoimmune Myasthenia Gravis (EAMG): from immunochemical characterization to therapeutic approaches.

    PubMed

    Fuchs, Sara; Aricha, Revital; Reuveni, Debby; Souroujon, Miriam C

    2014-11-01

    Myasthenia Gravis (MG) is an organ-specific autoimmune disease. In high percentage of patients there are autoantibodies to the nicotinic acetylcholine receptor (AChR) that attack AChR on muscle cells at the neuromuscular junction, resulting in muscle weakness. Experimental Autoimmune Myasthenia Gravis (EAMG) is an experimental model disease for MG. EAMG is induced in several animal species by immunization with acetylcholine receptor (AChR), usually isolated from the electric organ of electric fish, which is a rich source for this antigen. Our lab has been involved for several decades in research of AChR and of EAMG. The availability of an experimental autoimmune disease that mimics in many aspects the human disease, provides an excellent model system for elucidating the immunological nature and origin of MG, for studying various existing treatment modalities and for attempting the development of novel treatment approaches. In this review in honor of Michael Sela and Ruth Arnon, we report first on our early pioneering contributions to research on EAMG. These include the induction of EAMG in several animal species, early attempts for antigen-specific treatment for EAMG, elicitation and characterization of monoclonal antibodies and anti-idiotypic antibodies, measuring humoral and cellular AChR-specific immune responses in MG patient and more. In the second part of the review we discuss more recent studies from our lab towards developing and testing novel treatment approaches for myasthenia. These include antigen-dependent treatments aimed at specifically abrogating the humoral and cellular anti-AChR responses, as well as immunomodulatory approaches that could be used either alone, or in conjunction with antigen-specific treatments, or alternatively, serve as steroid-sparing agents.

  6. Myasthenia Gravis Complications

    MedlinePlus

    ... arms or hands Holding up your head Causes Antibodies Your nerves communicate with your muscles by releasing ... junction. In myasthenia gravis, your immune system produces antibodies that block or destroy many of your muscles' ...

  7. Treatment for Myasthenia Gravis (MG)

    MedlinePlus

    ... are individualized There are many effective treatments for myasthenia gravis. Spontaneous improvement and even remission (although uncommon) may ... Created by Kellen Interactive Web Design © copyright 2010 Myasthenia Gravis Foundation of America, Inc.

  8. Silencing miR-146a influences B cells and ameliorates experimental autoimmune myasthenia gravis.

    PubMed

    Zhang, JunMei; Jia, Ge; Liu, Qun; Hu, Jue; Yan, Mei; Yang, BaiFeng; Yang, Huan; Zhou, WenBin; Li, Jing

    2015-01-01

    MicroRNAs have been shown to be important regulators of immune homeostasis as patients with aberrant microRNA expression appeared to be more susceptible to autoimmune diseases. We recently found that miR-146a was up-regulated in activated B cells in response to rat acetylcholine receptor (AChR) α-subunit 97-116 peptide, and this up-regulation was significantly attenuated by AntagomiR-146a. Our data also demonstrated that silencing miR-146a with its inhibitor AntagomiR-146a effectively ameliorated clinical myasthenic symptoms in mice with ongoing experimental autoimmune myasthenia gravis. Furthermore, multiple defects were observed after miR-146a was knocked down in B cells, including decreased anti-R97-116 antibody production and class switching, reduced numbers of plasma cells, memory B cells and B-1 cells, and weakened activation of B cells. Previously, miR-146a has been identified as a nuclear factor-κB-dependent gene and predicted to base pair with the tumour necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) genes to regulate the immune response. However, our study proved that miR-146a inhibition had no effect on the expression of TRAF6 and IRAK1 in B cells. This result suggests that the function of miR-146a in B cells does not involve these two target molecules. We conclude that silencing miR-146a exerts its therapeutic effects by influencing the B-cell functions that contribute to the autoimmune pathogenesis of myasthenia gravis.

  9. The thymus in myasthenia gravis. Changes typical for the human disease are absent in experimental autoimmune myasthenia gravis of the Lewis rat.

    PubMed Central

    Meinl, E.; Klinkert, W. E.; Wekerle, H.

    1991-01-01

    In human myasthenia gravis (MG) formation of autoantibodies against acetylcholine receptor (AChR) is commonly associated with thymic changes termed lymphofollicular hyperplasia (LFH). To learn whether the thymic lesions of human MG are primary changes in the autoimmune pathogenesis, or rather secondary events caused by peripheral autoimmunization, the authors compared the pathologic changes of MG thymuses with the thymuses of Lewis rats with experimental autoimmune myasthenia gravis (EAMG). EAMG was induced either actively by immunization with AChR, or transferred passively with monoclonal antibodies (mAb) binding to AChR. The clinical diagnosis of EAMG was confirmed by electromyography. Germinal centers, which are typical for human MG thymuses, were not detectable in the thymus of EAMG rats. Scattered B cells were seen as normal components of the thymic medulla. In EAMG their number was not augmented, nor were they accumulated focally. The perivascular spaces (PVS) were not distended and the amount of reticulin was not increased. Thymic myoid cells were identified in EAMG as well as in control thymuses; their cellular microenvironment was inconspicuous. Both in normal and in EAMG thymuses, a subpopulation of myoid cells expressed the main immunogenic region of the AChR. Heavily affected rats showed a severe cortical involution, but no specific changes of the medulla. The fact that none of the thymic lesions characteristic for human MG was found in EAMG is compatible with the concept that the thymic changes in MG are primary events in the autoimmune pathogenesis of this disease. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1951638

  10. IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice.

    PubMed

    Huda, Ruksana; Strait, Richard T; Tüzün, Erdem; Finkelman, Fred D; Christadoss, Premkumar

    2015-04-15

    Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to neuromuscular junction (NMJ) damage by anti-acetylcholine receptor (AChR) auto-antibodies and complement. In experimental autoimmune myasthenia gravis (EAMG), which is induced by immunization with Torpedo AChR in CFA, anti-AChR IgG2b and IgG1 are the predominant isotypes in the circulation. Complement activation by isotypes such as IgG2b plays a crucial role in EAMG pathogenesis; this suggested the possibility that IgG1, which does not activate complement through the classical pathway, may suppress EAMG. In this study, we show that AChR-immunized BALB/c mice genetically deficient for IgG1 produce higher levels of complement-activating isotypes of anti-AChR, especially IgG3 and IgG2a, and develop increased IgG3/IgG2a deposits at the NMJ, as compared to wild type (WT) BALB/c mice. Consistent with this, AChR-immunized IgG1(-/-) BALB/c mice lose muscle strength and muscle AChR to a greater extent than AChR-immunized WT mice. These observations demonstrate that IgG1 deficiency leads to increased severity of EAMG associated with an increase in complement activating IgG isotypes. Further studies are needed to dissect the specific role or mechanism of IgG1 in limiting EAMG and that of EAMG exacerbating role of complement activating IgG3 and IgG2a in IgG1 deficiency.

  11. Role of tolerogen conformation in induction of oral tolerance in experimental autoimmune myasthenia gravis.

    PubMed

    Im, S H; Barchan, D; Souroujon, M C; Fuchs, S

    2000-10-01

    We recently demonstrated that oral or nasal administration of recombinant fragments of the acetylcholine receptor (AChR) prevents the induction of experimental autoimmune myasthenia gravis (EAMG) and suppresses ongoing EAMG in rats. We have now studied the role of spatial conformation of these recombinant fragments in determining their tolerogenicity. Two fragments corresponding to the extracellular domain of the human AChR alpha-subunit and differing in conformation were tested: Halpha1-205 expressed with no fusion partner and Halpha1-210 fused to thioredoxin (Trx), and designated Trx-Halpha1-210. The conformational similarity of the fragments to intact AChR was assessed by their reactivity with alpha-bungarotoxin and with anti-AChR mAbs, specific for conformation-dependent epitopes. Oral administration of the more native fragment, Trx-Halpha1-210, at the acute phase of disease led to exacerbation of EAMG, accompanied by an elevation of AChR-specific humoral and cellular reactivity, increased levels of Th1-type cytokines (IL-2, IL-12), decreased levels of Th2 (IL-10)- or Th3 (TGF-beta)-type cytokines, and higher expression of costimulatory factors (CD28, CTLA4, B7-1, B7-2, CD40L, and CD40). On the other hand, oral administration of the less native fragments Halpha1-205 or denatured Trx-Halpha1-210 suppressed ongoing EAMG and led to opposite changes in the immunological parameters. It thus seems that native conformation of AChR-derived fragments renders them immunogenic and immunopathogenic and therefore not suitable for treatment of myasthenia gravis. Conformation of tolerogens should therefore be given careful attention when considering oral tolerance for treatment of autoimmune diseases.

  12. Assays for myasthenia gravis

    SciTech Connect

    Lindstrom, J.M.

    1988-12-06

    This patent describes an improvement in a process for diagnosing myasthenia gravis. The process comprises the steps of preparing a complex of acetycholine receptor protein, toxin and a radioactive isotope, incubating the complex with a serum sample from a patient so as to join antibodies engendered in connection with myasthenia gravis to the complex, precipitating the complex joined with antibody with anti-immunoglobulin and measuring radioactivity, from the radioactive isotope, of the precipitated complex. The improvement is that the acetylcholine receptor protein is derived from cells of the TE671 Line.

  13. The thymus in autoimmune Myasthenia Gravis: Paradigm for a tertiary lymphoid organ.

    PubMed

    Weiss, J-M; Cufi, P; Le Panse, R; Berrih-Aknin, S

    2013-01-01

    In autoimmune Myasthenia Gravis (MG), a neuromuscular disease generally mediated by autoantibodies against the acetylcholine receptor (AChR), the muscle is the target organ of the autoimmune attack, while the thymus seems to be the primary production site of the autoantibodies. In the majority of patients with anti-AChR antibodies, it is characterized by the presence of germinal centers, which contain B cells that produce anti-AChR antibodies. In this review, we summarize recent results regarding neoangiogenic processes, cell infiltration and modified chemokine expression in the MG thymus, which are typical features of secondary lymphoid organs. The structural and functional changes in the MG thymus therefore allow us to declare it to be an archetype for tertiary lymphoid neogenesis providing optimal settings for the interaction between lymphocytes and antigen presenting cells in order to elicit an immune response. We further discuss factors that may have a key role in the transformation of the MG thymus into a tertiary lymphoid organ, such as IFN type I and dsRNA signaling. These factors could also be of importance in other autoimmune diseases, especially those characterized by tertiary lymphoid neogenesis.

  14. Juvenile myasthenia gravis.

    PubMed

    Snead, O C; Benton, J W; Dwyer, D; Morley, B J; Kemp, G E; Bradley, R J; Oh, S J

    1980-07-01

    We studied 32 children with myasthenia gravis over a period of 12 years. The mean age at onset was 7.7 years. Presentation was ocular in 63% of patients. Another major disease in addition to myasthenia occurred in 44% of patients; a seizure disorder was the most commonly associated disease. Serum IgG antibody to nicotinic acetylcholine receptor was present in 53% of patients and did not correlate with severity of disease or treatment. Medical management was effective in 63%; thymectomy was effective in only 28%. We conclude that myasthenia gravis appears commonly before age 10 and is associated with the risk of some disease other than hyperthyroidism. Serum IgG nicotinic acetylcholine receptor antibody is present less frequently than in normal adults, and vigorous medical management should be attempted before thymectomy.

  15. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies

    PubMed Central

    1976-01-01

    Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages

  16. Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis.

    PubMed

    Guptill, Jeffrey T; Soni, Madhu; Meriggioli, Matthew N

    2016-01-01

    Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

  17. Experimental neonatal autoimmune myasthenia gravis: an immunohistochemical, ultrastructural and electrophysiological study of the motor end-plate.

    PubMed

    Tetsuo, N; Tsujihata, M; Satoh, A; Yoshimura, T; Nakamura, T; Seto, M; Nagataki, S

    1995-10-01

    Neonatal rats born of and nursed by mothers immunized with Narke japonica acetylcholine receptor protein had elevated serum anti-acetylcholine receptor antibodies that reached the mother's level on day 10 after delivery and decreased rapidly after weaning. IgG was present at the motor end-plates up to day 170, and the motor end-plate fine structure remained abnormal up to day 80. Miniature end-plate potential amplitudes in the diaphragm were at the control levels within 10 days of birth, but were lower than those of the controls up to day 80 after birth. We could not obtain the direct evidence that transient synthesis of antibodies occurs in experimental autoimmune myasthenia gravis pups. This model can serve as an experimental model of transient neonatal myasthenia gravis in humans, exception for the route of antibody transfer and the time of the onset of illness.

  18. Thymus irradiation for myasthenia gravis

    SciTech Connect

    Currier, R.D.; Routh, A.; Hickman, B.T.; Douglas, M.A.

    1983-01-01

    Twenty-eight patients with progressive myasthenia gravis without thymoma received treatment of 3000 rads (30 Gy) to the anterior mediastinum, and a followup was conducted for five to 18 years. Twenty-four patients had generalized myasthenia, and four had ocular myasthenia gravis. Twenty patients with generalized myasthenia survived the several month post-treatment period and improved, but four died during that period. The improvement lasted a median of 1.5 years, and older patients had longer remissions than younger patients. The four patients who had ocular myasthenia did not change after treatment. Mediastinal irradiation produces a temporary remission in generalized myasthenia.

  19. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis.

    PubMed

    Meraouna, Amel; Cizeron-Clairac, Geraldine; Panse, Rozen Le; Bismuth, Jacky; Truffault, Frederique; Tallaksen, Chantal; Berrih-Aknin, Sonia

    2006-07-15

    Myasthenia gravis (MG) is associated with ectopic germinal centers in the thymus. Thymectomy and glucocorticoids are the main treatments but they induce operative risks and side effects, respectively. The aim of this study was to propose new therapies more efficient for MG. We hypothesized that molecules dysregulated in MG thymus and normalized by glucocorticoids may play a key role in thymic pathogenesis. Using gene chip analysis, we identified 88 genes complying with these criteria, the most remarkable being the B-cell chemoattractant (CXCL13). Its expression was increased in thymus and sera of glucocorticoid-untreated patients and decreased in response to treatment in correlation with clinical improvement. Normal B cells were actively chemoattracted by thymic extracts from glucocorticoid-untreated patients, an effect inhibited by anti-CXCL13 antibodies. In the thymus, CXCL13 was preferentially produced by epithelial cells and overproduced by epithelial cells from MG patients. Altogether, our results suggest that a high CXCL13 production by epithelial cells could be responsible for germinal center formation in MG thymus. Furthermore, they show that this gene is a main target of corticotherapy. Thus, new therapies targeting CXCL13 could be of interest for MG and other autoimmune diseases characterized by ectopic germinal center formation.

  20. Differential RNA Expression Profile of Skeletal Muscle Induced by Experimental Autoimmune Myasthenia Gravis in Rats

    PubMed Central

    Kaminski, Henry J.; Himuro, Keiichi; Alshaikh, Jumana; Gong, Bendi; Cheng, Georgiana; Kusner, Linda L.

    2016-01-01

    The differential susceptibility of skeletal muscle by myasthenia gravis (MG) is not well understood. We utilized RNA expression profiling of extraocular muscle (EOM), diaphragm (DIA), and extensor digitorum (EDL) of rats with experimental autoimmune MG (EAMG) to evaluate the hypothesis that muscles respond differentially to injury produced by EAMG. EAMG was induced in female Lewis rats by immunization with acetylcholine receptor purified from the electric organ of the Torpedo. Six weeks later after rats had developed weakness and serum antibodies directed against the AChR, animals underwent euthanasia and RNA profiling performed on DIA, EDL, and EOM. Profiling results were validated by qPCR. Across the three muscles between the experiment and control groups, 359 probes (1.16%) with greater than 2-fold changes in expression in 7 of 9 series pairwise comparisons from 31,090 probes were identified with approximately two-thirds being increased. The three muscles shared 16 genes with increased expression and 6 reduced expression. Functional annotation demonstrated that these common expression changes fell predominantly into categories of metabolism, stress response, and signaling. Evaluation of specific gene function indicated that EAMG led to a change to oxidative metabolism. Genes related to muscle regeneration and suppression of immune response were activated. Evidence of a differential immune response among muscles was not evident. Each muscle had a distinct RNA profile but with commonality in gene categories expressed that are focused on muscle repair, moderation of inflammation, and oxidative metabolism. PMID:27891095

  1. [Umbilical cord mesenchymal stem cell transplantation for treatment of experimental autoimmune myasthenia gravis in rats].

    PubMed

    Yu, Jing-Xia; Chen, Fang; Sun, Jun; Wang, Ji-Ming; Zhao, Qin-Jun; Ren, Xin-Jun; Ma, Feng-Xia; Yang, Shao-Guang; Han, Zhi-Bo; Han, Zhong-Chao

    2011-06-01

    Umbilical cord mesenchymal stem cell (UCMSC) transplantation has been widely used in the treatment of a variety of diseases due to their advantages such as abundant resources, low immunogenicity and large ex vivo expansion capacity. This study was aimed to investigate the effects of UCMSC on experimental autoimmune myasthenia gravis (EAMG) rats. The distribution of human-derived cells was observed by immunofluorescence method, the effect of MSC on B-cell in situ-secreted antibodies was assayed by ELISPOT, the secreted IFN-γ level was detected by using Transwell test. The results showed that UCMSC were able to migrate to inflammation region and lymph nudes, moreover human-derived cells could be detected in medulla zone of lymph nudes. In vitro in situ detection of AchR specific antibody secretion revealed that the full contact of MSC with lymphnode-derived lymphocytes could effectively inhibit production of AchR antibody. Transwell test indicated that the direct contact of UCMSC with CD4 T cells could effectively decrease production of IFN-γ, which modulated the unbalance between Th1/Th2 to a certain extent. It is concluded that UCMSC can regulate the immune system by direct cell-cell contact or/and release of cytokines, which bring a new insight into knowledge about MSC-based therapy for EAMG.

  2. Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18.

    PubMed

    Im, S H; Barchan, D; Maiti, P K; Raveh, L; Souroujon, M C; Fuchs, S

    2001-10-01

    Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine that plays an important role in interferon gamma (IFN-gamma) production and IL-12-driven Th1 phenotype polarization. Increased expression of IL-18 has been observed in several autoimmune diseases. In this study we have analyzed the role of IL-18 in an antibody-mediated autoimmune disease and elucidated the mechanisms involved in disease suppression mediated by blockade of IL-18, using experimental autoimmune myasthenia gravis (EAMG) as a model. EAMG is a T cell-regulated, antibody-mediated autoimmune disease in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1- and Th2-type responses are both implicated in EAMG development. We show that treatment by anti-IL-18 during ongoing EAMG suppresses disease progression. The protective effect can be adoptively transferred to naive recipients and is mediated by increased levels of the immunosuppressive Th3-type cytokine TGF-beta and decreased AChR-specific Th1-type cellular responses. Suppression of EAMG is accompanied by down-regulation of the costimulatory factor CD40L and up-regulation of CTLA-4, a key negative immunomodulator. Our results suggest that IL-18 blockade may potentially be applied for immunointervention in myasthenia gravis.

  3. Prevention of passively transferred experimental autoimmune myasthenia gravis by a phage library-derived cyclic peptide

    PubMed Central

    Venkatesh, Natarajan; Im, Sin-Heyog; Balass, Moshe; Fuchs, Sara; Katchalski-Katzir, Ephraim

    2000-01-01

    Many pathogenic antibodies in myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are directed against the main immunogenic region (MIR) of the acetylcholine receptor (AcChoR). These antibodies are highly conformation dependent; hence, linear peptides derived from native receptor sequences are poor candidates for their immunoneutralization. We employed a phage-epitope library to identify peptide-mimotopes capable of preventing the pathogenicity of the anti-MIR mAb 198. We identified a 15-mer peptide (PMTLPENYFSERPYH) that binds specifically to mAb 198 and inhibits its binding to AcChoR. A 10-fold increase in the affinity of this peptide was achieved by incorporating flanking amino acid residues from the coat protein as present in the original phage library. This extended peptide (AEPMTLPENYFSERPYHPPPP) was constrained by the addition of cysteine residues on both ends of the peptide, thus generating a cyclic peptide that inhibited the binding of mAb 198 to AcChoR with a potency that is three orders of magnitude higher when compared with the parent library peptide. This cyclic peptide inhibited the in vitro binding of mAb 198 to AcChoR and prevented the antigenic modulation of AcChoR caused by mAb 198 in human muscle cell cultures. The cyclic peptide also reacted with several other anti-MIR mAbs and the sera of EAMG rats. In addition, this peptide blocked the ability of mAb 198 to passively transfer EAMG in rats. Further derivatization of the cyclic peptide may aid in the design of suitable synthetic mimotopes for modulation of MG. PMID:10639153

  4. Myasthenia Gravis: Medical Aspects

    PubMed Central

    Zeldowicz, Ludmila R.; Buckler, William St. John

    1965-01-01

    The diagnosis of myasthenia gravis is often difficult and calls for a broader use of pharmacological and electrodiagnostic tests. The decamethonium-edrophonium test, which has proved superior to other procedures for this purpose, is based on neurophysiological principles and depicts the behaviour of the neuromuscular junction. A state of resistance to depolarizing agents in the limited form of myasthenia and a state of a non-depolarizing (competitive) block in advanced cases has been shown. This test has demonstrated that the neuromuscular defect exists throughout the skeletal musculature, including muscles clinically unaffected. It produced no false-positive results either in normal or neurasthenic persons or in patients with neurological diseases with myasthenic symptoms. In a patient with botulism and in a patient with ocular palsies from brain-stem encephalitis the edrophonium test gave a false-positive result, while the decamethonium-edrophonium test was negative. Diagnosis, treatment and management of myasthenic emergencies are described. PMID:14323662

  5. Myasthenia gravis: subgroup classification and therapeutic strategies.

    PubMed

    Gilhus, Nils Erik; Verschuuren, Jan J

    2015-10-01

    Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis.

  6. The role of the thymus in the pathogenesis of myasthenia gravis.

    PubMed

    Onodera, Hiroshi

    2005-10-01

    Myasthenia gravis is an organ-specific autoimmune disease characterized by the production of anti-acetylcholine receptor antibodies. In this review, I describe the pathophysiological importance of the altered chemokine receptor-mediated signaling in the thymus and peripheral blood of myasthenia gravis patients. The epidemiological and clinical features of myasthenia gravis are also discussed.

  7. "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis.

    PubMed

    Huang, Hai-Peng; Pan, Hong; Wang, Hong-Feng

    2016-03-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.

  8. Lymphocyte function in myasthenia gravis.

    PubMed Central

    Kawanami, S; Kanaide, A; Itoyama, Y; Kuroiwa, Y

    1979-01-01

    Mitogen-induced blastoid transformation of peripheral blood lymphocytes from patients with myasthenia gravis was studied using a microplate culture technique and evaluated with 3H-thymidine incorporation. It was found that both phytohaemagglutinin and pokeweed mitogen responses decreased significantly in patients with myasthenia gravis. In myasthenic crisis, indices of stimulation by phytohaemagglutination became very low. The autologous plasma neither inhibited nor facilitated mitogenic responses of lymphocytes. The decreased mitogen responsiveness of lymphocytes suggests that part of the T lymphocyte function is subnormal in myasthenia. PMID:490180

  9. Myasthenia Gravis Thymus

    PubMed Central

    Leite, Maria I.; Jones, Margaret; Ströbel, Philipp; Marx, Alexander; Gold, Ralf; Niks, Erik; Verschuuren, Jan J.G.M.; Berrih-Aknin, Sonia; Scaravilli, Francesco; Canelhas, Aurea; Morgan, B. Paul; Vincent, Angela; Willcox, Nick

    2007-01-01

    In early-onset myasthenia gravis, the thymus contains lymph node-type infiltrates with frequent acetylcholine receptor (AChR)-specific germinal centers. Our recent evidence/two-step hypothesis implicates hyperplastic medullary thymic epithelial cells (expressing isolated AChR subunits) in provoking infiltration and thymic myoid cells (with intact AChR) in germinal center formation. To test this, we screened for complement attack in a wide range of typical generalized myasthenia patients. Regardless of the exact serology, thymi with sizeable infiltrates unexpectedly showed patchy up-regulation of both C5a receptor and terminal complement regulator CD59 on hyperplastic epithelial cells. These latter also showed deposits of activated C3b complement component, which appeared even heavier on infiltrating B cells, macrophages, and especially follicular dendritic cells. Myoid cells appeared particularly vulnerable to complement; few expressed the early complement regulators CD55, CD46, or CR1, and none were detectably CD59+. Indeed, when exposed to infiltrates, and especially to germinal centers, myoid cells frequently labeled for C1q, C3b (25 to 48%), or even the terminal C9, with some showing obvious damage. This early/persistent complement attack on both epithelial and myoid cells strongly supports our hypothesis, especially implicating exposed myoid cells in germinal center formation/autoantibody diversification. Remarkably, the similar changes place many apparent AChR-seronegative patients in the same spectrum as the AChR-seropositive patients. PMID:17675582

  10. Modulation of the anti-acetylcholine receptor response and experimental autoimmune myasthenia gravis by recombinant fragments of the acetylcholine receptor.

    PubMed

    Barchan, D; Asher, O; Tzartos, S J; Fuchs, S; Souroujon, M C

    1998-02-01

    Myasthenia gravis (MG) is a neuromuscular disorder of man caused by a humoral response to the acetylcholine receptor (AChR). Most of the antibodies in MG and in experimental autoimmune myasthenia gravis (EAMG) are directed to the extracellular portion of the AChR alpha subunit, and within it, primarily to the main immunogenic region (MIR). We have cloned and expressed recombinant fragments, corresponding to the entire extracellular domain of the AChR alpha subunit (H alpha1-210), and to portions of it that encompass either the MIR (H alpha1-121) or the ligand binding site of AChR (H alpha122-210), and studied their ability to interfere with the immunopathological anti-AChR response in vitro and in vivo. All fragments were expressed as fusion proteins with glutathione S-transferase. Fragments H alpha1-121 and H alpha1-210 protected AChR in TE671 cells against accelerated degradation induced by the anti-MIR monoclonal antibody (mAb)198 in a dose-dependent manner. Moreover, these fragments had a similar effect on the antigenic modulation of AChR by other anti-MIR mAb and by polyclonal rat anti-AChR antibodies. Fragments H alpha1-121 and H alpha1-210 were also able to modulate in vivo muscle AChR loss and development of clinical symptoms of EAMG, passively transferred to rats by mAb 198. Fragment H alpha122-210 did not have such a protective activity. Our results suggest that the appropriate recombinant fragments of the human AChR may be employed in the future for antigen-specific therapy of myasthenia.

  11. A novel galectin-1 and interleukin 2 receptor β haplotype is associated with autoimmune myasthenia gravis.

    PubMed

    Pál, Zsuzsanna; Antal, Péter; Millinghoffer, András; Hullám, Gábor; Pálóczi, Krisztina; Tóth, Sára; Gabius, Hans-Joachim; Molnár, Mária Judit; Falus, András; Buzás, Edit Irén

    2010-12-15

    Galectin-1 (LGALS1) and interleukin receptor 2β (IL2Rβ) are regulators of T-cell activation. Here we evaluated the association of regulatory region polymorphisms of the LGALS1 (rs4820293, rs4820294) and IL2Rβ (rs743777, rs228941) genes in 146 Caucasian myasthenia gravis patients compared to 291 ethnically matched controls. A significant difference was found in the distribution of the rs4820293/rs743777 polymorphism haplotypes (p<0.01). The rs4820293 polymorphism, previously not described to be associated with any disease, does not affect LGALS1 expression in peripheral mononuclear cells and skeletal muscle. Pathway analysis revealed interaction between LGALS1 and IL2Rβ suggesting a role of these proteins in this rare disease.

  12. [Successful use of sugammadex for caesarean section in a patient with myasthenia gravis].

    PubMed

    Soyoral, Lokman; Goktas, Ugur; Cegin, Muhammed Bilal; Baydi, Volkan

    Myasthenia gravis is an autoimmune disorder that is characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. Diagnosis of myasthenia gravis is made following clinical and physical examination and is confirmed by serum immunoassays to measure autoantibody levels. Myasthenia gravis especially when associated with pregnancy is a high-risk disease, and its course is unpredictable. We described the second report about use of sugammadex after rocuronium for a caesarean delivery with myasthenia gravis, but, unlike our case that formerly was diagnosed with myasthenia gravis, the patient was extubated on postoperative successfully and we did not encounter any respiratory problems.

  13. Successful use of sugammadex for caesarean section in a patient with myasthenia gravis.

    PubMed

    Soyoral, Lokman; Goktas, Ugur; Cegin, Muhammed Bilal; Baydi, Volkan

    Myasthenia gravis is an autoimmune disorder that is characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. Diagnosis of myasthenia gravis is made following clinical and physical examination and is confirmed by serum immunoassays to measure autoantibody levels. Myasthenia gravis especially when associated with pregnancy is a high-risk disease, and its course is unpredictable. We described the second report about use of sugammadex after rocuronium for a caesarean delivery with myasthenia gravis, but, unlike our case that formerly was diagnosed with myasthenia gravis, the patient was extubated on postoperative successfully and we did not encounter any respiratory problems.

  14. Mouse models of myasthenia gravis.

    PubMed

    Ban, Joanne; Phillips, William D

    2015-01-01

    Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.

  15. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis.

    PubMed

    Balandina, Anna; Lécart, Sandrine; Dartevelle, Philippe; Saoudi, Abdelhadi; Berrih-Aknin, Sonia

    2005-01-15

    Thymus-derived CD4(+)CD25+ regulatory T (Treg) cells are essential for the maintenance of immunologic self-tolerance. Despite their critical role in the active suppression of experimental autoimmune disorders, little is known about their involvement in human autoimmune diseases. Myasthenia gravis (MG) is a CD4+ T cell-dependent autoimmune disease and the thymus is assumed to be the initiation site. To identify possible defects in the Treg cells in MG, we analyzed CD4(+)CD25+ cells in thymi from patients with MG compared to those from healthy subjects. We found a normal CD4(+)CD25+ number but a severe functional defect in their regulatory activity together with a decreased expression of the transcription factor, Foxp3, which is essential for T-cell regulatory function. The phenotypic analysis of CD4(+)CD25+ thymocytes revealed an increased number of activated effector cells with strong Fas expression in patients with MG. However, whatever their level of Fas, CD4(+)CD25+ thymocytes from patients with MG remained unable to suppress the proliferation of responding cells, indicating that the impaired Treg cell function is not due to contamination by activated effector T cells. These data are the first to demonstrate a severe functional impairment of thymic Treg cells in MG, which could contribute to the onset of this autoimmune disease.

  16. Myasthenia gravis and endurance exercise.

    PubMed

    Scheer, Bernd Volker; Valero-Burgos, Encarna; Costa, Ricardo

    2012-08-01

    This is the first report of a runner with myasthenia gravis who completed an ultra endurance event. Myasthenia gravis, a neuromuscular disease that usually results in skeletal muscle weakness, which worsens with exercise and strenuous aerobic exercise, is generally contraindicated. Our runner completed a 220-km, 5-day ultramarathon and presented with various symptoms including muscular skeletal weakness, cramps, generalized fatigue, unintelligible speech, involuntary eye and mouth movements, problems swallowing, food lodging in his throat, and problems breathing. Risk factors identified for exacerbations are running in extreme temperatures, prolonged runs (especially a distance of 30 km or more), running uphill, lack of sleep, and stress. The medical team was in the novel situation to look after a runner with myasthenia gravis and needed to be aware of the patient's condition, symptoms, and risk factors to safely care for him.

  17. Multiple Thymoma with Myasthenia Gravis

    PubMed Central

    Seo, Dong Hyun; Cho, Sukki

    2017-01-01

    The actual incidence of multiple thymoma is unknown and rarely reported because it remains controversial whether the cases represent a disease of multicentric origin or a disease resulting from intrathymic metastasis. In this case, a patient underwent total thymectomy for multiple thymoma with myasthenia gravis via bilateral video-assisted thoracic surgery. A well-encapsulated multinodular cystic mass, measuring 57 mm×50 mm×22 mm in the right lobe of the thymus, and a well-encapsulated mass, measuring 32 mm×15 mm×14 mm in the left lobe, were found. Both tumors were type B2 thymoma. Few cases of multiple thymoma with myasthenia gravis have ever been reported in the literature. We report a case of synchronous multiple thymoma associated with myasthenia gravis. PMID:28180109

  18. New diagnosis myasthenia gravis and preeclampsia in late pregnancy.

    PubMed

    Ozcan, John; Balson, Ian Frank; Dennis, Alicia T

    2015-02-26

    Myasthenia gravis is a chronic autoimmune disease of neuromuscular transmission resulting in fatigable skeletal muscle weakness. Preeclampsia is a multisystem disease of pregnancy which is characterised by hypertension and involvement of one or more organ systems. Both diseases are responsible for considerable morbidity and mortality for mother and fetus. The occurrence of both preeclampsia and myasthenia gravis in pregnancy is very rare, and conflicts arise when considering the optimal management of each disease.We present a case of a parturient who was newly diagnosed with both myasthenia gravis and preeclampsia in late pregnancy. Myasthenia treatment was started with prednisolone and pyridostigmine, and delivery was by caesarean section at 37 weeks gestation under spinal anaesthesia. Postnatally, the patient developed worsening of myasthenia and preeclampsia symptoms. We consider the anaesthetic implications for both diseases and describe our approach for the management of this case.

  19. Myasthenia gravis: an update for the clinician.

    PubMed

    Sieb, J P

    2014-03-01

    This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis (MG). Nowadays the term 'myasthenia gravis' includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte- macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective.

  20. Ocular myasthenia gravis: A review

    PubMed Central

    Nair, Akshay Gopinathan; Patil-Chhablani, Preeti; Venkatramani, Devendra V; Gandhi, Rashmin Anilkumar

    2014-01-01

    Myasthenia gravis (MG) is a disease that affects the neuro-muscular junction resulting in classical symptoms of variable muscle weakness and fatigability. It is called the great masquerader owing to its varied clinical presentations. Very often, a patient of MG may present to the ophthalmologist given that a large proportion of patients with systemic myasthenia have ocular involvement either at presentation or during the later course of the disease. The treatment of ocular MG involves both the neurologist and ophthalmologist. Thus, the aim of this review was to highlight the current diagnosis, investigations, and treatment of ocular MG. PMID:25449931

  1. Early-onset acquired myasthenia gravis secondary to anti-muscle-specific kinase autoantibodies.

    PubMed

    Yilmaz, Sanem; Gokben, Sarenur; Serdaroglu, Gul; Akcay, Ayfer

    2014-01-01

    Autoimmune myasthenia gravis is rarely seen during infancy. Similar to adults, 85% to 90% of generalized pediatric myasthenia gravis cases have acetylcholine receptor antibodies. Approximately 30% of the remaining cases have antibodies against muscle-specific kinase. Information on the clinical course, treatment alternatives, and prognosis of pediatric muscle-specific kinase antibody-positive myasthenia gravis is limited because of the small number of cases. Here, we present a 14-month-old girl with muscle-specific kinase antibody-positive myasthenia gravis as one of the youngest patients described so far in the literature.

  2. Isolated laryngeal myasthenia gravis for 26 years.

    PubMed

    Renard, Dimitri; Hedayat, Amir; Gagnard, Corinne

    2015-02-01

    Laryngeal myasthenia gravis is a relatively rare variant of myasthenia gravis. A vast portion of patients with initial laryngeal myasthenia gravis develop involvement of ocular and/or extra-ocular muscles during the years after symptom onset although a minority of laryngeal myasthenia gravis patients continues to have isolated laryngeal muscle involvement for several years. We present a 58-year-old woman with recurrent episodic isolated dysphonia (associated with diffuse bilateral vocal cord paresis on laryngoscopy) since the age of 32. Dysphonia became permanent since 6 months. A diagnosis of laryngeal myasthenia gravis was made based on abnormal single-fiber electromyography and spectacular response to pyridostigmine treatment. Repetitive nerve stimulation was normal and anti-acetylcholine receptor and anti-muscle specific tyrosine kinase antibodies were absent. This case shows that laryngeal myasthenia gravis can be isolated during 26 years of follow-up. We propose that even when myasthenia gravis seems unlikely as underlying mechanism of isolated dysphonia (because of lack of antibodies, normal repetitive nerve stimulation, and absence of extra-laryngeal involvement after years of follow-up), single-fiber electromyography should be performed and myasthenia gravis treatment should be tried.

  3. Myasthenia Gravis Medication Information Card (Drugs to be Avoided or Used with Caution in Myasthenia Gravis)

    MedlinePlus

    MYASTHENIA GRAVIS MEDICATION INFORMATION CARD Drugs to be Avoided or Used with Caution in MG My Name _______________________________________________ Address ________________________________________________ ... the MGFA web site; reference document “Medications and Myasthenia Gravis (A Reference for Health Care Professionals.” www.myasthenia. ...

  4. Myasthenia gravis: an update for the clinician

    PubMed Central

    Sieb, J P

    2014-01-01

    This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis (MG). Nowadays the term ‘myasthenia gravis’ includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte– macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective. PMID:24117026

  5. Seronegative Maternal Ocular Myasthenia Gravis and Delayed Transient Neonatal Myasthenia Gravis

    PubMed Central

    Townsel, Courtney; Keller, Rebecca; Johnson, Kendall; Hussain, Naveed; Campbell, Winston A.

    2016-01-01

    Background Myasthenia gravis (MG) is an autoimmune disorder with fluctuating muscle weakness, divided into generalized and localized (ocular) forms. Maternal antibodies to acetylcholine receptors cross the placenta and may cause transient neonatal myasthenia gravis (TNMG). We present a case of seronegative maternal ocular MG and delayed TNMG. Case A 29-year-old G3P1011 underwent cesarean birth of a male infant who developed oxygen desaturation requiring supplemental oxygen on day of life (DOL) 3. Based on the clinical course and after exclusion of other diagnoses, the infant was diagnosed with TNMG. Infant's condition improved spontaneously and he was weaned off supplemental oxygen and discharged home on DOL 12. Conclusion Infants born to mothers with seronegative localized (ocular) MG are also susceptible to TNMG which may be late in onset. PMID:26989568

  6. The thymus and myasthenia gravis.

    PubMed

    Ragheb, S; Lisak, R P

    2001-05-01

    Self acetylcholine receptor (AchR) is targeted by a wayward immune response in myasthenia gravis (MG). The current understanding of the pathogenesis of the AChR-directed immune response is reviewed. Furthermore, the thymus is suspected of initiating and perpetuating the disease process in the majority of patients; its role as a central and peripheral lymphoid organ in MG is discussed. MG seems to result from a failure of (1) establishing tolerance to the AChR and (2) regulating the immune response.

  7. Complement associated pathogenic mechanisms in myasthenia gravis.

    PubMed

    Tüzün, Erdem; Christadoss, Premkumar

    2013-07-01

    The complement system is profoundly involved in the pathogenesis of acetylcholine receptor (AChR) antibody (Ab) related myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG). The most characteristic finding of muscle pathology in both MG and EAMG is the abundance of IgG and complement deposits at the nerve-muscle junction (NMJ), suggesting that AChR-Ab induces muscle weakness by complement pathway activation and consequent membrane attack complex (MAC) formation. This assumption has been supported with EAMG resistance of complement factor C3 knockout (KO), C4 KO and C5 deficient mice and amelioration of EAMG symptoms following treatment with complement inhibitors such as cobra venom factor, soluble complement receptor 1, anti-C1q, anti-C5 and anti-C6 Abs. Moreover, the complement inhibitor decay accelerating factor (DAF) KO mice exhibit increased susceptibility to EAMG. These findings have brought forward improvisation of novel therapy methods based on inhibition of classical and common complement pathways in MG treatment.

  8. Innate immunity in myasthenia gravis thymus: pathogenic effects of Toll-like receptor 4 signaling on autoimmunity.

    PubMed

    Cordiglieri, Chiara; Marolda, Roberta; Franzi, Sara; Cappelletti, Cristina; Giardina, Carmelo; Motta, Teresio; Baggi, Fulvio; Bernasconi, Pia; Mantegazza, Renato; Cavalcante, Paola

    2014-08-01

    The thymus is the main site of immune sensitization to AChR in myasthenia gravis (MG). In our previous studies we demonstrated that Toll-like receptor (TLR) 4 is over-expressed in MG thymuses, suggesting its involvement in altering the thymic microenvironment and favoring autosensitization and autoimmunity maintenance processes, via an effect on local chemokine/cytokine network. Here, we investigated whether TLR4 signaling may favor abnormal cell recruitment in MG thymus via CCL17 and CCL22, two chemokines known to dictate immune cell trafficking in inflamed organs by binding CCR4. We also investigated whether TLR4 activation may contribute to immunodysregulation, via the production of Th17-related cytokines, known to alter effector T cell (Teff)/regulatory T cell (Treg) balance. We found that CCL17, CCL22 and CCR4 were expressed at higher levels in MG compared to normal thymuses. The two chemokines were mainly detected around medullary Hassall's corpuscles (HCs), co-localizing with TLR4(+) thymic epithelial cells (TECs) and CCR4(+) dendritic cells (DCs), that were present in higher number in MG thymuses compared to controls. TLR4 stimulation in MG TECs increased CCL17 and CCL22 expression and induced the production of Th17-related cytokines. Then, to study the effect of TLR4-stimulated TECs on immune cell interactions and Teff activation, we generated an in-vitro imaging model by co-culturing CD4(+) Th1/Th17 AChR-specific T cells, naïve CD4(+)CD25(+) Tregs, DCs and TECs from Lewis rats. We observed that TLR4 stimulation led to a more pronounced Teff activatory status, suggesting that TLR4 signaling in MG thymic milieu may affect cell-to-cell interactions, favoring autoreactive T-cell activation. Altogether our findings suggest a role for TLR4 signaling in driving DC recruitment in MG thymus via CCL17 and CCL22, and in generating an inflammatory response that might compromise Treg function, favoring autoreactive T-cell pathogenic responses.

  9. Myasthenia gravis developing in an HIV-negative patient with Kaposi's sarcoma.

    PubMed

    Mantero, Vittorio; Mascolo, Maria; Bandettini di Poggio, Monica; Caponnetto, Claudia; Pardini, Matteo

    2013-07-01

    Myasthenia gravis is a disorder of neuromuscular transmission caused by autoimmune mechanisms. We reported a possible association between seropositive myasthenia gravis and Kaposi's sarcoma in a HIV-negative subject and the observed interactions between the treatment regimen for these two conditions. A 62-year-old man came to our attention for ocular myasthenia gravis. He suffered from a classic form of Kaposi's sarcoma since about 1 year. When myasthenic symptoms worsened, the patient was started on prednisone and azathioprine. The patient had a significant worsening of Kaposi's sarcoma, so prednisone and azathioprine were reduced and he was treated with vinblastine, with improvement both in dermatologic than in neurological symptomatology. We propose some considerations: the potential correlation between Kaposi's sarcoma and myasthenia gravis through immunological mechanism; myasthenia gravis as a paraneoplastic manifestation of Kaposi's sarcoma, and the role of an antitumoral agent as a treatment for both the conditions.

  10. Standardization of the experimental autoimmune myasthenia gravis (EAMG) model by immunization of rats with Torpedo californica acetylcholine receptors — Recommendations for methods and experimental designs

    PubMed Central

    Losen, Mario; Martinez-Martinez, Pilar; Molenaar, Peter C.; Lazaridis, Konstantinos; Tzartos, Socrates; Brenner, Talma; Duan, Rui-Sheng; Luo, Jie; Lindstrom, Jon; Kusner, Linda

    2015-01-01

    Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR) is characterized by a chronic, fatigable weakness of voluntary muscles. The production of autoantibodies involves the dysregulation of T cells which provide the environment for the development of autoreactive B cells. The symptoms are caused by destruction of the postsynaptic membrane and degradation of the AChR by IgG autoantibodies, predominantly of the G1 and G3 subclasses. Active immunization of animals with AChR from mammalian muscles, AChR from Torpedo or Electrophorus electric organs, and recombinant or synthetic AChR fragments generates a chronic model of MG, termed experimental autoimmune myasthenia gravis (EAMG). This model covers cellular mechanisms involved in the immune response against the AChR, e.g. antigen presentation, T cell-help and regulation, B cell selection and differentiation into plasma cells. Our aim is to define standard operation procedures and recommendations for the rat EAMG model using purified AChR from the Torpedo californica electric organ, in order to facilitate more rapid translation of preclinical proof of concept or efficacy studies into clinical trials and, ultimately, clinical practice. PMID:25796590

  11. Protective molecular mimicry in experimental myasthenia gravis.

    PubMed

    Im, Sin Hyeog; Barchan, Dora; Feferman, Tali; Raveh, Lily; Souroujon, Miriam C; Fuchs, Sara

    2002-05-01

    Protein databases were searched for microbial sequences that bear amino acid similarities with identified T- or B-cell epitopes within the human alpha-subunit of acetylcholine receptor (AChR). One peptide, derived from Haemophilus influenzae, exhibits 50% homology to an identified T-cell epitope of AChR alpha-subunit. This peptide was shown to have a protective effect in experimental autoimmune myasthenia gravis (EAMG). Pretreatment of rats with the mimicry peptide attenuated the induction and progression of EAMG. These effects were accompanied by a reduced T-cell response to AChR, diminished IL-2, IL-12, IFN-gamma and IL-4 levels, as well as decreased humoral response to self-AChR.

  12. Acquired myasthenia gravis associated with oral sarcoma in a dog.

    PubMed

    Stepaniuk, Kevin; Legendre, Loïc; Watson, Shelby

    2011-01-01

    Acquired myasthenia gravis is a common neuromuscular disorder resulting from autoantibody directed against the post-synaptic acetylcholine nicotinic receptors in skeletal muscle. Myasthenia gravis has been reported previously as a paraneoplastic syndrome. This case report presents myasthenia gravis secondary to an oral sarcoma in a juvenile Mastiffdog.

  13. Metaplastic thymoma with myasthenia gravis presumably caused by an accumulation of intratumoral immature T cells: a case report.

    PubMed

    Tajima, Shogo; Yanagiya, Masahiro; Sato, Masaaki; Nakajima, Jun; Fukayama, Masashi

    2015-01-01

    Among human neoplasms, thymomas are well known for their association with paraneoplastic autoimmune diseases such as myasthenia gravis. However, regarding rare metaplastic thymoma, only one case of an association with myasthenia gravis has been reported. Here, we present the second case of a 44-year-old woman with metaplastic thymoma associated with myasthenia gravis. In metaplastic thymoma, intratumoral terminal deoxynucleotidyl transferase-positive T-cells (immature T-cells) are generally scarce, while they were abundant in the present case. We believe that these immature T-cells could be related to the occurrence of myasthenia gravis.

  14. Extraocular Muscle Characteristics Related to Myasthenia Gravis Susceptibility

    PubMed Central

    Wang, Guiping; Li, Jie; Gou, Lin; Zhang, Lihua; Miao, Jianting; Li, Zhuyi

    2013-01-01

    Background The pathogenesis of extraocular muscle (EOM) weakness in myasthenia gravis might involve a mechanism specific to the EOM. The aim of this study was to investigate characteristics of the EOM related to its susceptibility to myasthenia gravis. Methods Female F344 rats and female Sprague-Dawley rats were assigned to experimental and control groups. The experimental group received injection with Ringer solution containing monoclonal antibody against the acetylcholine receptor (AChR), mAb35 (0.25 mg/kg), to induce experimental autoimmune myasthenia gravis, and the control group received injection with Ringer solution alone. Three muscles were analyzed: EOM, diaphragm, and tibialis anterior. Tissues were examined by light microscopy, fluorescence histochemistry, and transmission electron microscopy. Western blot analysis was used to assess marker expression and ELISA analysis was used to quantify creatine kinase levels. Microarray assay was conducted to detect differentially expressed genes. Results In the experimental group, the EOM showed a simpler neuromuscular junction (NMJ) structure compared to the other muscles; the NMJ had fewer synaptic folds, showed a lesser amount of AChR, and the endplate was wider compared to the other muscles. Results of microarray assay showed differential expression of 54 genes in the EOM between the experimental and control groups. Conclusion Various EOM characteristics appear to be related to the increased susceptibility of the EOM and the mechanism of EOM weakness in myasthenia gravis. PMID:23409007

  15. CD1d(hi)CD5+ B cells expanded by GM-CSF in vivo suppress experimental autoimmune myasthenia gravis.

    PubMed

    Sheng, Jian Rong; Quan, Songhua; Soliven, Betty

    2014-09-15

    IL-10-competent subset within CD1d(hi)CD5(+) B cells, also known as B10 cells, has been shown to regulate autoimmune diseases. Whether B10 cells can prevent or suppress the development of experimental autoimmune myasthenia gravis (EAMG) has not been studied. In this study, we investigated whether low-dose GM-CSF, which suppresses EAMG, can expand B10 cells in vivo, and whether adoptive transfer of CD1d(hi)CD5(+) B cells would prevent or suppress EAMG. We found that treatment of EAMG mice with low-dose GM-CSF increased the proportion of CD1d(hi)CD5(+) B cells and B10 cells. In vitro coculture studies revealed that CD1d(hi)CD5(+) B cells altered T cell cytokine profile but did not directly inhibit T cell proliferation. In contrast, CD1d(hi)CD5(+) B cells inhibited B cell proliferation and its autoantibody production in an IL-10-dependent manner. Adoptive transfer of CD1d(hi)CD5(+) B cells to mice could prevent disease, as well as suppress EAMG after disease onset. This was associated with downregulation of mature dendritic cell markers and expansion of regulatory T cells resulting in the suppression of acetylcholine receptor-specific T cell and B cell responses. Thus, our data have provided significant insight into the mechanisms underlying the tolerogenic effects of B10 cells in EAMG. These observations suggest that in vivo or in vitro expansion of CD1d(hi)CD5(+) B cells or B10 cells may represent an effective strategy in the treatment of human myasthenia gravis.

  16. Reflections on the "intrathymic pathogenesis" of myasthenia gravis.

    PubMed

    Hohlfeld, Reinhard; Wekerle, Hartmut

    2008-09-15

    The beneficial effects of thymectomy argue for a causal role of the thymus in myasthenia gravis (MG). The MG thymus contains acetylcholine receptor (AChR), which is expressed by myoid cells (whole AChR), and by medullary thymic epithelial cells (AChR subunits). The myoid cells are closely associated with antigen-presenting dendritic cells, helper T cells, and antibody-producing B cells in lymphoid follicles ("lymphofollicular hyperplasia"). Thus, all the cellular components required to initiate and maintain an autoimmune response to AChR are present in the MG thymus. It is unlikely that the cellular alterations in the thymus are secondary to an ongoing peripheral immune response, because they are absent in experimental autoimmune myasthenia gravis.

  17. Sensory aspects in myasthenia gravis: A translational approach.

    PubMed

    Leon-Sarmiento, Fidias E; Leon-Ariza, Juan S; Prada, Diddier; Leon-Ariza, Daniel S; Rizzo-Sierra, Carlos V

    2016-09-15

    Myasthenia gravis is a paradigmatic muscle disorder characterized by abnormal fatigue and muscle weakness that worsens with activities and improves with rest. Clinical and research studies done on nicotinic acetylcholine receptors have advanced our knowledge of the muscle involvement in myasthenia. Current views still state that sensory deficits are not "features of myasthenia gravis". This article discusses the gap that exists on sensory neural transmission in myasthenia that has remained after >300years of research in this neurological disorder. We outline the neurobiological characteristics of sensory and motor synapses, reinterpret the nanocholinergic commonalities that exist in both sensory and motor pathways, discuss the clinical findings on altered sensory pathways in myasthenia, and propose a novel way to score anomalies resulting from multineuronal inability associated sensory troubles due to eugenic nanocholinergic instability and autoimmunity. This medicine-based evidence could serve as a template to further identify novel targets for studying new medications that may offer a better therapeutic benefit in both sensory and motor dysfunction for patients. Importantly, this review may help to re-orient current practices in myasthenia.

  18. Immune disease and HLA associations with myasthenia gravis.

    PubMed Central

    Behan, P O

    1980-01-01

    In the late 1950's laboratory and clinical evidence suggested that myasthenia gravis was an autoimmune disorder. Since then a voluminous literature has developed documenting the many immunological abnormalities that occur in this condition. Recent findings point to a central disorder of immunoregulation. It is postulated that the disease occurs as a result of host genetic and environmental influences-the latter being, as yet unidentified and possibly a virus. PMID:6967515

  19. Immune disease and HLA associations with myasthenia gravis.

    PubMed

    Behan, P O

    1980-07-01

    In the late 1950's laboratory and clinical evidence suggested that myasthenia gravis was an autoimmune disorder. Since then a voluminous literature has developed documenting the many immunological abnormalities that occur in this condition. Recent findings point to a central disorder of immunoregulation. It is postulated that the disease occurs as a result of host genetic and environmental influences-the latter being, as yet unidentified and possibly a virus.

  20. Extraocular muscle surgery in myasthenia gravis.

    PubMed Central

    Acheson, J F; Elston, J S; Lee, J P; Fells, P

    1991-01-01

    Myasthenia gravis is typically a disease of young people in active employment who need a field of binocular single vision. Although it is systemically controllable with a good chance of spontaneous remission, persistent loss of binocularity may cause chronic disability. We report our experience of extraocular muscle surgery in five patients with stable myasthenia gravis and persistent double vision. Extraocular muscle involvement was selective, giving rise to incomitant and concomitant squints, with individual muscle overactions as well as underactions. Treatment was by conventional recession and resection procedures with the additional use of Faden and adjustable sutures where appropriate. In all five cases a larger, stable field of binocular single vision was established. It is concluded that extraocular muscle surgery may be beneficial in selected cases of myasthenia gravis. PMID:2021593

  1. Refractory myasthenia gravis - clinical profile, comorbidities and response to rituximab.

    PubMed

    Sudulagunta, Sreenivasa Rao; Sepehrar, Mona; Sodalagunta, Mahesh Babu; Settikere Nataraju, Aravinda; Bangalore Raja, Shiva Kumar; Sathyanarayana, Deepak; Gummadi, Siddharth; Burra, Hemanth Kumar

    2016-01-01

    Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications. Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27-53 years. In our study 25 patients (32.89%) belonged to the age group of 21-30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% (p=3.3x10(-8)) to 94.6% (p=2.2x10(-14)) after the third cycle of rituximab treatment. Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low.

  2. [Myasthenia gravis and autoantibodies: Pathophysiology of the different subtypes].

    PubMed

    Berrih-Aknin, S; Le Panse, R

    2014-07-01

    Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are directed against the acetylcholine receptor (AChR). Recently, other targets have been described, such as muscle-specific kinase protein (MuSK) or lipoprotein related protein 4 (LRP4). The origin of the autoimmune response is not known, but thymic abnormalities and defects in immune regulation certainly play a major role in patients with anti-AChR antibodies. Genetic predisposition probably influences the occurrence of the disease. Sex hormones seem to play a role in the early form of the disease. Muscle weakness is fluctuating and worsens with exercise. Myasthenia gravis could be classified according to the location of the affected muscles (ocular versus generalized), the age of onset of symptoms, thymic abnormalities and profile of autoantibodies. These criteria are used to optimize the management and treatment of patients. In this review, we analyze the latest concepts of the pathophysiology of myasthenia gravis according to the different subgroups of the disease, including a description of the role of immunological, genetic and environmental factors. The potential viral hypothesis of this disease is discussed. Finally, we also discuss the biological assays available to validate the diagnosis.

  3. Specific Immunotherapy of Experimental Myasthenia Gravis by A Novel Mechanism

    PubMed Central

    Luo, Jie; Kuryatov, Alexander; Lindstrom, Jon

    2009-01-01

    Objective Myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG), are antibody-mediated autoimmune diseases, in which autoantibodies bind to and cause loss of muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. To develop a specific immunotherapy of MG, we treated rats with ongoing EAMG by intraperitoneal injection of bacterially-expressed human muscle AChR constructs. Methods Rats with ongoing EAMG received intraperitoneal treatment with the constructs weekly for 5 weeks beginning after the acute phase. Autoantibody concentration, subclassification, and specificity were analyzed to address underlying therapeutic mechanism. Results EAMG was specifically suppressed by diverting autoantibody production away from pathologically relevant specificities directed at epitopes on the extracellular surface of muscle AChRs toward pathologically irrelevant epitopes on the cytoplasmic domain. A mixture of subunit cytoplasmic domains was more effective than a mixture containing both extracellular and cytoplasmic domains or than only the extracellular domain of α1 subunits. Interpretation Therapy using only cytoplasmic domains, which lack pathologically relevant epitopes, avoids the potential liability of boosting the pathological response. Use of a mixture of bacterially-expressed human muscle AChR cytoplasmic domains for antigen-specific immunosuppression of myasthenia gravis has the potential to be specific, robust, and safe. PMID:20437579

  4. [The history of myasthenia gravis. Men and ideas.

    PubMed

    Mimenza-Alvarado, A; Tellez-Zenteno, Jf; Garcia-Ramos, G; Estañol, B

    2007-06-28

    The first description of a patient with myasthenia gravis was done by Thomas Willis (1621-1675). He was an eminent professor of natural history at Oxford University who also described the arteries of the brain and made the first precise drawings of it. At the present time myasthenia gravis is considered one of the most well described autoimmune diseases with great advances in its diagnosis, pathophysiology and treatment. In this review we summarize the most important events and ideas in the history of this disease since the original description by Willis; mention the most important clinicians, anatomists and physiologists that were concerned with its understanding and make reference of some the most recent advances in its diagnosis and treatment and finally discuss some present controversies. Neurología 2007;22(0):0-0.

  5. Acquired myasthenia gravis in a poodle.

    PubMed

    Richardson, Danielle

    2011-02-01

    An 11-year-old, spayed female, teacup poodle was evaluated for a chronic cough, lethargy, hindlimb weakness, and reluctance to exercise. Thoracic radiographs revealed megaesophagus and aspiration pneumonia. Serum antibodies against acetylcholine receptors confirmed the diagnosis of myasthenia gravis. The unusual clinical history and case outcome are discussed.

  6. Association of myasthenia gravis and Behçet's disease: A case report.

    PubMed

    Kisabay, Aysin; Sari, Ummu Serpil; Boyaci, Recep; Batum, Melike; Yilmaz, Hikmet; Selcuki, Deniz

    2016-01-01

    Myasthenia gravis is a disease of neuromuscular junction due to auto-immune destruction of the acetylcholine receptors. Behçet's disease, on the other hand, is a multisystemic vascular-inflammatory disease. Both conditions are not common in the general population although their association has not been reported in the literature. We wanted to present our patient who developed clinical course of myasthenia gravis following discontinuation of medications due to complications of corticosteroid for Behçet's disease. It was observed that clinical findings of myasthenia gravis recovered following restarting steroid treatment and he did not experience attacks of both conditions. Although Myasthenia gravis and Behçet's disease are distinct entities clinically as well as in terms of pathogenesis, they share common physiopathological features and their treatment is based on their common features.

  7. Early onset bilateral juvenile myasthenia gravis masquerading as simple congenital ptosis.

    PubMed

    Alam, Md Shahid; Devi Nivean, Pratheeba

    2017-01-01

    Myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction. Ocular myasthenia gravis presents as ptosis with extraocular motility restriction and is prone to be misdiagnosed as third nerve palsy or congenital or aponeurotic ptosis. Juvenile ocular myasthenia gravis in very young children is difficult to diagnose and can be easily labeled as a case of congenital ptosis, the more so when the condition is bilateral. We present a case of a two-year-old child who presented with bilateral ptosis and was diagnosed as a case of simple congenital ptosis elsewhere with the advice to undergo tarsofrontalis sling surgery. The child was diagnosed with juvenile myasthenia gravis on thorough history, examination, and systemic evaluation and was started on anti-myasthenic treatment.

  8. Early onset bilateral juvenile myasthenia gravis masquerading as simple congenital ptosis

    PubMed Central

    Alam, Md. Shahid; Devi Nivean, Pratheeba

    2017-01-01

    Myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction. Ocular myasthenia gravis presents as ptosis with extraocular motility restriction and is prone to be misdiagnosed as third nerve palsy or congenital or aponeurotic ptosis. Juvenile ocular myasthenia gravis in very young children is difficult to diagnose and can be easily labeled as a case of congenital ptosis, the more so when the condition is bilateral. We present a case of a two-year-old child who presented with bilateral ptosis and was diagnosed as a case of simple congenital ptosis elsewhere with the advice to undergo tarsofrontalis sling surgery. The child was diagnosed with juvenile myasthenia gravis on thorough history, examination, and systemic evaluation and was started on anti-myasthenic treatment. PMID:28293536

  9. Biological implications of thymectomy for myasthenia gravis.

    PubMed

    Okumura, Meinoshin; Inoue, Masayoshi; Kadota, Yoshihisa; Hayashi, Akio; Tokunaga, Toshiteru; Kusu, Takashi; Sawabata, Noriyoshi; Shiono, Hiroyuki

    2010-01-01

    Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies to the striated muscle tissue. It is often treated by thymectomy. We review recent studies to investigate the biological implications of thymectomy. In anti-acetylcholine receptor antibody (anti-AchR Ab)-positive patients without a thymoma, abnormal germinal center formation in the thymus seems to play an essential role in the pathogenesis of MG. Specific differentiation of B cells producing anti-AchR Ab takes place uniquely in the thymus, and thymectomy is thought to assist in terminating the provision of high-affinity anti-AchR antibody-producing cells to peripheral organs. Thymectomy is not indicated for anti-AchR Ab-negative MG patients who are antimuscle specific kinase antibody (anti-MuSK Ab)-positive, although some anti-MuSK Ab-negative patients may benefit from the procedure. A thymoma can be considered as an acquired thymus with insufficient function of negative selection. The resection of a thymoma is thought to terminate the production of self-reactive T cells. Thus, the biological implications of thymectomy for MG have been partially revealed. Nevertheless, additional studies are needed to elucidate the ontogeny of T cells that recognize AchR and the mechanism of the activation of anti-AchR antibodies producing B cells.

  10. [Thymic abnormalities in patients with myasthenia gravis].

    PubMed

    Utsugisawa, Kimiaki; Nagane, Yuriko

    2011-07-01

    Thymic abnormalities were first noticed at autopsies of patients with myasthenia gravis (MG) more than 100 years ago. The thymus is believed to play an important role in the pathogenesis of MG, an autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) of skeletal muscles. Production of these antibodies in B cells is T cell dependent. T cells potentially specific for AChR are probably generated in the thymus via nontolerogenic thymopoiesis by an aberrant function of thymic epithelial cells. However, generation of these AChR-specific T cells is not the cause of MG, because these cells are also found in healthy individuals. The pathogenetic step in MG involves the activation of these potentially AChR-specific T cells; this activation is the trigger to develop the disease and a therapeutic target. The intra-thymic activation of AChR-specific T cells is probably limited to particular types of MG patients: those with early-onset MG in whom the thymus exhibits lymphofollicular hyperplasia (TLFH) and a few patients in whom MG is associated with a thymoma. The majority of thymomas and atrophic thymuses of patients with late-onset MG, an increasingly common condition, do not exhibit this T cell-activation process. In this paper, we review the available literature on thymic changes (TLFH, thymoma, and atrophic thymus) and the relationship of these changes to the pathogenesis of MG.

  11. Randomized Trial of Thymectomy in Myasthenia Gravis

    PubMed Central

    Wolfe, G.I.; Kaminski, H.J.; Aban, I.B.; Minisman, G.; Kuo, H.-C.; Marx, A.; Ströbel, P.; Mazia, C.; Oger, J.; Cea, J.G.; Heckmann, J.M.; Evoli, A.; Nix, W.; Ciafaloni, E.; Antonini, G.; Witoonpanich, R.; King, J.O.; Beydoun, S.R.; Chalk, C.H.; Barboi, A.C.; Amato, A.A.; Shaibani, A.I.; Katirji, B.; Lecky, B.R.F.; Buckley, C.; Vincent, A.; Dias-Tosta, E.; Yoshikawa, H.; Waddington-Cruz, M.; Pulley, M.T.; Rivner, M.H.; Kostera-Pruszczyk, A.; Pascuzzi, R.M.; Jackson, C.E.; Ramos, G.S. Garcia; Verschuuren, J.J.G.M.; Massey, J.M.; Kissel, J.T.; Werneck, L.C.; Benatar, M.; Barohn, R.J.; Tandan, R.; Mozaffar, T.; Conwit, R.; Odenkirchen, J.; Sonett, J.R.; Jaretzki, A.; Newsom-Davis, J.; Cutter, G.R.

    2016-01-01

    BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS Thymectomy improved

  12. Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

    PubMed

    Del Mar Amador, Maria; Vandenberghe, Nadia; Berhoune, Nawel; Camdessanché, Jean-Philippe; Gronier, Sophie; Delmont, Emilien; Desnuelle, Claude; Cintas, Pascal; Pittion, Sophie; Louis, Sarah; Demeret, Sophie; Lenglet, Timothée; Meininger, Vincent; Salachas, François; Pradat, Pierre-François; Bruneteau, Gaëlle

    2016-06-01

    Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity.

  13. Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci.

    PubMed

    Giraud, M; Beaurain, G; Eymard, B; Tranchant, C; Gajdos, P; Garchon, H-J

    2004-08-01

    Autoantibodies against the muscle acetylcholine receptor (AChR) play an essential role in the pathophysiology of autoimmune myasthenia gravis (MG). Their serum titers, however, vary considerably among patients. Our aim was to investigate whether their variation might be explained by genetic factors. Using different methods, we have obtained strong evidence for a three-locus association influencing autoantibody titers in MG patients with thymus hyperplasia or with a normal thymus. Two of the loci, one encoding the AChR alpha-subunit, the other encoding the alpha-chain of the class II antigen-presentation molecule, HLA-DQ, demonstrated interaction to determine high autoantibody titers. The third locus was associated with the 8.1 ancestral HLA haplotype. It exerted an additive effect and it is postulated to have a nonantigen specific immunoregulatory function. Our study demonstrates for the first time that polymorphism of an autoantigen gene may quantitatively modify the immune response against it. Altogether, the data lend support to a three-gene model to explain autoantibody expression in a subset of MG patients.

  14. Emergency Management of Myasthenia Gravis

    MedlinePlus

    ... head and shoulders. • Keep a calm and peaceful atmosphere. • Support respirations if needed. SEVERE SWALLOWING DIFFICULTY Subjective ... secretions as needed. • Keep a calm and peaceful atmosphere. www.myasthenia.org 800.541.5454

  15. Epidemiology of myasthenia gravis in Ontario, Canada.

    PubMed

    Breiner, Ari; Widdifield, Jessica; Katzberg, Hans D; Barnett, Carolina; Bril, Vera; Tu, Karen

    2016-01-01

    Incidence and prevalence estimates in myasthenia gravis have varied widely. Recent studies based on administrative health data have large sample sizes but lack rigorous validation of MG cases, and have not examined the North American population. Our aim was to explore trends in MG incidence and prevalence for the years 1996-2013 in the province of Ontario, Canada (population 13.5 million). We employed a previously validated algorithm to identify MG cases. Linking with census data allowed for the calculation of crude- and age/sex-standardized incidence and prevalence rates for the years 1996-2013. The regional distribution of MG cases throughout the province was examined. Mean age at the first myasthenia gravis encounter was 60.2 ± 17.1 years. In 2013, there were 3611 prevalent cases in Ontario, and the crude prevalence rate was 32.0/100,000 population. Age- and sex-standardized prevalence rates rose consistently over time from 16.3/100,000 (15.4-17.1) in 1996 to 26.3/100,000 (25.4-27.3) in 2013. Standardized incidence rates remained stable between 1996 (2.7/100,000; 95% CL 2.3-3.0) and 2013 (2.3/100,000; 2.1-2.6). Incidence was highest in younger women and older men, and geographic variation was evident throughout the province. In conclusion, this large epidemiological study shows rising myasthenia gravis prevalence with stable incidence over time, which is likely reflective of patients living longer, possibly due to improved disease treatment. Our findings provide accurate information on the Canadian epidemiology of myasthenia gravis and burden for health care resources planning for the province, respectively.

  16. A study of the utility of azathioprine metabolite testing in myasthenia gravis.

    PubMed

    Rae, William; Burke, Georgina; Pinto, Ashwin

    2016-04-15

    Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterised by fatigable voluntary skeletal muscle weakness. The underlying pathogenesis is complex involving adaptive autoimmune responses. Azathioprine remains a first line broad acting immunosuppressant for MG. Due to varied clinical responses to azathioprine we aimed to investigate the relationship between azathioprine metabolites and symptom control. Mild correlations between Quantitative Myasthenia Gravis Score (QMG) vs. 6-thioguanine nucleotides (R=-0.317 p=0.186) and QMG vs. lymphocyte count (R=0.402 p=0.08) were found. Azathioprine metabolite measurement should be considered in MG patients with; pancytopenia, deranged liver function or recurrent infections.

  17. [Dysphagia as the sole manifestation of myasthenia gravis].

    PubMed

    Romo González, Ramiro Javier; Chaves, Emiliano; Copello, Hercilia

    2010-06-01

    Dysphagia as the sole manifestation of myasthenia gravis is very rare. Here we describe a case of an adult patient who developed an insidious onset of oropharyngeal dysphagia as the first and sole manifestation of myasthenia gravis. After multiple evaluations the underlying disease was recognized by electromyographics studies. English and Spanish literature on the matter was reviewed.

  18. AN ELECTROPHYSIOLOGICAL INVESTIGATION OF NEUROMUSCULAR TRANSMISSION IN MYASTHENIA GRAVIS,

    DTIC Science & Technology

    with myasthenia gravis . With repetitive nerve stimulation at frequencies above 2/sec, only the first few stimuli elicited muscle contractions in most...It is tentatively concluded that in myasthenia gravis there is a deficiency in the amount of ACh in the quanta of transmitter released from the motor nerve terminals. (Author)

  19. Survivin as a potential mediator to support autoreactive cell survival in myasthenia gravis: a human and animal model study.

    PubMed

    Kusner, Linda L; Ciesielski, Michael J; Marx, Alexander; Kaminski, Henry J; Fenstermaker, Robert A

    2014-01-01

    The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.

  20. Surgical approaches to the thymus in patients with myasthenia gravis.

    PubMed

    Magee, Mitchell J; Mack, Michael J

    2009-02-01

    Myasthenia gravis is an autoimmune disorder of neuromuscular transmission affecting 2 out of every 100,000 people. Neurologists and surgeons still debate what role surgery should play in its management. Many patients who might benefit from thymectomy are denied the opportunity because of misconceptions, ignorance, or trepidation. By offering effective methods of less invasive thymectomy to these patients, a significant number of patients and treating neurologists previously unwilling to consider surgery may realize the benefits of this established, proven treatment alternative. The surgical approaches reviewed include: transcervical, videothoracoscopic, robotic-assisted, transsternal, and combined transcervical-transsternal maximal thymectomy.

  1. Steroids induce acetylcholine receptors on cultured human muscle: implications for myasthenia gravis.

    PubMed Central

    Kaplan, I; Blakely, B T; Pavlath, G K; Travis, M; Blau, H M

    1990-01-01

    Antibodies to the acetylcholine receptor (AChR), which are diagnostic of the human autoimmune disease myasthenia gravis, block AChR function and increase the rate of AChR degradation leading to impaired neuromuscular transmission. Steroids are frequently used to alleviate symptoms of muscle fatigue and weakness in patients with myasthenia gravis because of their well-documented immunosuppressive effects. We show here that the steroid dexamethasone significantly increases total surface AChRs on cultured human muscle exposed to myasthenia gravis sera. Our results suggest that the clinical improvement observed in myasthenic patients treated with steroids is due not only to an effect on the immune system but also to a direct effect on muscle. We propose that the identification and development of pharmacologic agents that augment receptors and other proteins that are reduced by human genetic or autoimmune disease will have broad therapeutic applications. Images PMID:2236023

  2. Steroids induce acetylcholine receptors on cultured human muscle: Implications for myasthenia gravis

    SciTech Connect

    Kaplan, I.; Blakely, B.T.; Pavlath, G.K.; Travis, M.; Blau, H.M. )

    1990-10-01

    Antibodies to the acetylcholine receptor (AChR), which are diagnostic of the human autoimmune disease myasthenia gravis, block AChR function and increase the rate of AChR degradation leading to impaired neuromuscular transmission. Steroids are frequently used to alleviate symptoms of muscle fatigue and weakness in patients with myasthenia gravis because of their well-documented immunosuppressive effects. The authors show here that the steroid dexamethasone significantly increases total surface AChRs on cultured human muscle exposed to myasthenia gravis sera. The results suggest that the clinical improvement observed in myasthenic patients treated with steroids is due not only to an effect on the immune system but also a direct effect on muscle. They propose that the identification and development of pharmacologic agents that augment receptors and other proteins that are reduced by human genetic or autoimmune disease will have broad therapeutic applications.

  3. Treatment of experimental myasthenia gravis with total lymphoid irradiation

    SciTech Connect

    de Silva, S.; Blum, J.E.; McIntosh, K.R.; Order, S.; Drachman, D.B.

    1988-07-01

    Total lymphoid irradiation (TLI) has been reported to be effective in the immunosuppressive treatment of certain human and experimental autoimmune disorders. We have investigated the effects of TLI in Lewis rats with experimental autoimmune myasthenia gravis (EAMG) produced by immunization with purified torpedo acetylcholine receptor (AChR). The radiation is given in 17 divided fractions of 200 rad each, and nonlymphoid tissues are protected by lead shielding. This technique suppresses the immune system, while minimizing side effects, and permits the repopulation of the immune system by the patient's own bone marrow cells. Our results show that TLI treatment completely prevented the primary antibody response to immunization with torpedo AChR, it rapidly abolished the ongoing antibody response in established EAMG, and it suppressed the secondary (anamnestic) response to a boost of AChR. No EAMG animals died during TLI treatment, compared with six control animals that died of EAMG. TLI produces powerful and prompt immunosuppression and may eventually prove useful in the treatment of refractory human myasthenia gravis.

  4. Immunoglobulin G4-Related Inflammatory Abdominal Aortic Aneurysm Associated With Myasthenia Gravis, With Contained Rupture.

    PubMed

    Jun, Heungman; Jung, Cheol Woong

    2016-11-01

    Immunoglobulin (Ig) G4-related disease is reportedly among the various causes of inflammatory abdominal aortic aneurysm (IAAA). Many IgG4-related diseases are closely related to allergic constitution and autoimmune disease. We report a case of a 72-year-old man with IgG4-related IAAA associated with myasthenia gravis, with contained rupture.

  5. Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis.

    PubMed

    Berrih-Aknin, Sonia; Ragheb, Samia; Le Panse, Rozen; Lisak, Robert P

    2013-07-01

    Myasthenia gravis (MG) is an autoimmune disease mediated by antibodies directed to molecules of the endplate of the neuromuscular junction. B cells play a major role in MG disease since they produce the pathogenic antibodies and therapies targeting B cells are effective. The aim of this article was to review the role of B cells in myasthenia gravis. We will first describe what we know about B cells in this disease and examine the involvement of the B cells in the thymus of MG patients. We will detail the role of factors associated with B-cell function such as BAFF. Finally, we will discuss the effects of therapy targeting B cells.

  6. Immunological relationship between acetylcholine receptor and thymus: a possible significance in myasthenia gravis.

    PubMed Central

    Aharonov, A; Tarrab-Hazdai, R; Abramsky, O; Fuchs, S

    1975-01-01

    A defined immunological cross-reaction was observed between acetylcholine receptor fraction from the electric eel, Electrophorus electricus, and two calf thymus fractions. The cross-reaction was demonstrated on the cellular level by means of the lymphocyte transformation technique, and on the humoral level, by means of the microcomplement fixation assay. In the human disease myasthenia gravis both acetylcholine receptor at the neuromuscular junction and the thymus are affected, probably by an autoimmune mechanism. The immunological cross-reaction between acetylcholine receptor and thymic components may explain the association between endplate and thymus disorders in myasthenia gravis. PMID:1055418

  7. An update on laboratory diagnosis in myasthenia gravis.

    PubMed

    Oger, Joel; Frykman, Hans

    2015-09-20

    This review describes the state of the art for the use of laboratory testing in myasthenia gravis. The review brings a detailed description of the different clinical forms of auto-immune myasthenia and of the Lambert Eaton Myasthenic Syndrome (LEMS). They stress the differences between the different forms of acquired (auto-immune) myasthenia. Then they present a summary of the different antibodies found in the disease. They insist on the advantage of the RIPA assay to measure antibodies to the acetylcholine receptor. They stress the different types of contribution of each of these antibodies to the clinical diagnosis. They also describe the methods to measure each of the specific antibodies that have recently permitted to split the diagnosis: Abs to omega-conotoxin receptor in Lambert Eaton Myasthenic Syndrome (LEMS), abs to the acetylcholine receptor (AchR) in MG, Abs to muscle specific tyrosine kinase (MuSK) in Ab negative MG, and Abs to low molecular weight receptor related low-density lipo protein-4 (LRP-4). They also broach over the striated antibodies, less frequent and clinically less useful such as anti-titin, -ryanodine, -agrin and -rapsyn. This represent a 360° view of the field as presented in Toronto in October 2014.

  8. Animal models of myasthenia gravis: utility and limitations

    PubMed Central

    Mantegazza, Renato; Cordiglieri, Chiara; Consonni, Alessandra; Baggi, Fulvio

    2016-01-01

    Myasthenia gravis (MG) is a chronic autoimmune disease caused by the immune attack of the neuromuscular junction. Antibodies directed against the acetylcholine receptor (AChR) induce receptor degradation, complement cascade activation, and postsynaptic membrane destruction, resulting in functional reduction in AChR availability. Besides anti-AChR antibodies, other autoantibodies are known to play pathogenic roles in MG. The experimental autoimmune MG (EAMG) models have been of great help over the years in understanding the pathophysiological role of specific autoantibodies and T helper lymphocytes and in suggesting new therapies for prevention and modulation of the ongoing disease. EAMG can be induced in mice and rats of susceptible strains that show clinical symptoms mimicking the human disease. EAMG models are helpful for studying both the muscle and the immune compartments to evaluate new treatment perspectives. In this review, we concentrate on recent findings on EAMG models, focusing on their utility and limitations. PMID:27019601

  9. Myasthenia gravis and related disorders: Pathology and molecular pathogenesis.

    PubMed

    Ha, James C; Richman, David P

    2015-04-01

    Disorders affecting the presynaptic, synaptic, and postsynaptic portions of the neuromuscular junction arise from various mechanisms in children and adults, including acquired autoimmune or toxic processes as well as genetic mutations. Disorders include autoimmune myasthenia gravis associated with acetylcholine receptor, muscle specific kinase or Lrp4 antibodies, Lambert-Eaton myasthenic syndrome, nerve terminal hyperexcitability syndromes, Guillain Barré syndrome, botulism, organophosphate poisoning and a number of congenital myasthenic syndromes. This review focuses on the various molecular and pathophysiological mechanisms of these disorders, characterization of which has been crucial to the development of treatment strategies specific for each pathogenic mechanism. In the future, further understanding of the underlying processes may lead to more effective and targeted therapies of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

  10. Correlation between acetylcholine receptor antibody levels and thymic pathology in myasthenia gravis: a review.

    PubMed

    Huang, G Z; Lo, Y L

    2013-06-01

    Myasthenia gravis is the most common chronic autoimmune neuromuscular disease. Anti-acetylcholine receptor (AChR) antibodies are found in at least 80% of patients with generalized myasthenia and have been implicated in disease pathogenesis. Thymic abnormalities are frequently found in seropositive patients, and the thymus is thought to be involved in generation of autoimmunity. This article reviews existing literature on the role of AChR antibodies in the pathogenesis of myasthenia gravis, and the correlation between AChR antibody titers and thymic pathology. Most studies found that highest titers are seen in thymic hyperplasia, followed by intermediate titers in thymoma, and lowest titers in atrophic or normal thymus. One publication found no difference between titers in thymoma and normal thymus.

  11. Etiology of myasthenia gravis: innate immunity signature in pathological thymus.

    PubMed

    Cavalcante, Paola; Cufi, Perrine; Mantegazza, Renato; Berrih-Aknin, Sonia; Bernasconi, Pia; Le Panse, Rozen

    2013-07-01

    Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction (NMJ), whose clinical hallmark is muscle weakness and early fatigability. The main target of autoimmunity in MG is the acetylcholine receptor (AChR) located in the NMJ. It is now widely accepted that the thymus is probably the prime site of autoimmunity development and maintenance in AChR-positive MG patients; however, the exact mechanisms triggering and perpetuating the intra-thymic autoimmune response to AChR are still unknown. As with many autoimmune diseases, MG has a multifactorial etiology, resulting from complex interactions between genetic and environmental factors, as fully described in this review. Among environmental factors, viral infections could play a central role in autoimmunity, mainly through the induction of dysregulated Toll-like receptor (TLR)-mediated innate immune responses, which can lead to inflammation and adaptive autoimmune response. Growing evidence of chronic inflammation, TLR activation, and persistent viral infections in the thymus of MG patients, strongly supports the hypothesis that, in the context of a genetic susceptible background, the intrathymic innate immune responses to pathogen infections might contribute to MG etiology.

  12. Metastatic thymoma and acquired generalized myasthenia gravis in a beagle.

    PubMed

    Moffet, Adrienne C

    2007-01-01

    A 16-year-old, spayed female beagle was diagnosed with metastatic thymoma causing a probable paraneoplastic syndrome of generalized acquired myasthenia gravis. Anticholinesterase treatment was initiated; however, 5 days later the dog died.

  13. Worsening of myasthenia gravis after administration of injectable long-acting risperidone for treatment of schizophrenia; first case report and a call for caution.

    PubMed

    Al-Hashel, Jasem Y; Ismail, Ismail Ibrahim; John, John K; Ibrahim, Mohammed; Ali, Mahmoud

    2016-01-01

    Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to autoantibodies affecting the neuromuscular junction. Co-occurrence of myasthenia gravis and schizophrenia is very rare and raises a challenge in management of both diseases. Antipsychotic drugs exhibit anticholinergic side effects and have the potentials of worsening myasthenia. Long-acting risperidone is an injectable atypical antipsychotic drug that has not been previously reported to worsen myasthenia gravis in literature. We report the first case report of worsening of myasthenia after receiving long-acting risperidone injection for schizophrenia in a 29-year-old female with both diseases. She started to have worsening 2 weeks following the first injection and her symptoms persisted despite receiving plasma exchange. This could be explained by the pharmacokinetics of the drug. We recommend that long-acting risperidone should be used with caution in patients with myasthenia gravis, and clinicians must be aware of the potential risks of this therapy.

  14. Clinical features of myasthenia gravis in southern China: a retrospective review of 2,154 cases over 22 years.

    PubMed

    Huang, X; Liu, W B; Men, L N; Feng, H Y; Li, Y; Luo, C M; Qiu, L

    2013-06-01

    The objectives of the study are to study the clinical features of myasthenia gravis in southern China. A retrospective study was carried out on all patients who were diagnosed with myasthenia gravis at the First Affiliated Hospital of Sun Yat-sen University during 1987-2009. Of the 2,154 myasthenia gravis patients, the gender ratio (male:female) was 1:1.15. The median age at onset was 18 years. There was a single peak distribution of age at onset, and 44.8 % were children (≤ 14 years) at first onset. 1,766 patients (82.0 %) only had ocular symptoms at onset. 1,451 patients (67.4 %) were classified as Osserman grade I. 250 unselected patients received anti-acetylcholine receptor antibodies test, in which only 51.2 % were positive. Computed tomography scan/magnetic resonance Imaging of chest were done in 1,354 patients, of which 899 patients (66.4 %) had thymic hyperplasia and 201(14.8 %) had thymoma. There were 150 patients (7.0 %) with myasthenia gravis combined with other autoimmune diseases, in which hyperthyroidism was most common (84 %). 189 (8.8 %) patients experienced 267 episodes of crisis. The rate of family myasthenia gravis was 1.6 % (35/2,154). In conclusion, the clinical features and demography of myasthenia gravis patients in this study are significantly different from prior studies on other regions and ethnic groups.

  15. Myasthenia Gravis and the Myasthenic Syndrome

    PubMed Central

    Herrmann, Christian

    1970-01-01

    Two disorders of neuromuscular transmission producing muscle weakness and easy fatigability which may confront the physician are myasthenia gravis and the myasthenic syndrome. The former has early symptoms and signs of oculobulbar and then extremity weakness with rapid decline of action potential and contractile strength with repetitive use and nerve-muscle stimulation. Anticholinesterases improve strength. The myasthenic syndrome has early symptoms and signs of pelvic girdle, pectoral girdle and proximal limb muscle weakness. This is worst when first starting to use or carry out nerve muscle stimulation in the rested muscles. It improves significantly for a time with use or on rapid stimulation, and then declines with continued activation. Deep tendon reflexes are sluggish or absent. Small cell carcinoma of the lung is often associated. Guanidine improves the strength. Other features and possible underlying mechanisms of the two disorders help to differentiate and treat them. PMID:5457513

  16. Myasthenia gravis: a clinical-immunological update.

    PubMed

    Binks, Sophie; Vincent, Angela; Palace, Jacqueline

    2016-04-01

    Myasthenia gravis (MG) is the archetypic disorder of both the neuromuscular junction and autoantibody-mediated disease. In most patients, IgG1-dominant antibodies to acetylcholine receptors cause fatigable weakness of skeletal muscles. In the rest, a variable proportion possesses antibodies to muscle-specific tyrosine kinase while the remainder of seronegative MG is being explained through cell-based assays using a receptor-clustering technique and, to a lesser extent, proposed new antigenic targets. The incidence and prevalence of MG are increasing, particularly in the elderly. New treatments are being developed, and results from the randomised controlled trial of thymectomy in non-thymomatous MG, due for release in early 2016, will be of particular clinical value. To help navigate an evidence base of varying quality, practising clinicians may consult new MG guidelines in the fields of pregnancy, ocular and generalised MG (GMG). This review focuses on updates in epidemiology, immunology, therapeutic and clinical aspects of GMG in adults.

  17. Thymoma related myasthenia gravis in humans and potential animal models.

    PubMed

    Marx, Alexander; Porubsky, Stefan; Belharazem, Djeda; Saruhan-Direskeneli, Güher; Schalke, Berthold; Ströbel, Philipp; Weis, Cleo-Aron

    2015-08-01

    Thymoma-associated Myasthenia gravis (TAMG) is one of the anti-acetylcholine receptor MG (AChR-MG) subtypes. The clinico-pathological features of TAMG and its pathogenesis are described here in comparison with pathogenetic models suggested for the more common non-thymoma AChR-MG subtypes, early onset MG and late onset MG. Emphasis is put on the role of abnormal intratumorous T cell selection and activation, lack of intratumorous myoid cells and regulatory T cells as well as deficient expression of the autoimmune regulator (AIRE) by neoplastic thymic epithelial cells. We review spontaneous and genetically engineered thymoma models in a spectrum of animals and the extensive clinical and immunological overlap between canine, feline and human TAMG. Finally, limitations and perspectives of the transplantation of human and murine thymoma tissue into nude mice, as potential models for TAMG, are addressed.

  18. Idiopathic Pulmonary Fibrosis and Myasthenia Gravis: An Unusual Association

    PubMed Central

    Chogtu, Bharti; Malik, Daliparty Vasudev

    2016-01-01

    Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrosing lung condition with high morbidity and mortality, accounting for about 25% of the cases of interstitial lung diseases. It usually has a progressive course resulting in death due to respiratory failure. Myasthenia Gravis (MG) is an autoimmune neuromuscular disease, caused by antibody mediated activity against acetylcholine receptor at the neuromuscular junction. It is characterized by fluctuating muscle weakness and fatigue. Extensive literature search did not reveal any case report of an association between these two conditions. Here we present a case of a patient with IPF who also developed MG. The diagnosis of IPF was based on High Resolution Computed Tomography (HRCT) of the lung and that of MG was based on clinical criteria and electrophysiological testing. The case was successfully managed. PMID:27190866

  19. Severe Preeclampsia in the Setting of Myasthenia Gravis

    PubMed Central

    Keeney, Renée

    2017-01-01

    Myasthenia gravis (MG) is a rare autoimmune disease that leads to progressive muscle weakness and is common during female reproductive years. The myasthenic mother and her newborn must be observed carefully, as complications during all stages of pregnancy and the puerperium may arise suddenly. Preeclampsia is a common obstetrical condition for which magnesium sulfate is used for seizure prophylaxis. However, magnesium sulfate is strongly contraindicated in MG as it impairs already slowed nerve-muscle connections. Similarly, many first-line antihypertensive medications, including calcium channels blockers and β-blockers, may lead to MG exacerbation. This case describes the effective obstetrical management of a patient with MG who developed severe preeclampsia. The effective use of levetiracetam and various antihypertensive medications including intravenous labetalol is described. A review of the ten reported cases of MG complicated by preeclampsia is examined to aggregate observations of clinical care, with focus on delivery methods, anticonvulsants, and antihypertensive medications. PMID:28280642

  20. Misdiagnosis of Myasthenia Gravis and Subsequent Clinical Implication

    PubMed Central

    Al-Asmi, Abdullah; Nandhagopal, Ramachandiran; Jacob, P C; Gujjar, Arunodaya

    2012-01-01

    The autoimmune disease, myasthenia gravis (MG), can mimic a variety of neurological disorders leading to a delay in diagnosis and treatment. On occasions, misdiagnosis of MG could lead to unnecessary and potentially harmful therapeutic interventions. We report on a 12 year-old boy, in whom MG was mistaken for meningitic sequelae and subsequently for critical neuropathy/myopathy resulting in considerable morbidity for nearly a decade. Subsequent correct diagnosis and optimal management resulted in significant improvement in his functional status. We discuss the importance of considering MG as one of the potential differential diagnoses among cases of recurrent respiratory pump failure, or unexplained bulbar symptoms where documentary proof of the previous diagnoses including work-up for MG is lacking. We also review the literature on MG misdiagnosis and highlight the potential pitfalls in MG diagnosis. PMID:22375266

  1. Quality of life in 188 patients with myasthenia gravis in China.

    PubMed

    Yang, Yongxiang; Zhang, Min; Guo, Jun; Ma, Shan; Fan, Lingling; Wang, Xianni; Li, Chuan; Guo, Peng; Wang, Jie; Li, Hongzeng; Li, Zhuyi

    2016-01-01

    Myasthenia gravis (MG) is a kind of chronic autoimmune disease which can weaken patients' motor function and, furthermore, produce negative impact on the health-related quality of life (HRQoL). The primary purpose of this research was to evaluate factors that might affect the HRQoL of MG patients. A cross-sectional clinical research was carried out including 188 successive patients with MG. Myasthenia Gravis Foundation of America (MGFA) classification and Quantitative Myasthenia Gravis (QMG) score were applied to assess the severity of the disease. The Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36) was used to estimate the HRQoL. Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were utilized to measure the depression and anxiety symptom. Factors may influence the HRQoL of MG patients include age, educational level, occupation, the situation of the thymus, the type of MG and generalized myasthenia gravis (GMG), the severity of the disease and the psychological disorder. Higher QMG and HARS scores were two significant factors that can prognosticate lower Physical Composite Score (PCS) and Mental Composite Score (MCS), while older age was just a significant factor which has prognostic value for lower PCS. The results of this research may have a potential guiding significance for the clinical treatment strategy and improve the quality of life in patients with MG consequently. In addition to the treatment of physical symptoms, the psychological symptoms such as anxiety and depression should be concerned as well.

  2. Two patients with co-morbid myasthenia gravis in a Brazilian cohort of inflammatory bowel disease.

    PubMed

    Gondim, Francisco de A A; de Oliveira, Gisele R; Araújo, Davi F; Souza, Marcellus Henrique Loiola Ponte; Braga, Lúcia Libanez Bessa Campelo; Thomas, Florian P

    2014-11-01

    Co-morbid auto-immune disorders may affect 0.2% of the population. We present the clinical and electrodiagnostic findings of 2 patients with inflammatory bowel disease and myasthenia gravis from a Brazilian cohort of 218 inflammatory bowel disease patients. Patient 1: A 40year-old man was diagnosed with ulcerative colitis at age 37 and underwent total colectomy 3years later. After prednisone was tapered, he experienced a clinical relapse and was diagnosed with Crohn's disease. He then developed quadriparesis, bilateral ptosis, dysphagia and dysarthria. Patient 2: A 41year-old woman (diagnosed with ulcerative colitis and primary sclerosing cholangitis at age 35) developed speech impairment and ptosis. On both patients, symptoms quickly progressed over few weeks. Myasthenia gravis was diagnosed and confirmed by abnormal repetitive nerve stimulation and elevated anti-acetylcholine receptor antibody titers. Pyridostigmine and prednisone successfully treated both patients. Myasthenia gravis prevalence over 9years was 0.9%. Myasthenia gravis clinical course was not significantly modified by inflammatory bowel disease relapses and should be suspected with new onset weakness.

  3. Pembrolizumab-induced myasthenia gravis: A fatal case report.

    PubMed

    March, Katherine L; Samarin, Michael J; Sodhi, Amik; Owens, Ryan E

    2017-01-01

    Purpose Pembrolizumab, a monoclonal antibody which inhibits the programmed cell death 1 receptor, has been shown to efficaciously enhance pre-existing immune responses to malignancies. However, safety concerns must also be considered as pembrolizumab use has been associated with several life-threatening immune-related adverse events (irAEs). We report a fatal case of pembrolizumab-induced myasthenia gravis in a patient with no prior myasthenia gravis history. Case report A 63-year-old male presented with right eyelid drooping, puffiness, blurred vision, and shortness of breath two weeks after an initial infusion of pembrolizumab. He was subsequently diagnosed with new onset acetylcholine-receptor positive myasthenia gravis. Despite aggressive treatment with corticosteroids, pyridostigmine, intravenous immunoglobulin, and plasmapheresis, the patient clinically deteriorated and ultimately expired from acute respiratory failure after a 12-day hospitalization. Discussion Current package labeling for pembrolizumab warns against various irAEs associated with its use including pneumonitis, colitis, and endocrinopathies. To date, only one case of new onset myasthenia gravis and two case reports of myasthenia gravis exacerbation have been identified. This case further highlights the mortality risk associated with development of irAEs. Conclusion While rare, evidence for the development of MG associated with pembrolizumab is growing. Prompt recognition of symptoms and discontinuation of pembrolizumab is necessary to help improve prognosis.

  4. Differential Diagnosis of Hallucinations in a Patient with Myasthenia Gravis

    PubMed Central

    Hizem, Yosr; Ben Djebara, Mouna; Kacem, Imen; Gargouri, Amina; Gouider, Riadh

    2013-01-01

    We present the case of a 63-year-old woman with comorbidity of myasthenia gravis and psychosis. Different diagnostic hypotheses based on a review of the literature are discussed. A protracted history of physical spousal abuse, patient symptoms, and results of different investigations allowed us to conclude that the patient had a form of posttraumatic stress disorder with secondary psychotic features. Psychosis due to myasthenia gravis is rarely seen, and it remains unclear what is the pathophysiology, if any, for such an association. The present case highlights the difficulties the physician faces in disentangling psychosis as a potential manifestation of myasthenia gravis itself versus being caused by a medical side effect of treatment, or psychosis due to a distinct co-occurring neurologic or psychiatric condition. PMID:24307978

  5. Recent Advances in Genetic Predisposition of Myasthenia Gravis

    PubMed Central

    Kambouris, Manousos E.; Patrinos, George P.; Tzartos, Socrates J.

    2013-01-01

    Myasthenia gravis (MG) is an autoimmune disease mediated by the presence of autoantibodies that bind to components of the neuromuscular junction, causing the symptoms of muscular weakness and fatigability. Like most autoimmune disorders, MG is a multifactorial, noninherited disease, though with an established genetic constituent. The heterogeneity observed in MG perplexes genetic analysis even more, as it occurs in various levels, including diverse autoantigens, thymus histopathology, and age at onset. In this context of distinct subgroups, a plethora of association studies, discussed in this review, have assessed the involvement of various HLA and non-HLA related loci in MG susceptibility, over the past five years. As expected, certain HLA alleles were strongly associated with MG. Many of the non-HLA genes, such as PTPN22 and CTLA-4, have been previously studied in MG and other autoimmune diseases and their association with MG has been reevaluated in more cohesive groups of patients. Moreover, novel risk or protective loci have been revealed, as in the case of TNIP1 and FOXP3. Although the majority of these results have been derived from candidate gene studies, the focal point of all recent genetic studies is the first genome-wide association study (GWAS) conducted on early-onset MG patients. PMID:24294607

  6. Refractory myasthenia gravis – clinical profile, comorbidities and response to rituximab

    PubMed Central

    Sudulagunta, Sreenivasa Rao; Sepehrar, Mona; Sodalagunta, Mahesh Babu; Settikere Nataraju, Aravinda; Bangalore Raja, Shiva Kumar; Sathyanarayana, Deepak; Gummadi, Siddharth; Burra, Hemanth Kumar

    2016-01-01

    Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications. Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27–53 years. In our study 25 patients (32.89%) belonged to the age group of 21–30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% (p=3.3x10–8) to 94.6% (p=2.2x10–14) after the third cycle of rituximab treatment. Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low. PMID:27790079

  7. Myasthenia gravis and hypothyroidism in a dog with meningomyelitis.

    PubMed

    Levine, Jonathan M; Bergman, Robert L; Coates, Joan R; Shelton, G Diane

    2005-01-01

    A 12-year-old, spayed female miniature poodle was evaluated because of a 4-day history of paraparesis, dysuria, and tenesmus. Neurological assessment suggested peripheral nervous system dysfunction, predominantly pelvic limb weakness with a possible concurrent sixth lumbar (L(6)) to second sacral (S(2)) myelopathy. Further studies supported the diagnoses of myasthenia gravis, hypothyroidism, and meningomyelitis. To the authors' knowledge, this is the first reported case of concurrent myasthenia gravis and meningomyelitis in the dog. It was unclear whether the identified conditions evolved from a shared etiopathogenesis or were merely coincidental.

  8. Acquired myasthenia gravis and cholangiocellular carcinoma in a dog.

    PubMed

    Krotje, L J; Fix, A S; Potthoff, A D

    1990-08-15

    Acquired myasthenia gravis and cholangiocellular carcinoma were diagnosed in a 7-year-old English Setter referred because of forelimb lameness, exercise-induced weakness, and fever. Three months earlier, the dog had had a pleuropulmonary infection caused by a Fusobacterium sp. The concurrent development of myasthenia gravis and cholangiocellular carcinoma in this dog may be explained by a paraneoplastic syndrome, although it is unproven. The cholangiocellular carcinoma may have possessed an acetylcholine receptor-like antigen on the tumor surface, which induced autoantibodies to cross-react with acetylcholine receptors at the neuromuscular junction.

  9. T and B lymphocytes in myasthenia gravis.

    PubMed Central

    Itoyama, Y; Kawanami, S; Goto, I; Kuroiwa, Y

    1979-01-01

    Peripheral blood lymphocytes from seventeen non-thymectomized and nine thymectomized patients with myasthenia gravis (MG) and thirteen healthy controls were examined for the presence of surface markers characteristic of T and B lymphocytes by rosette formation with sheep red blood cells (SRBC). T cells were identified by their capacity to spontaneously form rosettes with SRBCs. The percentage of B lymphocytes was determined by the erythrocyte antibody complement (EAC) rosette-forming test. The EAC complex was prepared with either whole rabbit anti-SRBC serum or with the IgM fraction of rabbit anti-SRBC serum. The two kind of erythrocyte complement rosette-forming cells (EAC-RFC) are designated erythrocyte-haemolysin-complement RFC (EA(H)C-RFC), and erythrocyte-IgM-complement RFC (EA(M)C-RFC). The percentage of total lymphocytes and T cells was not altered in MG patients. The percentage of 'active' T cells, which have been considered to be more actively involved in cellular immunity, was also similar in MG patients and controls. A significant increase in EA(H)C-RFC occurred in both thymectomized and non-thymectomized MG patients, while in B cells detected by EA(M)C-RFC no alterations were found. The increase in EA(H)C-RFC in lymphocytes from MG patients may be due to an increase in the 19S antibody-forming B lymphocytes or to an increase in T cells which have Fc receptors on their surface. PMID:315844

  10. A Conceptual Framework for Evaluating Impairments in Myasthenia Gravis

    PubMed Central

    Barnett, Carolina; Bril, Vera; Kapral, Moira; Kulkarni, Abhaya; Davis, Aileen M.

    2014-01-01

    Background Myasthenia gravis is characterized by weakness and fatigability of different muscle groups, including ocular, bulbar and the limbs. Therefore, a measure of disease severity at the impairment level in myasthenia needs to reflect all the relevant impairments, as well as their variations with activity and fatigue. We conducted a qualitative study of patients with myasthenia, to explore their experiences and related impairments, aimed at developing a conceptual framework of disease severity at the impairment level in myasthenia gravis. Methods Twenty patients representing the spectrum of disease participated in semi-structured interviews. Interviews were recorded and the transcripts were analyzed by content analysis using an inductive approach with line-by-line open coding. Themes were generated from these codes. Results Two main themes were identified: the severity of the impairments and fatigability (i.e., triggering or worsening of an impairment with activity). The impairments were further classified within body regions (ocular, bulbar and axial/limbs). Fatigability was described as a phenomenon affecting the whole body but also affecting specific impairments, and was associated with fluctuation of the symptoms. Patients were concerned that clinical examination at a single point in time might not reflect their true clinical state due to fatigability and fluctuations in severity. Conclusions This conceptual framework reflects the relevance of both severity and fatigability in understanding impairment-based disease severity in myasthenia. This framework could inform the development of impairment measures in myasthenia gravis. PMID:24844418

  11. Determinants of quality of life in Brazilian patients with myasthenia gravis

    PubMed Central

    Mourão, Aline Mansueto; Gomez, Rodrigo Santiago; Barbosa, Luiz Sergio Mageste; da Silva Freitas, Denise; Comini-Frota, Elizabeth Regina; Kummer, Arthur; Lemos, Stella Maris Aguiar; Teixeira, Antonio Lucio

    2016-01-01

    OBJECTIVES: The aims of the current study were 1) to evaluate the reliability and validity of the Brazilian version of the 15-item Myasthenia Gravis Quality of Life Scale and 2) to investigate the quality of life of Brazilian patients with myasthenia gravis and its determinants. METHODS: This cross-sectional study included 69 patients with myasthenia gravis who underwent neurological evaluation and completed questionnaires regarding quality of life (the 36-item Short Form of the Medical Outcomes Study and the 15-item Myasthenia Gravis Quality of Life Scale), anxiety and depressive symptoms. RESULTS: The Brazilian version of the 15-item Myasthenia Gravis Quality of Life Scale showed high internal consistency and good concurrent validity with the 36-item Short Form of the Medical Outcomes Study and its subscales. Determinants of quality of life in Brazilian patients with myasthenia gravis included the current status of myasthenia gravis as assessed by the Myasthenia Gravis Composite, the current prednisone dose and the levels of anxiety and depression. CONCLUSION: The Brazilian version of the 15-item Myasthenia Gravis Quality of Life Scale is a valid instrument. Symptom severity, prednisone dosage and anxiety and depression levels impact the quality of life of patients with myasthenia gravis. PMID:27464292

  12. Thymic remodeling associated with hyperplasia in myasthenia gravis.

    PubMed

    Le Panse, Rozen; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Weiss, Julia Miriam; Cufi, Perrine; Dartevelle, Philippe; De Rosbo, Nicole Kerlero; Berrih-Aknin, Sonia

    2010-08-01

    Acquired myasthenia gravis (MG), a neurological autoimmune disease, is caused by autoantibodies against components of the neuromuscular junction that lead to disabling muscle fatigability. The thymus is clearly involved in the pathogenesis of early-onset MG with anti-acetylcholine receptor antibodies, and thymic hyperplasia of lympho-proliferative origin is a hallmark of the disease. In this review, we describe the structural and cellular changes associated with thymic hyperplasia, its main characteristics being the development of ectopic germinal centers (GCs) associated with active neoangiogenic processes, such as development of high endothelial venules and lymphangiogenesis. What triggers such thymic abnormalities in MG is not yet clear. A thymic transcriptome analysis has demonstrated a strong inflammatory signature in MG that could orchestrate the development of thymic hyperplasia. In this context, thymic epithelial cells (TECs) seem to play a central role, either by contributing or responding to the inflammatory environment and up-regulating the autoimmune response. In particular, MG TECs clearly overexpress various cytokines, among which chemokines play a crucial role in the recruitment of peripheral lymphocytes to the thymus via the newly expanded vessel network, thereby leading to the development of ectopic GCs. Clearly, a better understanding of major events that lead to thymic hyperplasia will help optimize strategies toward more specific therapy for MG.

  13. The auto-antigen repertoire in myasthenia gravis.

    PubMed

    Vrolix, Kathleen; Fraussen, Judith; Molenaar, Peter C; Losen, Mario; Somers, Veerle; Stinissen, Piet; De Baets, Marc H; Martínez-Martínez, Pilar

    2010-08-01

    Myasthenia Gravis (MG) is an antibody-mediated autoimmune disorder affecting the postsynaptic membrane of the neuromuscular junction (NMJ). MG is characterized by an impaired signal transmission between the motor neuron and the skeletal muscle cell, caused by auto-antibodies directed against NMJ proteins. The auto-antibodies target the nicotinic acetylcholine receptor (nAChR) in about 90% of MG patients. In approximately 5% of MG patients, the muscle specific kinase (MuSK) is the auto-antigen. In the remaining 5% of MG patients, however, antibodies against the nAChR or MuSK are not detectable (idiopathic MG, iMG). Although only the anti-nAChR and anti-MuSK auto-antibodies have been demonstrated to be pathogenic, several other antibodies recognizing self-antigens can also be found in MG patients. Various auto-antibodies associated with thymic abnormalities have been reported, as well as many non-MG-specific auto-antibodies. However, their contribution to the cause, pathology and severity of the disease is still poorly understood. Here, we comprehensively review the reported auto-antibodies in MG patients and discuss their role in the pathology of this autoimmune disease.

  14. Ocular myasthenia gravis after D-penicillamine administration.

    PubMed Central

    Katz, L J; Lesser, R L; Merikangas, J R; Silverman, J P

    1989-01-01

    A 68-year-old black woman who was put on D-penicillamine therapy (250-500 mg per day, total dose 15 g) for rheumatoid arthritis developed ocular myasthenia gravis. Two weeks after she discontinued D-penicillamine her signs and symptoms cleared with no other treatment. Review of previous cases and possible immunological mechanisms are discussed. PMID:2692700

  15. Myasthenia gravis and neuromyelitis optica spectrum disorder

    PubMed Central

    Leite, M.I.; Coutinho, E.; Lana-Peixoto, M.; Apostolos, S.; Waters, P.; Sato, D.; Melamud, L.; Marta, M.; Graham, A.; Spillane, J.; Villa, A.M.; Callegaro, D.; Santos, E.; da Silva, A. Martins; Jarius, S.; Howard, R.; Nakashima, I.; Giovannoni, G.; Buckley, C.; Hilton-Jones, D.; Vincent, A.

    2012-01-01

    Objective: To describe 16 patients with a coincidence of 2 rare diseases: aquaporin-4 antibody (AQP4-Ab)–mediated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and acetylcholine receptor antibody (AChR-Ab)–mediated myasthenia gravis (AChR-MG). Methods: The clinical details and antibody results of 16 patients with AChR-MG and AQP4-NMOSD were analyzed retrospectively. Results: All had early-onset AChR-MG, the majority with mild generalized disease, and a high proportion achieved remission. Fifteen were female; 11 were Caucasian. In 14/16, the MG preceded NMOSD (median interval: 16 years) and 11 of these had had a thymectomy although 1 only after NMOSD onset. In 4/5 patients tested, AQP4-Abs were detectable between 4 and 16 years prior to disease onset, including 2 patients with detectable AQP4-Abs prior to thymectomy. AChR-Abs decreased and the AQP4-Ab levels increased over time in concordance with the relevant disease. AChR-Abs were detectable at NMOSD onset in the one sample available from 1 of the 2 patients with NMOSD before MG. Conclusions: Although both conditions are rare, the association of MG and NMOSD occurs much more frequently than by chance and the MG appears to follow a benign course. AChR-Abs or AQP4-Abs may be present years before onset of the relevant disease and the antibody titers against AQP4 and AChR tend to change in opposite directions. Although most cases had MG prior to NMOSD onset, and had undergone thymectomy, NMOSD can occur first and in patients who have not had their thymus removed. PMID:22551731

  16. Passive transfer of experimental autoimmune myasthenia by lymph node cells in inbred guinea pigs

    PubMed Central

    1975-01-01

    Passive transfer of experimental autoimmune myasthenia (EAM) was performed with lymph node cells from donor guinea pigs immunized with purified acetylcholine receptor (AChR) from Torpedo californica. Recipient animals revealed the same clinical signs and electromyographic patterns as observed in actively challenged animals. These phenomena are parallel to the clinical manifestations of the human disease myasthenia gravis, in which cellular response to AChR was recently demonstrated. PMID:1165476

  17. Dysphonia as the primary complaint in a case of myasthenia gravis: diagnosis and speech therapy.

    PubMed

    Nemr, Nair Kátia; Simões-Zenari, Marcia; Ferreira, Tainá Soares; Fernandes, Heloisa Regina; Mansur, Letícia Lessa

    2013-01-01

    Myasthenia gravis is an autoimmune disease, manifested by progressive muscular weakness and fatigue. There are frequent ocular and bulbar symptoms, among them, dysphonia. This article reports a case of dysphonia that contributed to the diagnosis of myasthenia gravis through a speech evaluation. The patient sought speech therapy with the ENT diagnosis of presbyphonia. The perceptual voice assessment and acoustic analysis pointed out respiration, glottal voice source and resonance affections. Considering that some of the data obtained from anamnesis and vocal assessments were not directly related to presbyphonia, the speech therapist discussed the case with the physician and they both concluded it was necessary to refer the patient to a neurological evaluation. The neurologist then raised the diagnostic hypotheses of myasthenia gravis and requested further examinations. The patient underwent speech therapy and drug treatment. A vocal reassessment, which occurred two months after the initial treatment, showed improvement in voice quality, with great impact on quality of life. This article shows the importance of detailed clinical speech evaluation and participation of a speech therapist in an interdisciplinary team.

  18. Subcutaneous Immunoglobulin Therapy in the Chronic Management of Myasthenia Gravis: A Retrospective Cohort Study

    PubMed Central

    Bourque, P. R.; Pringle, C. E.; Cameron, W.; Cowan, J.; Chardon, J. Warman

    2016-01-01

    Background Immunoglobulin therapy has become a major treatment option in several autoimmune neuromuscular disorders. For patients with Myasthenia Gravis (MG), intravenous immunoglobulin (IVIg) has been used for both crisis and chronic management. Subcutaneous Immunoglobulins (SCIg), which offer the advantage of home administration, may be a practical and effective option in chronic management of MG. We analyzed clinical outcomes and patient satisfaction in nine cases of chronic disabling MG who were either transitioned to, or started de novo on SCIg. Methods and Findings This was a retrospective cohort study for the period of 2015–2016, with a mean follow-up period of 6.8 months after initiation of SCIg. All patients with MG treated with SCIg at the Ottawa Hospital, a large Canadian tertiary hospital with subspecialty expertise in neuromuscular disorders were included, regardless of MG severity, clinical subtype and antibody status. The primary outcome was MG disease activity after SCIg initiation. This outcome was measured by 1) the Myasthenia Gravis Foundation of America (MGFA) clinical classification, and 2) subjective scales of disease activity including the Myasthenia Gravis activities of daily living profile (MG-ADL), Myasthenia Gravis Quality-of-life (MG-QOL 15), Visual Analog (VA) satisfaction scale. We also assessed any requirement for emergency department visits or hospitalizations. Safety outcomes included any SCIg related complication. All patients were stable or improved for MGFA class after SCIg initiation. Statistically significant improvements were documented in the MG-ADL, MG-QOL and VAS scales. There were no exacerbations after switching therapy and no severe SCIg related complications. Conclusions SCIg may be a beneficial therapy in the chronic management of MG, with favorable clinical outcome and patient satisfaction results. PMID:27490101

  19. Investigation on the mechanism of exacerbation of myasthenia gravis by aminoglycoside antibiotics in mouse model.

    PubMed

    Liu, Changqin; Hu, Fang

    2005-01-01

    To investigate the underlying mechanism of the exacerbation of myasthenia gravis by aminoglycoside antibiotics. C57/BL6 mice were immunized with acetylcholine receptor (AChR), extracted from electric organ of Narcine timilei according to Xu Haopeng's methods, in complete Fruends adjuvant (CFA) to establish experimental autoimmune myasthenia gravis (EAMG). EAMG mice were divided randomly into 5 groups: MG group, NS group and three antibiotics groups. The clinical symptom scores of mice were evaluated on d7 after the last immunization and d14 of antibiotics treatment. Repetitive nerve stimulation (RNS) was performed and the levels of anti-AChR antibody (AChR-Ab) were tested at the same time. The mean clinical symptom grades of gentamycin group (1.312, 2.067), amikacin group (1.111, 1.889) and etimicin group (1.263, 1.632) were significantly higher than those of MG group (1.000, 1.200) (P<0.05). The positive rates of RNS of three antibiotics groups were 69.23%, 58.82% and 63.16% respectively, which were significantly higher than those of MG group and NS group (40.00%, 40.00%, P<0.05). The AChR-Ab level in serum and the expression of AChR on neuromuscular junction (NMJ) of mice in three antibiotics groups were also higher than those of MG group. Our results indicated that aminoglycoside antibiotics could aggravate the symptom of myasthenia gravis. The exacerbation of myasthenia gravis by these antibiotics probably involves competitively restraining the release of acetylcholine from presynaptic membrane, impairing the depolarization of postsynaptic membrane, depressing the irritability of myocyte membrane around the end-plate membrane and consequently leading to the blockade of neuromuscular junction.

  20. Myasthenia gravis and thymic neoplasms: A brief review.

    PubMed

    Kumar, Ritesh

    2015-12-16

    Thymoma is the most common mediastinal tumor. They have varied presentation ranging from asymptomatic incidental mediastinal masses to locally extensive tumor with compressive symptoms and distant metastases. They have frequent association with various paraneoplastic syndromes (PNS). The most common PNS associated with thymoma is myasthenia gravis (MG). Patients of thymoma with MG have a favourable outcome due to early disclosure of the disease. Histologically they are classified into five subtypes and Masaoka-Koga staging system is used for staging. Surgery, chemotherapy and radiotherapy play an important role along with anti-myasthenia drugs. This review would like to highlight the association of thymoma with MG and associated clinical and therapeutic issues.

  1. The mechanism of acetylcholine receptor in binding MuSK in myasthenia gravis and the role of HSP90 molecular chaperone.

    PubMed

    Chen, Rongbo; Chen, Siqia; Liao, Juan; Chen, Xiaopu; Xu, Xiaoling

    2016-01-01

    As an autoimmune disease, myasthenia gravis is caused by the dysfunction of neural transmission. Acetylcholine is known to exert its function after entering into synaptic cleft through binding onto postsynaptic membrane. The role of acetylcholine in binding MuSK in myasthenia gravis, however, remains unknown. A total of 38 myasthenia gravis patients and 27 healthy controls were included in this study for the detection of the expression of MuSK using immunofluorescent method. Expression of both MuSK and interleukin-6 (IL-6) were measured by Western blot, followed by the correlation analysis between heat shock protein 90 (HSP90) and IL-6 which were measured by enzyme-linked immunosorbent assay (ELISA). In myasthenia gravis patients, MuSK was co-localized with acetylcholine at the postsynaptic membrane. Such accumulation of MuSK, however, did not occur in normal people. Meanwhile we also observed elevated expression of IL-6 in myasthenia gravis patients (p<0.05). ELISA assay showed higher expression of HSP90 in patients. Further signaling pathway screening revealed the activation of IL-6-mediated pathways including STAT3 and SPH2. In conclusion, MuSK was co-localized with acetylcholine in myasthenia gravis patients, with elevated expression. HSP90 in disease people can activate IL-6 mediated signaling pathways.

  2. Effect of therapeutic plasma exchange on immunoglobulins in myasthenia gravis.

    PubMed

    Guptill, Jeffrey T; Juel, Vern C; Massey, Janice M; Anderson, Amanda C; Chopra, Manisha; Yi, John S; Esfandiari, Ehsanollah; Buchanan, Tim; Smith, Bryan; Atherfold, Paul; Jones, Emma; Howard, James F

    2016-11-01

    An integrated understanding of therapeutic plasma exchange (TPE) effects on immunoglobulins, autoantibodies, and natural or acquired (vaccine) protective antibodies in patients with autoimmune myasthenia gravis (MG) is lacking. Prior studies measured TPE effects in healthy volunteers or heterogeneous autoimmune disease populations. We prospectively profiled plasma IgA, IgM, IgG, IgG subclasses (IgG1-4), acetylcholine receptor autoantibodies (AChR+), and protective antibodies in patients with AChR + MG receiving TPE for an exacerbation. TPE was performed according to institutional practice and patients were profiled for up to 12 weeks. Ten patients were enrolled (median age = 72.9 years; baseline MG-Composite = 21; median TPE treatments = 6 during their first course) and all improved. The maximum decrease in all immunoglobulins, including AChR autoantibodies, was achieved on the final day of the first TPE course (∼60-70% reduction). Three weeks post-TPE, mean AChR autoantibody, total IgG, IgG1, and IgG2 titers were below the reference range and had not recovered within 20% of baseline, whereas other measured immunoglobulins approached baseline values. We did not generally observe an "overshoot" of immunoglobulins above pre-TPE levels or accelerated recovery of pathologic AChR autoantibodies. Protective antibody profiles showed similar patterns as other IgGs and were detectable at levels associated with protection from infection. A slow return to baseline for IgGs (except IgG3) was observed, and we did not observe any obvious effect of concomitant medications on this recovery. Collectively, these findings enhance our understanding of the immunological effects of TPE and further support the concept of rapid immunoglobulin depletion for the treatment of patients with MG.

  3. Future perspectives in target-specific immunotherapies of myasthenia gravis

    PubMed Central

    Dalakas, Marinos C.

    2015-01-01

    Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against acetylcholine receptors (AChR); antigen-specific CD4+ T cells, regulatory T cells (Tregs) and T helper (Th) 17+ cells are essential in antibody production. Target-specific therapeutic interventions should therefore be directed against antibodies, B cells, complement and molecules associated with T cell signaling. Even though the progress in the immunopathogenesis of the disease probably exceeds any other autoimmune disorder, MG is still treated with traditional drugs or procedures that exert a non-antigen specific immunosuppression or immunomodulation. Novel biological agents currently on the market, directed against the following molecular pathways, are relevant and specific therapeutic targets that can be tested in MG: (a) T cell intracellular signaling molecules, such as anti-CD52, anti-interleukin (IL) 2 receptors, anti- costimulatory molecules, and anti-Janus tyrosine kinases (JAK1, JAK3) that block the intracellular cascade associated with T-cell activation; (b) B cells and their trophic factors, directed against key B-cell molecules; (c) complement C3 or C5, intercepting the destructive effect of complement-fixing antibodies; (d) cytokines and cytokine receptors, such as those targeting IL-6 which promotes antibody production and IL-17, or the p40 subunit of IL-12/1L-23 that affect regulatory T cells; and (e) T and B cell transmigration molecules associated with lymphocyte egress from the lymphoid organs. All drugs against these molecular pathways require testing in controlled trials, although some have already been tried in small case series. Construction of recombinant AChR antibodies that block binding of the pathogenic antibodies, thereby eliminating complement and antibody-depended-cell-mediated cytotoxicity, are additional novel molecular tools that require exploration in experimental MG. PMID:26600875

  4. Microthymoma in elderly-onset myasthenia gravis detected preoperatively.

    PubMed

    Hino, Haruaki; Nishimura, Takashi; Seki, Atsuko; Nitadori, Jun-Ichi; Arai, Tomio; Nakajima, Jun

    2016-10-01

    A 77-year-old woman with a 3-month history of muscle weakness was diagnosed with elderly-onset generalized myasthenia gravis (Myasthenia Gravis Foundation of America classification IIa) based on a high serum acetylcholine receptor antibody level (25.4 nmol·L(-1)) and neurological findings. Computed tomography detected a small nodule (diameter 15 mm) in the anterior mediastinum, which was suspected to be a thymoma. An extended thymectomy was performed. The pathological examination revealed a 6-mm-diameter thymoma, termed a microthymoma, accompanied with a unilocular thymic cyst without capsule formation (type B2 according to the World Health Organization classification). Some fat tissue was also found within the tumor.

  5. Myasthenia gravis: new therapeutic approaches based on pathophysiology.

    PubMed

    Lewis, Richard A

    2013-10-15

    Over the past 40 years Dr. Robert Lisak has made important contributions to our understanding of the pathophysiology and therapy of myasthenia gravis. This review will touch upon some of his work as it discusses current therapies and the potential for new treatments based on the evolving knowledge of the underlying basis of the disease. The recognition of different immune mechanisms that can cause the phenotype that we acknowledge as myasthenia gravis coincides with the introduction of monoclonal antibodies and other new therapies that can target specific aspects of the disease. This has raised our hopes for treatments that will have less side effects and be more effective. In some cases these hopes have been realized. In other instances, the situation remains a "work in progress". Dr. Lisak's work and teachings remain cogent to our modern approach to this classic immunologic disease.

  6. Do associated auto-antibodies influence the outcome of myasthenia gravis after thymectomy?

    PubMed

    Keijzers, Marlies; Damoiseaux, Jan; Vigneron, Alain; Bodart, Nicolas; Kessels, Alfons; Dingemans, Anne-Marie C; Hochstenbag, Monique; Maessen, Jos; De Baets, Marc

    2015-01-01

    Myasthenia gravis (MG) is a neuromuscular autoimmune disease, where antibodies against the acetylcholine receptor destroy this receptor. The role of thymectomy in the treatment of MG remains controversial. Because of the frequent association with other autoimmune diseases, we hypothesized that patients with multiple autoantibodies (autoAbs) might have a lower chance of reaching complete stable remission after thymectomy. We analyzed sera of 85 MG patients who underwent a thymectomy between April 2004 and December 2012. We used four different immunodot kits (D-Tek, Mons, Belgium): ANA25 Quantrix, Synthetase 10 Diver, Myositis 7 Diver and Liver 10 profile Diver, all automatized on the BlueDiver Instrument (D-Tek). The Myasthenia Gravis Foundation of America (MGFA) postintervention status was used to determine the outcome after thymectomy. AutoAbs other than anti-acetylcholine receptor (AChR) antibodies were detected in 29.4% of the patients of whom 16.5% clinically had a second autoimmune disease. In none of the seronegative patients other autoAbs were detected. No significant difference was observed in the 3-years remission rate after thymectomy in patients with or without antibodies other than anti-AChR antibodies. Although these autoAbs do not predict outcome in our MG patient cohort, screening for multiple autoAbs in MG patients might be warranted to identify patients with additional autoimmune diseases.

  7. Dropped head as an unusual presenting sign of myasthenia gravis.

    PubMed

    D'Amelio, M; Di Benedetto, N; Ragonese, P; Daniele, O; Brighina, F; Fierro, B; Savettieri, G

    2007-04-01

    Prominent or isolated weakness of cervical extensor muscles is a relatively rare clinical sign. Commonly, this is known as "dropped-head syndrome". This abnormal flexion of the head may occur in a variety of neuromuscular diseases and in a few non-neurological disorders as well. The case we describe concerns a 61-year-old woman with dropped-head syndrome as the unique complaint of myasthenia gravis.

  8. Inferior oblique muscle paresis as a sign of myasthenia gravis.

    PubMed

    Almog, Yehoshua; Ben-David, Merav; Nemet, Arie Y

    2016-03-01

    Myasthenia gravis may affect any of the six extra-ocular muscles, masquerading as any type of ocular motor pathology. The frequency of involvement of each muscle is not well established in the medical literature. This study was designed to determine whether a specific muscle or combination of muscles tends to be predominantly affected. This retrospective review included 30 patients with a clinical diagnosis of myasthenia gravis who had extra-ocular muscle involvement with diplopia at presentation. The diagnosis was confirmed by at least one of the following tests: Tensilon test, acetylcholine receptor antibodies, thymoma on chest CT scan, or suggestive electromyography. Frequency of involvement of each muscle in this cohort was inferior oblique 19 (63.3%), lateral rectus nine (30%), superior rectus four (13.3%), inferior rectus six (20%), medial rectus four (13.3%), and superior oblique three (10%). The inferior oblique was involved more often than any other muscle (p<0.01). Eighteen (60%) patients had ptosis, six (20%) of whom had bilateral ptosis. Diagnosing myasthenia gravis can be difficult, because the disease may mimic every pupil-sparing pattern of ocular misalignment. In addition diplopia caused by paresis of the inferior oblique muscle is rarely encountered (other than as a part of oculomotor nerve palsy). Hence, when a patient presents with vertical diplopia resulting from an isolated inferior oblique palsy, myasthenic etiology should be highly suspected.

  9. Thymoma-associated exfoliative dermatitis with post-thymectomy myasthenia gravis in a cat.

    PubMed

    Singh, Ameet; Boston, Sarah E; Poma, Roberto

    2010-07-01

    Thymoma-associated exfoliative dermatitis was suspected in a cat with a cranial mediastinal mass. The dermatopathy resolved with surgical removal of a thymoma. The cat manifested neurologic signs consistent with myasthenia gravis 7 wk after surgery. Exfoliative dermatitis and post-thymectomy myasthenia gravis in the same cat has not been reported previously.

  10. Periductal lymphocytic infiltrates in salivary glands in myasthenia gravis patients lacking Sjögren's syndrome.

    PubMed Central

    Lindahl, G; Lefvert, A K; Hedfors, E

    1986-01-01

    In eight of eleven patients with clinical and serological evidence of myasthenia gravis (MG), immunohistological analysis of biopsies from labial salivary glands (LSG) showed focal periductal lymphocytic infiltrates, mainly composed of anti-Leu 3a+ T helper lymphocytes, a finding usually regarded as indicative for Sjögren's syndrome (SS). None of the patients could however, according to functional criteria, be considered as having SS. This study thus indicates that lymphocytic infiltrates in LSG can be seen in MG, which has been thought of as an organspecific autoimmune disease with symptoms and signs confined to striated muscles. Images Fig. 1 PMID:2948746

  11. Low-dose spinal anesthesia for urgent laparotomy in severe myasthenia gravis

    PubMed Central

    Rodríguez, Miguel Angel Palomero; Mencía, Teresa Pérez; Álvarez, Felipe Villar; Báez, Yolanda Laporta; Pérez, Gloria María Santos; García, Andrés López

    2013-01-01

    Myasthenia gravis (MG) is an autoimmune disease with an incidence of 2-10/100,000 cases per year, characterized by muscle weakness secondary to destruction of postsynaptic acetylcholine receptors. In these patients, important perioperative issues remain unresolved, namely, optimal administration of cholinesterase inhibitors, risks of regional anesthesia, and prediction of need of postoperative mechanical ventilation. We describe the use of a low-dose spinal anesthesia in a patient with MG who was submitted for emergence exploratory laparotomy. The utilization of low-dose spinal anesthesia allowed us to perform surgery with no adverse respiratory or cardiovascular events in this patient. PMID:23717241

  12. Overlooked non-motor symptoms in myasthenia gravis.

    PubMed

    Suzuki, Shigeaki; Utsugisawa, Kimiaki; Suzuki, Norihiro

    2013-09-01

    Patients with myasthenia gravis (MG) may have various non-motor symptoms in addition to fatigability and weakness of skeletal muscles. Thymomas contain abundant immature thymocytes and developing CD4 and CD8 T cells. Thymomas are found in 15-25% of patients with MG and are associated with severe symptoms. We suggest that non-motor symptoms are based on the autoimmune disorders probably owing to an abnormal T cell repertoire from thymomas. Using previously reported cases and cases from our multicentre cooperative study, we review the clinical characteristics of patients with thymoma-associated MG who have non-motor symptoms. CD8 T cell cytotoxicity against haematopoietic precursor cells in bone marrow and unidentified autoantigens in hair follicles lead to the development of pure red cell aplasia, immunodeficiency and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and the related molecules can evoke various neurological and cardiac disorders. About 25% of patients with thymoma-associated MG have at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad spectrum of disease, ranging from the impairment of quality of life to lethal conditions. Since relatively little attention is paid to non-motor symptoms in patients with thymoma-associated MG, the symptoms may be overlooked by many physicians. Early diagnosis is important, since non-motor symptoms can be treatable. A complete understanding of non-motor symptoms is necessary for the management of patients with thymoma-associated MG.

  13. Myasthenia gravis and thymoma coexisting with myotonic dystrophy type 1.

    PubMed

    Ekmekci, Ozgul; Karasoy, Hatice; Bademkiran, Fikret; Akkus, Dilek Evyapan; Yuceyar, Nur

    2014-01-01

    We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.

  14. The value of computed tomography in myasthenia gravis

    SciTech Connect

    Brown, L.R.; Muhm, J.R.; Sheedy, P.F. II; Unni, K.K.; Bernatz, P.E.; Hermann, R.C. Jr.

    1983-01-01

    In a 5 year study, 19 patients with myasthenia gravis were studied by computed tomography (CT) and underwent thymectomy. CT was accurate in detecting the nine true thymic masses but could not differentiate thymomas from nonthymomatous masses, including thymic cysts. No thymoma was found in a patient under 25 years of age. In one case, the 18 sec scanner could not differentiate a large gland from a thymoma. In eight cases, glands with histologic thymic hyperplasia and histologically normal thymus appeared to be similar and could not be differentiated by CT.

  15. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms

    PubMed Central

    Phillips, William D.; Vincent, Angela

    2016-01-01

    Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms. PMID:27408701

  16. Lack of evidence for Epstein-Barr virus infection in myasthenia gravis thymus.

    PubMed

    Meyer, Mandy; Höls, Ann-Kathrin; Liersch, Britta; Leistner, Rasmus; Gellert, Klaus; Schalke, Berthold; Marx, Alexander; Niedobitek, Gerald

    2011-09-01

    A role for Epstein-Barr virus (EBV) in myasthenia gravis pathogenesis has been suggested recently. Using in situ hybridization for the detection of the EBV-encoded RNAs and EBNA1-specific immunohistochemistry, we found no latently infected cells in a series of thymus specimens from patients with myasthenia gravis showing lymphofollicular thymitis. In addition, using immunohistochemistry and an antibody specific for the viral immediate early protein BZLF1, no evidence of lytic EBV infection was seen in these cases. Our results therefore do not support a direct role of thymic EBV infection in the pathogenesis of myasthenia gravis.

  17. Adhesive ileus complicating recurrent intestinal pseudo-obstruction in a patient with myasthenia gravis.

    PubMed

    Seretis, Charalampos; Seretis, Fotios; Gemenetzis, George; Gourgiotis, Stavros; Lagoudianakis, Emmanuel; Pappas, Apostolos; Keramidaris, Dimitrios; Salemis, Nikolaos

    2012-05-01

    Intestinal pseudo-obstruction is considered to be one of the most frequent gastrointestinal manifestations of myasthenia gravis, accompanied by the presence of neoplasia of the thymus gland in the vast majority of the cases presented in the international literature. Despite the fact that myasthenia gravis has been implicated to be the cause of recurrent episodes of intestinal pseudo-obstruction, adhesive ileus has never been reported to complicate this - in any sense rare - condition. We present a unique case of a patient with myasthenia gravis, free of thymus neoplasia, who was submitted to emergency surgery due to the presence of extended adhesive ileus as a complication of chronic intestinal functional obstruction.

  18. Myasthenia gravis with presynaptic neurophysiological signs: Two case reports and literature review.

    PubMed

    Alboini, Paolo Emilio; Damato, Valentina; Iorio, Raffaele; Luigetti, Marco; Evoli, Amelia

    2015-08-01

    The distinction between myasthenia gravis and Lambert-Eaton myasthenic syndrome is based on clinical, neurophysiological and immunological features. We hereby report two cases with a clinical diagnosis of myasthenia gravis and neurophysiological features consistent with a pre-synaptic neuromuscular transmission defect. Both patients had increased anti-acetylcholine receptor antibody titres and showed a good response to cholinesterase inhibitors, along with a >100% facilitation of the compound muscle action potential on electrophysiological studies. We provide a review of English literature studies on co-existing features of myasthenia gravis and Lambert-Eaton myasthenic syndrome, and discuss diagnostic controversies.

  19. Muscle-specific kinase antibody associated myasthenia gravis after bone marrow transplantation.

    PubMed

    Heidarzadeh, Zeinab; Mousavi, Seyyed-Asadollah; Ostovan, Vahid Reza; Nafissi, Shahriar

    2014-02-01

    Myasthenia gravis is a rare complication of bone marrow transplantation and graft versus host disease. We report a 30-year-old woman presented with oculobulbar and proximal limb weakness after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Also, she developed graft versus host disease following bone marrow transplantation. Investigations led to the diagnosis of muscle specific kinase antibody related myasthenia gravis. There have been only two case reports of muscle specific kinase antibody positive myasthenia gravis after bone marrow transplantation in the literature, but none of the previously reported cases had graft versus host disease.

  20. NEUROMUSCULAR DISEASE MIMICKING MYASTHENIA GRAVIS IN A NIGERIAN FEMALE ADOLESCENT: COULD THIS BE NEMALINE ROD DISEASE?

    PubMed Central

    Oyinlade, O.A.; Lagunju, I.A.; Adebayo, B.E.

    2016-01-01

    Background: Nemaline rod disease is a congenital myopathy, presentation of which may mimic myasthenia gravis. Method: We report a suspected case of nemaline rod disease in a female adolescent who presented with features similar to myasthenia gravis but failed to respond effectively to its conventional management. She had features of respiratory failure and cardiomyopathy. Results: Patient had a turbulent clinical course and finally succumbed to illness on the fifth day of admission. Conclusion: This report is meant to sensitize child neurologists and general paediatricians on the need to have a broad spectrum of considerations in the management of suspected myasthenia gravis, especially when response to anticholinesterase is poor.

  1. Myasthenia gravis mimicking stroke: a case series with sudden onset dysarthria.

    PubMed

    Tremolizzo, Lucio; Giopato, Federico; Piatti, Maria Luisa; Rigamonti, Andrea; Ferrarese, Carlo; Appollonio, Ildebrando

    2015-06-01

    Myasthenia gravis (MG) is an immune-mediated disorder characterized by fluctuating fatigue of skeletal muscles, often involving extrinsic ocular or bulbar districts. Myasthenia gravis in the elderly is an under-recognized condition, sometimes confused with cerebrovascular disease. Here we present a case series of myasthenia patients which onset was characterized by sudden dysarthria, clearly raising this diagnostic dilemma. In the workout of sudden onset isolated dysarthria, MG should be always considered. In fact, even if myasthenia is a rare condition, lacunar stroke only with this clinical presentation is also unusual, and significant risks may arise (e.g., unexpected myasthenic crisis).

  2. The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics.

    PubMed

    Alahgholi-Hajibehzad, Mahdi; Kasapoglu, Pinar; Jafari, Reza; Rezaei, Nima

    2015-01-01

    T regulatory cells (Tregs) are crucial for the development of self-tolerance and are the major focus in many studies interpreting the pathogenesis of myasthenia gravis (MG), an autoimmune-based disease. In normal conditions, Tregs regulate the immune responses, while impaired regulatory function of these cells can lead to autoimmunity. Recent studies have confirmed that the thymic and peripheral blood CD4(+)CD25(+) Tregs of MG are defective in functions and/or in numbers, which are associated with disease severity; approaches to correct the defects of these Tregs may be promising in the treatment of MG. This review discusses recent studies on characteristics, quantitative and qualitative changes of Tregs and possible mechanisms that are involved in the impairment of these cells in MG pathogenesis. In addition, new approaches inducing Treg generation that are currently being investigated as therapies for MG, will be discussed as well as proposed approaches for future therapies.

  3. International consensus guidance for management of myasthenia gravis

    PubMed Central

    Wolfe, Gil I.; Benatar, Michael; Evoli, Amelia; Gilhus, Nils E.; Illa, Isabel; Kuntz, Nancy; Massey, Janice M.; Melms, Arthur; Murai, Hiroyuki; Nicolle, Michael; Palace, Jacqueline; Richman, David P.; Verschuuren, Jan; Narayanaswami, Pushpa

    2016-01-01

    Objective: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. Results: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. Conclusion: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide. PMID:27358333

  4. Myasthenia Gravis Development and Crisis Subsequent to Multiple Sclerosis

    PubMed Central

    Gharagozli, Kurosh; Shojaei, Maziar; Harandi, Ali Amini; Akbari, Nayyereh; Ilkhani, Manouchehr

    2011-01-01

    During the last decade, sporadic combination of multiple sclerosis (MS) and myasthenia gravis (MG) has been reported repeatedly. Although these are anecdotal, they are important enough to raise concerns about co-occurrence of MG and MS. Here, we present a case of an MS patient who developed an MG crisis. She had received interferon for relapsing remitting MS. Interestingly, she developed an MG crisis 4 years after the diagnosis of MS. MS and MG have relatively the same distribution for age, corresponding to the younger peak of the bimodal age distribution in MG. They also share some HLA typing characteristics. Furthermore, some evidences support the role of systemic immune dysregulation due to a genetic susceptibility that is common to these two diseases. The association may be underdiagnosed because of the possible overlap of symptoms especially bulbar manifestations in which either MG or MS can mimic each other, leading to underestimating incidence of the combination. The evidence warrants physicians, especially neurologists, to always consider the possibility of the other disease when encountering any patients either with MS or MG. Anecdotal and sporadic reports of combination of multiple sclerosis (MS) and myasthenia gravis (MG) have been raised concerns about co-occurrence of them. PMID:21629802

  5. [Advances in the research on immunopathogenesis of myasthenia gravis].

    PubMed

    Zieliński, Marcin; Kuzdzał, Jarosław; Soja, Jerzy; Szlubowski, Artur

    2003-01-01

    Microscopic structure and immunologic function of the thymus gland are outlined, with an emphasis on its role in the process of T and B lymphocytes maturation. Other types of thymic cells are also described, including epithelial and myoid cells that presumably have a central role in initiation of an autoimmunologic process leading to myasthenic symptoms development. A detailed account is presented of issues concerning pathophysiology of myasthenia, the structure of nicotinic acetylcholine receptor (AchR) at neuromuscular junctions, and mechanisms underlying its destruction by autoantibodies. The role of T and B lymphocytes, of various cytokine types, of autoantibodies to various striated muscle antigens, as well as a possible role of genetic and bacterial factors in the development of myasthenia gravis are discussed. In conclusion it is stressed that since recent research findings go beyond the classic theory of myasthenia, a new consistent theory of the disease immunopathogenesis must be created in the future to place all the newly discovered phenomena in a logical conceptual structure.

  6. The susceptibility of Aire(-/-) mice to experimental myasthenia gravis involves alterations in regulatory T cells.

    PubMed

    Aricha, Revital; Feferman, Tali; Scott, Hamish S; Souroujon, Miriam C; Berrih-Aknin, Sonia; Fuchs, Sara

    2011-02-01

    The autoimmune regulator (Aire) is involved in the prevention of autoimmunity by promoting thymic expression of tissue restricted antigens which leads to elimination of self-reactive T cells. We found that Aire knockout (KO) mice as well as mouse strains that are susceptible to experimental autoimmune myasthenia gravis (EAMG) have lower thymic expression of acetylcholine receptor (AChR- the main autoantigen in MG), compared to wild type (WT) mice and EAMG-resistant mouse strains, respectively. We demonstrated that Aire KO mice have a significant and reproducible lower frequency of CD4+Foxp3+ cells and a higher expression of Th17 markers in their thymus, compared to wild type (WT) mice. These findings led us to expect that Aire KO mice would display increased susceptibility to EAMG. Surprisingly, when EAMG was induced in young (2 month-old) mice, EAMG was milder in Aire KO than in WT mice for several weeks until the age of about 5 months. However, when EAMG was induced in relatively aged (6 month-old) mice, Aire KO mice presented higher disease severity than WT controls. This age-related change in susceptibility to EAMG correlated with an elevated proportion of Treg cells in the spleens of young but not old KO, compared to WT mice, suggesting a role for peripheral Treg cells in the course of disease. Our observations point to a possible link between Aire and Treg cells and suggest an involvement for both in the pathogenesis of myasthenia.

  7. Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma.

    PubMed

    Shirai, Takushi; Sano, Tasuku; Kamijo, Fuminao; Saito, Nana; Miyake, Tomomi; Kodaira, Minori; Katoh, Nagaaki; Nishie, Kenichi; Okuyama, Ryuhei; Uhara, Hisashi

    2016-01-01

    We reported an 81-year-old woman with metastatic melanoma, in whom myasthenia gravis and rhabdomyolysis developed after nivolumab monotherapy. The first symptom of myasthenia gravis was dyspnea. Ultrasonography detected hypokinesis of the bilateral diaphragm suggesting myasthenia gravis, although there was no abnormal finding of the lungs in computed tomography images. Acetylcholine receptor binding antibodies were low-titer positive in the preserved serum before administration of nivolumab, strongly suggesting that the myasthenia gravis was a nivolumab-related immune adverse event. Despite the remarkable clinical benefits of immune checkpoint inhibitors for patients with advanced melanoma, it is important to recognize unexpected immune-related adverse events.

  8. Study of demographic, clinical, laboratory and electromyographic symptoms in Myasthenia Gravis patients referred to the neurology clinic of Rasoul Akram hospital in 2015.

    PubMed

    Sadri, Y; Haghi-Ashtiani, B; Zamani, B; Akhundi, F H

    2015-01-01

    Introduction. Myasthenia Gravis is an autoimmune disorder, which is clinically a neuromuscular illness that shows itself as muscular weakness and fatigue. The diagnosis of Myasthenia Gravis depends on clinical evaluation, electrophysiological assessment, and autoantibody detection in serum. Known antibodies could be found in about 90% of the patients, which had a causative relation with disease symptoms. Therefore, the purpose of this paper was a survey on demographic features, clinical, laboratorial, and electromyographic signs of patients with Myasthenia Gravis referred to the neurology clinic of Rasoul Akram hospital. Materials and methods. This study was a descriptive cross-sectional one that used an easy sampling method: 54 patients with Myasthenia Gravis who were referred to the neurology clinic of Rasoul Akram were elected in 2015. The patients' information was recorded in the checklists based on the variables and the data were analyzed by using SPSS software version 21. The results. The demographic and the clinical symptoms data of 54 known Myasthenia Gravis patients, whose diagnosis was made according to the clinical symptoms, electrophysiological findings and autoantibody detection, were analyzed in this paper. There were 31 females (57.4%) and 23 males (42.6%) with an average age of 47.3 years. The average age of diagnosis of Myasthenia Gravis in these patients was 42.8 years. Among the patients, 19 (35.2%) had a hospitalization history because of their disease. Due to laboratory findings, 10 patients (18.5%) had Musk antibody, 34 patients (62.9%) had acetylcholine receptor antibodies and 10 patients (18.5%) had none of these two antibodies. Moreover, in electromyographic findings, 38 patients (70.37%) had positive findings and 16 patients (29.6%) had normal findings. Discussion and Conclusion. Due to the chronic nature of this disease, and its rising trend, educating the people for the early detection of the disease, was necessary as soon as possible so

  9. Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment.

    PubMed

    Fattorossi, Andrea; Battaglia, Alessandra; Buzzonetti, Alexia; Ciaraffa, Francesca; Scambia, Giovanni; Evoli, Amelia

    2005-09-01

    Accumulating evidence indicates an immunosuppressive role of the thymus-derived CD4+ T-cell population constitutively expressing high level of CD25, T regulatory (Treg) cells, in autoimmune diseases. Here we show that the number of Treg cells in the blood is significantly lower in untreated myasthenia gravis patients than in age-matched healthy subjects, whereas it is normal or elevated in patients on immunosuppressive therapy (prednisone frequently associated with azathioprine). Therapeutic thymectomy (Tx) for either the thymoma or non-neoplastic thymic alterations that are often associated with myasthenia gravis provided unique material for studying intrathymic Treg cells and correlating them with their peripheral counterparts. We observed that Tx prevents the increase of Treg cells in the circulation that follows immunosuppressive therapy (particularly evident if the thymus is not neoplastic), indicating that the thymus contributes to Treg-cell normalization. However, thymic Treg cells are not modulated by immunosuppressive therapy and even in thymectomized patients Treg-cell numbers in the blood eventually recover. The present findings suggest that a deficiency in Treg cells favours the development of myasthenia gravis and that their normalization is an important clinical benefit of immunosuppressive therapy. Treg normalization appears to be largely thymus independent and possibly reflects the reported capacity of corticosteroids to promote Treg-cell development.

  10. Verapamil-associated cardiogenic shock in a 71-year-old man with myasthenia gravis: a case report

    PubMed Central

    2009-01-01

    Introduction Myasthenia gravis is a rare neuromuscular disorder associated with a reduction in the availability of acetylcholine receptors at the post-synaptic membranes of skeletal muscles. This is caused by the production of anti-acetylcholine receptor antibodies at the neuromuscular junction due to an autoimmune insult, leading to a compromised neuromuscular transmission. Verapamil can influence, in a dose-dependent fashion, the neuromuscular transmission in myasthenia gravis. Case presentation We report a 71-year-old Caucasian man with myasthenia gravis suffering from a cardiogenic shock following a single dose of verapamil. The patient had uncontrolled atrial fibrillation with a heart rate of 120 beats/min. Atenolol 100 mg was started. The next day, verapamil SR 240 mg was started. Two hours after the first dose of verapamil, the patient complained of weakness and dyspnea with signs of shock; his blood pressure was 70/50 mm Hg and heart rate at 101 beats/min. An echocardiogram showed diffuse hypokinesis of both ventricles with an ejection fraction of 20%. Cardiac catheterization was performed and coronary arteries appeared without significant stenosis, but there was a diffuse hypokinesis. Verapamil was stopped and the patient received intravenous glucagon and calcium chloride. Both the anti-acetylcholine receptor and anti-striated muscle antibodies tested positive. A few hours later, another echocardiogram showed an improvement in the ventricular function, which returned to normal five days later. Conclusion Caution is needed when administering verapamil to patients with myasthenia gravis, especially when the anti-acetylcholine receptor and anti-striated muscle antibodies titres are positive. PMID:19830220

  11. AMP-deaminase from thymus of patients with myasthenia gravis.

    PubMed

    Rybakowska, I; Szydłowska, M; Szrok, S; Bakuła, S; Kaletha, K

    2015-01-01

    Myasthenia gravis (MG) is characterized clinically by skeletal muscle fatigue following the excessive exercise. Interestingly most of MG patients manifest parallely also some abnormalities of the thymus.AMP-deaminase (AMPD) from human thymus was not a subject of studies up to now. In this paper, mRNA expression and some physico-chemical and immunological properties of AMPD purified from the thymus of MG patients were described. Experiments performed identified the liver isozyme (AMPD2) as the main isoform of AMPD expressed in this organ. The activity of AMPD found in this organ was higher than in other human non-(skeletal) muscle tissues indicating on role the enzyme may play in supplying of guanylates required for the intensive multiplication of thymocytes.

  12. Dropped head with positive intravenous edrophonium, progressing to myasthenia gravis.

    PubMed

    Sawa, Nobuhiro; Kataoka, Hiroshi; Eura, Nobuyuki; Ueno, Satoshi

    2013-01-31

    'Dropped head syndrome' (DHS) may be associated with a variety of neurological diseases. The absence of neurological clues to the underlying cause of DHS can make management particularly challenging. We review six patients who presented with only DHS, responded to intravenous edrophonium and turned out to have myasthenia gravis (MG) including similar patients who were previously documented. Six patients presented with neck weakness and three had bulbar symptoms. Acetylcholine receptor (AchR) was positive in four patients. One patient had thymoma. The interval from the onset of DH to the presentation of typical MG features was shorter in patients who tested positive for anti-Ach antibody (1-2 months) than in patients who tested negative for anti-AchR antibody (13 months, 4 years). Our results suggest that patients with DHS responding to intravenous edrophonium might turn out to have MG and such patients might respond to a combination of anticholinesterase agents and steroids.

  13. Evaluation of maximal respiratory pressures in myasthenia gravis. Prognostic value.

    PubMed

    Muñoz Fernández, Carmen; Díez Tejedor, Exuperio; Frank Garcia, Ana; Pino, Jose María; Pérez Conde, Concepción; Barreiro Tella, Pablo

    2004-01-01

    We assess the prognosis of mild forms of myasthenia gravis (MG) by maximal respiratory pressures (MRP) and single fiber electromyography (SFEMG). Fifty MG patients (12 form I, 21 form IIa and 17 form IIb) are valued by MRP [maximal expiratory pressure (MEP) and maximal inspiratory pressure (MIP)] and SFEMG, and are followed-up clinically. We have found in form I patients developing form IIa and form IIa worsening to form IIb, MEP and MIP mean relative values significantly lower than the rest. Inversely, IIb form patients improving to IIa form display MIP mean relative values higher than the rest; no difference appears with MEP. A reduction under 50% of fifth-percentile implies clinical deterioration in forms I and IIa, while its surpassing in IIb form suggests a tendency to improvement. No evident differences are found by SFEMG. MRP allow the follow-up of MG patients and could warn us of a clinical prognosis.

  14. Overcoming challenges in the diagnosis and treatment of myasthenia gravis.

    PubMed

    Evoli, Amelia; Iorio, Raffaele; Bartoccioni, Emanuela

    2016-01-01

    In recent years, the discovery of new autoantigens and the use of sensitive assays have expanded the clinical spectrum of myasthenia gravis (MG). In particular, antibodies binding to clustered acetylcholine receptors and to the low-density lipoprotein receptor-related protein 4 have not only bridged a significant gap in diagnosis but also have relevant clinical implications. MG management includes different therapeutic options, from symptomatic agents as the only therapy in mildly affected cases to combined long-term immunosuppression and thymectomy in patients with severe disabling disease. MG biological diversity can influence the response to therapies and should be taken into account when planning treatment. Biologic agents are promising, though their use is currently limited to patients with refractory disease.

  15. Remarkably increased resistin levels in anti-AChR antibody-positive myasthenia gravis.

    PubMed

    Zhang, Da-Qi; Wang, Rong; Li, Ting; Li, Xin; Qi, Yuan; Wang, Jing; Yang, Li

    2015-06-15

    Resistin is a pro-inflammatory cytokine involved in the pathogenesis of autoimmune diseases. To investigate serum resistin levels in patients with myasthenia gravis (MG) and determine if there are associations between resistin levels and disease severity, we measured serum resistin levels in 102 patients with anti-acetylcholine receptor antibody-positive MG (AChR-MG). We further analyzed associations between serum resistin levels and clinical variables in patients with MG. Our findings demonstrate that serum resistin levels are elevated in patients with AChR-generalized MG and AChR-MG with thymoma and are correlated with disease severity. Resistin has potential as a useful serum biomarker for inflammation in AChR-MG.

  16. Clinical characteristics and therapeutic evaluation of childhood myasthenia gravis

    PubMed Central

    YANG, ZHI-XIAO; XU, KAI-LI; XIONG, HUI

    2015-01-01

    This study aimed to analyze the clinical characteristics, classification and treatment of childhood myasthenia gravis (MG) and address the prognosis through follow-up. The clinical data of 135 children with MG were grouped according to clinical type and therapeutic drugs, retrospectively analyzed and prospectively monitored. Of the 135 MG patients, 85.2% had type I (ocular type), with only 4.2% progressing to systemic MG; 13.4% had type II (general type); and 1.5% had type III (fulminating type). Relapse occurred in 46.1% of the 102 patients that were followed up. The positive rate for the primary acetylcholine receptor antibody was 40.19%, without significant differences among clinical subtypes. The positive rate of the repetitive nerve stimulation frequency test by electromyography was 37.97%. Decreased expression of CD4+, CD8+, or CD3+ was present in 71% of the patients. Thymic hyperplasia was present in 5.93% of the patients, while 1.48% had thymoma. Steroid treatment was effective in the majority of the patients. Ocular type MG was common in this cohort of patients. The incidence and mortality of myasthenia crisis were low, the presence of concurrent thymoma was rare and only a limited number of children developed neurological sequelae. PMID:25780436

  17. Mechanism of nasal tolerance induced by a recombinant fragment of acetylcholine receptor for treatment of experimental myasthenia gravis.

    PubMed

    Im, S H; Barchan, D; Fuchs, S; Souroujon, M C

    2000-11-01

    Acetylcholine receptor (AChR) is the major autoantigen in myasthenia gravis (MG) and experimental autoimmune MG (EAMG). Here we analyze the mechanisms involved in suppression of ongoing EAMG in rats by nasal administration of a recombinant fragment from the human AChR alpha-subunit. We demonstrate that such a fragment, expressed without a fusion partner, confers nasal tolerance that can be adoptively transferred. Our observations suggest that the underlying mechanism of this nasal tolerance is active suppression involving a shift from a Th1 to a Th2/Th3-regulated AChR-specific response which may be mediated by down regulation of costimulatory factors.

  18. Dendritic cells in hyperplastic thymuses from patients with myasthenia gravis.

    PubMed

    Nagane, Yuriko; Utsugisawa, Kimiaki; Obara, Daiji; Yamagata, Munehisa; Tohgi, Hideo

    2003-05-01

    To investigate the role of dendritic cells (DCs) in the hyperplastic myasthenia gravis (MG) thymus, we studied the frequency and distribution of three mature DC phenotypes (CD83(+)CD11c(+), CD86(+)CD11c(+), and HLA-DR(+)CD11c(+)) in samples from patients with MG whose symptoms dramatically improved following thymectomy and in non-MG control thymuses. In hyperplastic MG thymuses, mature DCs were much more numerous in nonmedullary areas, such as the subcapsular/outer cortex; around the germinal centers; and in extralobular connective tissue, particularly around blood vessels. Mature DCs strongly coexpressed CD44 and appeared to be components of a CD44-highly positive (CD44(high)) cell population migrating from the vascular system. Furthermore, in the hyperplastic MG thymus, the expression of secondary lymphoid-tissue chemokine (SLC) markedly increased especially around extralobular blood vessels, where the CD44(high) cell population accumulated. These findings suggest that DCs may migrate into the hyperplastic thymus from the vascular system via mechanisms that involve CD44 and SLC. DCs may present self-antigens, thereby promoting the priming and/or boosting of potentially autoreactive T cells against the acetylcholine receptor.

  19. Changes in inflammatory cytokine networks in myasthenia gravis

    PubMed Central

    Uzawa, Akiyuki; Kanai, Tetsuya; Kawaguchi, Naoki; Oda, Fumiko; Himuro, Keiichi; Kuwabara, Satoshi

    2016-01-01

    Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation-inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late-onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology. PMID:27172995

  20. Thymectomy: role in the treatment of myasthenia gravis.

    PubMed

    Spillane, J; Hayward, M; Hirsch, N P; Taylor, C; Kullmann, D M; Howard, R S

    2013-07-01

    Thymectomy is a frequently used treatment for myasthenia gravis (MG) and is virtually always indicated in MG patients who have a thymoma. However, the evidence for thymectomy in non-thymomatous MG remains less certain-no randomised controlled trials have been published to date, although one is currently underway. We reviewed the management and clinical outcome of patients with MG who underwent thymectomy over a 12 year period. Eighty-nine patients who underwent transsternal thymectomy were identified. A thymoma was identified on histology in 24 %, whereas 48, 9 and 19 % had hyperplastic, atrophic and normal thymic histology, respectively. One patient developed post operative myasthenic crisis but generally the procedure was well tolerated. Outcome was favourable for the majority of patients, with 34 % achieving complete stable remission (CSR) and an additional 33 % achieving pharmacological remission. Moreover, steroid requirements fell progressively during follow-up. Patients with a hyperplastic gland had a significantly greater chance of achieving CSR compared to other histological subtypes and the incidence of CSR increased with a longer duration of follow-up. Thymectomy for MG is generally safe and well tolerated and is associated with a sustained improvement of symptoms in the majority of patients.

  1. Azathioprine therapy for acquired myasthenia gravis in five dogs.

    PubMed

    Dewey, C W; Coates, J R; Ducoté, J M; Meeks, J C; Fradkin, J M

    1999-01-01

    Five dogs with acquired myasthenia gravis (MG), verified via positive serum acetylcholine (ACh) receptor antibody concentrations, were treated with a drug protocol including azathioprine (AZA). Four of the five dogs were concurrently treated with pyridostigmine. Azathioprine was used as the sole immunosuppressive agent in four dogs. One dog was temporarily treated with a combination of an immunosuppressive dose of prednisone and AZA, then maintained on AZA as the sole immunosuppressive drug. Three patients experienced complete remission of clinical signs within three months of therapy. In the four dogs for which follow-up serum ACh receptor antibody concentrations were available, initial versus final concentrations decreased substantially (81%), coincident with clinical improvement. One dog died suddenly due to a suspected myasthenic crisis before attaining the target dose of AZA. Two of the four surviving dogs were euthanized approximately one and seven years after diagnosis. One of these two dogs was euthanized because of a rib osteosarcoma, and the other dog was euthanized because of paraparesis of undetermined cause. The remaining two dogs were alive and doing well at the time of final follow-up evaluation, approximately six months and one year after diagnosis. The use of AZA as a therapeutic agent for acquired canine MG has not been investigated. The cases presented in this report suggest a potentially important role for AZA in the treatment of acquired MG in dogs.

  2. Anesthetic implications for video assisted thoracoscopic thymectomy in myasthenia gravis.

    PubMed

    El-Dawlatly, Abdelazeem A; Al Kattan, Khaled; Hajjar, Waseem; Essa, Mohamed; Delvi, Bilal; Khoja, Abdulaziz

    2005-06-01

    Thymectomy is an established therapy in the management of generalized myasthenia gravis (MG). However, the optimal surgical approach to thymectomy has remained controversial. There are advocates for transternal, transcervical approaches for "maximal" thymectomy. Video-assisted thoracoscopic thymectomy (VATT) presents new approach to thymectomy. By minimizing chest wall trauma, VATT not only causes less postoperative pain, shortens hospital stay, gives better cosmetic results but also leads to wider acceptance by patients for earlier surgery. Anesthesia for thymectomy in MG is challenging. Currently we are using non-muscle relaxant technique (NMRT) which we adopted in 1994, for maximal thymectomy. In this paper, we present our limited experience with two cases of VATT using two different NMRTs. Two cases of MG underwent VATT under general anesthesia (GA) and one lung ventilation (OLV) using double lumen tube (DLT). In both cases NMRT was used which encompass, light GA plus thoracic epidural analgesia (TEA) in one case and without TEA in the other case. We believe that the use of NMRT provides good operative and postoperative conditions. In this report we have described two different NMRTs, one with TEA and the other without. Further studies are needed on large number of cases to establish an anesthetic protocol for VATT.

  3. Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization.

    PubMed

    Tuzun, Erdem; Berrih-Aknin, Sonia; Brenner, Talma; Kusner, Linda L; Le Panse, Rozen; Yang, Huan; Tzartos, Socrates; Christadoss, Premkumar

    2015-08-01

    Myasthenia gravis (MG) is an autoimmune disorder characterized by generalized muscle weakness due to neuromuscular junction (NMJ) dysfunction brought by acetylcholine receptor (AChR) antibodies in most cases. Although steroids and other immunosuppressants are effectively used for treatment of MG, these medications often cause severe side effects and a complete remission cannot be obtained in many cases. For pre-clinical evaluation of more effective and less toxic treatment methods for MG, the experimental autoimmune myasthenia gravis (EAMG) induced by Torpedo AChR immunization has become one of the standard animal models. Although numerous compounds have been recently proposed for MG mostly by using the active immunization EAMG model, only a few have been proven to be effective in MG patients. The variability in the experimental design, immunization methods and outcome measurements of pre-clinical EAMG studies make it difficult to interpret the published reports and assess the potential for application to MG patients. In an effort to standardize the active immunization EAMG model, we propose standard procedures for animal care conditions, sampling and randomization of mice, experimental design and outcome measures. Utilization of these standard procedures might improve the power of pre-clinical EAMG experiments and increase the chances for identifying promising novel treatment methods that can be effectively translated into clinical trials for MG.

  4. Low serum albumin concentrations are associated with disease severity in patients with myasthenia gravis

    PubMed Central

    Weng, Yi-Yun; Yang, De-Hao; Qian, Mei-Zi; Wei, Mao-Mao; Yin, Fang; Li, Jia; Li, Xiang; Chen, Ying; Ding, Zhang-Na; He, Yi-Bo; Zhang, Xu

    2016-01-01

    Abstract Serum albumin (S-Alb) is a widely used biomarker of nutritional status and disease severity in patients with autoimmune diseases. We investigated the correlation between S-Alb and the severity of myasthenia gravis (MG). A total number of 166 subjects were recruited in the study. Subjects were divided into 3 groups (T1 to T3) by S-Alb levels: T1: 21.1 to 38.4 g/L, T2: 38.5 to 41.5 g/L, T3: 41.6 to 48.9 g/L. Regression analysis was performed to determine the correlation of initial albumin concentrations and the severity of disease of MG. Lower levels of S-Alb were observed in subjects with increased disease severity than those with slight disease severity, meanwhile, incidence of myasthenia crisis increased in the lower albumin tertiles (P < 0.001). The disease severity assessment was performed according to the criteria established by the Myasthenia Gravis Foundation of America. After adjusting for age, sex, body mass index (BMI), and duration of disease, it showed that higher S-Alb concentrations were associated with lower disease severity. Odds ratios (ORs) of T2 to T3 were 0.241 (95% CI: 0.103–0.566, P < 0.001), 0.140 (95% CI: 0.054–0.367, P < 0.001) when compared with subjects in the T1, respectively. When subjects were stratified into hypoalbuminemia and normal albumin groups, we found that the association between S-Alb and MG remained significant in the hypoalbuminemia group only (OR: 0.693, 95% CI: 0.550–0.874, P = 0.002) after further adjustment for age, sex, BMI, and duration of disease. This is the first study to demonstrate that S-Alb was independently associated with MG severity. In patients with low S-Alb, S-Alb concentration could be a potential biomarker for MG disability. PMID:27684858

  5. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes.

    PubMed

    Marx, Alexander; Pfister, Frederick; Schalke, Berthold; Saruhan-Direskeneli, Güher; Melms, Arthur; Ströbel, Philipp

    2013-07-01

    The thymus plays distinct roles in the pathogenesis of the different Myasthenia gravis (MG) subtypes. Inflammatory, neoplastic and age-related alterations of the thymus are of pivotal relevance for the initiation of anti-acetylcholine receptor (AChR) autoimmunity in early onset MG, thymoma-associated MG and, likely, late onset MG, respectively. By contrast, the thymus is presumably not related to MG that is due to autoantibodies to the muscle specific kinase, MuSK. Finally, the role of the thymus is still obscure in MG defined by antibodies against the agrin receptor LRP4 and in MG without all of the above autoantibdies (triple sero-negative MG) since these MG subtypes have been described only recently and thymectomy has not been their standard treatment. This review aims to give an update on intrathymic mechanisms of tolerance breakdown in MG, including abnormal T cell selection and activation, the role of thymic myoid cells, the autoimmune regulator (AIRE) and regulatory T cells.

  6. Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model

    PubMed Central

    Sudres, Muriel; Maurer, Marie; Robinet, Marieke; Bismuth, Jacky; Truffault, Frédérique; Girard, Diane; Dragin, Nadine; Attia, Mohamed; Fadel, Elie; Santelmo, Nicola; Sicsic, Camille; Brenner, Talma

    2017-01-01

    Myasthenia gravis (MG) with anti–acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro–preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell–related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases.

  7. Disability and Functional Profiles of Patients with Myasthenia Gravis Measured with ICF Classification

    ERIC Educational Resources Information Center

    Leonardi, Matilde; Raggi, Alberto; Antozzi, Carlo; Confalonieri, Paolo; Maggi, Lorenzo; Cornelio, Ferdinando; Mantegazza, Renato

    2009-01-01

    The objective of this study is to describe functional profiles of patients with myasthenia gravis (MG), and the relationships among symptoms, activities and environmental factors (EF), by using WHO's International Classification of Functioning Disability and Health (ICF). Patients were consecutively enrolled at the Besta Institute of Milan, Italy.…

  8. A sequence of pathologic events in a patient after thymectomy for myasthenia gravis.

    PubMed

    Hrycek, Antoni

    2012-01-01

    The case of a rare coexistence of myasthenia gravis (MG) with systemic lupus erythematosus (SLE) is described. MG was diagnosed prior to SLE which developed after thymectomy. The patient was affected by HCV viremia. Therefore, there were therapeutic problems. Metylase treatment was continued for several years and dopamine receptor agonist was effectively administered as adjunctive therapy in SLE.

  9. Acute treatment of myasthenia gravis with intranasal neostigmine: clinical and electromyographic evaluation.

    PubMed Central

    Ricciardi, R; Rossi, B; Nicora, M; Sghirlanzoni, A; Muratorio, A

    1991-01-01

    The effectiveness of intranasal neostigmine (9.3-13.8 mg) was tested in 20 subjects with myasthenia gravis, classified as Osserman grades 2A and 2B. In all cases the drug produced significant clinical and electromyographic improvement. No side effects were reported during the treatment. PMID:1783916

  10. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis.

    PubMed

    Tolosa, Eva; Li, Weijie; Yasuda, Yoshiyuki; Wienhold, Wolfgang; Denzin, Lisa K; Lautwein, Alfred; Driessen, Christoph; Schnorrer, Petra; Weber, Ekkehard; Stevanovic, Stefan; Kurek, Raffael; Melms, Arthur; Bromme, Dieter

    2003-08-01

    Stepwise degradation of the invariant chain (Ii) is required for the binding of antigenic peptides to MHC class II molecules. Cathepsin (Cat) L in the murine thymus and Cat S in peripheral APCs have both been implicated in the last step of Ii degradation that gives rise to the class II-associated invariant chain peptides (CLIP). Cat V has been recently described as highly homologous to Cat L and exclusively expressed in human thymus and testis, but with no mouse orthologue. We report that Cat V is the dominant cysteine protease in cortical human thymic epithelial cells, while Cat L and Cat S seem to be restricted to dendritic and macrophage-like cells. Active Cat V in thymic lysosomal preparations was demonstrated by active-site labeling. Recombinant Cat V was capable of converting Ii into CLIP efficiently, suggesting that Cat V is the protease that controls the generation of alphabeta-CLIP complexes in the human thymus, in analogy to Cat L in mouse. Comparison of Cat V expression between thymi from patients with myasthenia gravis and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of myasthenia gravis, an autoimmune disease almost invariably associated with thymic pathology.

  11. Associated thyreoiditis, myasthenia gravis, thymectomy, Chron's disease, and erythema nodosum: pathogenetic and clinical correlations, immune system involvement, and systemic infectious complications.

    PubMed

    Manfredi, Roberto; Fasulo, Giovanni; Fulgaro, Ciro; Sabbatani, Sergio

    2008-09-01

    The case of a young woman suffering from multiple autoimmune-dysreactive disorders (including thyreoiditis, myasthenia gravis, thymectomy, Crohn's disease, and erythema nodosum), while undergoing steroideal therapy, was complicated by a severe infectious disorder (severe upper urinary tract infection). While the pathogenetic and clinical relationship between the different autoimmune-dysreactive complications is still unclear, and the supporting role of the frequent immunosuppressive treatment may add significantly to these risk factors, clinicians who are engaged in the management of these patients should be aware that multiple, concurrent or subsequent disorders might occur in these subjects, and also that severe infections might be of relevant concern.

  12. Imaging of thymus in myasthenia gravis: from thymic hyperplasia to thymic tumor.

    PubMed

    Priola, A M; Priola, S M

    2014-05-01

    Myasthenia gravis (MG) is an autoimmune disorder often associated with thymic abnormalities. At onset, thymic lymphoid hyperplasia (TLH) and thymoma can be found in up to 65% and 15% of patients, respectively. Diagnostic imaging is crucial in this setting in order to detect the presence and type of the thymic abnormality and in the preoperative planning, when indicated. Chest radiography has a minor role due to its low accuracy. Computed tomography is the imaging modality of choice, although the differentiation between a small thymoma and TLH that appears as a focal soft-tissue mass may be not possible. Magnetic resonance imaging (MRI) is not usually employed, but it is useful in equivocal cases, especially in differentiating focal TLH from thymoma by using chemical-shift sequences for defining the proper management. In addition, diffusion-weighted (DW)-MRI can differentiate lipid-poor normal/hyperplastic thymus from thymoma and could be useful in differentiating non-advanced from advanced thymomas. Positron emission tomography (PET)-CT is not helpful in distinguishing early from advanced thymoma but can be used to differentiate thymic carcinoma from thymoma. Hereby, we discuss the imaging features of thymic abnormalities in MG, even focusing on novel aspects of chemical-shift and DW-MRI.

  13. Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients

    PubMed Central

    Molin, Carl Johan; Westerberg, Elisabet; Punga, Anna Rostedt

    2017-01-01

    This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG. PMID:28045063

  14. Intercommunication between the neuroendocrine and immune systems: focus on myasthenia gravis.

    PubMed

    Mays, Jacqueline; Butts, Cherié L

    2011-01-01

    Crosstalk exists between the nervous, endocrine, and immune systems, and perturbations in these interactions have been associated with disease. This includes production of neuroendocrine factors that alter immune system activity and increase susceptibility to or severity of immune-related conditions, such as myasthenia gravis (MG)--a T-cell-dependent, B-cell-mediated autoimmune disorder. MG results from impairment of transmission to the neuromuscular junction and involves the thymus--especially in early-onset disease, but the exact mechanism by which the thymus impacts disease is unclear. MG afflicts millions of individuals worldwide each year, and both men and women can develop symptoms. However, prevalence and age of onset differs between men and women. Women exhibit higher incidence and earlier age of onset compared to men, and disease fluctuates during pregnancy. This suggests that sex hormones play a role in influencing disease outcome. In this review, we will consider what is known about the manifestation of MG, theories on how different forms of MG are influenced or alleviated by steroid hormones, current treatment options, and what measures could be important to consider in the future.

  15. B10 Cell Frequencies and Suppressive Capacity in Myasthenia Gravis Are Associated with Disease Severity

    PubMed Central

    Yi, John S.; Russo, Melissa A.; Massey, Janice M.; Juel, Vern; Hobson-Webb, Lisa D.; Gable, Karissa; Raja, Shruti M.; Balderson, Kristina; Weinhold, Kent J.; Guptill, Jeffrey T.

    2017-01-01

    Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated disease. The mechanisms for loss of self-tolerance in this disease are not well understood, and recently described regulatory B cell (Breg) subsets have not been thoroughly investigated. B10 cells are a subset of Bregs identified by the production of the immunosuppressive cytokine, interleukin-10 (IL-10). B10 cells are known to strongly inhibit B- and T-cell inflammatory responses in animal models and are implicated in human autoimmunity. In this study, we examined quantitative and qualitative aspects of B10 cells in acetylcholine receptor autoantibody positive MG (AChR-MG) patients and healthy controls. We observed reduced B10 cell frequencies in AChR-MG patients, which inversely correlated with disease severity. Disease severity also affected the function of B10 cells, as B10 cells in the moderate/severe group of MG patients were less effective in suppressing CD4 T-cell proliferation. These results suggest that B10 cell frequencies may be a useful biomarker of disease severity, and therapeutics designed to restore B10 cell frequencies could hold promise as a treatment for this disease through restoration of self-tolerance. PMID:28239367

  16. Specific immunotherapy of experimental myasthenia gravis in vitro: the "guided missile" strategy.

    PubMed

    Wu, J M; Wu, B; Miagkov, A; Adams, R N; Drachman, D B

    2001-03-15

    We describe a strategy for specific immunotherapy of myasthenia gravis (MG) based on genetic engineering of antigen presenting cells (APCs) to present the autoantigen acetylcholine receptor (AChR) and express the "warhead" Fas ligand (FasL). For transduction of APCs we prepared recombinant attenuated vaccinia virus vectors carrying the following three gene constructs: (i) AChR fused to LAMP1 to present AChR and target AChR-specific T cells; (ii) FasL to eliminate the targeted T cells; and (iii) truncated FADD to protect APCs from self-destruction by FasL. The engineered APCs effectively expressed the genes of interest and killed AChR-specific T cells in culture by the Fas/FasL pathway. T cells specific for an unrelated antigen were spared. Our in vitro demonstration that engineered APCs target and kill antigen-specific T cells represents a promising novel strategy for specific immunotherapy of MG and other autoimmune diseases.

  17. Genotypes of CCR2 and CCR5 chemokine receptors in human myasthenia gravis.

    PubMed

    Zhao, Xiaoyan; Gharizadeh, Baback; Hjelmström, Peter; Pirskanen, Ritva; Nyrén, Pål; Lefvert, Ann-Kari; Ghaderi, Mehran

    2003-11-01

    The aim of this study was to examine the association of human autoimmune myasthenia gravis (MG) with two DNA polymorphisms of the chemokine receptors CCR5-Delta 32 and CCR2-64I. CCR2 and CCR5 interact primarily with the human CC family ligands CCL2 (formerly called monocyte chemoattractant protein; MCP-1), CCL3 and CCL4 (macrophage inflammatory protein-1 alpha and -1 beta; MIP-1 alpha/beta), and their main function is to recruit leukocytes from circulation into the tissues, thus playing an important role in human inflammatory disorders. A PCR-based genotyping method was used to determine the genetic variation at the CCR5 gene and an automated real-time Pyrosequencing technology was employed for the analysis of G right curved arrow A point mutation at the CCR2 gene. Results obtained from 158 patients and 272 healthy controls demonstrate no evidence of association between genetic variants of CCR2 and CCR5 with MG and its clinical manifestations. CCR2-64I and CCR5-Delta 32 genotypes are thus unlikely to be involved in protection or predisposition to MG.

  18. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis.

    PubMed

    Romi, Fredrik; Suzuki, Shigeaki; Suzuki, Norihiro; Petzold, Axel; Plant, Gordon T; Gilhus, Nils Erik

    2012-07-01

    Myasthenia gravis (MG) is an autoimmune disease characterized by skeletal muscle weakness mainly caused by acetylcholine receptor antibodies. MG can be divided into generalized and ocular, and into early-onset (<50 years of age) and late-onset (≥50 years of age). Anti-Kv1.4 antibodies targeting α-subunits (Kv1.4) of the voltage-gated potassium K(+) channel occurs frequently among patients with severe MG, accounting for 18% of a Japanese MG population. The aim of this study was to characterize the clinical features and serological associations of anti-Kv1.4 antibodies in a Caucasian MG population with mild and localized MG. Serum samples from 129 Caucasian MG patients with mainly ocular symptoms were tested for the presence of anti-Kv1.4 antibodies and compared to clinical and serological parameters. There were 22 (17%) anti-Kv1.4 antibody-positive patients, most of them women with late-onset MG, and all of them with mild MG. This contrasts to the Japanese anti-Kv1.4 antibody-positive patients who suffered from severe MG with bulbar symptoms, myasthenic crisis, thymoma, myocarditis and prolonged QT time on electrocardiography, despite equal anti-Kv1.4 antibody occurrence in both populations. No other clinical or serological parameters influenced anti-Kv1.4 antibody occurrence.

  19. T-cell receptor V alpha and C alpha alleles associated with multiple and myasthenia gravis.

    PubMed Central

    Oksenberg, J R; Sherritt, M; Begovich, A B; Erlich, H A; Bernard, C C; Cavalli-Sforza, L L; Steinman, L

    1989-01-01

    Polymorphic markers in genes encoding that alpha chain of the human T-cell receptor (TcR) have been detected by Southern blot analysis in Pss I digests. Polymorphic bands were observed at 6.3 and 2.0 kilobases (kb) with frequencies of 0.30 and 0.44, respectively, in the general population. Using the polymerase chain reaction (PCR) method, we amplified selected sequences derived from the full-length TcR alpha cDNA probe. These PCR products were used as specific probes to demonstrate that the 6.3-kb polymorphic fragment hybridizes to the variable (V)-region probe and the 2.0-kb fragment hybridizes to the constant (C)-region probe. Segregation of the polymorphic bands was analyzed in family studies. To look for associations between these markers and autoimmune diseases, we have studied the restriction fragment length polymorphism distribution of the Pss I markers in patients with multiple sclerosis, myasthenia gravis, and Graves disease. Significant differences in the frequency of the polymorphic V alpha and C alpha markers were identified between patients and healthy individuals. Images PMID:2915992

  20. B cells produce less IL-10, IL-6 and TNF-α in myasthenia gravis.

    PubMed

    Yilmaz, Vuslat; Oflazer, Piraye; Aysal, Fikret; Parman, Yeşim G; Direskeneli, Haner; Deymeer, Feza; Saruhan-Direskeneli, Güher

    2015-06-01

    B cells from myasthenia gravis (MG) patients with autoantibodies (Aab) against acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or with no detectable Aab were investigated as cytokine producing cells in this study. B cells were evaluated for memory phenotypes and expressions of IL-10, IL-6 and IL-12A. Induced productions of IL-10, IL-6, IL-12p40, TNF-α and LT from isolated B cells in vitro were measured by immunoassays. MG patients receiving immunosuppressive treatment had higher proportions of memory B cells compared with healthy controls and untreated patients. With CD40 stimulation MG patients produced significantly lower levels of IL-10, IL-6. With CD40 and B cell receptor stimulation of B cells, TNF-α production also decreased in addition to these cytokines. The lower levels of these cytokine productions were not related to treatment. Our results confirm a disturbance of B cell subpopulations in MG subgroups on immunosuppressive treatment. B cell derived IL-10, IL-6 and TNF-α are down-regulated in MG, irrespective of different antibody productions. Ineffective cytokine production by B cells may be a susceptibility factor in dysregulation of autoimmune Aab production.

  1. Binding affinities of anti-acetylcholine receptor autoantibodies in myasthenia gravis

    SciTech Connect

    Bray, J.J.; Drachman, D.B.

    1982-01-01

    Antibodies directed against acetylcholine (ACh) receptors are present in the sera of nearly 90% of patients with myasthenia gravis (MG), and are involved in the pathogenesis of this autoimmune disease. However, the antibody titers measured by the standard radioimmunoassay correspond poorly with the clinical severity of the disease. To determine whether this disparity could be accounted for by differences in the binding affinities of anti-ACh receptor antibodies in different patients, we have measured the binding affinities of these autoantibodies in 15 sera from MG patients. The affinity constants (K/sub o/), as determined by Scatchard analysis, were all in the range of 10/sup 10/ M/sup -1/, comparable to the highest values reported in immunized animals. The affinity constants were truly representative of the population of autoantibodies detected by the radioimmunoassay, as shown by the remarkable linearity of the Scatchard plots (r/sup 2/>0.90) and the close correlation between the antibody titers determined by extrapolation of the Scatchard plots and by saturation analysis (r = 0.99; p < 0.001). There was only a 6-fold variation in affinity constants measured in this series of patients despite widely differing antibody titers and severity of the disease. Factors other than the titer and affinity of anti-ACh receptor antibodies may correlate better with the clinical manifestations of MG.

  2. Titin antibodies in "seronegative" myasthenia gravis--A new role for an old antigen.

    PubMed

    Stergiou, C; Lazaridis, K; Zouvelou, V; Tzartos, J; Mantegazza, R; Antozzi, C; Andreetta, F; Evoli, A; Deymeer, F; Saruhan-Direskeneli, G; Durmus, H; Brenner, T; Vaknin, A; Berrih-Aknin, S; Behin, A; Sharshar, T; De Baets, M; Losen, M; Martinez-Martinez, P; Kleopa, K A; Zamba-Papanicolaou, E; Kyriakides, T; Kostera-Pruszczyk, A; Szczudlik, P; Szyluk, B; Lavrnic, D; Basta, I; Peric, S; Tallaksen, C; Maniaol, A; Gilhus, N E; Casasnovas Pons, C; Pitha, J; Jakubíkova, M; Hanisch, F; Bogomolovas, J; Labeit, D; Labeit, S; Tzartos, S J

    2016-03-15

    Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.

  3. Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

    PubMed Central

    Lopomo, Angela; Ricciardi, Roberta; Maestri, Michelangelo; De Rosa, Anna; Melfi, Franca; Lucchi, Marco; Mussi, Alfredo; Coppedè, Fabio; Migliore, Lucia

    2016-01-01

    Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood. PMID:27999265

  4. [A 46-year-old woman with myasthenia gravis associated with macromastia, erythroderma and hypogeusia].

    PubMed

    Sera, I; Shibayama, K; Motomura, M; Tsujihata, M; Nagataki, S

    1994-01-01

    A 46-year-old woman developed blepharoptosis, diplopia and hypogeusia in 1984, and was diagnosed as having myasthenia gravis and malignant thymoma. Her symptoms improved by thymectomy and oral prednisolone administration. In 1988 she complained of breast pain and swelling during menstruation. In 1990 her breast was enlarged to the size of an adult head, and she developed erythroderma and hypogeusia. She was admitted to Nagasaki University Hospital in August, 1990. On admission, erythema was seen in the whole body especially in the face, anterior chest, abdomen and the thigh. Her breast was the size of an adult head. Muscle strength was weak, and ocular movement was limited. She had blepharoptosis. Papillae of the tongue were atrophic. Endoclinological investigations revealed an elevation of PRL to 14.6 ng/ml (normal < 10), antibodies to the acetylcholine receptor to 118.0 nM (normal < 0.5). In TRH stimulation test the response of PRL was amplified. Four intrathoracic masses suspected of recurrence of malignant thymoma were seen in CT. Her macromastia depended upon the amount of PRL, and was reduced by bromocriptine. Erythroderma and hypogeusia were relieved by plasmaphersis. Therefore autoimmune mechanism may be related to these symptoms.

  5. Inflammation and epstein-barr virus infection are common features of myasthenia gravis thymus: possible roles in pathogenesis.

    PubMed

    Cavalcante, Paola; Maggi, Lorenzo; Colleoni, Lara; Caldara, Rosa; Motta, Teresio; Giardina, Carmelo; Antozzi, Carlo; Berrih-Aknin, Sonia; Bernasconi, Pia; Mantegazza, Renato

    2011-01-01

    The thymus plays a major role in myasthenia gravis (MG). Our recent finding of a persistent Epstein-Barr (EBV) virus infection in some MG thymuses, combined with data showing that the thymus is in a proinflammatory state in most patients, supports a viral contribution to the pathogenesis of MG. Aim of this study was to gain further evidence for intrathymic chronic inflammation and EBV infection in MG patients. Transcriptional profiling by low density array and real-time PCR showed overexpression of genes involved in inflammatory and immune response in MG thymuses. Real-time PCR for EBV genome, latent (EBER1, EBNA1, LMP1) and lytic (BZLF1) transcripts, and immunohistochemistry for LMP1 and BZLF1 proteins confirmed an active intrathymic EBV infection, further supporting the hypothesis that EBV might contribute to onset or perpetuation of the autoimmune response in MG. Altogether, our results support a role of inflammation and EBV infection as pathogenic features of MG thymus.

  6. Structural and ultrastructural localization of NGF and NGF receptors in the thymus of subjects affected by myasthenia gravis.

    PubMed

    Marinova, Tsvetana T; Velikova, Kamelia K; Petrov, Danail B; Kutev, Nikolai S; Stankulov, Ivan S; Chaldakov, George N; Triaca, Viviana; Manni, Luigi; Aloe, Luigi

    2004-12-01

    We have previously reported that the thymus of patients affected by myasthenia gravis (MG) is characterized by an elevated level of nerve growth factor (NGF), an endogenous polypeptide which plays a marked role in the cell biology of nervous and immune system. A consistent number of studies has shown altered expression of NGF in diseases associated with inflammatory and/or autoimmune responses. To evaluate the biochemical and molecular mechanisms implicated in NGF action in human myasthenic thymus, it is important to identify the cellular and structural organization of NGF receptors. To address this question, we investigated, both at light and electron microscopic levels, the cellular distribution of immunoreactivity for NGF and its low-affinity receptors, (p75) and its high-affinity receptor (TrkA) in the thymus of patients with MG. The present investigation shows that NGF and NGF receptors are overexpressed in the thymic cells of patients with MG compared to control subjects.

  7. Immunodominant regions for T helper-cell sensitization on the human nicotinic receptor alpha subunit in myasthenia gravis.

    PubMed Central

    Protti, M P; Manfredi, A A; Straub, C; Howard, J F; Conti-Tronconi, B M

    1990-01-01

    In myasthenia gravis an autoimmune response against the nicotinic acetylcholine receptor (AChR) occurs. The alpha subunit of the AChR contains both the epitope(s) that dominates the antibody response (main immunogenic region) and epitopes involved in T helper cell sensitization. In this study, overlapping synthetic peptides corresponding to the complete AChR alpha-subunit sequence were used to propagate polyclonal AChR-specific T helper cell lines from four myasthenic patients of different HLA types. Response of the T helper lines to the individual peptides was studied. Four immunodominant sequence segments were identified--i.e., residues 48-67, 101-120, 304-322, and 419-437. These regions did not include residues known to form the main immunogenic region or the cholinergic binding site, and they frequently contained sequence motifs that have been proposed to be related to T-epitope formation. Images PMID:2145582

  8. Circulating regulatory anti–T cell receptor antibodies in patients with myasthenia gravis

    PubMed Central

    Jambou, Florence; Zhang, Wei; Menestrier, Monique; Klingel-Schmitt, Isabelle; Michel, Olivier; Caillat-Zucman, Sophie; Aissaoui, Abderrahim; Landemarre, Ludovic; Berrih-Aknin, Sonia; Cohen-Kaminsky, Sylvia

    2003-01-01

    Serum anti–T cell receptor (TCR) Ab’s are involved in immune regulation directed against pathogenic T cells in experimental models of autoimmune diseases. Our identification of a dominant T cell population expressing the Vβ5.1 TCR gene (TCRBV5-1), which is responsible for the production of pathogenic anti-acetylcholine receptor (AChR) autoantibodies in HLA-DR3 patients with early-onset myasthenia gravis (EOMG), prompted us to explore the occurrence, reactivity, and regulatory role of anti-TCR Ab’s in EOMG patients and disease controls with clearly defined other autoantibodies. In the absence of prior vaccination against the TCR, EOMG patients had elevated anti-Vβ5.1 Ab’s of the IgG class. This increase was restricted largely to EOMG cases with HLA-DR3 and with less severe disease, and it predicted clinical improvement in follow-up studies. EOMG patient sera containing anti-TCR Ab’s bound specifically the native TCR on intact Vβ5.1-expressing cells and specifically inhibited the proliferation and IFN-γ production of purified Vβ5.1-expressing cells to alloantigens in mixed lymphocyte reaction and the proliferation of a Vβ5.1-expressing T cell clone to an AChR peptide, indicating a regulatory function for these Ab’s. This evidence of spontaneously active anti-Vβ5.1 Ab’s in EOMG patients suggests dynamic protective immune regulation directed against the excess of pathogenic Vβ5.1-expressing T cells. Though not sufficient to prevent a chronic, exacerbated autoimmune process, it might be boosted using a TCR peptide as vaccine. PMID:12865414

  9. Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing.

    PubMed

    Vander Heiden, Jason A; Stathopoulos, Panos; Zhou, Julian Q; Chen, Luan; Gilbert, Tamara J; Bolen, Christopher R; Barohn, Richard J; Dimachkie, Mazen M; Ciafaloni, Emma; Broering, Teresa J; Vigneault, Francois; Nowak, Richard J; Kleinstein, Steven H; O'Connor, Kevin C

    2017-02-15

    Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20-50 people per 100,000. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the BCR repertoire of AChR-MG, MuSK-MG, and healthy subjects to generate ∼518,000 unique VH and VL sequences from sorted naive and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naive and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the VH CDR and altered VH CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V-J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naive and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK-MG, indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG.

  10. Analysis of Serum miRNA Profiles of Myasthenia Gravis Patients

    PubMed Central

    Nogales-Gadea, Gisela; Ramos-Fransi, Alba; Suárez-Calvet, Xavier; Navas, Miquel; Rojas-García, Ricard; Mosquera, Jose Luis; Díaz-Manera, Jordi; Querol, Luis; Gallardo, Eduard; Illa, Isabel

    2014-01-01

    Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of autoantibodies, mainly against the acetylcholine receptor (AChR). The mechanisms triggering and maintaining this chronic disease are unknown. MiRNAs are regulatory molecules that play a key role in the immune system and are altered in many autoimmune diseases. The aim of this study was to evaluate miRNA profiles in serum of 61 AChR MG patients. We studied serum from patients with early onset MG (n = 22), late onset MG (n = 27) and thymoma (n = 12), to identify alterations in the specific subgroups. In a discovery cohort, we analysed 381 miRNA arrays from 5 patients from each subgroup, and 5 healthy controls. The 15 patients had not received any treatment. We found 32 miRNAs in different levels in MG and analysed 8 of these in a validation cohort that included 46 of the MG patients. MiR15b, miR122, miR-140-3p, miR185, miR192, miR20b and miR-885-5p were in lower levels in MG patients than in controls. Our study suggests that different clinical phenotypes in MG share common altered mechanisms in circulating miRNAs, with no additional contribution of the thymoma. MG treatment intervention does not modify the profile of these miRNAs. Novel insights into the pathogenesis of MG can be reached by the analysis of circulating miRNAs since some of these miRNAs have also been found low in MG peripheral mononuclear cells, and have targets with important roles in B cell survival and antibody production. PMID:24637658

  11. Myasthenia gravis as a 'stroke mimic'--it's all in the history.

    PubMed

    Shaik, Saiffuddin; Ul-Haq, Mian Ayaz; Emsley, Hedley C A

    2014-12-01

    An 85-year-old man presented to hospital as an emergency having difficulties with swallowing and speech. In the emergency department, he was assessed as having acute onset dysphagia and dysarthria in keeping with an acute stroke. Subsequently, it became apparent that although the symptoms were indeed of relatively acute onset, there was a clear description by the patient of fatigability and diurnal variation, prompting a working clinical diagnosis of myasthenia gravis. The patient followed a turbulent clinical course, and interpretation of investigation results proved not to be straightforward in the acute setting. Myasthenia gravis is an uncommon disorder but it is more common in the elderly. This case provides key learning points, particularly highlighting the value of prompt, accurate clinical assessment and the importance of adhering to the clinical diagnostic formulation.

  12. A case report of subclinical hypercortisolism due to adrenal incidentaloma complicated by myasthenia gravis after adrenalectomy.

    PubMed

    Petramala, Luigi; Marinelli, Cristiano; Giallonardo, Anna Teresa; Concistrè, Antonio; Lucia, Piernatale; Venuta, Federico; Cerbelli, Bruna; Ciardi, Antonio; De Toma, Giorgio; Letizia, Claudio

    2016-11-11

    A 62-year-old woman was admitted for evaluation of an incidentally discovered adrenal mass and hypertension. CT scan revealed a 7 cm mass in the right adrenal gland. After careful examination, the patient was diagnosed with subclinical hypercortisolism (SH). Adrenalectomy was performed. Histopathological examination showed an adrenocortical adenoma. Symptoms and signs of myasthenia gravis appeared 5 months later. CT of the chest showed a solid tissue mass in the mediastinum. The patient underwent a sternotomy with excision of the tumor, which histologically proved to be a type 2B thymoma. We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in a patient who manifested myasthenia gravis after surgical remission of the cortisol excess.

  13. Myasthenia gravis as a cause of head drop in Parkinson disease.

    PubMed

    Uludag, Irem Fatma; Korucuk, Meltem; Sener, Ufuk; Zorlu, Yasar

    2011-05-01

    Head drop is characterized by marked anterior flexion of the cervical spine. As a result, the affected patient presents with the head tilted forward and the chin resting on the chest. We report a 75-year-old male patient with parkinsonism and head drop caused by isolated myasthenic weakness of the neck extensor muscles. Our case is the second report of isolated head drop as a presenting symptom of myasthenia gravis in a patient with parkinsonism.

  14. A comparison between IVIG and plasma exchange as preparations before thymectomy in myasthenia gravis patients.

    PubMed

    Alipour-Faz, Athena; Shojaei, Maziar; Peyvandi, Hassan; Ramzi, Davood; Oroei, Mahbobeh; Ghadiri, Fereshteh; Peyvandi, Maryam

    2017-03-01

    Myasthenia gravis (MG) is one of the curable neurologic disorders. Various pharmacological therapies are administered for these patients and a thymectomy plays an important role in the therapy of myasthenia gravis, which develops a permanent or relative remission. We investigated the efficacy of intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) as a preparation before thymectomy in patients with MG. This randomized clinical trial was conducted on 24 patients with MG referred for thymectomy, which were randomized to two groups of IVIG and PLEX. The IVIG group received IVIG 1 g/kg/day for two consecutive days and the PLEX group underwent 1-L plasma exchange five times with 5 % albumin replacement fluid, every other day, 10-30 days before the procedure. The duration of hospitalization (day), length of intensive care unit (ICU) stay after surgery (day), length of intubation period (h), duration of surgery (h) and dose of steroid administered were compared between the two groups. Analysis was performed via SPSS version 20. In the PLEX group, post-operative outcomes (duration of hospitalization, ICU length of stay after surgery, intubation period and duration of surgery) were longer than those in the IVIG group. There was significant difference in intubation period (p value = 0.01) and duration of surgery (p value = 0.05) between the PLEX and IVIG groups. The administration of IVIG in comparison to PLEX can be more effective in the preparation before thymectomy in myasthenia gravis patients.

  15. Is thymectomy in non-thymomatous myasthenia gravis of any benefit?

    PubMed

    Diaz, Andres; Black, Edward; Dunning, Joel

    2014-03-01

    A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was if thymectomy in non-thymomatous myasthenia gravis was of any benefit? Overall, 137 papers were found using the reported search, of which 16 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The outcome variables were similar in all of the papers, including complete stable remission (CSR), pharmacological remission, age at presentation, gender, duration of symptoms, preoperative classification (Oosterhius, Osserman or myasthenia gravis Foundation of America (MGFA)), thymic pathology, preoperative medications (steroids, immunosuppressants), mortality and morbidity. We conclude that evidence-based reviews have shown that relative rates of thymectomy patients compared with non-thymectomy patients attaining outcome indicate that the former group of patients is more likely to achieve medication-free remission, become asymptomatic and clinically improve (54%, P < 0.01), particularly patients with severe and generalized symptoms (P = 0.007). Patients with generalized myasthenia gravis showed 11% stronger association with favourable outcomes after thymectomy. Some studies show early remission rates (RRs), as early as 6 months post-thymectomy, of 44%. Overall, the reported remission rate for non-thymomatous myasthenia gravis is between 38 and 72% up to 10 years of follow-up. Among these patients, those with thymic hyperplasia show the best complete stable remission rates (42%, P < 0.04) in the majority of studies. Age showed variability across the studies and the cut-off was also different among them. Overall age < 45 years showed a higher probability of achieving complete stable remission during follow-up (81% benefit rate (BR), P < 0.02). Pharmacological improvement is reported between 6 and 42

  16. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms.

    PubMed

    Berrih-Aknin, Sonia; Le Panse, Rozen

    2014-08-01

    Autoimmune myasthenia gravis (MG) is characterized by muscle weakness caused by antibodies directed against proteins of the neuromuscular junction. The main antigenic target is the acetylcholine receptor (AChR), but the muscle Specific Kinase (MuSK) and the low-density lipoprotein receptor-related protein (LRP4) are also targets. This review summarizes the clinical and biological data available for different subgroups of patients, who are classified according to antigenic target, age of onset, and observed thymic abnormalities, such as follicular hyperplasia or thymoma. Here, we analyze in detail the role of the thymus in the physiopathology of MG and propose an explanation for the development of the thymic follicular hyperplasia that is commonly observed in young female patients with anti-AChR antibodies. The influence of the pro-inflammatory environment is discussed, particularly the role of TNF-α and Th17-related cytokines, which could explain the escape of thymic T cells from regulation and the chronic inflammation in the MG thymus. Together with this immune dysregulation, active angiogenic processes and the upregulation of chemokines could promote thymic follicular hyperplasia. MG is a multifactorial disease, and we review the etiological mechanisms that could lead to its onset. Recent global genetic analyses have highlighted potential susceptibility genes. In addition, miRNAs, which play a crucial role in immune function, have been implicated in MG by recent studies. We also discuss the role of sex hormones and the influence of environmental factors, such as the viral hypothesis. This hypothesis is supported by reports that type I interferon and molecules mimicking viral infection can induce thymic changes similar to those observed in MG patients with anti-AChR antibodies.

  17. Characterization of CD4 and CD8 T Cell Responses in MuSK Myasthenia Gravis

    PubMed Central

    Yi, JS; Guidon, A; Sparks, S; Osborne, R; Juel, VC; Massey, JM; Sanders, DB; Weinhold, KJ; Guptill, JT

    2014-01-01

    Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T-cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4+ and CD8+ T-cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T-cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8+ T-cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4+ T-cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4+ T-cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in Treg function or number. PMID:24378287

  18. Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis.

    PubMed

    Yi, J S; Guidon, A; Sparks, S; Osborne, R; Juel, V C; Massey, J M; Sanders, D B; Weinhold, K J; Guptill, J T

    2014-08-01

    Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4+ and CD8+ T cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8+ T cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4+ T cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4+ T cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in CD39 expression or Treg number.

  19. Characterization of B cells in muscle-specific kinase antibody myasthenia gravis

    PubMed Central

    Yi, John S.; Sanders, Donald B.; Guidon, Amanda C.; Juel, Vern C.; Massey, Janice M.; Howard, James F.; Scuderi, Flavia; Bartoccioni, Emanuela; Evoli, Amelia; Weinhold, Kent J.

    2015-01-01

    Objective: To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). Methods: In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell–activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures. Results: As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease. Conclusions: We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody–positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG. PMID:25745635

  20. Proteins with epitopes of the acetylcholine receptor in epithelial cell cultures of thymomas in myasthenia gravis.

    PubMed Central

    Marx, A.; Kirchner, T.; Hoppe, F.; O'Connor, R.; Schalke, B.; Tzartos, S.; Müller-Hermelink, H. K.

    1989-01-01

    Thymomas from 12 patients with myasthenia gravis (MG) were investigated for the presence of epitopes of the alpha-subunit of the nicotinic acetylcholine receptor (AchR) using monoclonal antibodies (MAb) reacting against the AchR. In all but two of the tumors epitopes corresponding to antigenic determinants located on the cytoplasmic side of the AchR were identified. From eight thymomas cell lines were established that have been kept in culture for up to 6 months. The cultured cells expressed the same AchR-epitopes as did the primary tumors. During early passages the percentage of epithelial cells positive for the AchR epitopes approximately mirrored the percentage of positive cells in the original tumors. With passaging the relative number of positive cells usually declined but in some cultures an increase was observed. Three cell lines that showed extensive staining with an MAb against the AchR were radiolabeled to characterize the antigen. From protein extracts of these three cell lines proteins of 45 kd and 156 kd molecular weight (MW) were precipitated. These proteins are different from other proteins described in the context of both thymomas and MG. The negative reactivity with MAb against other epitopes of the alpha-subunit, especially against the main immunogenic region (MIR), speaks in favor of membrane-associated proteins of only limited crossreactivity to the AchR. A previous study found an almost exclusive occurrence of these AchR-epitopes in thymomas associated with MG, but not in other thymomas of similar histologic type. The expression of the proteins described here could therefore play a role in the triggering of the autoimmune process against the AchR of the motor, endplate in MG patients. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:2468286

  1. Using Xenopus tissue cultures for the study of myasthenia gravis pathogenesis.

    PubMed

    Yeo, Hwee Li; Lim, Jorain Yu Ni; Fukami, Yuki; Yuki, Nobuhiro; Lee, Chi Wai

    2015-12-15

    Myasthenia gravis (MG), the most common autoimmune disease of neuromuscular junction (NMJ), is heterogeneous in terms of pathophysiology, which is determined by the pathogenic antigen of autoantibodies targeting to synaptic proteins at the NMJs. Currently, patients suspected with MG are routinely screened for the presence of autoantibodies against acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) using a cell-based assay (CBA) that involves the expression of target synaptic membrane protein in heterologous cell lines. However, some autoantibodies may only show reactivity for binding to densely clustered AChR in the physiological conformation, while AChR clustering is known to involve signaling events orchestrated by over a dozen of postsynaptic proteins. To improve the existing serological diagnosis of MG, this study explored the possibility of using the well-established Xenopus primary culture system as a novel CBA for MG. Here, by examining the pathogenic effects of four MG human plasma samples, we found that the samples from both seropositive and seronegative MG patients effectively induced the disassembly of aneural AChR clusters in cultured Xenopus muscle cells, as well as the nerve-induced AChR clusters in the nerve-muscle co-cultures. Importantly, the disassembly of AChR clusters was spatio-temporally correlated to the disappearance of actin depolymerizing factor (ADF)/cofilin, an actin regulator involved in AChR trafficking and clustering. Taken together, this study develops a reliable CBA using Xenopus primary cultures for screening the pathogenicity of human MG plasma samples, and providing a platform for investigating the pathogenic mechanisms underlying the endocytic trafficking and degradation of AChRs at NMJs in MG patients.

  2. Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

    SciTech Connect

    Newsom-Davis, J.; Willcox, N.; Calder, L.

    1981-11-26

    We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.

  3. Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus.

    PubMed Central

    Schwimmbeck, P L; Dyrberg, T; Drachman, D B; Oldstone, M B

    1989-01-01

    The large majority of patients with the autoimmune disease myasthenia gravis characteristically have detectable antibodies against the acetylcholine receptor (AChR). We used synthetic peptides to identify antibodies in sera of myasthenia gravis patients reactive with the human acetylcholine receptor (HuAChR) alpha-subunit, residues 160-167. Affinity purification of these antibodies, using the HuAChR alpha-subunit 157-170 peptide immobilized on thiopropyl-Sepharose, yielded IgG antibodies that bound to the native AChR and inhibited the binding of alpha-bungarotoxin to the receptor. The HuAChR alpha-subunit 160-167 peptide demonstrated specific immunological cross-reactivity with a shared homologous domain on herpes simplex virus glycoprotein D, residues 286-293, by both binding and inhibition studies. Thus, HuAChR alpha-subunit, residues 160-167, elicits antibodies in myasthenic patients that binds to the native AChR protein and is capable of eliciting a biologic effect. Immunologic cross-reactivity of this "self" epitope with herpes simplex virus suggest that this virus may be associated with the initiation of some cases of myasthenia. Images PMID:2551924

  4. FOXP3 -3279 and IVS9+459 polymorphisms are associated with genetic susceptibility to myasthenia gravis.

    PubMed

    Zhang, Junmei; Chen, Yuqian; Jia, Ge; Chen, Xiaoli; Lu, Jiayin; Yang, Huan; Zhou, Wenbin; Xiao, Bo; Zhang, Ning; Li, Jing

    2013-02-08

    Myasthenia gravis (MG) is an autoimmune disorder in which CD4(+)CD25(+) FOXP3(+)regulatory T cells (Tregs) are thought to play important roles in driving the ongoing autoimmune response. Although it is known that single-nucleotide polymorphisms (SNPs) in the fork head/winged-helix transcription factor 3 (FOXP3) gene contribute to some autoimmune diseases, information about the role of this gene in MG is limited. We therefore evaluated the association between FOXP3 gene SNPs and susceptibility to MG in a Han Chinese population. In a hospital-based, case-control study, two SNPs in the FOXP3 gene (-3279 and IVS9+459) were investigated in 118 MG and 124 healthy controls, and their relationship with the four parameters of gender, onset age, thymus pathology, and clinical classification of MG were performed with a stratified analysis. We found that the frequency of the FOXP3 IVS9+459 G allele was significantly lower in MG patients than in healthy controls (P=0.041), while the frequency of the FOXP3 -3279 polymorphisms was not significantly different between the two groups. Our results suggest that FOXP3 IVS9+459 polymorphisms appear to have an effect on the risk of MG in a Han Chinese population, and the G allele may be a genetic protective factor to MG.

  5. Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis

    PubMed Central

    Baggi, Fulvio; Andreetta, Francesca; Caspani, Elisabetta; Milani, Monica; Longhi, Renato; Mantegazza, Renato; Cornelio, Ferdinando; Antozzi, Carlo

    1999-01-01

    The mucosal administration of the native antigen or peptide fragments corresponding to immunodominant regions is effective in preventing or treating several T cell–dependent models of autoimmune disease. No data are yet available on oral tolerance with immunodominant T-cell peptides in experimental autoimmune myasthenia gravis (EAMG), an animal model of B cell–dependent disease. We report that oral administration of the T-cell epitope α146-162 of the Torpedo californica acetylcholine receptor (TAChR) α-subunit suppressed T-cell responses to AChR and ameliorated the disease in C57Bl/6 (B6) mice. Protection from EAMG was associated with reduced serum Ab’s to mouse AChR and reduced AChR loss in muscle. The effect of Tα146-162 feeding was specific; treatment with a control peptide did not affect EAMG manifestations. The protective effect induced by peptide Tα146-162 was mediated by reduced production of IFN-γ, IL-2, and IL-10 by TAChR-reactive cells, suggesting T-cell anergy. TGF-β–secreting Th3 cells did not seem to be involved in tolerance induction. We therefore demonstrate that feeding a single immunodominant epitope can prevent an Ab-mediated experimental model of autoimmune disease. PMID:10545527

  6. The contribution of Dr. Mary Walker towards myasthenia gravis and periodic paralysis whilst working in poor law hospitals in London.

    PubMed

    Johnston, J D

    2005-06-01

    Dr. Mary Walker discovered in 1934 that physostigmine and Prostigmin temporarily restored muscle function in patients with myasthenia gravis. In the next five years, Dr. Walker and colleagues provided clinical evidence for the weakness of myasthenia gravis being caused by a "disturbance of transmission of excitation from motor nerve to voluntary muscle presumably caused by a deficiency of acetylcholine. Physostigmine (or Prostigmin) compensated for the lack of acetylcholine by delaying its destruction." Dr. Walker and colleagues also described the association between familial periodic paralysis and hypokalaemia.

  7. Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab.

    PubMed

    Unal, Sule; Sag, Erdal; Kuskonmaz, Baris; Kesici, Selman; Bayrakci, Benan; Ayvaz, Deniz C; Tezcan, Ilhan; Yalnızoglu, Dilek; Uckan, Duygu

    2014-05-01

    Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up.

  8. Antigen-specific modulation of experimental myasthenia gravis: nasal tolerization with recombinant fragments of the human acetylcholine receptor alpha-subunit.

    PubMed

    Barchan, D; Souroujon, M C; Im, S H; Antozzi, C; Fuchs, S

    1999-07-06

    Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AcChoR) is the major autoantigen. The immune response in these diseases is heterogeneous and is directed to a wide variety of T and B cell epitopes of AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore, have a broad specificity. We used recombinant fragments of the human AcChoR, encompassing the extracellular domain of the alpha-subunit, or shorter fragments derived from it, in experiments to modulate EAMG. We have demonstrated that intranasal administration of these recombinant fragments, which represent a major portion of epitopes involved in MG, prevents the induction of EAMG in rats and immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight loss, and muscle AcChoR content. These effects on EAMG were accompanied by a marked reduction in the proliferative T-cell response and IL-2 production in response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal tolerance induced by appropriate recombinant fragments of human AcChoR is effective in suppressing EAMG and might possibly be considered as a therapeutic modality for MG.

  9. Antigen-specific modulation of experimental myasthenia gravis: Nasal tolerization with recombinant fragments of the human acetylcholine receptor α-subunit

    PubMed Central

    Barchan, Dora; Souroujon, Miriam C.; Im, Sin-Hyeog; Antozzi, Carlo; Fuchs, Sara

    1999-01-01

    Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AcChoR) is the major autoantigen. The immune response in these diseases is heterogeneous and is directed to a wide variety of T and B cell epitopes of AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore, have a broad specificity. We used recombinant fragments of the human AcChoR, encompassing the extracellular domain of the α-subunit, or shorter fragments derived from it, in experiments to modulate EAMG. We have demonstrated that intranasal administration of these recombinant fragments, which represent a major portion of epitopes involved in MG, prevents the induction of EAMG in rats and immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight loss, and muscle AcChoR content. These effects on EAMG were accompanied by a marked reduction in the proliferative T-cell response and IL-2 production in response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal tolerance induced by appropriate recombinant fragments of human AcChoR is effective in suppressing EAMG and might possibly be considered as a therapeutic modality for MG. PMID:10393952

  10. TCR-Vbeta usage in the thymus and blood of myasthenia gravis patients.

    PubMed

    Navaneetham, D; Penn, A S; Howard, J F; Conti-Fine, B M

    1998-12-01

    In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an autoimmune response. The anti-AChR response may originate in the thymus, which is abnormal in most MG patients and contains anti-AChR T and B cells. Microbial superantigens (sAg) may trigger autoimmune responses and in this study we sought clues as to whether sAg play a role in the pathogenesis of MG. We investigated the frequency of use of the different TCR Vbeta families by the thymus and blood T cells in MG patients and in control subjects, using a multi-primer PCR assay. Identical TCR-Vbeta usage was found in the thymi of MG patients and controls, except Vbeta2, which showed a small increase in MG patients' thymi. Blood T cells of MG patients used Vbeta4, Vbeta6, Vbeta15, Vbeta16 and Vbeta24 significantly more than those of the controls. Vbeta4 and Vbeta6 are the gene families most frequently used by anti-AChR CD4(+) cells in MG patients. Blood T cells from MG patients used Vbeta12, Vbeta14, Vbeta17 and Vbeta18 significantly less than controls. MG patients used Vbeta4 and Vbeta6 significantly more in the blood than in the thymus, while the opposite occurred for Vbeta7, Vbeta12 and Vbeta14. Controls used Vbeta17 more and Vbeta24 less in the blood than in the thymus. The preferential expansion of Vbeta4 and Vbeta6 in MG patients might reflect the immunodominance of certain AChR epitopes, or the action of a sAg outside the thymus. The minimal differences in the TCR-Vbeta usage in the blood and thymus of control subjects might be due to expansion of T cell clones specific for common antigens. Identical Vbeta usage in the thymi of MG patients and controls does not support an important role of the thymus as the location of anti-AChR sensitization when MG is clinically evident. The differences observed in the Vbeta usage in blood and thymi of MG patients are likely to be due to preferential Vbeta usage by the anti-AChR T cells in the blood.

  11. Thymus and Myasthenia Gravis: what can we learn from DNA microarrays?

    PubMed

    Cizeron-Clairac, Géraldine; Le Panse, Rozen; Frenkian-Cuvelier, Mélinée; Meraouna, Amel; Truffault, Frédérique; Bismuth, Jacky; Mussot, Sacha; Kerlero de Rosbo, Nicole; Berrih-Aknin, Sonia

    2008-09-15

    This review is dedicated to John Newsom-Davis, who was an exceptional colleague and friend, always exchanging ideas with respect and consideration. We shall not forget his involvement and passion in search for the truth on the role of thymectomy in the management of Myasthenia Gravis (MG). In this short review, we shall summarize what we learnt from DNA microarrays applied to MG thymus. We shall focus on three main comparisons of the thymic transcriptomes: 1) highly hyperplastic MG patients versus non-MG adults; 2) corticosteroid-treated versus untreated seropositive MG patients; and 3) seronegative versus seropositive MG patients.

  12. True epithelial hyperplasia in the thymus of early-onset myasthenia gravis patients: implications for immunopathogenesis.

    PubMed

    Roxanis, I; Micklem, K; Willcox, N

    2001-01-01

    The early-onset myasthenia gravis (EOMG) thymus shows characteristic medullary epithelial bands (MEB), greatly expanded perivascular infiltrates and fenestrations of the intervening basement membranes. We now compare epithelial expression of epidermal growth factor receptor (EGFR) and many integrins in EOMG and control samples. The main differences are striking/consistent thickening (in MEB) of what is normally a monolayer of perivascular epithelium, with focal protrusion into the infiltrates. This evidently hyperplastic epithelial subpopulation also strongly expresses EGFR and certain integrins. We suggest that its enhanced interactions with the locally increased extracellular matrix protein deposits may play an important role in autosensitization.

  13. Altered levels of nerve growth factor in the thymus of subjects with myasthenia gravis.

    PubMed

    Stampachiacchiere, Barbara; Marinova, Tsvetana; Velikova, Kamelia; Philipov, Stanislav; Stankulov, Ivan S; Chaldakov, George N; Fiore, Marco; Aloe, Luigi

    2004-01-01

    We have previously reported that nerve growth factor (NGF), a polypeptide known for its neurotrophic activities, is also involved in the differentiation and survival of immune cells, and that NGF and its high-affinity receptor are present in the thymus. We here demonstrate that the thymus of humans affected by myasthenia gravis (MG) contains significant concentrations of NGF. These observations support our hypothesis of a role for NGF in the thymus and suggest that the changes observed in the thymus of subject with MG may have functional significance.

  14. Specific immunotherapy of experimental myasthenia gravis in vitro and in vivo: the Guided Missile strategy.

    PubMed

    Sun, W; Adams, R N; Miagkov, A; Lu, Y; Juon, H-S; Drachman, D B

    2012-10-15

    Current immunotherapy of myasthenia gravis (MG) is often effective, but entails risks of infection and neoplasia. The "Guided Missile" strategy described here is designed to target and eliminate the individual's unique AChR-specific T cell repertoire, without otherwise interfering with the immune system. We genetically engineered dendritic cells to present AChR epitopes and simultaneously express Fas ligand in an ongoing EAMG model. In both in vitro and in vivo experiments, these engineered cells specifically killed AChR-responsive T cells without otherwise damaging the immune system. AChR antibodies were markedly reduced in the treated mice. Translation of this method to treat human MG is possible.

  15. Primary Ectopic Mediastinal Goiter in a Patient With Crohn's Disease Presenting as Myasthenia Gravis.

    PubMed

    Kumar, Sunil; Sultania, Mahesh; Vatsal, Shivam; Sharma, M C

    2015-12-01

    Mediastinum is an uncommon location for ectopic goiter. Primary ectopic mediastinal goiter has been reported to present mostly with compressive symptoms. We report a case of a 62-year-old man with history of Crohn's disease, who presented with symptoms of myasthenia gravis and was found to have an anterior mediastinal mass. The mass was resected completely with successful outcome. On histopathologic examination this mass turned out to be colloid goiter. This is an extremely rare presentation of a primary ectopic mediastinal goiter.

  16. Focal myasthenia gravis as a paraneoplastic syndrome of canine thymoma: improvement following thymectomy.

    PubMed

    Lainesse, M F; Taylor, S M; Myers, S L; Haines, D; Fowler, J D

    1996-01-01

    A 10-year-old, neutered male cocker spaniel-cross experienced regurgitation, dry retching, and weight loss. A large, mediastinal mass and dilatation of the esophagus were seen on thoracic radiographs. Cytological, histopathological, immunohistochemical, and serological findings were consistent with a lymphoepithelial thymoma and focal, esophageal myasthenia gravis. Surgical removal of the mass resulted in rapid resolution of the megaesophagus and a decrease in serum acetylcholine-receptor antibody concentration. The dog was clinically normal until the thymoma recurred six months postoperatively. Clinical signs, diagnostic evaluation, management, and treatment of a dog with thymoma and megaesophagus are described.

  17. Major motor-functional determinants associated with poor self-reported health-related quality of life in myasthenia gravis patients.

    PubMed

    Cioncoloni, David; Casali, Stefania; Ginanneschi, Federica; Carone, Marisa; Veronica, Boni; Rossi, Alessandro; Giannini, Fabio

    2016-05-01

    Myasthenia gravis (MG) is an autoimmune neuromuscular disorder in which disabling muscle weakness may affect health-related quality of life (HRQoL). The aim of this study was to investigate which common motor-functional deficits and corresponding severity are most determinant of poor HRQoL in these patients. In 41 patients, the dichotomized first item of the Italian Myasthenia Gravis Questionnaire (IMGQ), categorizing patients who report "good" and "poor" HRQoL, was chosen as dependent-outcome variable. All items composing the myasthenia gravis-specific scale (MG-ADL), i.e. talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to rise from chair, double vision, and eyelid droop were acquired as independent variables and dichotomized. Stepwise backward LR multivariable logistic regression analysis was performed. In addition, the main characteristics of patients were compared. MG-ADL items "chewing" ≥1, i.e. "fatigue chewing solid food", and "breathing" ≥2, i.e. "shortness of breath at rest" proved to be significant determinants. Higher dose of corticosteroid therapy was significantly (p = 0.027; r s  = -0.35), correlated with poor HRQoL. At diagnosis, a decremental response to repetitive nerve stimulation (RNS) from the abductor pollicis brevis was significantly more frequent in patients with poor HRQoL. In conclusion, impaired "chewing" and "breathing" functions indicate the need for careful planning of rehabilitation, re-education and patient management. Moreover, decremental response to RNS at diagnosis may identify patients at risk for poor HRQoL.

  18. Transcervical excision of thymoma and video-assisted thoracoscopic extended thymectomy (VATET) for ectopic cervical thymoma with myasthenia gravis: report of a case.

    PubMed

    Kumazawa, Sachiko; Ishibashi, Hironori; Takahashi, Ken; Okubo, Kenichi

    2016-12-01

    Myasthenia gravis is the most common disease associated with thymoma, but it is rarely accompanied by ectopic thymoma. We describe a 47-year-old woman who presented with an ectopic cervical thymoma with myasthenia gravis. She was admitted to our neurology department with ptosis, diplopia, and mandibular muscle fatigue, and was diagnosed with myasthenia gravis. The mass was located posterior to the right lobe of thyroid gland on computed tomography and was diagnosed as ectopic thymoma on fine-needle aspiration biopsy examination. Transcervical excision of thymoma and VATET were performed. The patient has been free of neurological symptoms and has displayed no evidence of recurrent thymoma for 2 years.

  19. Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis.

    PubMed

    Kanatli, Irem; Akkaya, Bahar; Uysal, Hilmi; Kahraman, Sevim; Sanlioglu, Ahter Dilsad

    2017-02-01

    Myasthenia Gravis is an autoantibody-mediated, neuromuscular junction disease, and is usually associated with thymic abnormalities presented as thymic tumors (~10%) or hyperplastic thymus (~65%). The exact role of thymus in Myasthenia Gravis development is not clear, yet many patients benefit from thymectomy. The apoptotic ligand TNF-Related Apoptosis-Inducing Ligand is thought to be involved in the regulation of thymocyte counts, although conflicting results are reported. We investigated differential expression profiles of TNF-Related Apoptosis-Inducing Ligand and its transmembrane receptors, Nuclear Factor-kB activation status, and apoptotic cell counts in healthy thymic tissue and pathological thymus from Myasthenia Gravis patients. All tissues expressed TNF-Related Apoptosis-Inducing Ligand and its receptors, with hyperplastic tissue having the highest expression levels of death receptors DR4 and DR5. No detectable Nuclear Factor-kB activation, at least via the canonical Protein Kinase A-mediated p65 Ser276 phosphorylation, was evident in any of the tissues studied. Apoptotic cell counts were higher in MG-associated tissue compared to the normal thymus. Possible use of the TNF-Related Apoptosis-Inducing Ligand within the concept of an apoptotic ligand-mediated medical thymectomy in thymoma- or thymic hyperplasia-associated Myasthenia Gravis is also discussed.

  20. Ocular myasthenia gravis induced by human acetylcholine receptor ϵ subunit immunization in HLA DR3 transgenic mice.

    PubMed

    Wu, Xiaorong; Tuzun, Erdem; Saini, Shamsher S; Wang, Jun; Li, Jing; Aguilera-Aguirre, Leopoldo; Huda, Ruksana; Christadoss, Premkumar

    2015-12-01

    Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ϵ-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ϵ-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ϵ-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ϵ-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ϵ-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ϵ-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ϵ-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG.

  1. Serum uric acid levels in patients with myasthenia gravis are inversely correlated with disability

    PubMed Central

    Yang, Dehao; Weng, Yiyun; Lin, Haihua; Xie, Feiyan; Yin, Fang; Lou, Kangliang; Zhou, Xuan; Han, Yixiang; Li, Xiang

    2016-01-01

    Uric acid (UA), the final product of purine metabolism, has been reported to be reduced in patients with various neurological disorders and is considered to be a possible indicator for monitoring the disability and progression of multiple sclerosis. However, it remains unclear whether there is a close relationship between UA and myasthenia gravis (MG), or whether UA is primarily deficient or secondarily reduced because of its peroxynitrite scavenging activity. We investigated the correlation between serum UA levels and the clinical characteristics of MG. We assessed 338 serum UA levels obtained in 135 patients with MG, 47 patients with multiple sclerosis, and 156 healthy controls. In addition, we compared serum UA levels when MG patients were stratified according to disease activity and classifications performed by the Myasthenia Gravis Foundation of America, age of onset, duration, and thymus histology (by means of MRI or computed tomography). MG patients had significantly lower serum UA levels than the controls (P<0.001). Moreover, UA levels in patients with MG were inversely correlated with disease activity and disease progression (P=0.013). However, UA levels did not correlate significantly with disease duration, age of onset, and thymus histology. Our findings suggest that serum level of UA was reduced in patients with MG and serum UA might be considered a surrogate biomarker of MG disability and progression. PMID:26836463

  2. Leflunomide treatment in corticosteroid-dependent myasthenia gravis: an open-label pilot study.

    PubMed

    Chen, Pei; Feng, Huiyu; Deng, Juan; Luo, Yufei; Qiu, Li; Ou, Changyi; Liu, Weibin

    2016-01-01

    Leflunomide is an effective drug used in the treatment of rheumatoid arthritis. Here we report the findings of an open-label pilot study, which found that leflunomide is also an effective treatment for myasthenia gravis (MG). This study recruited 15 corticosteroid-dependent MG patients. For 6 months, leflunomide 20 mg was given to these patients daily along with prednisone. The quantitative myasthenia gravis (QMG) scores and MG activities of daily living (MG-ADL) profiles were measured in these MG patients. After 6 months of treatment, 9 of the 15 patients enrolled in this study showed improvements in both QMG and MG-ADL. The mean QMG scores (13.4 to 8.5) and MG-ADL profiles (5.8 to 2.8) were significantly decreased (P = 0.01, 0.006 respectively). Furthermore, we found that the mean corticosteroid doses were reduced after treatment with leflunomide (24.3 to 12.3 mg per day). Leflunomide is a well-tolerated and efficacious treatment for corticosteroid-dependent MG, which may also enable lower doses of corticosteroids to be administered.

  3. Altered expression of miR-125a-5p in thymoma-associated myasthenia gravis and its down-regulation of foxp3 expression in Jurkat cells.

    PubMed

    Li, Jinpin; Qiu, Di; Chen, Zezhi; Du, Weiwei; Liu, Jingli; Mo, Xuean

    2016-04-01

    Myasthenia gravis is an autoantibody-mediated and T cell-dependent autoimmune disease of neuromuscular junctions. Thymomas may play a crucial role in the pathogenesis of thymoma-associated myasthenia gravis (TAMG), but the thymic pathogenesis of TAMG is unknown. MicroRNAs (miRNAs) are non-coding RNA molecules 21-24 nt in length that regulate the expression of their target genes in a post-transcriptional manner. In this study, we used a miRNA microarray chip to identify, for the first time, 137 miRNAs in normal tissue adjacent to the thymoma from TAMG patients that were significantly dysregulated compared with normal thymus controls. We confirmed the differential expression of miR-125a-5p in larger samples using quantitative real-time polymerase chain reaction (qRT-PCR). Using bioinformatics analysis, we identified the foxp3 3' untranslated region (UTR) as a target of miR-125a-5p. Importantly, miR-125a-5p expression exhibited a negative correlation with foxp3 expression in normal tissue adjacent to the thymoma from TAMG patients. Furthermore, we demonstrated that the expression of the foxp3 gene was modulated by miR-125a-5p in Jurkat cells. Taken together, our results suggest that the abnormal expression of miR-125a-5p and its effect on foxp3 expression are likely involved in the pathogenesis of TAMG.

  4. T-cell receptor V sub. alpha. and C sub. alpha. alleles associated with multiple sclerosis and myasthenia gravis

    SciTech Connect

    Oksenberg, J.R.; Cavalli-Sforza, L.L.; Steinman, L. ); Sherritt, M.; Bernard, C.C. ); Begovich, A.B.; Erlich, H.A. )

    1989-02-01

    Polymorphic markers in genes encoding the {alpha} chain of the human T-cell receptor (TcR) have been detected by Southern blot analysis in Pss I digests. Polymorphic bands were observed at 6.3 and 2.0 kilobases (kb) with frequencies of 0.30 and 0.44, respectively, in the general population. Using the polymerase chain reaction (PCR) method, the authors amplified selected sequences derived from the full-length TcR {alpha} cDNA probe. These PcR products were used as specific probes to demonstrate that the 6.3-kb polymorphic fragment hybridizes to the variable (V)-region probe and the 2.0-kb fragment hybridizes to the constant (C)-region probe. Segregation of the polymorphic bands was analyzed in family studies. To look for associations between these markers and autoimmune diseases, the authors have studied the restriction fragment length polymorphism distribution of the Pss I markers in patients with multiple sclerosis, myasthenia gravis, and Graves disease. Significant differences in the frequency of the polymorphic V{sub {alpha}} and C{sub {alpha}} markers were identified between patients and healthy individuals.

  5. Concomitant presentation of Anderson-Tawil syndrome and myasthenia gravis in an adult patient: A case report

    PubMed Central

    Fan, Rui; Ji, Ruirui; Zou, Wenxin; Wang, Guoliang; Wang, Hu; Penney, Daniel James; Luo, Jin Jun; Fan, Yuxin

    2016-01-01

    Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge. PMID:27698745

  6. Concomitant presentation of Anderson-Tawil syndrome and myasthenia gravis in an adult patient: A case report.

    PubMed

    Fan, Rui; Ji, Ruirui; Zou, Wenxin; Wang, Guoliang; Wang, Hu; Penney, Daniel James; Luo, Jin Jun; Fan, Yuxin

    2016-10-01

    Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge.

  7. Construction of an miRNA-regulated drug-pathway network reveals drug repurposing candidates for myasthenia gravis

    PubMed Central

    Cao, Yuze; Lu, Xiaoyan; Wang, Jianjian; Zhang, Huixue; Liu, Zhaojun; Xu, Si; Wang, Tianfeng; Ning, Shangwei; Xiao, Bo; Wang, Lihua

    2017-01-01

    Myasthenia gravis (MG) is a rare debilitating autoimmune neuromuscular disorder. Many studies have focused on the mechanism and treatment strategies of MG. However, the exact pathogenesis of MG and effective treatment strategies remain unclear. Recent studies have indicated that microRNAs (miRNAs or miRs) can regulate the pathological pathways of MG, suggesting their potential role in novel treatments. In the present study, we created a comprehensive catalog of experimentally confirmed MG risk genes and miRNAs by manually mining published literature and public databases. Based on these genes and miRNAs, we identified 41 MG risk pathways and 105 approved drugs that can affect these pathways. Some important MG-related pathways, such as hsa04060 (cytokine-cytokine receptor interaction) and hsa05200 (pathway in cancer), were found to be regulated by MG risk miRNAs and drugs. Furthermore, we constructed an miRNA-regulated drug-pathway network and identified miRNAs and drugs that synergistically regulate key MG pathways and biological processes. We developed a drug repurposing strategy to identify 25 drug repurposing candidates for MG; several of these drugs, such as rituximab, adalimumab, sunitinib, and muromonab, have the potential to be novel MG treatment drugs. This study provides novel insight into the pathogenesis of MG and potential drug candidates for MG were identified. PMID:28075449

  8. A comparison of stapedial reflex fatigue with repetitive stimulation and single-fiber EMG in myasthenia gravis.

    PubMed

    Kramer, L D; Ruth, R A; Johns, M E; Sanders, D B

    1981-06-01

    The pattern of stapedial reflex fatigue in response to pulsed acoustic stimulation was measured and compared to results of repetitive nerve stimulation and single-fiber electromyography (EMG) in 89 patients with myasthenia gravis. Studies were also made on 22 patients with other neuromuscular disorders and 40 control subjects with no evidence of neuromuscular impairment. Stapedial reflex fatigue exceeded normal control values in 84% of the patients with myasthenia gravis. Repetitive stimulation and single-fiber EMG measurements were abnormal in 56% and 91% of this same population, respectively. Stapedial reflex abnormalities were most prevalent in patients with mild forms of myasthenia (predominantly ocular or oropharyngeal weakness). Of 22 nonmyasthenic patients with neuromuscular disease tested, 6 had abnormal stapedial reflex fatigue according to our normal values, indicating that this form of testing also detects other diseases of the motor unit. The measurement of stapedial reflex fatigue is painless, is easy to perform, and requires minimal patient cooperation. Due to the relatively high occurrence of abnormal stapedial reflex fatigue in patients with myasthenia gravis, this procedure appears to have considerable potential value in screening and monitoring patients for the presence of defects in neuromuscular transmission.

  9. Video-assisted thoracoscopic surgery or transsternal thymectomy in the treatment of myasthenia gravis?

    PubMed

    Zahid, Imran; Sharif, Sumera; Routledge, Tom; Scarci, Marco

    2011-01-01

    A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was how video-assisted thoracoscopic surgery (VATS) compares to median sternotomy in the surgical management of patients with myasthenia gravis (MG)? Overall 74 papers were found using the reported search, of which 15 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that VATS produces equivalent postoperative mortality and complete stable remission (CSR) rates, with superior results in terms of hospital stay, operative blood loss and patient satisfaction at the expense of a doubling of operative time. Six studies comparing VATS and transsternal sternotomy in non-thymomatous myasthenia gravis (NTMG) patients found VATS to have lower operative blood loss (73.8±70.7 vs. 155.3±91.7 ml; P<0.05), reduced total hospital stay (5.6±2.2 vs. 8.1±3.0 days; P=0.008), whilst maintaining equivalent remission rates (33 vs. 44.7%; P=0.16) and mass of thymic tissue resection (37 vs. 34 g; P>0.05). One study comparing video-assisted thoracoscopic extended thymectomy to transsternal thymectomy in only thymoma-associated myasthenia gravis (T-MG) patients found equivalent CSR (11.3 vs. 8.7%, P=0.1090) at six-year follow-up. Thymoma recurrence rate (9.64%) was not significantly different (P=0.1523) between the two groups. Eight studies comparing VATS and transsternal approach in mixed T-MG and NTMG patients found a lower hospital stay (1.9±2.6 vs. 4.6±4.2 days, P<0.001), reduced need for postoperative medication (76.5 vs. 35.7%, P=0.022), lower intensive care unit stay (1.5 vs. 3.2 days, P=0.018), greater symptom improvement (100 vs. 77.9%, P=0.019) and better cosmetic satisfaction (100 vs. 83, P=0.042) with VATS. In concordance with NTMG and T-MG alone patient groups, VATS and transsternal methods had equivalent

  10. Postoperative Respiratory Failure in a Patient with Undiagnosed Myastenia Gravis

    PubMed Central

    Özel, Funda; Altunkan, Ali Aydın; Azizoğlu, Mustafa

    2016-01-01

    Myasthenia gravis (MG) is an autoimmune disease caused by the development of antibodies against the nicotinic acetylcholine receptor. There is hypersensitivity against non-depolarizing muscle relaxants in these patients. Sugammadex eliminates the effects of steroid non-depolarizing muscle relaxants, such as rocuronium and vecuronium, by selectively encapsulating their molecules. In this case report, we present a case of recurarization and respiratory failure after the use of sugammadex and rocuronium in a patient with preoperatively undiagnosed myasthenia gravis. PMID:27366570

  11. A randomised clinical trial comparing prednisone and azathioprine in myasthenia gravis. Results of the second interim analysis. Myasthenia Gravis Clinical Study Group.

    PubMed Central

    1993-01-01

    From January 1983 to October 1990, 41 patients with generalised myasthenia gravis were randomly given either prednisone or azathioprine. The main goal was to record the time to the occurrence of the first episode of deterioration. During a mean follow-up of 30 months, 21 patients showed deterioration, 12 in the prednisone group and nine in the azathioprine group (p = 0.40). No difference was observed between the two groups in muscular score and functional grade, assessed at the end of each treatment year, or in tolerance. Treatment failure occurred in 17 patients, 12 in the prednisone group and five in the azathioprine group (p = 0.02); even after adjustment for imbalances in prognostic features, the failure rate remained 2.8 times higher in the prednisone group than in the azathioprine group (p = 0.5). In the patients in whom treatment failed, symptoms were initially more severe than in the others, but the combination of prednisone and azathioprine resulted in clinical improvement, consisting of remission or only minor deficits in half of the patients after two years of treatment. These findings indicate that azathioprine increases treatment response compared with prednisone, although no difference in the duration of improvement was demonstrated. Nevertheless, it appears that the most severe forms of the disease, often resistant to prednisone or azathioprine alone, could benefit from the combination of both drugs. PMID:8229026

  12. Thymic expression of the main immunogenic region of titin in thymomatous myasthenia gravis.

    PubMed

    He, Z F; Lv, W; Qiao, J; Chen, Z M; Pang, L W; Chen, X J

    2010-01-01

    Antititin antibody occurs in the serum of myasthenia gravis (MG) patients with thymoma (MGT), and is a diagnostic marker for the disease. The mechanism that triggers MGT development is, however, unclear. This study evaluated the role of the main immunogenic region (MIR) of titin in MGT pathogenesis. Titin MIR antiserum (antibody titre 1:16) was obtained and an in situ immunohistochemical study of thymomatous tissue samples was performed. Strong immunostaining for titin MIR was observed on epithelial cell membranes in MGT patients, and the degree of immunostaining was directly proportional to the number of epithelial cells in thymomatous tissue. Serum antititin antibody levels were closely related to titin MIR levels in thymoma cells; however, titin MIR levels did not appear to be related to MG severity. Antititin antibody may be a good surrogate marker for thymoma but is probably not involved in the pathogenesis of MGT.

  13. Elevated plasma interleukin-17A in a subgroup of Myasthenia Gravis patients.

    PubMed

    Xie, Yanchen; Li, Hai-feng; Jiang, Bin; Li, Yao; Kaminski, Henry J; Kusner, Linda L

    2016-02-01

    To better define the role of IL-17A in myasthenia gravis (MG), we assessed plasma concentrations in 69 adult patients with MG prior to initiation of immunosuppression and monitored their clinical course for the subsequent 2years with quantitative MG scores (QMGS) and Osserman classification. IL-17A was higher among patients than healthy control subjects. Early-onset women without thymoma had greater elevations of IL-17A. Logistic regression analysis indicated that the absence of thymoma rather than women gender or early-onset was the significant determinant associated with IL-17A elevation. Elevated IL-17A levels were associated with more severe MG. In summary, IL-17A has role in the pathogenesis of a subgroup of patients with early-onset women with MG with greater disease severity who are most likely to have thymic hyperplasia. This subgroup may be a target for IL-17 treatments, which are under development.

  14. Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis.

    PubMed

    Maeda, Osamu; Yokota, Kenji; Atsuta, Naoki; Katsuno, Masahisa; Akiyama, Masashi; Ando, Yuichi

    2016-02-01

    A 79-year-old man with lymph node recurrence of malignant melanoma received nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody. He had pre-existing ocular myasthenia gravis (MG) and a continued small amount of corticosteroid. Grade 3 creatine phosphokinase elevation appeared after two doses of nivolumab, and the treatment was postponed until it improved to grade 1. After three doses of nivolumab, he experienced diplopia and facial muscle weakness which were consistent with an acute exacerbation of MG, and the symptoms relieved without additional treatment for MG. He achieved shrinkage of metastasis after ten doses of nivolumab. Although a case who died due to MG after administration of nivolumab was reported recently, pre-existing MG is considered not to be always a contraindication of nivolumab.

  15. Myasthenia gravis and myasthenic syndrome: simulation of twitch strength with or without therapy.

    PubMed

    Nigrovic, Vladimir; Amann, Anton; Bhatt, Shashi

    2005-12-01

    To examine the quantitative relationship between indirectly evoked twitch and decreases in the number of either postsynaptic receptors or acetylcholine molecules released by a single stimulus, we studied these variables in a computer-simulated model of neuromuscular transmission. Twitch strength decreased if the number of receptors decreased to below 30% of normal or the number of acetylcholine molecules released by a stimulus decreased to below 80%. Inhibition of acetylcholine hydrolysis to 50% restored twitch strength in the presence of a decreased number of receptors. However, twitch strength was more easily restored to normalcy by augmenting the release of acetylcholine, if the release was diminished by disease. The simulations mimic the clinically known therapeutic outcomes in certain disorders of neuromuscular transmission. These results provide useful quantitative insights into the relationship between acetylcholine receptors or the stimulus-induced release of acetylcholine and muscle function in myasthenia gravis or Lambert-Eaton myasthenic syndrome.

  16. Longitudinal epitope mapping in MuSK myasthenia gravis: implications for disease severity.

    PubMed

    Huijbers, Maartje G; Vink, Anna-Fleur D; Niks, Erik H; Westhuis, Ruben H; van Zwet, Erik W; de Meel, Robert H; Rojas-García, Ricardo; Díaz-Manera, Jordi; Kuks, Jan B; Klooster, Rinse; Straasheijm, Kirsten; Evoli, Amelia; Illa, Isabel; van der Maarel, Silvère M; Verschuuren, Jan J

    2016-02-15

    Muscle weakness in MuSK myasthenia gravis (MG) is caused predominantly by IgG4 antibodies which block MuSK signalling and destabilize neuromuscular junctions. We determined whether the binding pattern of MuSK IgG4 antibodies change throughout the disease course ("epitope spreading"), and affect disease severity or treatment responsiveness. We mapped the MuSK epitopes of 255 longitudinal serum samples of 53 unique MuSK MG patients from three independent cohorts with ELISA. Antibodies against the MuSK Iglike-1 domain determine disease severity. Epitope spreading outside this domain did not contribute to disease severity nor to pyridostigmine responsiveness. This provides a rationale for epitope specific treatment strategies.

  17. The Effect of Immunonutrition on the Postoperative Complications in Thymoma with Myasthenia Gravis

    PubMed Central

    Xin, Yanzhong; Cai, Hongfei; Wu, Lihui

    2016-01-01

    Object. To test whether preoperative immunonutrition is efficacious in reducing postoperative complications in patients of thymoma with myasthenia gravis (MG). Material and Methods. A total of 244 patients operated on for thymoma with myasthenia gravis were prospectively assigned to two groups, each receiving seven-day preoperative and seven-day postoperative nutrition. The patients in immunonutrition group were given oral immunonutrition (IN). The patients in control group received oral standard nutrition. Immunonutritional and inflammatory biomarkers (IgA, IgG, IgM, CD3t, CD4t, CD8t, CD4t/CD8t ratio, NK-cell, prealbumin, albumin, white blood cells counts, and C-reactive protein) and clinical variables (age, gender, BMI, performance status, type of thymoma, type of MG, operative time, pathology, operative approach, postoperative complications, quantity of drainage, hospital stays) were examined. Results. A significant reduction in the length of hospital stay, quantity of drainage, and postoperative complications was observed in the IN group (p < 0.05). An increase in the level of IgA, IgG, IgM, CD3+T, CD4+T, CD4+T/CD8+T, WBC, CRP, and NK-cell in the IN group was observed after thymectomy, while a decrease was seen with regard to prealbumin and albumin (p < 0.05). Conclusion. Preoperative immunonutrition support is effective in reducing postoperative complications in patients of thymoma with MG. It helps to lower the risk of postoperative infectious complications and hospital stays. PMID:27956763

  18. Aberrant decrease of microRNA19b regulates TSLP expression and contributes to Th17 cells development in myasthenia gravis related thymomas.

    PubMed

    Wang, Zhongkui; Chen, Yuping; Xu, Shengjie; Yang, Yanhua; Wei, Dongning; Wang, Wei; Huang, Xusheng

    2015-11-15

    Myasthenia gravis (MG) is an organ-specific autoimmune disease. The imbalance of T helper type 17 cells (Th17) plays a key role in the pathogenesis of thymomatous MG. But the regulatory mechanism for Th17 cell development in MG-related thymoma remains undefined. Here we demonstrated that thymic stromal lymphopoietin (TSLP) is significantly decreased in thymomas. We also proved that TSLP was post-trancriptionally regulated by microRNA-19b. The expression of microRNA-19b was negatively correlated with the expression of TSLP mRNA and protein in thymomas. This study indicated that the elevation of microRNA-19b suppressed TSLP expression and then influenced T cell development in thymomatous MG.

  19. Anesthetic Management of a Patient With Antimuscle-Specific Kinase Antibody-Positive Myasthenia Gravis Undergoing an Open Cholecystectomy: A Case Report.

    PubMed

    Akatsu, Masahiko; Ikegami, Yukihiro; Tase, Choichiro; Nishikawa, Koichi

    2017-03-15

    Myasthenia gravis (MG) is an autoimmune disease characterized by the production of antibodies against the acetylcholine receptor, muscle-specific kinase (MuSK), or other proteins at the neuromuscular junction. MG with antibodies against MuSK (MuSK-MG) has been described recently. Here, we report the first case of anesthetic management of a patient with MuSK-MG undergoing an open cholecystectomy. In our case, propofol and remifentanil-based anesthesia were used for successful management without using muscle relaxants. Patients with MuSK-MG have predominantly ocular, bulbar, and respiratory symptoms that may increase the risk of aspiration. Anesthesiologists need to pay attention to perioperative respiratory failure and respiratory crisis.

  20. Altered Active Zones, Vesicle Pools, Nerve Terminal Conductivity, and Morphology during Experimental MuSK Myasthenia Gravis

    PubMed Central

    Patel, Vishwendra; Oh, Anne; Voit, Antanina; Sultatos, Lester G.; Babu, Gopal J.; Wilson, Brenda A.; Ho, Mengfei; McArdle, Joseph J.

    2014-01-01

    Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG. PMID:25438154

  1. Acute Respiratory Failure Induced by Magnesium Replacement in a 62-Year-Old Woman with Myasthenia Gravis.

    PubMed

    Singh, Paramveer; Idowu, Olakunle; Malik, Imrana; Nates, Joseph L

    2015-10-01

    Magnesium is known to act at the neuromuscular junction by inhibiting the presynaptic release of acetylcholine and desensitizing the postsynaptic membrane. Because of these effects, magnesium has been postulated to potentiate neuromuscular weakness. We describe the case of a 62-year-old woman with myasthenia gravis and a metastatic thymoma who was admitted to our intensive care unit for management of a myasthenic crisis. The patient's neuromuscular weakness worsened in association with standard intravenous magnesium replacement, and the exacerbated respiratory failure necessitated intubation, mechanical ventilation, and an extended stay in the intensive care unit. The effect of magnesium replacement on myasthenia gravis patients has not been well documented, and we present this case to increase awareness and stimulate research. In addition, we discuss the relevant medical literature.

  2. T-lymphocyte-rich Thymoma and Myasthenia Gravis in a Siberian Tiger (Panthera tigris altaica)☆

    PubMed Central

    Allan, K.; Masters, N.; Rivers, S.; Berry, K.; Routh, A.; Lamm, C.

    2014-01-01

    Summary A 10-year-old captive male Siberian tiger (Panthera tigris altaica) presented with acute onset collapse, vomiting and dyspnoea, preceded by a 6-month period of progressive muscle wasting. Following humane destruction, post-mortem examination revealed a large multilobulated mass in the cranial mediastinum, which was diagnosed as a T-lymphocyte-rich thymoma with the aid of immunohistochemistry. Retrospective serology for acetylcholine receptor antibodies (titre 3.90 nmol/l) confirmed a diagnosis of thymoma-associated myasthenia gravis. Thymomas are reported rarely in wild carnivores, but when detected they appear to be similar in morphology to those seen in domestic carnivores and may also be accompanied by paraneoplastic syndromes. The clinical signs of myasthenia gravis in the tiger were consistent with those reported in cats and dogs and the condition is proposed as an important differential diagnosis for generalized weakness in captive Felidae. PMID:24444818

  3. Concurrent massive breast enlargement, myasthenia gravis and dermopathy as manifestations of penicillamine toxicity in a Wilson's disease patient.

    PubMed

    Tan, S S; Latif, S Abdul; Poh, W Y

    2012-06-01

    Penicillamine toxicity in Wilson's disease has been well reported but rarely seen now as newer agents are being used. We present a case who developed multiple rare complications of Penicillamine concurrently. Our patient is one of three siblings on Penicillamine, she was the only one who developed massive breast enlargement four months after commencing Penicillamine therapy, as well as dermatological adverse reactions and myasthenia gravis three more months later. All the adverse effects improved soon after substitution of the offending agent with Trientine.

  4. Myasthenia Gravis

    MedlinePlus

    ... Association National Office - 222 S. Riverside Plaza Suite 1500 Chicago IL Chicago, IL 60606 mda@mdausa.org http://www.mda. ... Association National Office - 222 S. Riverside Plaza Suite 1500 Chicago IL Chicago, IL 60606 mda@mdausa.org http:// ...

  5. Myasthenia Gravis

    MedlinePlus

    ... inadequate, creating a medical emergency and requiring a respirator for assisted ventilation. In individuals whose respiratory muscles ... is a greater understanding about the structure and function of the neuromuscular junction, the fundamental aspects of ...

  6. Regulation of acetylcholine receptor alpha subunit variants in human myasthenia gravis. Quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction.

    PubMed Central

    Guyon, T; Levasseur, P; Truffault, F; Cottin, C; Gaud, C; Berrih-Aknin, S

    1994-01-01

    Myasthenia gravis (MG) is an autoimmune disease mediated by auto-antibodies that attack the nicotinic acetylcholine receptor (AChR). To elucidate the molecular mechanisms underlying the decrease in AChR levels at the neuromuscular junction, we investigated the regulation of AChR expression by analyzing mRNA of the two AChR alpha subunit isoforms (P3A+ and P3A-) in muscle samples from myasthenic patients relative to controls. We applied a quantitative method based on reverse transcription of total RNA followed by polymerase chain reaction (PCR), using an internal standard we constructed by site-directed mutagenesis. An increased expression of mRNA coding for the alpha subunit of the AChR isoforms was observed in severely affected patients (P < 0.003 versus controls) but not in moderately affected patients, independently of the anti-AChR antibody titer. Study of mRNA precursor levels indicates a higher expression in severely affected patients compared to controls, suggesting an enhanced rate of transcription of the message coding for the alpha subunit isoforms in these patients. We have also reported that mRNA encoding both isoforms are expressed at an approximate 1:1 ratio in controls and in patients. We have thus identified a new biological parameter correlated with disease severity, and provide evidence of a compensatory mechanism to balance the loss of AChR in human myasthenia gravis, which is probably triggered only above a certain degree of AChR loss. Images PMID:8040257

  7. Amplification of Anti-Tumor Immunity Without Autoimmune Complications

    DTIC Science & Technology

    2007-05-01

    porcine, or human collagen, generating comple- ment-Wxing autoantibodies [17]. Autoantibodies are gener- ated in experimental autoimmune myasthenia gravis ...animal model of autoimmunity, Life Sci. 61 (1997) 1861–1878. [18] P. Christadoss, M. Poussin, C. Deng, Animal models of myasthenia gravis , Clin...Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated Antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that

  8. Thymic epithelial cells of human patients affected by myasthenia gravis overexpress IGF-I immunoreactivity.

    PubMed

    Marinova, Tsvetana T; Kuerten, Stefanie; Petrov, Danail B; Angelov, Doychin N

    2008-01-01

    Accumulating evidence shows that several kinds of thymic cells express insulin-like growth factor-I (IGF-I), which is known to play an important role in T cell ontogeny under both physiological and pathological conditions. Still, little is known about the mechanisms of IGF-I involvement in the pathological transformation of the thymocyte microenvironment. The present study focuses on a comparative analysis of the IGF-I immunoreactivity of thymic epithelial cells (EC) from human patients with hyperplasia-associated myasthenia gravis (MG) versus physiological thymic tissue from healthy controls using immunohistochemistry and immunoelectron microscopy. We show that myasthenic EC overexpress IGF-I in comparison to EC from control subjects. The IGF-I immunoreactivity in the medullary and cortical EC from MG patients was stronger than in the normal gland. The increased expression of IGF-I and more frequent distribution of IGF-I and IGF-I-receptor (IGF-IR) immunopositive EC correlated with modulation in the immunoreactivity of double (IGF-I/IGF-IR) positive EC. Our data provide new immunocytochemial evidence for alterations of IGF-I and IGF-IR immunoreactivity in EC from pathological thymi. The persisting expression of IGF-I and IGF-IR most likely indicates that the myasthenic thymus is still capable of governing IGF-I signaling pathways, which are involved in the local regulation of T cell development and plasticity.

  9. CD4(+) FoxP3(+) T regulatory cell subsets in myasthenia gravis patients.

    PubMed

    Kohler, Siegfried; Keil, Thomas Oskar Philipp; Hoffmann, Sarah; Swierzy, Marc; Ismail, Mahmoud; Rückert, Jens Carsten; Alexander, Tobias; Meisel, Andreas

    2017-03-09

    Although myasthenia gravis (MG) is a classic autoantibody-mediated disease, T cells are centrally involved in its pathogenesis. In recent years a number of studies have analyzed the role of CD4(+) FoxP3(+) regulatory T cells (Treg) in the disease with contradictory results. Here, the generation of Treg was significantly reduced in thymoma as compared to thymic hyperplasia and normal thymus tissue (p=0.0002). In the peripheral blood, Treg subsets classified according to CD49d, HELIOS and CD45RA expression changed after thymectomy and in the long-term course of immunosuppression. Compared to healthy volunteers the frequency of CD45RA(+)FoxP3(low) Treg was reduced in MG patients in general (p=0.037) and in particular in patients without immunosuppression (p=0.036). In our study, thymectomy and immunosuppressive treatment were associated with changes in Treg subpopulations. The reduced frequency of CD45RA(+)FoxP3(low) Treg we observed in MG patients might play a role in MG pathogenesis.

  10. Intrathymic Epstein-Barr virus infection is not a prominent feature of myasthenia gravis.

    PubMed

    Kakalacheva, Kristina; Maurer, Michael A; Tackenberg, Björn; Münz, Christian; Willcox, Nick; Lünemann, Jan D

    2011-09-01

    Lymph node-type T- and B-cell infiltrates with germinal centers are characteristic features of the hyperplastic thymus in early onset myasthenia gravis (EOMG).Epstein-Barr virus (EBV) infection confers survival advantages on B cells, and has recently been implicated in tertiary lymphoid tissue formation in EOMG. We evaluated the frequency of intrathymic EBV-infected B-lineage cells and antiviral immune responses in treatment-naive patients with EOMG. Real-time polymerase chain reaction was performed to quantify the content of genomic EBV DNA (BamHI-W repeat region) in thymic cell suspensions. Serial paraffin sections of EOMG thymi were analyzed for the presence of EBV-encoded RNA by in situ hybridization and for viral gene expression by immunohistochemistry. Humoral and cellular immune responses to viral antigens were quantified by enzyme-linked immunosorbent assay and flow cytometry-based intracellular cytokine staining. We detected minimal levels of viral DNA-corresponding to single viral genomes-in only 6 of 16 hyperplastic EOMG thymi, indicating extreme rarity of viral copy numbers in the investigated thymic samples. That was confirmed by similar rarity of EBV-encoded RNA and viral proteins identified in thymic sections. Furthermore, EBV-specific T- and B-cell responses were unchanged in patients with EOMG. These findings do not support an etiologic role for EBV in the initiation of EOMG.

  11. The effect of myasthenia gravis as a prognostic factor in thymoma treatment

    PubMed Central

    Aydemir, Bulent

    2016-01-01

    OBJECTIVE: Thymoma is a standard epithelial tumor. Though it is rare, it constitutes 50% of anterior mediastinal masses. Variety of immunological diseases may accompany thymoma; however, myasthenia gravis (MG) is the most frequently associated paraneoplastic syndrome. Most effective treatment for thymoma is complete surgical resection. In this study, impact of MG on prognosis of thymoma cases was examined. METHODS: Records of 61 patients who underwent surgery with diagnosis of thymoma between January 2003 and September 2016 were retrospectively reviewed. All cases were analyzed for data related to age, gender, complaint, localization of lesion, surgical procedure, histopathological diagnosis, stage, MG, and long-term follow-up results. RESULTS: Total of 58 cases were included in the study. Of those, 37 patients were male and 21 were female. Mean age was 48 years. While 24 cases of thymoma were accompanied by MG, 34 cases were not. Duration of follow-up ranged from 1 month to 155 months. CONCLUSION: It was found that in group with MG, 5-year survival rate was 87.5% while it was 82.4% in group without MG. Despite longer duration of survival in group of thymoma associated with MG, there was no significant statistical difference between groups (p=0.311). PMID:28275751

  12. Identification of haemopoietic biglycan in hyperplastic thymus associated with myasthenia gravis.

    PubMed

    Tomoyasu, H; Kikuchi, A; Kamo, I

    1998-08-14

    Generally biglycan, a small proteoglycan, has been thought to play a role as an extracellular matrix and/or a reservoir for other factors, such as TGF-beta and collagens. Recently, we have found that a soluble 100 kDa biglycan, produced from the rat thymic myoid cells and the brain glial cells, predominantly stimulates growth and differentiation of monocytic lineage cells from various lymphatic organs, including microglias. In the present study, we attempted to identify biological significance of the corresponding molecules in human, using five myasthenic thymuses (three with hyperplasia and two with thymoma) that had been surgically removed for therapeutic purpose. With immunohistochemistry, many biglycan positive cells were detected in the germinal center of the three hyperplastic thymuses, but not in the two thymuses associated with lymphocytic thymoma. Biglycan purified from the hyperplastic thymuses by an immunoaffinity column was found as a monomer with apparent molecular size of 95-100 kDa and self associated oligomers of greater than 201 kDa. The purified biglycan markedly stimulated the growth and differentiation of monocytic cells from haemopoietic stem cells of the rat bone marrow. These results suggest that particular cells, which produce haemopoietic biglycan, play significant roles in generation and maintenance of the hyperplastic changes associated with myasthenia gravis.

  13. Thymectomy for Myasthenia Gravis: A 10-year Review of Cases at the Hospital Universiti Sains Malaysia

    PubMed Central

    Muhammed, Julieana; Chen, Chui Yin; Wan Hitam, Wan Hazabbah; Ghazali, Mohamad Ziyadi

    2016-01-01

    Background A thymectomy is considered effective for patients with myasthenia gravis (MG). Although a few studies have described the role of a thymectomy in the treatment of MG in Asians countries, there are no published data on the application of this surgical approach for MG in Malaysia. We aimed to describe the clinical outcomes of MG patients who underwent a thymectomy and the factors affecting these outcomes. Methods This was a retrospective study involving 16 patients with MG who underwent a thymectomy at the Hospital Universiti Sains Malaysia (HUSM) from January 2002 until December 2012, with a follow-up period ranging from 3–120 months. Results The study consisted of 16 patients aged 22–78 years, 10 of whom were males. The overall remission/improvement rate was 87.5%, and the rate of clinical outcomes classified as unchanged/worsened was 12.5%. Thymomamatous or non-thymomamatous MG, histology features, Osserman stage and the duration of follow-up were not significant prognostic factors. Post-operative mortality was 6.2% (1 of 16 patients died of septic shock). Conclusion A thymectomy seems to be an effective treatment for MG, with low surgical morbidity. Patients with a lower Osserman stage and those with/without thymomas had favourable outcomes. PMID:27660548

  14. Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients.

    PubMed

    Nguyen, Bella H V; Kuo, James; Budiman, Anadian; Christie, Hayden; Ali, Sayed

    2017-04-01

    Immune checkpoint inhibitors have changed the landscape of the treatment of multiple solid malignancies, and have been used increasingly in the recent years. Although usually well tolerated, given the relative inexperience of using immune checkpoint inhibitors, we are still learning of new side effects from the treatment. We report on two cases of ocular myasthenia gravis that occurred after treatment with pembrolizumab, an antiprogrammed-death (anti-PD1) monoclonal antibody for advanced melanoma in responding patients. One case is in an 81-year-old man and the second case in an 86-year-old woman, both with BRAF-negative metastatic melanoma receiving pembrolizumab. These two cases of ocular only associated myasthenic syndrome appeared 7 and 11 weeks after the initiation of pembrolizumab. We conclude that the condition is most likely associated with pembrolizumab as symptoms started after treatment with pembrolizumab, neither patient had other evidence of neurological cause for presentation, and symptoms also improved rapidly with administration of steroids. Both patients showed good oncological response to anti-PD1 treatment and one patient successfully continued to receive ongoing treatment with no further complications.

  15. Determination of neostigmine and pyridostigmine in the urine of patients with myasthenia gravis

    PubMed Central

    Nowell, P. T.; Scott, Carol A.; Wilson, A.

    1962-01-01

    A method has been described for the estimation of neostigmine and pyridostigmine in urine by ion exchange treatment and colorimetric estimation of the blue complex produced when either of the drugs is made to react with bromophenol blue. Urine containing 2 μg/ml. or more of neostigmine or 3 μg/ml. or more of pyridostigmine can be quantitatively estimated. After intramuscular injection of neostigmine to patients with myasthenia gravis, up to 67% of the drug is excreted, whilst after oral administration less than 5% is excreted. When pyridostigmine is given by mouth, the amount of drug excreted in the urine varies between approximately 2 and 16%. It has been established by chromatographic analysis that the blue complexes formed under these conditions are due only to neostigmine and pyridostigmine respectively and that the quantitative estimation described is a true measure of the amount of these drugs excreted in the urine. The significance of these results is discussed in relation to the absorption and metabolism of the two drugs. PMID:14480648

  16. Antibodies against low-density lipoprotein receptor–related protein 4 induce myasthenia gravis

    PubMed Central

    Shen, Chengyong; Lu, Yisheng; Zhang, Bin; Figueiredo, Dwight; Bean, Jonathan; Jung, Jiung; Wu, Haitao; Barik, Arnab; Yin, Dong-Min; Xiong, Wen-Cheng; Mei, Lin

    2013-01-01

    Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ). MG is frequently caused by autoantibodies against acetylcholine receptor (AChR) and a kinase critical for NMJ formation, MuSK; however, a proportion of MG patients are double-negative for anti-AChR and anti-MuSK antibodies. Recent studies in these subjects have identified autoantibodies against low-density lipoprotein receptor–related protein 4 (LRP4), an agrin receptor also critical for NMJ formation. LRP4 autoantibodies have not previously been implicated in MG pathogenesis. Here we demonstrate that mice immunized with the extracellular domain of LRP4 generated anti-LRP4 antibodies and exhibited MG-associated symptoms, including muscle weakness, reduced compound muscle action potentials (CMAPs), and compromised neuromuscular transmission. Additionally, fragmented and distorted NMJs were evident at both the light microscopic and electron microscopic levels. We found that anti-LRP4 sera decreased cell surface LRP4 levels, inhibited agrin-induced MuSK activation and AChR clustering, and activated complements, revealing potential pathophysiological mechanisms. To further confirm the pathogenicity of LRP4 antibodies, we transferred IgGs purified from LRP4-immunized rabbits into naive mice and found that they exhibited MG-like symptoms, including reduced CMAP and impaired neuromuscular transmission. Together, these data demonstrate that LRP4 autoantibodies induce MG and that LRP4 contributes to NMJ maintenance in adulthood. PMID:24200689

  17. Double filtration plasmapheresis benefits myasthenia gravis patients through an immunomodulatory action.

    PubMed

    Zhang, Lei; Liu, Junfeng; Wang, Hongna; Zhao, Chongbo; Lu, Jiahong; Xue, Jun; Gu, Yong; Hao, Chuanming; Lin, Shanyan; Lv, Chuanzheng

    2014-09-01

    Double filtration plasmapheresis (DFPP) is used to treat myasthenia gravis (MG). However, the definite mechanism is unclear. This study investigated whether DFPP improves MG through an immunomodulatory action. Thirty-five MG patients were randomly divided into two treatment groups: Group A (DFPP combined with oral methylprednisolone) and Group B (oral methylprednisolone alone). Their antibody levels, clinical scores, cytokine levels, and CD4(+)CD25(high)Foxp3(+) (regulatory T cell [Treg]) levels were then determined. Anti-titin antibody levels were significantly lower in Group A compared with Group B after treatment. The clinical remission rate in Group A was significantly higher than in Group B. The changes in cytokine levels (interleukin [IL]-2, IL-4, IL-10, and interferon-γ) in sera and the peripheral blood mononuclear cell culture supernatants did not significantly differ before and after the treatments in both groups (p<0.05). The soluble intercellular adhesion molecule-1 (sICAM-1) levels were lower in Group A than in Group B (p<0.05). MG patients exhibited a lower percentage of Treg cells than normal patients. DFPP combined with methylprednisolone treatment increased the Treg cell percentage more than treatment with methylprednisolone alone (p<0.05). DFPP treatment more effectively lowers sICAM-1 and increases Treg cell expression, consequently benefiting MG patients.

  18. Effect of Gender, Disease Duration and Treatment on Muscle Strength in Myasthenia Gravis

    PubMed Central

    Citirak, Gülsenay; Cejvanovic, Sanja; Andersen, Henning; Vissing, John

    2016-01-01

    Introduction The aim of this observational, cross-sectional study was to quantify the potential presence of muscle weakness among patients with generalized myasthenia gravis (gMG). The influence of gender, treatment intensity and disease duration on muscle strength and disease progression was also assessed. Methods Muscle strength was tested in 8 muscle groups by manual muscle testing and by hand-held dynamometry in 107 patients with gMG and 89 healthy age- and gender-matched controls. Disease duration, severity and treatment history were reviewed and compared with muscle strength. Results Patients had reduced strength in all tested muscle group compared to control subjects (p<0.05). Women with gMG were stronger than men (decrease in strength 22.6% vs. 32.7% in men, P<0.05). Regional differences in muscle weakness were also evident, with proximal muscles being more affected. Interestingly, muscle strength did not correlate with disease duration and treatment intensity. Conclusions The results of this study show that in patients with gMG; 1) there is significant muscle weakness, 2) muscle weakness is more pronounced in men than women, 3) shoulder abductors, hip flexors, and neck muscles are the most affected muscle groups and 4) disease duration or treatment intensity alone are not predictors of loss of muscle strength in gMG. PMID:27741232

  19. Direct and indirect cost of myasthenia gravis: A prospective study from a tertiary care teaching hospital in India.

    PubMed

    Sonkar, Kamlesh Kumar; Bhoi, Sanjeev Kumar; Dubey, Deepanshu; Kalita, Jayantee; Misra, Usha Kant

    2017-04-01

    Myasthenia gravis (MG) requires lifelong treatment. The cost of management MG is very high in developed countries but there is no information on the cost of management of MG in the developing countries. This study reports the direct and indirect cost and predictors of cost of MG in a tertiary care teaching hospital in India. In a prospective hospital based study, from a tertiary hospital in India 66 consecutive patient during 2014-2015 were included. The age of the patients ranged between 6 and 75years. The severity of MG was assessed by myasthenia gravis foundation association (MGFA) class (MGFA) I-V. The patient data was collected s and their direct cost was calculated from the computerized Hospital information system. The indirect cost was calculated from patient's memory, checking the bills of transportation and wages loss by the patient or the care giver. Total annual cost of MG ranged between INR (4560-532227) with median INR 61390.5 (US$911.64). The median cost of outpatient department (OPD) consultation of 16 patients was INR 20439.9 (US$303.53), of 50 admitted patients was INR 44311.8 (US$658.03) and 21 intensive care unit (ICU) patients was INR 59574.3 (US$ 884.6) and the direct cost of thymectomy was INR 45000 (US$ 668.25). Direct cost was related to indirect cost (r=0.55; p=0.0001). Predictors of patient outcome were severity of MG, ICU admission, and thymectomy. The total median cost for management of myasthenia gravis was INR 61390.5 (4560-532227, US$911.64) per year, and the cost was mainly determined by the severity of MG.

  20. Myasthenia gravis: predictive factors associated with the synchronized elevation of anti-acetylcholine receptor antibody titer in Kanazawa, Japan.

    PubMed

    Iwasa, Kazuo; Yoshikawa, Hiroaki; Samuraki, Miharu; Shinohara, Moeko; Hamaguchi, Tsuyoshi; Ono, Kenjiro; Nakamura, Hiroyuki; Yamada, Masahito

    2014-02-15

    For a brief period, an increased incidence of elevated anti-acetylcholine receptor antibody titer was observed in patients with myasthenia gravis (MG) in Kanazawa, Japan. The purpose of this study was to examine the predictive factors associated with this antibody titer elevation. Decreased odds of titer elevation were seen in patients with early-onset MG than in those with late-onset MG. In patients with non-thymoma-related MG, thymectomy prevented the antibody titer elevation. Our data suggest that late-onset MG may have a different immunogenic response and the thymus might play an immunoregulatory role against extrinsic factors in some types of MG.

  1. Dropped head syndrome as prominent clinical feature in MuSK-positive Myasthenia Gravis with thymus hyperplasia.

    PubMed

    Spengos, Konstantinos; Vassilopoulou, Sofia; Papadimas, Georgios; Tsivgoulis, Georgios; Karandreas, Nikos; Zambelis, Thomas; Manta, Panagiota

    2008-02-01

    MuSK-positive Myasthenia Gravis is in most cases clinically characterized by a progressive course with severe oculobulbar involvement or prominent neck, shoulder and respiratory muscle weakness. It is also distinguished from other forms of myastehnia through its lack of germinal centers or lymphocytic infiltrates in the thymic tissue. We present the case of a MuSK-positive female myasthenic patient with over four years slowly progressive weakness of the neck extensor muscles in the presence of thymus hyperplasia and discuss its uncommon and markedly focal clinical and electrophysiological features, as well as the excellent course under medication with pyridostigmine and prednisone, especially after thymectomy.

  2. Response to suxamethonium during propofol-fentanyl-N2O/O2 anaesthesia in a patient with active myasthenia gravis receiving long-term anticholinesterase therapy.

    PubMed

    Vanlinthout, L E; Robertson, E N; Booij, L H

    1994-06-01

    We describe the effect of repeated suxamethonium doses during propofol-fentanyl-N2O/O2 anaesthesia in a 29-year-old woman with active myasthenia gravis receiving chronic pyridostigmine therapy. Despite adequate pre-operative pseudocholinesterase activity, suxamethonium resistance occurred. Neither bradycardia nor residual neuromuscular block were seen after repeated doses of suxamethonium.

  3. Altered expression of chemokine receptor CXCR5 on T cells of myasthenia gravis patients.

    PubMed

    Saito, Ryuji; Onodera, Hiroshi; Tago, Hideaki; Suzuki, Yasushi; Shimizu, Masayuki; Matsumura, Yuji; Kondo, Takashi; Itoyama, Yasuto

    2005-12-30

    Myasthenia gravis (MG) is characterized by the T cell-dependent production of anti-acetylcholine receptor (AChR) antibodies. The chemokine receptor CXCR5 regulates lymphocyte migration and is expressed on a subset of CD4+ T cells named follicular helper T cells (T(FH)), the key modulators of antibody production by B cells. We studied the frequency of CXCR5-positive lymphocytes in the peripheral blood of MG patients before and after therapy (thymectomy plus glucocorticoid). Before therapy, the MG patients showed a significantly higher frequency of CXCR5+ CD4+ T cells in the peripheral blood compared with the control group, while no significant difference in the percentages of CXCR5+ CD4+ T cells was observed between the patients of the hyperplasia group and those of the thymoma group. The CXCR5+ CD4+ T cell frequency correlated with the disease severity. The CXCR5+ CD4+ T cell frequency of MG patients positive for other autoantibodies together with anti-AChR antibodies was significantly higher than in those having only anti-AChR antibodies. After therapy, the CXCR5+ CD4+ T cell percentage decreased gradually to the control level with a significant inverse correlation between the CXCR5+ CD4+ T cell frequency and duration after the initiation of MG therapy. The CXCR5+ CD4+ T cell populations in the hyperplastic thymuses and thymomas were not significantly different from those in the control thymuses. These results suggest that CXCR5+ CD4+ T cells play an important role in the disease activity of MG and that some MG patients have a systemic abnormality in T cell-dependent antibody production.

  4. Evaluation of the Quality of Guidelines for Myasthenia Gravis with the AGREE II Instrument

    PubMed Central

    Zhang, Zhenchang; Guo, Jia; Su, Gang; Li, Jiong; Wu, Hua; Xie, Xiaodong

    2014-01-01

    Background Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioners in making decisions about appropriate healthcare in specific clinical circumstances. The methodological quality of CPGs for myasthenia gravis (MG) are unclear. Objective To critically evaluate the methodological quality of CPGs for MG using AGREE II instrument. Method A systematical search strategy on PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC) and the Chinese Biomedical Literature database (CBM) was performed on September 20th 2013. All guidelines related to MG were evaluated with AGREE II. The software used for analysis was SPSS 17.0. Results A total of 15 CPGs for MG met the inclusion criteria (12 CPGs in English, 3 CPGs in Chinese). The overall agreement among reviews was moderate or high (ICC >0.70). The mean scores (mean ± SD) for al six domains were presented as follows: scope and purpose (60.93% ±16.62%), stakeholder involvement (40.93% ±20.04%), rigor of development (37.22% ±30.46%), clarity of presentation (64.26% ±16.36%), applicability (28.19% ±20.56%) and editorial independence (27.78% ±28.28%). Compared with non-evidence-based CPGs, evidence-based CPGs had statistically significant higher quality scores for all AGREE II domains (P<0.05). All domain scores appear slightly higher for CPGs published after AGREE II instrument development and validation (P>0.05). The quality scores of CPGs developed by NGC/AAN were higher than the quality scores of CPGs developed by other organizations for all domains. The difference was statistically significant for all domains with the exception of clarity of presentation (P = 0.07). Conclusions The qualities of CPGs on MG were generally acceptable with several flaws. The AGREE II instrument should be adopted by guideline developers, particularly in China. PMID:25402504

  5. Validation of the MG-DIS: a disability assessment for myasthenia gravis.

    PubMed

    Raggi, Alberto; Leonardi, Matilde; Schiavolin, Silvia; Antozzi, Carlo; Brenna, Greta; Maggi, Lorenzo; Mantegazza, Renato

    2016-05-01

    This paper is aimed to present the validation of the myasthenia gravis disability assessment (MG-DIS), a MG-specific patient-reported disability outcome measure. Consecutive MG patients were enrolled, followed-up for 12 months and administered the SF-36, the WHO disability assessment schedule (WHODAS 2.0) and the preliminary 31-item MG-DIS addressing impairments and activity limitations. Factor structure and metric properties were assessed. In total, 109 patients were enrolled: 76 were females, mean age 50, mean MG duration 10.4 years, 86 were AChR-positive. The MG-DIS was reduced to 20 items, explaining 70.6 % of the original questionnaire variance, four subscales (generalized impairment-related problems; bulbar function-related problems; mental health and fatigue-related problems; vision-related problems) and an overall disability index. The MG-DIS has good metric properties (Cronbach's alpha ranging between .808 and .930), is stable, showed to be more sensitive than the WHODAS 2.0 and SF-36 to detect group differences and longitudinal changes and was well correlated with the MG-composite (.642). The MG-DIS includes items representing ocular, generalized, bulbar and respiratory symptoms, and is therefore well-built around MG-specific features. MG-DIS can be used in clinical trials as well as in observational or epidemiological studies to characterize patients' disability level and address the amount of improvement in disability. Further studies are needed to explore the possibility of a shorter disability scale.

  6. Social disadvantages associated with myasthenia gravis and its treatment: a multicentre cross-sectional study

    PubMed Central

    Nagane, Yuriko; Murai, Hiroyuki; Imai, Tomihiro; Yamamoto, Daisuke; Tsuda, Emiko; Minami, Naoya; Suzuki, Yasushi; Kanai, Tetsuya; Uzawa, Akiyuki; Kawaguchi, Naoki; Masuda, Masayuki; Konno, Shingo; Suzuki, Hidekazu; Aoki, Masashi; Utsugisawa, Kimiaki

    2017-01-01

    Objectives To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. Design Cross-sectional study. Setting and participants We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. Outcome measures All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose ≥20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry. Results We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. Conclusions Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as

  7. Metastatic Thymoma-Associated Myasthenia Gravis: Favorable Response to Steroid Pulse Therapy Plus Immunosuppressive Agent

    PubMed Central

    Qi, Guoyan; Liu, Peng; Dong, Huimin; Gu, Shanshan; Yang, Hongxia; Xue, Yinping

    2017-01-01

    Background Our study retrospectively reviewed the therapeutic effect of steroid pulse therapy in combination with an immunosuppressive agent in myasthenia gravis (MG) patients with metastatic thymoma. Material/Methods MG patients with metastatic thymoma that underwent methylprednisolone pulse therapy plus cyclophosphamide were retrospectively analyzed. Patients initially received methylprednisolone pulse therapy followed by oral methylprednisolone. Cyclophosphamide was prescribed simultaneously at the beginning of treatment. Clinical outcomes, including therapeutic efficacy and adverse effects of MG and thymoma, were assessed. Results Twelve patients were recruited. According to histological classification, 4 cases were type B2 thymoma, 3 were type B3, 2 were type B1, and 1 was type AB. After combined treatment for 15 days, both the thymoma and MG responded dramatically to high-dose methylprednisolone plus cyclophosphamide. The symptoms of MG were improved in all patients, with marked improvement in 6 patients and basic remission in 4. Interestingly, complete remission of thymoma was achieved in 5 patients and partial remission in 7 patients. Myasthenic crisis was observed in 1 patient and was relieved after intubation and ventilation. Adverse reactions were observed in 7 patients (58.3%), most commonly infections, and all were resolved without discontinuation of therapy. During the follow-up, all patients were stabilized except for 1 with pleural metastasis who received further treatment and another 1 who died from myasthenic crisis. Conclusions The present study in a series of MG patients with metastatic thymoma indicated that steroid pulse therapy in combination with immunosuppressive agents was an effective and well-tolerated for treatment of both metastatic thymoma and MG. Glucocorticoid pulse therapy plus immunosuppressive agents should therefore be considered in MG patients with metastatic thymoma. PMID:28278141

  8. Myopathy, muscle atrophy and tongue lipid composition in MuSK myasthenia gravis.

    PubMed

    Nikolić, Ana V; Bačić, Goran G; Daković, Marko Ž; Lavrnić, Slobodan Đ; Rakočević Stojanović, Vidosava M; Basta, Ivana Z; Lavrnić, Dragana V

    2015-09-01

    Myasthenia gravis (MG) associated with anti-muscle-specific tyrosine kinase (MuSK) antibodies differs in many aspects from typical presentation of acetylcholine receptor (AChR)-positive MG. Myopathy and muscle atrophy are observed in MuSK-positive MG patients, unlike AChR-positive patients with MG. That is why the aim of this study was to assess the presence of myopathy and muscle atrophy as well as the tongue lipid composition in our cohort of MuSK-positive MG patients. Clinical examination, electromyography (EMG) and proton magnetic resonance spectroscopy were performed in 31 MuSK-positive and 28 AChR-positive MG patients. Myopathic EMG was more frequent in MuSK compared to AChR MG patients. In AChR MG patients, myopathic EMG in facial muscles was more frequent after long-term corticosteroid treatment, which was not the case with MuSK-positive MG patients. Facial and/or tongue muscle atrophy was registered in 23 % of MuSK MG patients. Longer disease duration was observed in patients with clinical signs of tongue and/or facial muscle atrophy compared to those with normal tongue muscle. Intramyocellular lipid deposition in the tongue was present in 85.2 % of MuSK and 20 % of AChR MG patients. Female MuSK MG patients had more frequently electrophysiological signs of myopathy on the facial muscles and signs of intramyocellular lipid deposition in the tongue, compared to male patients with MuSK-positive MG. Myopathy, muscle atrophy and intramyocellular lipid deposition in the tongue are more frequent in MuSK-positive compared to AChR-positive MG patients.

  9. Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis.

    PubMed

    Phillips, W D; Christadoss, P; Losen, M; Punga, A R; Shigemoto, K; Verschuuren, J; Vincent, A

    2015-08-01

    Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.

  10. Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4.

    PubMed

    Im, S H; Barchan, D; Maiti, P K; Fuchs, S; Souroujon, M C

    2001-06-01

    Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent Ab-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1-type cells and costimulatory factors such as CD40 ligand (CD40L) contribute to disease pathogenesis by producing proinflammatory cytokines and by activating autoreactive B cells. In this study we demonstrate the capacity of CD40L blockade to modulate EAMG, and analyze the mechanism underlying this disease suppression. Anti-CD40L Abs given to rats at the chronic stage of EAMG suppress the clinical progression of the autoimmune process and lead to a decrease in the AChR-specific humoral response and delayed-type hypersensitivity. The cytokine profile of treated rats suggests that the underlying mechanism involves down-regulation of AChR-specific Th1-regulated responses with no significant effect on Th2- and Th3-regulated AChR-specific responses. EAMG suppression is also accompanied by a significant up-regulation of CTLA-4, whereas a series of costimulatory factors remain unchanged. Adoptive transfer of splenocytes from anti-CD40L-treated rats does not protect recipient rats against subsequently induced EAMG. Thus it seems that the suppressed progression of chronic EAMG by anti-CD40L treatment does not induce a switch from Th1 to Th2/Th3 regulation of the AChR-specific immune response and does not induce generation of regulatory cells. The ability of anti-CD40L treatment to suppress ongoing chronic EAMG suggests that blockade of CD40L may serve as a potential approach for the immunotherapy of MG and other Ab-mediated autoimmune diseases.

  11. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients.

    PubMed

    Koneczny, Inga; Stevens, Jo A A; De Rosa, Anna; Huda, Saif; Huijbers, Maartje G; Saxena, Abhishek; Maestri, Michelangelo; Lazaridis, Konstantinos; Zisimopoulou, Paraskevi; Tzartos, Socrates; Verschuuren, Jan; van der Maarel, Silvère M; van Damme, Philip; De Baets, Marc H; Molenaar, Peter C; Vincent, Angela; Ricciardi, Roberta; Martinez-Martinez, Pilar; Losen, Mario

    2017-02-01

    Autoimmunity mediated by IgG4 subclass autoantibodies is an expanding field of research. Due to their structural characteristics a key feature of IgG4 antibodies is the ability to exchange Fab-arms with other, unrelated, IgG4 molecules, making the IgG4 molecule potentially monovalent for the specific antigen. However, whether those disease-associated antigen-specific IgG4 are mono- or divalent for their antigens is unknown. Myasthenia gravis (MG) with antibodies to muscle specific kinase (MuSK-MG) is a well-recognized disease in which the predominant pathogenic IgG4 antibody binds to extracellular epitopes on MuSK at the neuromuscular junction; this inhibits a pathway that clusters the acetylcholine (neurotransmitter) receptors and leads to failure of neuromuscular transmission. In vitro Fab-arm exchange-inducing conditions were applied to MuSK antibodies in sera, purified IgG4 and IgG1-3 sub-fractions. Solid-phase cross-linking assays were established to determine the extent of pre-existing and inducible Fab-arm exchange. Functional effects of the resulting populations of IgG4 antibodies were determined by measuring inhibition of agrin-induced AChR clustering in C2C12 cells. To confirm the results, κ/κ, λ/λ and hybrid κ/λ IgG4s were isolated and tested for MuSK antibodies. At least fifty percent of patients had IgG4, but not IgG1-3, MuSK antibodies that could undergo Fab-arm exchange in vitro under reducing conditions. Also MuSK antibodies were found in vivo that were divalent (monospecific for MuSK). Fab-arm exchange with normal human IgG4 did not prevent the inhibitory effect of serum derived MuSK antibodies on AChR clustering in C2C12 mouse myotubes. The results suggest that a considerable proportion of MuSK IgG4 could already be Fab-arm exchanged in vivo. This was confirmed by isolating endogenous IgG4 MuSK antibodies containing both κ and λ light chains, i.e. hybrid IgG4 molecules. These new findings demonstrate that Fab-arm exchanged antibodies

  12. Schwann cells and myasthenia gravis. Preferential uptake of soluble and membrane-bound AChR by normal and immortalized Schwann cells, and immunogenic presentation to AChR-specific T line lymphocytes.

    PubMed Central

    Zhang, Y. P.; Porter, S.; Wekerle, H.

    1990-01-01

    The normal neuromuscular synapse is formed by the intimate association of nerve endings, postsynaptic end-plate foldings in the muscle fiber, and nonmyelinating Schwann cells (SC) sealing the synaptic ramifications. Because SC have been recognized recently to have an immunogenic potential inducible to present protein autoantigens to autoimmune T lymphocytes, and considering their close proximity to the acetylcholine receptor (AChR)-bearing postsynaptic membranes, presentation of soluble and membrane vesicle-bound AChR to appropriate T cells was investigated. Short-term monolayer cultures of SC isolated from neonatal rat sciatic nerves, as well as cells of an immortalized SC line of similar origin, were fully able to present the relevant molecular epitopes to major histocompatibility complex (MHC) compatible AChR-specific T line lymphocytes immunogenically. Presentation of AChR was restricted by RT1.B (I-A) MHC class II products. Both types of cultured rat SC were inducible to expression of MHC class I and II products, and they were able to phagocytose AChR-enriched membrane vesicles preferentially. In contrast, phagocytosis of latex particles by SC was negligible. These data qualify perisynaptic SC as potential presenter cells of autoimmunogenic AChR in myasthenia gravis. Thus, SC may play a critical and as-yet unpredicted regulatory role in the cellular pathogenesis of myasthenia gravis. Images Figure 5 Figure 3 Figure 6 PMID:1688688

  13. Effects of the ß2-Adrenoceptor Agonist, Albuterol, in a Mouse Model of Anti-MuSK Myasthenia Gravis

    PubMed Central

    Ghazanfari, Nazanin; Morsch, Marco; Tse, Nigel; Reddel, Stephen W.; Phillips, William D.

    2014-01-01

    The β2-adrenergic receptor agonist, albuterol, has been reported beneficial in treating several forms of congenital myasthenia. Here, for the first time, we examined the potential benefit of albuterol in a mouse model of anti-Muscle Specific Kinase (MuSK) myasthenia gravis. Mice received 15 daily injections of IgG from anti-MuSK positive patients, which resulted in whole-body weakness. At neuromuscular junctions in the tibialis anterior and diaphragm muscles the autoantibodies caused loss of postsynaptic acetylcholine receptors, and reduced the amplitudes of the endplate potential and spontaneous miniature endplate potential in the diaphragm muscle. Treatment with albuterol (8 mg/kg/day) during the two-week anti-MuSK injection series reduced the degree of weakness and weight loss, compared to vehicle-treated mice. However, the compound muscle action potential recorded from the gastrocnemius muscle displayed a decremental response in anti-MuSK-injected mice whether treated with albuterol or vehicle. Ongoing albuterol treatment did not increase endplate potential amplitudes compared to vehicle-treated mice nor did it prevent the loss of acetylcholine receptors from motor endplates. On the other hand, albuterol treatment significantly reduced the degree of fragmentation of endplate acetylcholine receptor clusters and increased the extent to which the remaining receptor clusters were covered by synaptophysin-stained nerve terminals. The results provide the first evidence that short-term albuterol treatment can ameliorate weakness in a robust mouse model of anti-MuSK myasthenia gravis. The results also demonstrate that it is possible for albuterol treatment to reduce whole-body weakness without necessarily reversing myasthenic impairment to the structure and function of the neuromuscular junction. PMID:24505322

  14. Protection of immunoreactivity of dry immobilized proteins on microtitration plates in ELISA: application for detection of autoantibodies in myasthenia gravis.

    PubMed

    Nguyen, V K; Leclerc, N; Wolff, C M; Kennel, P; Fonteneau, P; Deyes, R; Warter, J M; Poindron, P

    1999-06-11

    We show the ability of the BSA-trehalose film to convert normally fragile proteins such as mouse monoclonal antibody to the Alzheimer precursor protein A4 (APP695) and cell line TE671 acetylcholine receptor (AChRTE671) into a stable reagent, after its immobilization on microtitration plates. The remarkable property of the dry immobilized proteins are their stability under prolonged exposure to temperatures as high as 50 degrees C. Using the AChRTE671, the proposed method was applied for the measurement of anti-AChR autoantibodies in Myasthenia gravis by means of an enzyme-linked immunosorbent assay (ELISA). The test was shown to be specific and able to detect anti-AChR autoantibodies at concentrations as low as 3 nM. Using the same AchRTE671 as antigen, the results of examination of 34 serum samples for detection of anti-AChR autoantibodies by ELISA were compared with those of the conventional radioimmunoprecipitation assay (RIA). It was concluded that ELISA is another useful method for the diagnosis of M. gravis. The ELISA method offers a rapid, simple, safe and inexpensive means for mass screening of M. gravis.

  15. Microarrays reveal distinct gene signatures in the thymus of seropositive and seronegative myasthenia gravis patients and the role of CC chemokine ligand 21 in thymic hyperplasia.

    PubMed

    Le Panse, Rozen; Cizeron-Clairac, Géraldine; Bismuth, Jacky; Berrih-Aknin, Sonia

    2006-12-01

    Myasthenia gravis (MG) is an autoimmune disease mainly caused by antiacetylcholine receptor autoantibodies (seropositive (SP) disease) or by Abs against unknown autoantigenic target(s) (seronegative (SN) disease). Thymectomy is usually beneficial although thymic hyperplasia with ectopic germinal centers is mainly observed in SP MG. To understand the role of thymus in the disease process, we compared the thymic transcriptome of non-MG adults to those of SP patients with a low or high degree of hyperplasia or SN patients. Surprisingly, an overexpression of MHC class II, Ig, and B cell marker genes is observed in SP but also SN MG patients. Moreover, we demonstrate an overexpression of CXCL13 in all MG thymuses leading probably to the generalized B cell infiltration. However, we find different chemotactic properties for MG subgroups and, especially, a specific overexpression of CCL21 in hyperplastic thymuses triggering most likely ectopic germinal center development. Besides, SN patients present a peculiar signature with an abnormal expression of genes involved in muscle development and synaptic transmission, but also genes implicated in host response, suggesting that viral infection might be related to SN MG. Altogether, these results underline differential pathogenic mechanisms in the thymus of SP and SN MG and propose new research areas.

  16. A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

    PubMed Central

    Heckmann, J M; Uwimpuhwe, H; Ballo, R; Kaur, M; Bajic, V B; Prince, S

    2009-01-01

    Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5′-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression. PMID:19675582

  17. A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis.

    PubMed

    Heckmann, J M; Uwimpuhwe, H; Ballo, R; Kaur, M; Bajic, V B; Prince, S

    2010-01-01

    Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5'-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.

  18. Imbalance of circulating CD4(+)CXCR5(+)FOXP3(+) Tfr-like cells and CD4(+)CXCR5(+)FOXP3(-) Tfh-like cells in myasthenia gravis.

    PubMed

    Wen, Yanbin; Yang, Baifeng; Lu, Jiayin; Zhang, Junmei; Yang, Huan; Li, Jing

    2016-09-06

    Follicular regulatory T (Tfr) cells are defined as a specialized subset of regulatory T cells (Tregs) that act to control the overactivation of follicular helper T (Tfh) cells and B cells in germinal centers. Accumulating evidence has demonstrated that the dysregulation of either Tfr cells or Tfh cells results in abnormal germinal center responses that contribute to the pathogenesis of autoimmune diseases. However, the role that Tfr cells and Tfh cells play in myasthenia gravis (MG) remains unclear. This study revealed a significantly decreased frequency of CD4(+)CXCR5(+)FOXP3(+) Tfr-like cells and an increased frequency of CD4(+)CXCR5(+)FOXP3(-) Tfh-like cells in the peripheral blood of MG patients compared with healthy controls. Moreover, the Tfr-like/Tfh-like ratio was inversely correlated with the clinical severity of the MG patients. Interestingly, glucocorticoid (GC) treatment can restore the imbalance of circulating Tfr-like/Tfh-like cells, and this restoration is accompanied by reduced clinical symptoms. These results suggested, for the first time, that an imbalance of circulating Tfr-like and Tfh-like cells may be involved in the immunopathogenesis of MG and may provide novel insight for the development of MG therapies.

  19. Central role of interferon-beta in thymic events leading to myasthenia gravis.

    PubMed

    Cufi, Perrine; Dragin, Nadine; Ruhlmann, Nathalie; Weiss, Julia Miriam; Fadel, Elie; Serraf, Alain; Berrih-Aknin, Sonia; Le Panse, Rozen

    2014-08-01

    The thymus plays a primary role in early-onset Myasthenia Gravis (MG) mediated by anti-acetylcholine receptor (AChR) antibodies. As we recently showed an inflammatory and anti-viral signature in MG thymuses, we investigated in detail the contribution of interferon (IFN)-I and IFN-III subtypes in thymic changes associated with MG. We showed that IFN-I and IFN-III subtypes, but especially IFN-β, induced specifically α-AChR expression in thymic epithelial cells (TECs). We also demonstrated that IFN-β increased TEC death and the uptake of TEC proteins by dendritic cells. In parallel, we showed that IFN-β increased the expression of the chemokines CXCL13 and CCL21 by TECs and lymphatic endothelial cells, respectively. These two chemokines are involved in germinal center (GC) development and overexpressed in MG thymus with follicular hyperplasia. We also demonstrated that the B-cell activating factor (BAFF), which favors autoreactive B-cells, was overexpressed by TECs in MG thymus and was also induced by IFN-β in TEC cultures. Some of IFN-β effects were down-regulated when cell cultures were treated with glucocorticoids, a treatment widely used in MG patients that decreases the number of thymic GCs. Similar changes were observed in vivo. The injections of Poly(I:C) to C57BL/6 mice triggered a thymic overexpression of IFN-β and IFN-α2 associated with increased expressions of CXCL13, CCL21, BAFF, and favored the recruitment of B cells. These changes were not observed in the thymus of IFN-I receptor KO mice injected with Poly(I:C), even if IFN-β and IFN-α2 were overexpressed. Altogether, these results demonstrate that IFN-β could play a central role in thymic events leading to MG by triggering the overexpression of α-AChR probably leading to thymic DC autosensitization, the abnormal recruitment of peripheral cells and GC formation.

  20. Myasthenia gravis in patients with thymoma affects survival rate following extended thymectomy

    PubMed Central

    ZHANG, ZHEFENG; CUI, YOUBIN; JIA, RUI; XUE, LEI; LIANG, HUAGANG

    2016-01-01

    Thymomas are the most common adult tumors in the anterior mediastinal compartment, and a significant amount of thymomas are complicated by myasthenia gravis (MG). Extended thymectomy (ET) is the primary treatment method for thymomas and is used to completely resect possible ectopic thymus to avoid recurrence. Studies on the effect of MG in thymoma patients following ET are limited. The aim of the present study was to determine whether the presence of MG affects the prognosis of patients with thymoma. The present study consisted of 104 patients with thymoma that underwent ET; 61 men (58.7%) and 43 women (41.3%) (mean age, 54.6 years). In total, 38 patients had MG (36.5%). MG was most frequently observed in World Health Organization (WHO) classification type B2 thymoma compared with other types of thymoma. During the 5-year follow-up period, 11 patients succumbed to a recurrence of thymoma or respiratory failure due to MG. The overall 5-year survival rate in patients without MG or with MG was 89.1 and 76.0%, respectively. The overall survival (OS) rate in patients with Masaoka stages I + II and III + IV was 90.0 and 68.0%, respectively. The OS rate in patients with WHO type A + AB + B1 and type B2 + B3 was 96.9 and 76.8%, respectively. The patients with MG (P=0.026), Masaoka stages III + IV (P=0.008) and WHO type B2 + B3 (P=0.032) had a poorer prognosis compared with patients without these characteristics. Furthermore, multivariate analysis by Cox regression revealed that age [P=0.032; relative risk (RR)=1.097; 95% confidence interval (CI)=1.097–1.192] and MG (P=0.042; RR=0.167; 95% CI=0.037–0.940) significantly affected OS rate. In summary, ET is a reliable method for the treatment of thymoma. Long-term survival is expected for patients at early Masaoka stages, and for patients without MG. The prognosis of patients with thymomas with MG is poorer compared with patients without MG. The present findings provide useful information for the future management of

  1. Shenqi Fuzheng Injection Alleviates the Transient Worsening Caused by Steroids Pulse Therapy in Treating Myasthenia Gravis

    PubMed Central

    Qi, Guo-Yan; Liu, Peng

    2013-01-01

    Purpose. To evaluate the treatment effect and side effect of Shenqi Fuzheng Injection (SFI) on alleviating transient worsening of myasthenia gravis (MG) symptoms caused by high-dose steroids pulse therapy. Methods. Sixty-six consecutive patients with MG were randomly divided into two groups: the treatment group treated with SFI and methylprednisolone pulse therapy (MPT) and the control group treated with MPT alone. The severity of MG before, during, and after MPT and the duration of transient worsening (TW) were evaluated and compared with the clinical absolute scoring (AS) and relative scoring (RS) system. Results. Twenty-nine patients experienced TW in each group. At TW, the AS was significantly increased (P < 0.000) in both groups compared with baseline data, with the AS increase in the treatment group (16.8 ± 2) significantly smaller (P < 0.05) than in the control group (24.9 ± 2.5). At the end of the treatment course, the AS for the treatment group was significantly decreased (7.5 ± 0.9) compared with at TW, although no significant difference compared with the control (9.7 ± 1.1). The TW lasted 1–6 days (mean 3.7) for the treatment group, significantly shorter (P < 0.05) than 2–12 days (mean 7.8) for the control. The RS for the treatment group at the end of treatment was 43.8%–100% (mean 76.8% ± 2.6%), significantly better than the control group: 33.3%–100% (mean 67.2 ± 3.6%). Slight side effects (18.75%) included maldigestion and rash in the treatment group. Conclusion. SFI has a better treatment effect and few side effects and can alleviate the severity and shorten the duration of the transient worsening of MG during steroids pulse therapy. PMID:24348721

  2. Reduced thymic expression of ErbB receptors without auto-antibodies against synaptic ErbB in myasthenia gravis.

    PubMed

    Vrolix, Kathleen; Niks, Erik H; Le Panse, Rozen; van Ostaijen-Ten Dam, Monique M; Muris, Anne-Hilde; Jol-van der Zijde, Cornelia M; van Tol, Maarten J D; Losen, Mario; Molenaar, Peter C; van Zoelen, Everardus J J; Berrih-Aknin, Sonia; De Baets, Marc H; Verschuuren, Jan J G M; Martínez-Martínez, Pilar

    2011-03-01

    In myasthenia gravis (MG), the neuromuscular transmission is impaired mainly by auto-antibodies against the acetylcholine receptor (AChR) or MuSK. In about 5% of the MG patients, however, the auto-antigen is still unknown. We investigated whether these idiopathic MG patients (iMG) have auto-antibodies against ErbB proteins, which influence the AChR density at the NMJ. Our results show reduced mRNA expression levels of ErbB4 in thymus tissue of iMG patients compared to AChR-MG and non-MG patients, but we could not detect anti-ErbB antibodies in sera of iMG patients. Therefore, our results do not support a role for ErbB receptors as auto-antigens in iMG patients.

  3. Disease specific enrichment of circulating let-7 family microRNA in MuSK+ myasthenia gravis.

    PubMed

    Punga, Tanel; Bartoccioni, Emanuela; Lewandowska, Marta; Damato, Valentina; Evoli, Amelia; Punga, Anna Rostedt

    2016-03-15

    Myasthenia gravis (MG) patients with antibodies against the muscle specific tyrosine kinase (MuSK+) have predominantly involvement of cranio-bulbar muscles and do not display thymus pathology, as do acetylcholine receptor antibody seropositive (AChR+) MG patients. In search of novel biomarkers for MuSK+ MG, we evaluated circulating serum microRNAs. Four analyzed microRNAs were specifically elevated in MuSK+ MG patient serum samples: let-7a-5p, let-7f-5p, miR-151a-3p and miR-423-5p. The circulating microRNA profile in MuSK+ MG differs from the profile previously observed in the serum of AChR+ MG, thus indicating the etiological difference between these two entities. We propose that the identified microRNAs could serve as potential serum biomarkers for MuSK+ MG.

  4. Treatment of myasthenia gravis with dropped head: a report of 2 cases and review of the literature.

    PubMed

    Tamai, Michihiro; Hashimoto, Takao; Isobe, Takashi; Sato, Hiromasa; Doden, Tadashi; Nakano, Takeshi

    2015-05-01

    We report two patients with myasthenia gravis (MG) who showed dropped head as an early myasthenic manifestation. They had elevated anti-acetylcholine receptor antibody and showed improvement of the symptoms after intravenous injection of edorophonium chloride. One patient had thymoma and developed myasthenic crisis two weeks after thymectomy. The patient recovered from the crisis after a combination of immunoadsorption plasmapheresis (IAPP) and initiation of steroid and tacrolimus. The other patient without thymoma initiated treatment with steroid, tacrolimus and IAPP and showed complete recovery one month later. Dropped head in MG can recover well with immunosuppression therapy using steroid, and IAPP is helpful in getting a rapid improvement of dropped head as well as recovery from myasthenic crisis. When we consider treatment for MG with dropped head, we should take into account that MG of this type can develop myasthenic crisis and use the same treatment strategy as that for generalized MG.

  5. Double Seronegative Myasthenia Gravis with Anti-LRP4 Antibodies Presenting with Dropped Head and Acute Respiratory Insufficiency

    PubMed Central

    Beck, Goichi; Yabumoto, Taiki; Baba, Kousuke; Sasaki, Tsutomu; Higuchi, Osamu; Matsuo, Hidenori; Mochizuki, Hideki

    2016-01-01

    We herein report the case of a 72-year-old man demonstrating myasthenia gravis (MG) with a dropped head and acute respiratory insufficiency. There was no ocular, bulbar, or limb involvement. The patient was seronegative for anti-acetylcholine receptor (AChR) antibodies and anti-muscle-specific tyrosine kinase (MuSK) antibodies. Subsequent tests showed seropositivity for anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies. The addition of steroid pulse therapy resulted in a full remission of his respiratory symptoms. This presentation suggests that LRP4-positive MG should be considered in the differential diagnosis of patients presenting with acute respiratory insufficiency without either cranial or limb involvement. PMID:27853084

  6. Morphological and Molecular Characterization of Exophiala polymorpha sp. nov. Isolated from Sporotrichoid Lymphocutaneous Lesions in a Patient with Myasthenia Gravis

    PubMed Central

    Yong, Lee K.; Sutton, Deanna A.; Lindner, Jonathan R.; Fan, Hongxin; Sanders, Carmita; Guarro, Josep

    2015-01-01

    Exophiala species are capable of causing cutaneous and subcutaneous infections in immunocompromised patients. An Exophiala isolate was cultured from a biopsy specimen of a lesion on the forearm of a patient with myasthenia gravis. The patient also had lesions on the palm and distal aspects of the hand, which were successfully treated with a long-term course of itraconazole. A detailed morphological and molecular characterization of the isolate was undertaken. Phylogenetic analysis of the internal transcribed spacer region and portions of the β-tubulin and translation elongation factor 1-alpha genes indicated that the isolate was a novel species closely related to but genetically distinct from species within the Exophiala spinifera clade; the name Exophiala polymorpha sp. nov. is proposed. Morphologically, E. polymorpha most closely resembles E. xenobiotica but it differs in possessing phialides bearing prominent, wide collarettes, and it does not produce chlamydospores. PMID:26085612

  7. Correlation of single-breath count test and neck flexor muscle strength with spirometry in myasthenia gravis

    PubMed Central

    Elsheikh, Bakri; Arnold, W. David; Gharibshahi, Shahram; Reynolds, Jerold; Freimer, Miriam; Kissel, John T.

    2015-01-01

    Introduction Although formal spirometry is the gold standard for monitoring respiratory function in patients with myasthenia gravis (MG), such testing is often delayed or unavailable. There is a need for a simple bedside test that can accurately measure respiratory function. Method We conducted a prospective, cross-sectional, single-blind study in adults with acetylcholine receptor antibody positive MG. Participants performed the single breath count test (SBCT) and underwent manual muscle strength testing, while a respiratory therapist performed spirometry blinded to SBCT and strength results. Results Thirty-one patients, aged 57 ±19 years participated. SBCT showed significant correlations with forced vital capacity (FVC), negative inspiratory force (NIF), and neck flexor strength (P<0.01). FVC showed significant correlation with neck flexor strength (P=0.02) but no correlation with shoulder abductor strength. Discussion These data suggest that the SBCT and neck flexor strength testing are valuable tools for bedside assessment of respiratory function in MG patients. PMID:26437790

  8. Application of digital technology in the prosthodontic management of a patient with myasthenia gravis: A clinical report.

    PubMed

    AlHelal, Abdulaziz; Jekki, Rami; Richardson, Paul M; Kattadiyil, Mathew T

    2016-05-01

    Application of digital technology in the treatment of a patient with myasthenia gravis and an excessively resorbed mandibular residual alveolar ridge is presented. The patient requested replacement of worn maxillary and mandibular prostheses. Treatment involved fabricating a new maxillary complete denture that was similar in appearance to the one being replaced and rebasing the existing and clinically acceptable mandibular fixed framework. The interim phase of treatment involved fabricating a mandibular milled prosthesis similar in morphology to the existing fixed complete denture with computer-aided design and computer-aided manufacturing technology. This facilitated conversion of an interim prosthesis by using an orientation device and eliminated the need for the patient to adapt to an interim removable complete denture.

  9. Influence of human myasthenia gravis thymus on the differentiation of human cord blood stem cells in SCID mice.

    PubMed

    Li, Qian Ru; Liu, Ping Ping; Xuan, Xiao Yan; Guan, Sha Sha; Du, Ying; Gao, Feng; Zhang, Qing Yong

    2014-02-01

    The normal thymus contributes to T lymphocytes differentiation and induction of tolerance to self-antigens. Myasthenia gravis (MG) is characterized by abnormal thymic hyperplasia. To assess the potential influence of MG-thymus on the differentiation of T lymphocytes differentiation, we used the MG-thymus transplanted severe combined immunodeficiency (SCID) mice model to evaluate the human cord blood stem cells differentiation. Thymus fragments from MG patient and human cord blood stem cells were transplanted into SCID mice successively. SCID mice were observed to develop sustained human T lymphocytes and a functional anti-tumor immune. The levels of various T cell subsets in SCID mice with MG-thymus were different from that of control group. Among that, the frequency of CD4(+)CD25(+) T cells was significant lower in SCID mice with MG-thymus. The deficiency of CD4(+)CD25(+) T cells seens to contribute to the pathogenesis of MG.

  10. [Thymoma and autoimmune diseases].

    PubMed

    Jamilloux, Y; Frih, H; Bernard, C; Broussolle, C; Petiot, P; Girard, N; Sève, P

    2017-03-29

    The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection.

  11. CD19+ Tim-1+ B cells are decreased and negatively correlated with disease severity in Myasthenia Gravis patients.

    PubMed

    Zhang, Yong; Zhang, Xiuying; Xia, Yan; Jia, Xiao; Li, Hao; Zhang, Yanyan; Shao, Zhen; Xin, Ning; Guo, Mingfeng; Chen, Jing; Zheng, ShuangShuang; Wang, YuZhong; Fu, Linlin; Xiao, Chenghua; Geng, Deqin; Liu, Yonghai; Cui, Guiyun; Dong, Ruiguo; Huang, Xiaoyu; Yu, Tingyan

    2016-12-01

    T cell immunoglobulin mucin domain-1(Tim-1) was recently identified to be critical and essential for optimal regulatory B cells function in maintaining immune tolerance. We aimed to measure the expression levels of Tim-1 on B cells from patients with Myasthenia Gravis (MG) and to investigate whether the expression of Tim-1 is associated with pathogenesis of MG. A total of 34 patients with MG (18 generalized MG (GMG) and 16 ocular MG (OMG) and 24 healthy donors were recruited in this study. The quantitative myasthenia gravis score (QMGS) was used to evaluate the clinical severity. Real-time PCR and flow cytometry were used to measure the levels of Tim-1 expressed on peripheral B cells. Peripheral CD138+ plasma cells were assayed by flow cytometry. Serum Th17-related cytokines (IL-6, IL-1β and IL-17) and anti-AChR antibody (Ab) titers were tested by enzyme-linked immunosorbent assay (ELISA). Our data demonstrated that the mRNA and protein expression levels of B cell Tim-1 in both the GMG and OMG groups were significantly lower than those in healthy controls, with lower expression in GMG than in OMG. Tim-1 expression on B cells from OMG/GMG was negatively correlated with clinical severity, plasma cells frequency, serum Th17-related cytokines and anti-AChR Ab levels. Our results indicated that aberrant expression of Tim-1 exists on B cells and may contribute to the Th17 polarization and antibody-secreting plasma cells differentiation in MG patients.

  12. Long-term efficacy and side effects of low-dose tacrolimus for the treatment of Myasthenia Gravis.

    PubMed

    Tao, Xiaoyong; Wang, Wei; Jing, Feng; Wang, Zhongkui; Chen, Yuping; Wei, Dongning; Huang, Xusheng

    2017-02-01

    The study evaluated the efficacy of low-dose tacrolimus for treating Myasthenia Gravis (MG). Data were collected from 97 patients treated with low-dose tacrolimus from February 2011 to April 2015. Metabolic analysis was performed to determine more accurate tacrolimus dosing and patients were followed-up within clinic every 6 months for up to 4 years. The myasthenia gravis-specific activities of daily living scale was used to assess MG symptoms and their effects on patients' daily activities. All side effects and adverse reactions were thoroughly documented. At the end of follow-up, 6 patients were in complete stable remission, 17 patients were in pharmacological remission, 26 patients were in minimal manifestation status, 32 patients were improved, 2 patients were unchanged, 11 patients had worsening symptoms, and 3 patients died. Side effects were reported and/or observed in 24 patients, of which 7 patients experienced elevated blood glucose, 2 patients developed neoplasms, 3 patients developed gastrointestinal symptoms, 3 showed mild increases in aminotransferases, 3 patients suffered from bone marrow suppression, 2 patients suffered from skin rashes and erythema, and 1 patient required discontinuation of therapy. Transient renal insufficiency was also observed in 1 patient and 3 other patients had minor miscellaneous side effects. This study adds some knowledge on the efficacy and side effects of low-dose tacrolimus in the treatment of MG. Tacrolimus immunotherapy is a valid option for the management of MG, and can be gradually reduced in dose once symptoms are improved until complete withdrawal is achieved.

  13. In vitro proliferative responses and antibody titers specific to human acetylcholine receptor synthetic peptides in patients with myasthenia gravis and relation to HLA class II genes.

    PubMed Central

    Brocke, S; Brautbar, C; Steinman, L; Abramsky, O; Rothbard, J; Neumann, D; Fuchs, S; Mozes, E

    1988-01-01

    To investigate which parts of the acetylcholine receptor are involved in the initiation and development of myasthenia gravis (MG), peptides representing different sequences of the human acetylcholine receptor alpha-subunit were synthesized. These peptides were tested for their ability to stimulate T cells of myasthenic patients and healthy control patients in proliferation assays and to bind to sera antibodies. Three of eight peptides discriminated significantly between the two groups in the proliferation assay, as well as in their ability to bind to serum antibodies. HLA-DR3 and DR5 were associated with proliferative responses to specific AChR peptides in the group of myasthenics. Acetylcholine receptor epitopes that might play a specific role in myasthenia gravis thus were demonstrated. PMID:2461962

  14. miR-20b Inhibits T Cell Proliferation and Activation via NFAT Signaling Pathway in Thymoma-Associated Myasthenia Gravis

    PubMed Central

    Xin, Yanzhong; Cai, Hongfei; Lu, Tianyu; Zhang, Yan; Yang, Yue

    2016-01-01

    Purpose. We examined the role of miR-20b in development of thymoma-associated myasthenia gravis, especially in T cell proliferation and activation. Materials and Methods. Using qRT-PCR, we assessed expression levels of miR-20b and its target genes in cultured cells and patient samples and examined the proliferation of cultured cells, using MTT cell proliferation assays and flow cytometry based cell cycle analysis. Activation of T cells was determined by both flow cytometry and qRT-PCR of activation-specific marker genes. Results. Expression of miR-20b was downregulated in samples of thymoma tissues and serum from patients with thymoma-associated myasthenia gravis. In addition, T cell proliferation and activation were inhibited by ectopic overexpression of miR-20b, which led to increased T cell proliferation and activation. NFAT5 and CAMTA1 were identified as targets of miR-20b. Expression levels of NFAT5 and CAMTA1 were inhibited by miR-20b expression in cultured cells, and the expression levels of miR-20b and NFAT5/CAMTA1 were inversely correlated in patients with thymoma-associated myasthenia gravis. Conclusion. miR-20b acts as a tumor suppressor in the development of thymoma and thymoma-associated myasthenia gravis. The tumor suppressive function of miR-20b in thymoma could be due to its inhibition of NFAT signaling by repression of NFAT5 and CAMTA1 expression. PMID:27833920

  15. Myasthenia Gravis and the Tops and Bottoms of AChRs Antigenic Structure of the MIR and Specific Immunosuppression of EAMG Using AChR Cytoplasmic Domains

    PubMed Central

    Lindstrom, Jon; Luo, Jie; Kuryatov, Alexander

    2009-01-01

    The main immunogenic region (MIR), against which half or more of the autoantibodies to acetylcholine receptors (AChRs) in myasthenia gravis (MG) or experimental autoimmune MG (EAMG) are directed, is located at the extracellular end of α1 subunits. Rat monoclonal antibodies (mAbs) to the MIR efficiently compete with MG patient autoantibodies for binding to human muscle AChRs. Antibodies bound to the MIR do not interfere with cholinergic ligand binding or AChR function, but target complement and trigger antigenic modulation. Rat mAbs to the MIR also bind to human ganglionic AChR α3 subunits, but MG patient antibodies do not. By making chimeras of α1 subunits with α7 subunits or ACh binding protein, the structure of the MIR and its functional effects are being investigated. Many mAbs to the MIR bind only to the native conformation of α1 subunits because they bind to sequences that are adjacent only in the native structure. The MIR epitopes recognized by these mAbs are not recognized by most patient antibodies whose epitopes must be nearby. The presence of the MIR epitopes in α1/α7 chimeras greatly promotes AChR expression and sensitivity to activation. EAMG can be suppressed by treatment with denatured, bacterially expressed mixtures of extracellular and cytoplasmic domains of human α1, β1, γ, δ, and ε subunits. A mixture of only the cytoplasmic domains not only avoids the potential liability of provoking formation antibodies to pathologically significant epitopes on the extracellular surface, but also potently suppresses the development of EAMG. PMID:18567851

  16. Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein-Barr virus infection.

    PubMed

    Cavalcante, Paola; Galbardi, Barbara; Franzi, Sara; Marcuzzo, Stefania; Barzago, Claudia; Bonanno, Silvia; Camera, Giorgia; Maggi, Lorenzo; Kapetis, Dimos; Andreetta, Francesca; Biasiucci, Amelia; Motta, Teresio; Giardina, Carmelo; Antozzi, Carlo; Baggi, Fulvio; Mantegazza, Renato; Bernasconi, Pia

    2016-04-01

    Considerable data implicate the thymus as the main site of autosensitization to the acetylcholine receptor in myasthenia gravis (MG), a B-cell-mediated autoimmune disease affecting the neuromuscular junction. We recently demonstrated an active Epstein-Barr virus (EBV) infection in the thymus of MG patients, suggesting that EBV might contribute to the onset or maintenance of the autoimmune response within MG thymus, because of its ability to activate and immortalize autoreactive B cells. EBV has been reported to elicit and modulate Toll-like receptor (TLR) 7- and TLR9-mediated innate immune responses, which are known to favor B-cell dysfunction and autoimmunity. Aim of this study was to investigate whether EBV infection is associated with altered expression of TLR7 and TLR9 in MG thymus. By real-time PCR, we found that TLR7 and TLR9 mRNA levels were significantly higher in EBV-positive MG compared to EBV-negative normal thymuses. By confocal microscopy, high expression levels of TLR7 and TLR9 proteins were observed in B cells and plasma cells of MG thymic germinal centers (GCs) and lymphoid infiltrates, where the two receptors co-localized with EBV antigens. An increased frequency of Ki67-positive proliferating B cells was found in MG thymuses, where we also detected proliferating cells expressing TLR7, TLR9 and EBV antigens, thus supporting the idea that EBV-associated TLR7/9 signaling may promote abnormal B-cell activation and proliferation. Along with B cells and plasma cells, thymic epithelium, plasmacytoid dendritic cells and macrophages exhibited enhanced TLR7 and TLR9 expression in MG thymus; TLR7 was also increased in thymic myeloid dendritic cells and its transcriptional levels positively correlated with those of interferon (IFN)-β. We suggested that TLR7/9 signaling may be involved in antiviral type I IFN production and long-term inflammation in EBV-infected MG thymuses. Our overall findings indicate that EBV-driven TLR7- and TLR9-mediated innate immune

  17. Myopathic changes detected by quantitative electromyography in patients with MuSK and AChR positive myasthenia gravis.

    PubMed

    Nikolic, Ana; Basta, Ivana; Stojanovic, Vidosava Rakocevic; Stevic, Zorica; Peric, Stojan; Lavrnic, Dragana

    2016-05-01

    Myopathic changes are frequent a electrophysiological finding in patients with muscle specific tyrosine kinase (MuSK) positive myasthenia gravis (MG). The aim of this study was to explore the importance of quantitative electromyography (EMG) in the detection of myopathic changes in MuSK MG patients. Classical and quantitative EMG were performed in 31 MuSK and 28 acetylcholine receptor (AChR) positive MG patients, matched by sex, age, disease duration and severity. Classical EMG revealed the presence of myopathic changes more frequently in MuSK MG compared to AChR MG patients, especially in the facial muscles. Quantitative EMG registered myopathic lesions more frequently than classical EMG, but the frequency was similar between MuSK and AChR MG patients. Quantitative EMG revealed myopathic changes in the majority of both MuSK and AChR positive MG patients. This examination is sensitive, but it cannot be used to differentiate between MG patients belonging to the different disease groups. It should not be used in isolation. Rather, it should complement classical EMG in the detection of myopathic changes.

  18. Preoperative Anxiety in Patients With Myasthenia Gravis and Risk for Myasthenic Crisis After Extended Transsternal Thymectomy: A CONSORT Study.

    PubMed

    Zou, Jianyong; Su, Chunhua; Lun, Xueping; Liu, Weibing; Yang, Weiling; Zhong, Beilong; Zhu, Haoshuai; Lei, Yiyan; Luo, Honghe; Chen, Zhenguang

    2016-03-01

    A thymectomy can ameliorate the symptoms of myasthenia gravis (MG) and prevent the progression of ocular MG (OMG) to generalized MG (GMG). However, postoperative myasthenic crisis (POMC) is a serious post-thymectomy complication. Preoperative anxiety (POA) is common but typically neglected in MG patients. The association of POA with POMC has not yet been examined.From June 2007 to December 2013, 541 cases of MG were admitted to the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). All cases underwent extended transsternal thymectomy (ETT). The clinical and pathological characteristics of these patients, including POA and POMC, were analyzed.A total of 179 patients experienced POA and 67 patients experienced POMC. Patients with POA were more likely to have POMC, a thymoma, and an ectopic thymus. Univariate analysis showed that POMC correlated with POA, presence of an ectopic thymus, dose of pyridostigmine bromide (PYR), presence of a thymoma, MGFA stage, preoperative myasthenic crisis, and postoperative pneumonia. Multivariate logistic regression analysis showed that the independent risk factors for POMC were POA, preoperative myasthenic crisis, higher dose of PYR, and postoperative pneumonia.Our results suggest that clinicians should consider the risk factors for POMC-especially preoperative anxiety-before performing a thymectomy in patients with MG.

  19. Enhancement of noradrenergic neural transmission: an effective therapy of myasthenia gravis: a report on 52 consecutive patients.

    PubMed

    Lechin, F; van der Dijs, B; Pardey-Maldonado, B; John, E; Jimenez, V; Orozco, B; Baez, S; Lechin, M E

    2000-01-01

    Neurochemical, neuroautonomic and neuropharmacological assessments carried out on all our myasthenia gravis (MG) patients showed that they presented a neural sympathetic deficit plus excessive adrenal-sympathetic activity. These abnormalities were registered during the basal (supine-resting) state, as well as after several stress tests (orthostasis, exercise, oral glucose and buspirone). In addition, MG patients showed increased levels of free-serotonin (f5HT) in the plasma, supposedly associated with the increased platelet aggregability which we found in all MG patients. As the above trio of neurochemical disorders (low noradrenergic-activity + high adrenergic-activity + increased f-5HT plasma levels) is known to favor Th-1 immunosuppression + Th-2 predominance, we outlined a neuropharmacological strategy for reverting the above neurochemical disorder. This treatment provoked sudden (acute), and late sustained improvements. Acute effects have been attributed to the increase of alpha-1 activity at the spinal motoneuron level. Late improvements always paralleled a significant normalization of immunological disorders. Complete normalization was registered only in non-thymectomized MG patients.

  20. Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational autoantibodies reacting with myosin, alpha actinin, or actin

    PubMed Central

    1986-01-01

    Striational autoantibodies (StrAb), which react with elements of skeletal muscle cross-striations, occur frequently in patients with thymoma associated with myasthenia gravis (MG). Dissociated thymic lymphocytes from 22 of 72 MG patients secreted StrAb when cultured with PWM. A high yield of EBV-transformed B cell lines was established from thymus, thymoma, and peripheral blood of seven patients with MG, but clones secreting StrAb arose only from the three patients who had StrAb in their sera. The monoclonal StrAb bound to A bands or I bands in skeletal muscle of human, rat, and frog. One bound to mitochondria in addition to myofibrillar I bands. None bound to nuclei, smooth muscle, or gastric mucosal cells. In immunoblot analyses and ELISAs the monoclonal StrAb bound to muscle and nonmuscle isotypes of myosin, alpha actinin, and/or actin. All bound to contractile proteins common to thymus and muscle, and one selectively immunostained epithelial cells of the thymic medulla. From these antigenic specificities we suggest that StrAb might arise as an immune response directed against the cytoskeletal anchoring proteins associated with nicotinic acetylcholine receptors in thymic epithelial cells undergoing neoplastic transformation to thymoma. PMID:3020150

  1. T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits.

    PubMed Central

    Manfredi, A A; Protti, M P; Dalton, M W; Howard, J F; Conti-Tronconi, B M

    1993-01-01

    We tested the response of CD4+ cells and/or total lymphocytes from the blood of 22 myasthenic patients and 10 healthy controls to overlapping synthetic peptides, 20 residues long, to screen the sequence of the gamma and delta subunits of human muscle acetylcholine receptor (AChR). The gamma subunit is part of the AChR expressed in embryonic muscle and is substituted in the AChRs of most adult muscles by an epsilon subunit. The delta subunit is present in both embryonic and adult AChRs. Adult extrinsic ocular muscles, which are preferentially and sometimes uniquely affected by myasthenic symptoms, and thymus, which has a still obscure but important role in the pathogenesis of myasthenia gravis, express the embryonic gamma subunit. Anti-AChR CD4+ responses were more easily detected after CD8+ depletion. All responders recognized epitopes on both the gamma and delta subunits and had severe symptoms. In four patients the CD4+ cell response was tested twice, when the symptoms were severe and during a period of remission. Consistently, the response was only detectable, or larger, when the patients were severely affected. Images PMID:7688757

  2. The MG-QOL15 for following the health-related quality of life of patients with myasthenia gravis.

    PubMed

    Burns, Ted M; Grouse, C K; Wolfe, Gil I; Conaway, Mark R; Sanders, Donald B

    2011-01-01

    The MG-QOL15 is helpful in informing the clinician about the patient's perception of the extent of and dissatisfaction with myasthenia gravis (MG)-related dysfunction. The aims of this study were to determine the usefulness of the MG-QOL15 for following individuals with MG and to guide clinical researchers who plan to use the MG-QOL15. We assessed sensitivity and specificity for detecting clinical change and evaluated test-retest reliability. Sensitivities and specificities of various cut-points of change in scores are presented. Also presented are means and standard deviations of MG-QOL15 scores for all patients and for subgroups of patients. The test-retest reliability coefficient was 98.6%. The MG-QOL15 has an acceptable longitudinal construct validity. We consider this instrument to be most useful for informing the clinician about the patient's perception and tolerance of MG-related dysfunction. More objective measures, such as the MG Composite, should also be used to follow disease severity.

  3. Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: roles of IL-17 and TNF-α.

    PubMed

    Gradolatto, Angeline; Nazzal, Dani; Truffault, Frédérique; Bismuth, Jacky; Fadel, Elie; Foti, Maria; Berrih-Aknin, Sonia

    2014-08-01

    Myasthenia gravis (MG) is an autoimmune disease in which the thymus frequently presents follicular hyperplasia and signs of inflammation and T cells display a defect in suppressive regulation. Defects in a suppressive assay can indicate either the defective function of Treg cells or the resistance of Tconv cells to suppression by Treg cells. The aim of this study was to determine which cells were responsible for this defect and to address the mechanisms involved. We first performed cross-experiment studies using purified thymic Treg cells and Tconv cells from controls (CTRL) and MG patients. We confirmed that MG Treg cells were defective in suppressing CTRL Tconv proliferation, and we demonstrated for the first time that MG Tconv cells were resistant to Treg cell suppression. The activation of MG Tconv cells triggered a lower upregulation of FoxP3 and a higher upregulation of CD4 and CD25 than CTRL cells. To investigate the factors that could explain these differences, we analyzed the transcriptomes of purified thymic Treg and Tconv cells from MG patients in comparison to CTRL cells. Many of the pathways revealed by this analysis are involved in other autoimmune diseases, and T cells from MG patients exhibit a Th1/Th17/Tfh signature. An increase in IL-17-related genes was only observed in Treg cells, while increases in IFN-γ, IL-21, and TNF-α were observed in both Treg and Tconv cells. These results were confirmed by PCR studies. In addition, the role of TNF-α in the defect in Tconv cells from MG patients was further confirmed by functional studies. Altogether, our results indicate that the immunoregulatory defects observed in MG patients are caused by both Treg cell and Tconv cell impairment and involve several pro-inflammatory cytokines, with TNF-α playing a key role in this process. The chronic inflammation present in the thymus of MG patients could provide an explanation for the escape of thymic T cells from regulation in the MG thymus.

  4. Thymopoiesis, regulatory T cells, and TCRVbeta expression in thymoma with and without myasthenia gravis, and modulatory effects of steroid therapy.

    PubMed

    Fattorossi, Andrea; Battaglia, Alessandra; Buzzonetti, Alexia; Minicuci, Giacomo; Riso, Raffaella; Peri, Laura; Scambia, Giovanni; Evoli, Amelia

    2008-03-01

    We analyzed thymocyte and thymic regulatory T cell (CD4SPCD25+Foxp3+cells, Treg) development in thymoma with and without myasthenia gravis (MG, MG-thymoma, non-MG-thymoma) and in MG-associated non-neoplastic thymus (MG-NNT). An increased number of immature CD4+CD8(-)CD3(-) thymocytes through the CD4+CD8+ to CD4+CD8(-) transition and an abnormal T cell receptor Vbeta (TCRVbeta) development through the CD4+CD8+ to CD4(-)CD8+ transition were seen both in MG-and non-MG-thymomas. Terminal thymopoiesis, i.e., CD45RA+ cells within the CD4+CD8(-)CD3+ and CD8+CD4(-)CD3+ subsets, was skewed towards the CD4+ compartment in MG-thymoma and CD8+ compartment in non-MG-thymoma, but thymic export was increased only in the latter in keeping with the hypothesis that CD8+ lymphocytes may play a role in the initial stages of autosensitization and in disagreement with the relevance of an increased output of CD4+ T lymphocytes in paraneoplastic MG. Treg level in normal thymus and MG-NNT and both MG- and non-MG-thymoma was similar, and TCRVbeta development in Treg cells was slightly altered in thymoma but irrespective of MG presence. Thus, the relevance of a defective Treg development in MG context remains to be established. Most alterations in thymopoiesis were corrected by therapeutic corticosteroid administration, and the effects of steroid administration may be mediated by thymic microenvironment.

  5. Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review.

    PubMed

    Truffault, Frédérique; de Montpreville, Vincent; Eymard, Bruno; Sharshar, Tarek; Le Panse, Rozen; Berrih-Aknin, Sonia

    2017-02-01

    The most common form of Myasthenia gravis (MG) is due to anti-acetylcholine receptor (AChR) antibodies and is frequently associated with thymic pathology. In this review, we discuss the immunopathological characteristics and molecular mechanisms of thymic follicular hyperplasia, the effects of corticosteroids on this thymic pathology, and the role of thymic epithelial cells (TEC), a key player in the inflammatory thymic mechanisms. This review is based not only on the literature data but also on thymic transcriptome results and analyses of pathological and immunological correlations in a vast cohort of 1035 MG patients without thymoma. We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women. The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies. The degree of hyperplasia is not dependent upon the time from the onset, implying that either the antigen is chronically expressed and/or that the mechanisms of the resolution of the GC are not efficiently controlled. Glucocorticoids, a conventional therapy in MG, induce a significant reduction in the GC number, together with changes in the expression of chemokines and angiogenesis. These changes are likely related to the acetylation molecular process, overrepresented in corticosteroid-treated patients, and essential for gene regulation. Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients.

  6. Direct binding of a myasthenia gravis related epitope to MHC class II molecules on living murine antigen-presenting cells.

    PubMed Central

    Mozes, E; Dayan, M; Zisman, E; Brocke, S; Licht, A; Pecht, I

    1989-01-01

    MHC gene products present antigenic epitopes to the antigen receptor on T cells. Nevertheless, direct binding of such epitopes to MHC class II proteins on normal living antigen-presenting cells (APCs) has not yet been demonstrated. We have previously shown a significant difference in the ability of T cells of myasthenia gravis (MG) patients to proliferate in response to the synthetic peptide p195-212 of the human acetylcholine receptor (AChR) alpha-subunit in comparison to healthy controls. The observed proliferative responses correlated significantly with HLA-DR5. Moreover, lymph node cells of various mouse strains that were primed with the T cell epitope, p195-212, were found to proliferate to different extents. To investigate these observations further, we designed an assay for direct binding of p195-212 to MHC class II proteins on the surface of freshly prepared splenic adherent cells. Binding of a biotinylated p195-212 was monitored using phycoerythrin-avidin by flow cytometry. Fifteen to sixty per cent of the cells were labeled following incubation with the biotinylated peptide. Binding was observed only to splenic adherent cells derived from mouse strains of which T cells were capable of proliferating in response to p195-212. The binding specificity, in terms of epitope structure and its site of interaction on the cells, was shown by its inhibition with an excess of the unlabeled peptide or with the relevant monoclonal anti-I-A antibodies. These results constitute the first direct evidence for the specific binding of a T cell epitope to live APC. PMID:2480232

  7. Association of the AChRalpha-subunit gene (CHRNA), DQA1*0101, and the DR3 haplotype in myasthenia gravis. Evidence for a three-gene disease model in a subgroup of patients.

    PubMed

    Djabiri, F; Caillat-Zucman, S; Gajdos, P; Jaïs, J P; Gomez, L; Khalil, I; Charron, D; Bach, J F; Garchon, H J

    1997-08-01

    Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction having multigene control. HLA-linked loci and the HB*14 micro-satellite marker located within the CHRNA gene which encodes the muscular acetylcholine receptor (AChR) alpha-subunit, the target self-antigen, were previously associated with MG. Combined analysis of these loci revealed a significant increase of DQA1*0101 alleles in HB*14+ vs. HB*14- patients and of DQA1*0501 alleles in HB*14/DQA1*0101 patients. Importantly, the effect of DQA1*0101 was independent of allelically associated DQB1 and DRB1 genes. In contrast, the effect of DQA1*0501 could not be dissociated from that of DRB1*03 and DQB1*0201 on the extended DR3 haplotype. These results indicate that a combination of three genes, of which two are linked to HLA, contributes to disease susceptibility in a subgroup of MG patients.

  8. Thymic TFH cells involved in the pathogenesis of myasthenia gravis with thymoma.

    PubMed

    Zhang, Min; Zhou, Yongan; Guo, Jun; Li, Hongzeng; Tian, Feng; Gong, Li; Wang, Xianni; Lan, Miao; Li, Zhuyi; Zhang, Wei

    2014-04-01

    Follicular helper CD4+ T (TFH) cells are the specialized providers of B cell help in germinal centers (GCs). Formation of GCs in thymi is the primary thymi characteristic in MG patients. TFH cells are involved in the pathogenic process of many autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and autoimmune thyroid disease. The role thymic TFH cells played in MG with thymoma has not been elucidated. Here, we analyzed surface markers CXCR5, Bcl-6, ICOS and IL-21 on TFH cells in thymus derived from thymoma patients with ocular MG (OMG), generalized MG (GMG) or without MG using immunohistochemical staining, immunofluorescence, western blotting, and real-time PCR analysis. We show that clinical severity of MG is correlated with higher mRNA expression of the four markers. Indeed, results show higher expression of all four markers in thymoma with GMG patients compared with both OMG and non-MG patients. We found no significant difference in the expression of CXCR5, Bcl-6 and ICOS in OMG compared with non-MG patients. Regression analysis shows a positive correlation between thymic CXCR5, BCL-6, ICOS and IL-21 levels and quantitative MG score (QMGS) in GMG patients. In addition, we found no significant correlation between TFH cell expression and QMGS in OMG patients. Our findings show that higher expression of TFH cells in the thymoma is related to the clinical severity of MG and suggests a role in the pathogenesis of MG. However, the real source of these TFH cells is still uncertain and needs further study.

  9. Temporal deterioration of neurological symptoms and increase of serum acetylcholine receptor antibody levels after thymectomy: a case report of a cat with myasthenia gravis

    PubMed Central

    NAGATA, Nao; MIYOSHI, Takuma; OTAKE, Yuzo; SUZUKI, Hitomi; KAGAWA, Yumiko; YAMAGAMI, Tetsushi; IRIE, Mitsuhiro

    2016-01-01

    Neurological signs and serum acetylcholine receptor antibody (AChR-Ab) levels before and after thymectomy were monitored in a 6-year-old male cat with acquired Myasthenia Gravis (MG) as a paraneoplastic syndrome of thymoma. Soon after surgery, the neurological symptoms relapsed, and the cholinesterase inhibitor was administered to control them. The AChR-Ab levels increased postoperatively until 90 days after surgery. This is the first report on long term measurements of serum AChR-Ab levels in a cat with MG. Although thymectomy is valuable for the removal of thymoma, it may not resolve MG symptoms, neurological signs and serum AChR-Ab levels, without medication early after surgery. Also, this case report indicates that the AChR-Ab level might be a guide to detect a deterioration of MG symptoms. PMID:27593682

  10. Nutrition and Myasthenia Gravis

    MedlinePlus

    ... lungs because they travel quickly down the throat. Commercial thickeners can be added to thin liquids to ... time period, evaluations by a nutritionist and a speech language pathologist may be helpful. Special Diet Modifications ...

  11. Ocular Myasthenia Gravis

    MedlinePlus

    ... preferable to drug therapy that alters the immune system using agents such as glucocorticoids (prednisone or similar ... symptoms are severe or disabling, treatment with immune system modulating therapy may be considered. Agents that improve ...

  12. Myasthenia Gravis Fact Sheet

    MedlinePlus

    ... the binding of acetylcholine to the muscle. The thymus gland, part of the immune system, is abnormal in ... people with MG have benign tumors of the thymus gland called thymomas. Doctors do not fully understand the ...

  13. Myasthenia Gravis Tests

    MedlinePlus

    ... services. Advertising & Sponsorship: Policy | Opportunities PLEASE NOTE: Your web browser does not have JavaScript enabled. Unless you enable Javascript , your ability to navigate and access the features of this website will be limited. ... | Tests | Treatment | Related Pages Tests The goals with testing ...

  14. Employees with Myasthenia Gravis

    MedlinePlus

    ... lot of communication Allow periodic rest breaks Fine Motor Impairment: Implement ergonomic workstation design Provide alternative computer ... a book holder Provide a note taker Gross Motor Impairment: Provide parking close to the work-site ...

  15. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment.

    PubMed

    Im, S H; Barchan, D; Fuchs, S; Souroujon, M C

    1999-12-01

    Myasthenia gravis (MG) is an autoimmune disorder in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. In an attempt to develop an antigen-specific therapy for MG, we administered a nonmyasthenogenic recombinant fragment of AChR orally to rats. This fragment, corresponding to the extracellular domain of the human AChR alpha-subunit (Halpha1-205), protected rats from subsequently induced experimental autoimmune myasthenia gravis (EAMG) and suppressed ongoing EAMG when treatment was initiated during either the acute or chronic phases of disease. Prevention and suppression of EAMG were accompanied by a significant decrease in AChR-specific humoral and cellular responses. The underlying mechanism for the Halpha1-205-induced oral tolerance seems to be active suppression, mediated by a shift from a T-helper 1 (Th1) to a Th2/Th3 response. This shift was assessed by changes in the cytokine profile, a deviation of anti-AChR IgG isotypes from IgG2 to IgG1, and a suppressed AChR-specific delayed-type hypersensitivity response. Our results in experimental myasthenia suggest that oral administration of AChR-specific recombinant fragments may be considered for antigen-specific immunotherapy of myasthenia gravis.

  16. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment

    PubMed Central

    Im, Sin-Hyeog; Barchan, Dora; Fuchs, Sara; Souroujon, Miriam C.

    1999-01-01

    Myasthenia gravis (MG) is an autoimmune disorder in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. In an attempt to develop an antigen-specific therapy for MG, we administered a nonmyasthenogenic recombinant fragment of AChR orally to rats. This fragment, corresponding to the extracellular domain of the human AChR α-subunit (Hα1-205), protected rats from subsequently induced experimental autoimmune myasthenia gravis (EAMG) and suppressed ongoing EAMG when treatment was initiated during either the acute or chronic phases of disease. Prevention and suppression of EAMG were accompanied by a significant decrease in AChR-specific humoral and cellular responses. The underlying mechanism for the Hα1-205–induced oral tolerance seems to be active suppression, mediated by a shift from a T-helper 1 (Th1) to a Th2/Th3 response. This shift was assessed by changes in the cytokine profile, a deviation of anti-AChR IgG isotypes from IgG2 to IgG1, and a suppressed AChR-specific delayed-type hypersensitivity response. Our results in experimental myasthenia suggest that oral administration of AChR-specific recombinant fragments may be considered for antigen-specific immunotherapy of myasthenia gravis. J. Clin. Invest. 104:1723–1730 (1999). PMID:10606626

  17. PROTECTIVE EFFECT OF ScFv-DAF FUSION PROTEIN ON THE COMPLEMENT ATTACK TO ACETYLCHOLINE RECEPTOR: A POSSIBLE OPTION FOR TREATMENT OF MYASTHENIA GRAVIS

    PubMed Central

    XU, JIANG; WU, XINGAN; ZHANG, FANGLIN; LIN, HONG; LI, ZHUYI; KAMINSKI, HENRY J.

    2015-01-01

    Introduction Autoantibody-induced complement activation, which causes disruption of the postsynaptic membrane, is recognized as a key pathogenic factor in myasthenia gravis (MG). Therefore, specific targeting of complement inhibitors to the site of complement activation is a potential therapeutic strategy for treatment of MG. Methods We assessed expression of single-chain antibody fragment–decay accelerating factor (scFv-DAF), comprising a single-chain fragment scFv1956 based on the rat complement inhibitor DAF in prokaryotic systems, and studied its inhibitory effect on complement deposition in vitro. Results The recombinant conjugate scFv-DAF completely retained the wild-type binding activity of scFv1956 to AChR and inhibited complement activation of DAF in vitro. Conclusions We found that scFv-DAF could bind specifically to TE671 cells, and it is significantly more potent at inhibiting complement deposition than the untargeted parent molecule DAF. scFv-DAF may be a candidate for in vivo protection of the AChR in MG. PMID:22499093

  18. Surgical approaches for stage I and II thymoma-associated myasthenia gravis: feasibility of complete video-assisted thoracoscopic surgery (VATS) thymectomy in comparison with trans-sternal resection

    PubMed Central

    He, Zhicheng; Zhu, Quan; Wen, Wei; Chen, Liang; Xu, Hai; Li, Hai

    2013-01-01

    Complete resection could be achieved in virtually all myasthenic patients with Masaoka stage I and II thymoma using the trans-sternal technique. Whether this is appropriate for minimally invasive approach is not yet clear. We evaluated the feasibility of complete video-assisted thoracoscopic surgery (VATS) thymectomy for the treatment of Masaoka stage I and II thymoma-associated myasthenia gravis, compared to conventional trans-sternal thymectomy. We summarized 33 patients with Masaoka stage I and II thymoma-associated myasthenia gravis between April 2006 and September 2011. Of these, 15 patients underwent right-sided complete VATS (the VATS group) by using adjuvant pneuomomediastinum, comparing with 18 patients using the trans-sternal approach (the T3b group). No intraoperative death was found and no VATS case required conversion to median sternotomy. Significant differences between the two groups regarding duration of surgery and volume of intraoperative blood loss (P = 0.001 and P < 0.001, respectively) were observed. Postoperative morbidities were 26.7% and 33.3% for the VATS and T3b groups, respectively. All 33 patients were followed up for 12 to 61 months in the study. The cumulative probabilities of reaching complete stable remission and effective rate were 26.7% (4/15) and 93.3% (14/15) in the VATS group, which had a significantly higher complete stable remission and effective rate than those in the T3b group (P = 0.026 and P = 0.000, respectively). We conclude that VATS thymectomy utilizing adjuvant pneuomomediastinum for the treatment of stage I and II thymoma-associated myasthenia gravis is technically feasible but deserves further investigation in a large series with long-term follow-up. PMID:23554796

  19. Myf5 and Myogenin in the development of thymic myoid cells - Implications for a murine in vivo model of myasthenia gravis.

    PubMed

    Hu, Bo; Simon-Keller, Katja; Küffer, Stefan; Ströbel, Philipp; Braun, Thomas; Marx, Alexander; Porubsky, Stefan

    2016-03-01

    Myasthenia gravis (MG) is caused by autoantibodies against the neuromuscular junction of striated muscle. Most MG patients have autoreactive T- and B-cells directed to the acetylcholine receptor (AChR). To achieve immunologic tolerance, developing thymocytes are normally eliminated after recognition of self-antigen-derived peptides. Presentation of muscle-specific antigens is likely achieved through two pathways: on medullary thymic epithelial cells and on medullary dendritic cells cross-presenting peptides derived from a unique population of thymic myoid cells (TMC). Decades ago, it has been hypothesized that TMC play a key role in the induction of immunological tolerance towards skeletal muscle antigens. However, an experimental model to address this postulate has not been available. To generate such a model, we tested the hypothesis that the development of TMC depends on myogenic regulatory factors. To this end, we utilized Myf5-deficient mice, which lack the first wave of muscle cells but form normal skeletal muscles later during development, and Myogenin-deficient mice, which fail to form differentiated myofibers. We demonstrate for the first time that Myf5- and Myogenin-deficient mice showed a partial or complete, respectively, loss of TMC in an otherwise regularly structured thymus. To overcome early postnatal lethality of muscle-deficient, Myogenin-knockout mice we transplanted Myogenin-deficient fetal thymuses into Foxn1(nu/nu) mice that lack their own thymus anlage. We found that the transplants are functional but lack TMC. In combination with established immunization strategies (utilizing AChR or Titin), this model should enable us in the future testing the hypothesis that TMC play an indispensable role in the development of central tolerance towards striated muscle antigens.

  20. The association of systemic lupus erythematosus and myasthenia gravis: a series of 17 cases, with a special focus on hydroxychloroquine use and a review of the literature.

    PubMed

    Jallouli, M; Saadoun, D; Eymard, B; Leroux, G; Haroche, J; Le Thi Huong, D; De Gennes, C; Chapelon, C; Benveniste, O; Wechsler, B; Cacoub, P; Amoura, Z; Piette, J C; Costedoat-Chalumeau, N

    2012-07-01

    The coexistence of systemic lupus erythematosus (SLE) and myasthenia gravis (MG) is rarely reported, and most of the published studies are case reports. Hydroxychloroquine, an antimalarial agent, is an essential treatment in patients with SLE but special caution is recommended when used in MG patients. We retrospectively analyzed the clinical features, laboratory findings, and outcome of 17 patients with both diseases with a special focus regarding hydroxychloroquine use and with a review of the literature. All patients were women. The mean age at MG onset and SLE diagnosis was 34.5 [14-64] and 37.8 [18-72] years, respectively. The presenting symptoms of MG were limb weakness (94%), ocular (88%) and bulbar involvement (53%). Autoantibodies against the acetylcholine receptor were positive in 94% of cases. The main manifestations of SLE included arthritis (88%), cytopenias (53%) and skin rash (41%). Treatment of SLE required hydroxychloroquine (94%), steroids (47%) and immunosuppressive drugs (18%). Among eight patients (47%) who developed MG after initiation of hydroxychloroquine, the question of induction of MG by hydroxychloroquine was raised in one patient. On the other hand, an exacerbation of myasthenic symptoms was only seen in one of the eight patients who received hydroxychloroquine after the diagnosis of MG. Including our cases, we reviewed a total of 70 patients with SLE and MG. Compared with a large series of 1,000 unselected SLE patients, those with associated MG were older, had lower incidence of cutaneous, renal, and neurological manifestations, and higher frequency of anticardiolipin antibodies and lupus anticoagulant. In conclusion, the clinical pattern of patients with SLE and MG seems to be characterized by a less severe course of SLE and higher frequency of antiphospholipid antibodies. Hydroxychloroquine treatment appears to be safe in this setting.

  1. Late-onset myasthenia gravis - CTLA4(low) genotype association and low-for-age thymic output of naïve T cells.

    PubMed

    Chuang, Wen-Yu; Ströbel, Philipp; Bohlender-Willke, Anna-Lena; Rieckmann, Peter; Nix, Wilfred; Schalke, Berthold; Gold, Ralf; Opitz, Andreas; Klinker, Erdwine; Inoue, Masayoshi; Müller-Hermelink, Hans Konrad; Saruhan-Direskeneli, Güher; Bugert, Peter; Willcox, Nick; Marx, Alexander

    2014-08-01

    Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60.

  2. The Relationship of Symptoms of Anxiety and Depression with Disease Severity and Treatment Modality in Myasthenia Gravis: A Cross-sectional Study

    PubMed Central

    AYSAL, Fikret; KARAMUSTAFALIOĞLU, Oğuz; ÖZÇELİK, Başak; YILMAZ, Meltem; KARAMUSTAFALIOĞLU, Nesrin; YUMRUKÇAL, Hüseyin; TANKAYA, Onur

    2013-01-01

    Introduction Findings about the relationship between psychopathology and severity of myasthenia gravis (MG) seem scarce and conflicting. The aim of this study was to investigate the relationship of depressive and anxiety symptoms with disease severity and treatment modalities among a cohort of patients with MG. Methods Sixty-seven patients, who presented to the neuromuscular outpatient clinic, at a neuropsychiatry hospital in Istanbul, Turkey in a two-month period, were recruited consecutively. A total of 42 patients with MG were invited to participate in the study. None of the patients refused to participate. Severity of MG was assessed according to the Osserman and Genkins classification. The participants were evaluated by a sociodemographic form, the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Hamilton Depression Rating Scale 17-item version (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). Results The patients with stage IIB MG had significantly higher scores on the BAI, HAM-D, HAM-A total and somatic anxiety than those with stage I and IIA MG (p<0.05). Likewise, the patients taking a combination of prednisolone+pyridostigmine/azathioprine had significantly higher scores on the BAI, HAM-D, HAM-A total and somatic anxiety than those taking only prednisolone (p<0.05). Linear regression analysis revealed that disease severity and stressful life events were the factors associated with the HAM-D scores. Disease severity, treatment modalities, and gender were the factors associated with the HAM-A scores. Conclusion The results of the present study may suggest that patients with relatively more severe MG or those taking a combination of immunosupressive and anticholinesterase medications need psychiatric/psychological evaluation. PMID:28360560

  3. Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors

    PubMed Central

    Lee, Hyo Eun; Kim, Yool-hee; Kim, Seung Min

    2016-01-01

    Background and Purpose Acetylcholinesterase inhibitors (AChEIs) are widely used to treat myasthenia gravis (MG). Although AChEIs are usually tolerated well, some MG patients suffer from side effects. Furthermore, a small proportion of MG patients show cholinergic hypersensitivity and cannot tolerate AChEIs. Because repetitive compound muscle action potentials (R-CMAPs) are an electrophysiologic feature of cholinergic neuromuscular hyperactivity, we investigated the clinical characteristics of MG patients with R-CMAPs to identify their clinical usefulness in therapeutic decision-making. Methods We retrospectively reviewed the clinical records and electrodiagnostic findings of MG patients who underwent electrodiagnostic studies and diagnostic neostigmine testing (NT). Results Among 71 MG patients, 9 could not tolerate oral pyridostigmine bromide (PB) and 17 experienced side effects of PB. R-CMAPs developed in 24 patients after NT. The highest daily dose of PB was lower in the patients with R-CMAPs (240 mg/day vs. 480 mg/day, p<0.001). The frequencies of PB intolerance and side effects were higher in the patients with R-CMAPs than in those without R-CMAPs [37.5% vs. 0% (p<0.001) and 45.8% vs. 12.8% (p=0.002), respectively]. The MG Foundation of America postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response to immunotherapy was also good in both groups. Conclusions Side effects of and intolerance to AChEIs are more common in MG patients with R-CMAPs than in those without R-CMAPs. AChEIs should be used carefully in MG patients with R-CMAPs. The presence of R-CMAPs after NT may be a good indicator of the risks of PB side effects and intolerance. PMID:27819419

  4. Autoimmune diseases in a Nigerian woman--a case report.

    PubMed

    Talabi, O A; Owolabi, M O; Osotimehin, B O

    2003-12-01

    Autoimmune diseases (AD) are conditions in which there is the development of antibodies against self cells/ organs. AD could either be organ-specific or non-organ specific (systemic) in clinical presentation. Commonly reported ADs includes: Myasthenia gravis, Hashimoto thyroiditis, Guillian-Barre syndrome, vitiligo, type 1 diabetes mellitus, Graves diseases, Goodpastures syndrome, pemphigus, rheumatoid arthritis, systemic lupus erythematosis, Addisons disease, multiple sclerosis, pernicious anaemia, autoimmune haemolytic anaemia, chronic active hepatitis, idiopathic thrombocytopenic purpura. There is paucity of locally documented information on the occurrence of AD in same patient in our environment. We therefore report the case of a 66 year old woman who presented at the University College Hospital (UCH), Ibadan, with a spectrum of the AD, Vitiligo, rheumatoid arthritis, myasthenia gravis, impaired glucose tolerance.

  5. Myasthenia Gravis Foundation of America

    MedlinePlus

    ... Clinical Overview of MG Emergency Management Scientific Session International Symposium Medical/Scientific Advisory Board Nurses Advisory Board Educational Materials Research Current Research Agenda Latest news Clinical Trials Clinical results ...

  6. Myasthenia Gravis (MG): Medical Management

    MedlinePlus

    Skip to main content MDA For Strength Independence & Life Toggle navigation About Neuromuscular Diseases About neuromuscular diseases Full List of Diseases Amyotrophic Lateral Sclerosis (ALS) Charcot-Marie-Tooth Disease ( ...

  7. A case of autoimmune urticaria accompanying autoimmune polyglandular syndrome type III associated with Hashimoto's disease, type 1 diabetes mellitus, and vitiligo.

    PubMed

    Kasznicki, Jacek; Drzewoski, Józef

    2014-01-01

    We present a case of autoimmune polyglandular syndrome type III (APS III) associated with Hashimoto's disease, type 1 diabetes mellitus, vitiligo and autoimmune urticaria. This rare genetic disorder occurs with unknown frequency in the Polish population. It is characterised by endocrine tissue destruction resulting in the malfunction of multiple organs.Several cases of APS III associated with organ-specific autoimmune diseases such as coeliac disease, hypogonadism and myasthenia gravis, as well as organ-nonspecific or systemic autoimmune diseases such as sarcoidosis, Sjögren syndrome, and rheumatoid arthritis have been described. To the best of our knowledge, we here describe the first case of APS III associated with autoimmune thyroiditis, type 1 diabetes mellitus, vitiligo and autoimmune urticaria in an adult patient.

  8. Curcumin and autoimmune disease.

    PubMed

    Bright, John J

    2007-01-01

    The immune system has evolved to protect the host from microbial infection; nevertheless, a breakdown in the immune system often results in infection, cancer, and autoimmune diseases. Multiple sclerosis, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, myocarditis, thyroiditis, uveitis, systemic lupus erythromatosis, and myasthenia gravis are organ-specific autoimmune diseases that afflict more than 5% of the population worldwide. Although the etiology is not known and a cure is still wanting, the use of herbal and dietary supplements is on the rise in patients with autoimmune diseases, mainly because they are effective, inexpensive, and relatively safe. Curcumin is a polyphenolic compound isolated from the rhizome of the plant Curcuma longa that has traditionally been used for pain and wound-healing. Recent studies have shown that curcumin ameliorates multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease in human or animal models. Curcumin inhibits these autoimmune diseases by regulating inflammatory cytokines such as IL-1beta, IL-6, IL-12, TNF-alpha and IFN-gamma and associated JAK-STAT, AP-1, and NF-kappaB signaling pathways in immune cells. Although the beneficial effects of nutraceuticals are traditionally achieved through dietary consumption at low levels for long periods of time, the use of purified active compounds such as curcumin at higher doses for therapeutic purposes needs extreme caution. A precise understanding of effective dose, safe regiment, and mechanism of action is required for the use of curcumin in the treatment of human autoimmune diseases.

  9. Congenital Myasthenia

    MedlinePlus

    ... throat muscles are involved, children may have difficulty speaking or swallowing. An important characteristic of myasthenia is ... throat muscles are involved, children may have difficulty speaking or swallowing. An important characteristic of myasthenia is ...

  10. Ectopic Lymphoid Structures: Powerhouse of Autoimmunity

    PubMed Central

    Corsiero, Elisa; Nerviani, Alessandra; Bombardieri, Michele; Pitzalis, Costantino

    2016-01-01

    Ectopic lymphoid structures (ELS) often develop at sites of inflammation in target tissues of autoimmune diseases, such as rheumatoid arthritis, Sjögren’s syndrome, multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus. ELS are characterized by the formation of organized T/B cells aggregates, which can acquire follicular dendritic cells network supporting an ectopic germinal center response. In this review, we shall summarize the mechanisms that regulate the formation of ELS in tertiary lymphoid organs, with particular emphasis on the role of lymphoid chemokines in both formation and maintenance of ELS, the role of emerging positive and negative regulators of ELS development and function, including T follicular helper cells and IL-27, respectively. Finally, we shall discuss the main functions of ELS in supporting the affinity maturation, clonal selection, and differentiation of autoreactive B cells contributing to the maintenance and perpetuation of humoral autoimmunity. PMID:27799933

  11. Immunoadsorption in patients with autoimmune ion channel disorders of the peripheral nervous system.

    PubMed

    Antozzi, Carlo

    2013-01-01

    Autoimmune ion channel disorders of the peripheral nervous system include myasthenia gravis, the Lambert-Eaton myasthenic syndrome, acquired neuromyotonia and autoimmune autonomic ganglionopathies. These disorders are characterized by the common feature of being mediated by IgG autoantibodies against identified target antigens, i.e. the acetylcholine receptor, the voltage-gated calcium and potassium channels, and the neuronal acetylcholine receptor. Moreover, experimental animal models have been identified for these diseases that respond to immunotherapy and are improved by plasmapheresis. On this basis, autoimmune ion channel disorders represent the ideal candidate for therapeutic apheresis. Immunoadsorption can be the treatment of choice when intensive apheretic protocols or long-term treatments must be performed, in patients needing frequent apheresis to keep a stable clinical condition, in case of unresponsiveness to corticosteroids and immunosuppressive treatments, or failure with TPE or intravenous immunoglobulins, and in patients with severe contraindications to long-term corticosteroids.

  12. Autoimmune diseases and HIV infection

    PubMed Central

    Virot, Emilie; Duclos, Antoine; Adelaide, Leopold; Miailhes, Patrick; Hot, Arnaud; Ferry, Tristan; Seve, Pascal

    2017-01-01

    Abstract To describe the clinical manifestations, treatments, prognosis, and prevalence of autoimmune diseases (ADs) in human immunodeficiency virus (HIV)-infected patients. All HIV-infected patients managed in the Infectious Diseases Department of the Lyon University Hospitals, France, between January 2003 and December 2013 and presenting an AD were retrospectively included. Thirty-six ADs were found among 5186 HIV-infected patients which represents a prevalence of 0.69% including immune thrombocytopenic purpura (n = 15), inflammatory myositis (IM) (n = 4), sarcoidosis (n = 4), Guillain–Barré syndrome (GBS) (n = 4), myasthenia gravis (n = 2), Graves’ disease (n = 2), and 1 case of each following conditions: systemic lupus erythematosus, rheumatoid arthritis, autoimmune hepatitis, Hashimoto thyroiditis and autoimmune hemolytic anemia. One patient presented 2 ADs. Thirty patients were known to be HIV-infected when they developed an AD. The AD preceded HIV infection in 2 patients. GBS and HIV infection were diagnosed simultaneously in 3 cases. At AD diagnosis, CD4 T lymphocytes count were higher than 350/mm3 in 63% of patients, between 200 and 350/mm3 in 19% and less than 200/mm3 in 19%. Twenty patients benefited from immunosuppressant treatments, with a good tolerance. ADs during HIV infection are uncommon in this large French cohort. Immune thrombocytopenic purpura, sarcoidosis, IM, and GBS appear to be more frequent than in the general population. Immunosuppressant treatments seem to be effective and well tolerated. PMID:28121924

  13. Myasthenia Gravis: Tests and Diagnostic Methods

    MedlinePlus

    ... in several ways, including the following: Anti-MuSK Antibody testing----a blood test for the remaining 15% ... confirm a clinical diagnosis of MG. Acetylcholine Receptor Antibody — a blood test for the abnormal antibodies can ...

  14. Myasthenia Gravis: Drugs to be Avoided

    MedlinePlus

    ... for irregular heart rhythm. • Magnesium in patients with kidney disease; potentially dangerous if given intravenous, for example, for eclampsia treatment during late pregnancy. (Many multivitamins contain small amounts of magnesium, which ...

  15. Myasthenia Crisis Induced by Pegylated-Interferon in Patient With Chronic Hepatitis C

    PubMed Central

    Baik, Su Jung; Kim, Tae Hun; Kim, Hye In; Rhie, Jeong Yeon

    2016-01-01

    Abstract Myasthenia gravis is occasionally associated with thymoma that needs surgical resection and may progress to severe respiratory failure. We experienced a rare case of myasthenia crisis during antiviral therapy for chronic hepatitis C, in whom mediastinal thymoma was discovered and successfully managed with surgical thymectomy and meticulous medical care. A 47-year-old-male patient complained of sudden diplopia 1 week after stopping 11-week administration of pegylated-interferon and ribavirin for chronic hepatitis C. Ophthalmologic examinations revealed ptosis on the right eyelid and restricted right eye movement. Myasthenia gravis was confirmed by positive repetitive nerve stimulation test and positive serum antiacetylcholine receptor antibody test, and mediastinal thymoma was found on chest CT scan. The ocular myasthenia gravis progressed to respiratory failure even after discontinuing antiviral treatment but eventually recovered with thymectomy, anticholinesterase administration, steroid pulse therapy, and prolonged ventilator care. We describe the clinical features of this life-threatening complication of interferon treatment along with previous myasthenia crisis cases by interferon for chronic hepatitis C. In patients with chronic hepatitis C who is going to receive interferon-based antiviral treatment, physicians need to keep in mind the potential life-threatening manifestations of myasthenia gravis before and during antiviral treatment especially when patients complain of muscular weakness and easy fatigability. PMID:27227948

  16. PD-1/PD-L and autoimmunity: A growing relationship.

    PubMed

    Zamani, Mohammad Reza; Aslani, Saeed; Salmaninejad, Arash; Javan, Mohammad Reza; Rezaei, Nima

    2016-12-01

    Programmed death 1 (PD-1) and its ligands, namely PD-L1 and PD-L2, are one of the key factors responsible for inhibitory T cell signaling, mediating the mechanisms of tolerance and providing immune homeostasis. Mounting evidence demonstrates that impaired PD-1:PD-L function plays an important role in a variety of autoimmune diseases such as Type 1 diabetes (T1D), encephalomyelitis, inflammatory bowel diseases (IBD), Rheumatoid Arthritis (RA), autoimmune hepatitis (AIH), Behcet's disease (BD), myasthenia gravis (MG), autoimmune uveitis (AU), Sjögren's syndrome (SjS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), myocarditis, and ankylosing spondylitis (AS). By investigating the candidate genes, genome-wide association studies, and identification of single nucleotide polymorphisms (SNPs) in PD-1 gene in humans, it has been shown that there is a higher risk in relevant genetic associations with developing autoimmune diseases in certain ethnic groups. In this review we have tried to present a comprehensive role of PD-1:PD-L in all recently studied autoimmune diseases.

  17. Ice test in diagnosis of ocular myasthenia.

    PubMed

    Quddus, M A; Rahman, H Z; Ali, Z M; Khan, O S; Aftabuddin, M

    2013-10-01

    This observational, non-control, non equivalent pretest and post test descriptive study was carried out at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from June 2009 to December 2009 to compare the efficacy of ice test and repetitive nerve stimulation (RNS) in diagnosis of ocular myasthenia gravis. Ten patients with fluctuating ptosis (4 male and 6 female) who were suspected of having ocular myasthenia were included in the study. Male and female ratio in the study was 2:3. The mean age of the patients was 28.1 years. Positive response to pyridostigmine was taken as confirmation of ocular myasthenia. A piece of ice (2cm × 1cm) was placed over the upper eyelid for 2 minutes and the vertical eye lid fissure height was noted before and after the application of ice. Repetitive nerve stimulation was performed in the same subjects subsequently. Results of two tests were compared. Eight patients shows good (>2mm) elevation of eyelid with ice and three patients had abnormal RNS. In conclusion, ice test appears as more sensitive clinical test to detect ocular myasthenia than RNS test.

  18. Graft-versus-host disease-like erythroderma: a manifestation of thymoma-associated multiorgan autoimmunity

    PubMed Central

    Warren, Shay; Nehal, Kishwer; Querfeld, Christiane; Wong, Richard; Huang, James; Pulitzer, Melissa

    2016-01-01

    Thymoma associated multiorgan autoimmunity is a rare paraneoplastic disorder, clinicopathologically similar to graft versus host disease, which is thought to be mediated by dysfunctional negative thymocyte selection and abnormally low levels of Tregs. We report a 50 year old Chinese women with a history of malignant thymoma and myasthenia gravis who developed graft versus host disease- like erythroderma after instituting chemotherapy and undergoing myasthenia crisis. Clinically her rash presented as erythematous scaly papules, which evolved to psoriasiform patches and plaques with foci of vitiligo. Histopathologically the biopsy showed a predominantly interface dermatitis with necrotic keratinocytes extending to the upper levels of the epidermis, and florid basket weave orthokeratosis. Clinical and laboratory work-up ruled out common inflammatory or infectious causes, eventually favoring the diagnosis of TAMA with GVHD-like erythroderma. Unfortunately, the patient underwent multi-organ compromise and death due to respiratory failure from myasthenia crisis. Patients with TAMA have a poor clinical outlook; rare successful treatments include high dose oral steroids and additional modalities including bone marrow transplant and chemotherapeutic or biologic agents. As the predominant findings are in the skin, dermatologists and dermatopathologists are in a unique position to enable the early diagnosis and treatment of this unusual disease. PMID:26509934

  19. Ocular myasthenia: evaluation of Tensilon tonography and electronystagmography as diagnostic tests

    PubMed Central

    Campbell, M. J.; Simpson, E.; Crombie, A. L.; Walton, J. N.

    1970-01-01

    The value of electronystagmography (ENG) and of tonography in monitoring the beneficial effect of edrophonium chloride (Tensilon) on the extraocular muscles in myasthenia gravis has been assessed. Studies were performed on 17 patients with myasthenia gravis and on 18 control subjects, of whom nine had extraocular muscle weakness due to myopathic or neurogenic lesions. Electronystagmography recorded the repetitive following movements of the eyes elicited during optokinetic nystagmus. Neuromuscular fatigue with the subsequent beneficial response to Tensilon was clearly seen in 50% of patients with myasthenia. False positive responses were not seen in control subjects but in many of these, as in the remaining myasthenic patients, the amplitude and rate of nystagmus seen in the ENG was very variable. These difficulties suggest that the ENG is of limited value as a diagnostic test in myasthenia gravis. Tonography, recording the intraocular pressure of the eye continuously over four minutes, was found to be of considerable value. We found that the intraocular pressure fell on average by 1·6 to 1·8 mm Hg over a one minute period in the control recordings but increased by a mean of 1·6 mm Hg in patients with myasthenia, with a peak effect 35 seconds after Tensilon. In only one patient was there a complete failure of response. This patient, and also another woman who showed a less striking response, had severe myasthenia with a fixed ocular weakness. It is suggested that an absence of any increase in tension with Tensilon may be seen in patients with permanent neostigmine-resistant myopathic change. A small false positive response was seen on one occasion only in a patient with a sympathetic nerve lesion. Tensilon tonography, as a simple painless procedure, would appear to be of considerable value in the diagnosis of ocular myasthenia and also as a diagnostic test in the exclusion of myasthenia as a cause of isolated extraocular neuromuscular weakness. PMID:4249171

  20. Asymptomatic maternal myasthenia as a cause of the Pena-Shokeir phenotype.

    PubMed

    Brueton, L A; Huson, S M; Cox, P M; Shirley, I; Thompson, E M; Barnes, P R; Price, J; Newsom-Davis, J; Vincent, A

    2000-05-01

    We report six sibs with arthrogryposis multiplex congenita and a Pena-Shokeir phenotype, born to a healthy woman who was discovered to have asymptomatic myasthenia gravis (MG). This is the first report of anti-acetylcholine receptor (AChR) antibodies causing fetal akinesia/hypokinesia sequence in the offspring of an asymptomatic mother.

  1. Therapeutic gymnastics in comprehensive treatment of patients with generalized myasthenia

    NASA Technical Reports Server (NTRS)

    Kapelovich, R. L.

    1980-01-01

    The technique of therapeutic gymnastics was used for patients with mayasthenia gravis to control the consequences of hypodynamia induced by the myasthenic process. It is concluded that during myasthenia, the severity of the disease is due to the affection of the cross striated musculature. The most life threatening are the disorders in respiration and swallowing, that can be intensified by forced stay in bed and immobility. It is also concluded that the use of therapeutic gymnastics in patients which myasthenia promotes efficient presurgical preparation, and in the post surgical period; prevention of pulmonary complications and normalization of respiration. Therapeutic gymnastics with regard to the severity and localization of the myasthenic disorders must be a component part of the presurgical preparation and postsurgical management of patients with generalized myasthenia.

  2. Practical considerations on the use of rituximab in autoimmune neurological disorders

    PubMed Central

    Kosmidis, Mixalis L.; Dalakas, Marinos C.

    2010-01-01

    Rituximab (Mabthera, Rituxan) is a chimeric human/murine monoclonal antibody against CD-20 surface antigen expressed on B-cells. Rituximab, by causing B-cell depletion, appears to be effective in several autoimmune disorders; it has been approved for rheumatoid arthritis and is a promising new agent in the treatment of several autoimmune neurological disorders. A controlled study in patients with relapsing remitting multiple sclerosis has shown that rituximab significantly reduces the number of new MRI lesions and improves clinical outcome; it also showed some promise in a subset of patients with primary progressive MS. The drug is also effective in a number of patients with Devic’s disease, myasthenia gravis, autoimmune neuropathies, and inflammatory myopathies. The apparent effectiveness of rituximab has moved B-cells into the center stage of clinical and laboratory investigation of autoimmune neurological disorders. We review the evidence-based effectiveness of rituximab in neurological disorders based on controlled trials and anecdotal reports, including our own experience, and address the immunobiology of B-cells in autoimmune central nervous system (CNS) and peripheral nervous system (PNS) disorders. In addition, we provide practical guidelines on how best to use this drug in clinical practice and highlight its potential toxicity. PMID:21179602

  3. Autoimmune diseases and HIV infection: A cross-sectional study.

    PubMed

    Virot, Emilie; Duclos, Antoine; Adelaide, Leopold; Miailhes, Patrick; Hot, Arnaud; Ferry, Tristan; Seve, Pascal

    2017-01-01

    To describe the clinical manifestations, treatments, prognosis, and prevalence of autoimmune diseases (ADs) in human immunodeficiency virus (HIV)-infected patients.All HIV-infected patients managed in the Infectious Diseases Department of the Lyon University Hospitals, France, between January 2003 and December 2013 and presenting an AD were retrospectively included.Thirty-six ADs were found among 5186 HIV-infected patients which represents a prevalence of 0.69% including immune thrombocytopenic purpura (n = 15), inflammatory myositis (IM) (n = 4), sarcoidosis (n = 4), Guillain-Barré syndrome (GBS) (n = 4), myasthenia gravis (n = 2), Graves' disease (n = 2), and 1 case of each following conditions: systemic lupus erythematosus, rheumatoid arthritis, autoimmune hepatitis, Hashimoto thyroiditis and autoimmune hemolytic anemia. One patient presented 2 ADs. Thirty patients were known to be HIV-infected when they developed an AD. The AD preceded HIV infection in 2 patients. GBS and HIV infection were diagnosed simultaneously in 3 cases. At AD diagnosis, CD4 T lymphocytes count were higher than 350/mm in 63% of patients, between 200 and 350/mm in 19% and less than 200/mm in 19%. Twenty patients benefited from immunosuppressant treatments, with a good tolerance.ADs during HIV infection are uncommon in this large French cohort. Immune thrombocytopenic purpura, sarcoidosis, IM, and GBS appear to be more frequent than in the general population. Immunosuppressant treatments seem to be effective and well tolerated.

  4. Characterization of the in vitro expressed autoimmune rippling muscle disease immunogenic domain of human titin encoded by TTN exons 248-249

    SciTech Connect

    Zelinka, L.; McCann, S.; Budde, J.; Sethi, S.; Guidos, M.; Giles, R.; Walker, G.R.

    2011-08-05

    Highlights: {yields} Affinity purification of the autoimmune rippling muscle disease immunogenic domain of titin. {yields} Partial sequence analysis confirms that the peptides is in the I band region of titin. {yields} This region of the human titin shows high degree of homology to mouse titin N2-A. -- Abstract: Autoimmune rippling muscle disease (ARMD) is an autoimmune neuromuscular disease associated with myasthenia gravis (MG). Past studies in our laboratory recognized a very high molecular weight skeletal muscle protein antigen identified by ARMD patient antisera as the titin isoform. These past studies used antisera from ARMD and MG patients as probes to screen a human skeletal muscle cDNA library and several pBluescript clones revealed supporting expression of immunoreactive peptides. This study characterizes the products of subcloning the titin immunoreactive domain into pGEX-3X and the subsequent fusion protein. Sequence analysis of the fusion gene indicates the cloned titin domain (GenBank ID: (EU428784)) is in frame and is derived from a sequence of N2-A spanning the exons 248-250 an area that encodes the fibronectin III domain. PCR and EcoR1 restriction mapping studies have demonstrated that the inserted cDNA is of a size that is predicted by bioinformatics analysis of the subclone. Expression of the fusion protein result in the isolation of a polypeptide of 52 kDa consistent with the predicted inferred amino acid sequence. Immunoblot experiments of the fusion protein, using rippling muscle/myasthenia gravis antisera, demonstrate that only the titin domain is immunoreactive.

  5. Dermatomyositis and myastenia gravis: An uncommon association with therapeutic implications.

    PubMed

    Sangüesa Gómez, Clara; Flores Robles, Bryan Josué; Méndez Perles, Clara; Barbadillo, Carmen; Godoy, Hildegarda; Andréu, José Luis

    2015-01-01

    The association of dermatomyositis with myasthenia gravis (MG) is uncommon, having been reported so far in only 26 cases. We report the case of a 69 year-old man diagnosed with MG two years ago and currently treated with piridostigmyne. The patient developed acute proximal weakness, shoulder pain and elevated creatine-kinase (CK). He also developed generalized facial erythema and Gottron's papules. Laboratory tests showed positive antinuclear and anti-Mi2 antibodies. Further analysis confirmed CK levels above 1000 U/l. The clinical management of the patient and the therapeutic implications derived from the coexistence of both entities are discusssed.

  6. Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue.

    PubMed

    Zheng, J; Ibrahim, S; Petersen, F; Yu, X

    2012-12-01

    Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison's disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn's disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations.

  7. Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome & Congenital Myasthenic Syndromes

    MedlinePlus

    ... treatment plan, adjust to your diagnosis and take control in maintaining the quality of your life. This pamphlet will provide you with essential information about the symptoms of MG and the best treatments ... control breathing, MG usually doesn’t shorten life expectancy. ...

  8. Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases.

    PubMed

    Fernández-Mestre, Mercedes; Sánchez, Karen; Balbás, Omar; Gendzekhzadze, Ketevan; Ogando, Violeta; Cabrera, Mayra; Layrisse, Zulay

    2009-07-01

    Cell-mediated immunity requires costimulatory activity to initiate or inhibit antigen-specific T-cell responses. CTLA-4 is an inhibitory receptor expressed by activated and regulatory T cells. The single nucleotide polymorphism (SNP) +49 A/G of the CTLA-4 gene alters intracellular distribution of CTLA-4, interleukin-2 production, and, as a consequence, T-cell proliferation. The aim of this study was to analyze the only coding SNP CTLA-4 +49 A/G polymorphism in patients with either infectious (Chagas's, Dengue, and American cutaneous leishmaniasis) or autoimmune diseases (myasthenia gravis, pemphigus, and psoriasis). No statistically significant differences were reported when all patients of each disease group were compared with healthy individuals. However, the +49 G/G genotype was moderately increased in pemphigus and myasthenia gravis. Patients with diffuse cutaneous leishmaniasis (DCL) exhibited an increased frequency of the A/G +49 genotype compared with patients with localized cutaneous leishmaniasis (LCL; p = 0.009; odds ratio [OR] = 4.25; 95% confidence interval [CI] = 1.245-14.501) and intermediate cutaneous leishmaniasis (ICL; p = 0.027; OR = 4.44; 95% CI = 1.273-15.516), indicating that the heterozygous genotype, associated with overactivation of T-cell proliferation, could confer susceptibility to the development of the more severe clinical form of cutaneous leishmaniasis. The A/A +49 genotype was increased in LCL patients compared with DCL patients (p = 0.019; OR = 0.25; 95% CI = 0.067-0.953), indicating that this genotype, which has been associated with normal proliferation of T cells, could confer protection to the development of DCL. The results indicate that the polymorphism of CTLA-4 is an important genetic factor associated with risk or protection for the development of diffuse cutaneous leishmaniasis and has influence in the pathogenesis of autoimmune diseases. However, other closely linked candidate genes in linkage disequilibrium with CTLA4

  9. Toxicities of Immunosuppressive Treatment of Autoimmune Neurologic Diseases

    PubMed Central

    Lallana, Enrico C; Fadul, Camilo E

    2011-01-01

    In parallel to our better understanding of the role of the immune system in neurologic diseases, there has been an increased availability in therapeutic options for autoimmune neurologic diseases such as multiple sclerosis, myasthenia gravis, polyneuropathies, central nervous system vasculitides and neurosarcoidosis. In many cases, the purported benefits of this class of therapy are anecdotal and not the result of good controlled clinical trials. Nonetheless, their potential efficacy is better known than their adverse event profile. A rationale therapeutic decision by the clinician will depend on a comprehensive understanding of the ratio between efficacy and toxicity. In this review, we outline the most commonly used immune suppressive medications in neurologic disease: cytotoxic chemotherapy, nucleoside analogues, calcineurin inhibitors, monoclonal antibodies and miscellaneous immune suppressants. A discussion of their mechanisms of action and related toxicity is highlighted, with the goal that the reader will be able to recognize the most commonly associated toxicities and identify strategies to prevent and manage problems that are expected to arise with their use. PMID:22379461

  10. Immunoglobulin variable-region gene mutational lineage tree analysis: application to autoimmune diseases.

    PubMed

    Steiman-Shimony, Avital; Edelman, Hanna; Barak, Michal; Shahaf, Gitit; Dunn-Walters, Deborah; Stott, David I; Abraham, Roshini S; Mehr, Ramit

    2006-04-01

    Lineage trees have frequently been drawn to illustrate diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. In order to extract more information from IGV sequences, we developed a novel mathematical method for analyzing the graphical properties of IgV gene lineage trees, allowing quantification of the differences between the dynamics of SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we investigated trees generated from published IGV sequence data from B cell clones participating in autoimmune responses in patients with Myasthenia Gravis (MG), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). At present, as no standards exist for cell sampling and sequence extraction methods, data obtained by different research groups from two studies of the same disease often vary considerably. Nevertheless, based on comparisons of data groups within individual studies, we show here that lineage trees from different individual patients are often similar and can be grouped together, as can trees from two different tissues in the same patient, and even from IgG- and IgA-expressing B cell clones. Additionally, lineage trees from most studies reflect the chronic character of autoimmune diseases.

  11. Same-sex marriage, autoimmune thyroid gland dysfunction and other autoimmune diseases in Denmark 1989-2008.

    PubMed

    Frisch, Morten; Nielsen, Nete Munk; Pedersen, Bo Vestergaard

    2014-01-01

    Autoimmune diseases have been little studied in gay men and lesbians. We followed 4.4 million Danes, including 9,615 same-sex married (SSM) persons, for 47 autoimmune diseases in the National Patient Registry between 1989 and 2008. Poisson regression analyses provided first hospitalization rate ratios (RRs) comparing rates between SSM individuals and persons in other marital status categories. SSM individuals experienced no unusual overall risk of autoimmune diseases. However, the risk of autoimmune thyroid dysfunction was increased, notably Hashimoto's thyroiditis (women(SSM), RR = 2.92; 95% confidence interval (CI) 1.74-4.55) and Graves' disease (men(SSM), RR = 1.88; 95% CI 1.08-3.01). There was also an excess of primary biliary cirrhosis (women(SSM), RR = 4.09; 95% CI 1.01-10.7), and of psoriasis (men(SSM), RR = 2.48; 95% CI 1.77-3.36), rheumatic fever (men(SSM), RR = 7.55; 95% CI 1.87-19.8), myasthenia gravis (men(SSM), RR = 5.51; 95% CI 1.36-14.4), localized scleroderma (men(SSM), RR = 7.16; 95% CI 1.18-22.6) and pemphigoid (men(SSM), RR = 6.56; 95% CI 1.08-20.6), while Dupuytren's contracture was reduced (men(SSM), RR = 0.64; 95% CI 0.39-0.99). The excess of psoriasis was restricted to same-sex married men with HIV/AIDS (men(SSM), RR = 10.5; 95% CI 6.44-15.9), whereas Graves' disease occurred in excess only among same-sex married men without HIV/AIDS (men(SSM), RR = 1.99; 95% CI 1.12-3.22). Lesbians and immunologically competent gay men in same-sex marriage face no unusual overall risk of autoimmune diseases. However, the observed increased risk of thyroid dysfunction in these lesbians and gay men deserves further study.

  12. A Molecular Epidemiologic Case-Case Study of Prostate Cancer Susceptibility.

    DTIC Science & Technology

    1999-09-01

    and Krolick., K. A. Acetylcholine receptor-reactive antibodies in experimental Autoimmune myasthenia gravis differing in disease-causing potential...and Krolick, K. A. Preferential use of a T cell receptor VB gene by acetylcholine receptor-reactive T cells from myasthenia gravis susceptible mice. J...on the induction of experimental myasthenia gravis . Ann. New York Acad. Sci. 681:179-197, 1993. Thompson, P. A., McAtee, R., Infante, A. J., Currier

  13. Direct evidence for a β1-adrenergic receptor–directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy

    PubMed Central

    Jahns, Roland; Boivin, Valérie; Hein, Lutz; Triebel, Sven; Angermann, Christiane E.; Ertl, Georg; Lohse, Martin J.

    2004-01-01

    Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health. About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected. Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac β1-adrenergic receptor may play a causal role in DCM. First, we immunized inbred rats against the second extracellular β1-receptor loop (β1-ECII; 100% sequence identity between human and rat) every month. All these rats developed first, receptor-stimulating anti–β1-ECII Ab’s and then, after 9 months, progressive severe left ventricular dilatation and dysfunction. Second, we transferred sera from anti–β1-ECII–positive and Ab-negative animals every month to healthy rats of the same strain. Strikingly, all anti–β1-ECII–transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab’s. As a consequence, β1-adrenergic receptor–targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis. Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti–β1-ECII in receptor Ab–positive DCM patients. PMID:15146239

  14. Influence of alloferin on neuromuscular function in myasthenia patients undergoing thymectomy.

    PubMed

    Luo, X; Yie, T; Luo, A; Ren, H; Jin, Y

    1994-03-01

    Myasthenia gravis patients are hypersensitive to nondepolarizing relaxants, such as alcuronium, an intermediate-long nondepolarizing agent. This study observed the effects of alcuronium treatment in myasthenia gravis patients as compared with non-MG patients during operation. Ten MG patients (Ossermann class I-IV, scheduled for thymectomy) and 10 non-MG patients (ASA class I-II, scheduled for operation) were selected. An induction dose of alcuronium 0.2 mg/kg and thiopental 4-6 mg/kg was given, followed by intubation and ventilation with 50% nitrous oxide in oxygen and 0.5-1.5% ethrane. Neuromuscular transmission was monitored using an accelerograph and degrees of neuromuscular function at different depths were recorded. There were statistically significant differences between the two groups. The effect of alloferin in the MG group was quicker and deeper. This study also found a relation between MG class and the recovery of respiration: Respiratory recovery was quicker in classes I-II than in classes III-IV.

  15. Autoimmune Hepatitis

    MedlinePlus

    ... Cholangitis Wilson Disease Liver Disease A-Z Autoimmune Hepatitis What is autoimmune hepatitis? Autoimmune hepatitis is a chronic—or long lasting— ... bacteria, viruses, toxins, and medications. What causes autoimmune hepatitis? A combination of autoimmunity, environmental triggers, and a ...

  16. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis†

    PubMed Central

    Leite, Maria Isabel; Jacob, Saiju; Viegas, Stuart; Cossins, Judy; Clover, Linda; Morgan, B. Paul; Beeson, David; Willcox, Nick

    2008-01-01

    Only around 80% of patients with generalized myasthenia gravis (MG) have serum antibodies to acetylcholine receptor [AChR; acetylcholine receptor antibody positive myasthenia gravis (AChR-MG)] by the radioimmunoprecipitation assay used worldwide. Antibodies to muscle specific kinase [MuSK; MuSK antibody positive myasthenia gravis (MuSK-MG)] make up a variable proportion of the remaining 20%. The patients with neither AChR nor MuSK antibodies are often called seronegative (seronegative MG, SNMG). There is accumulating evidence that SNMG patients are similar to AChR-MG in clinical features and thymic pathology. We hypothesized that SNMG patients have low-affinity antibodies to AChR that cannot be detected in solution phase assays, but would be detected by binding to the AChRs on the cell membrane, particularly if they were clustered at the high density that is found at the neuromuscular junction. We expressed recombinant AChR subunits with the clustering protein, rapsyn, in human embryonic kidney cells and tested for binding of antibodies by immunofluorescence. To identify AChRs, we tagged either AChR or rapsyn with enhanced green fluorescence protein, and visualized human antibodies with Alexa Fluor-labelled secondary or tertiary antibodies, or by fluorescence-activated cell sorter (FACS). We correlated the results with the thymic pathology where available. We detected AChR antibodies to rapsyn-clustered AChR in 66% (25/38) of sera previously negative for binding to AChR in solution and confirmed the results with FACS. The antibodies were mainly IgG1 subclass and showed ability to activate complement. In addition, there was a correlation between serum binding to clustered AChR and complement deposition on myoid cells in patients’ thymus tissue. A similar approach was used to demonstrate that MuSK antibodies, although mainly IgG4, were partially IgG1 subclass and capable of activating complement when bound to MuSK on the cell surface. These observations throw new

  17. Computed tomography of the anterior mediastinum in myasthemia gravis: a radiologic-pathologic correlative study

    SciTech Connect

    Fon, G.T.; Bein, M.E.; Mancuso, A.A.; Keesey, J.C.; Lupetin, A.R.; Wong, W.S.

    1982-01-01

    Chest radiographs and computed tomographic (CT) scans of the mediastinum were correlated with pathologic findings of the thymus following thymectomy in 57 patients with myasthenia gravis. Based on the patient's age and the overall morphology of the anterior mediastinum, CT scans were assigned one of four grades in an attempt to predict thymus pathologic findings. Using this grading, 14 of 16 cases of thymoma were suspected or definitely diagnosed. One of the two cases not diagnosed on CT was a microscopic tumor. There were no false-positive diagnoses in 11 cases graded as definitely thymoma. We conclude that thymoma can be sensitively diagnosed in patients older than 40 years of age. However, thymoma cannot be predicted with a high level of confidence in patients younger than 40 because of the difficulty in differentiating normal thymus or hyperplasia from thymoma. Recommendations for the use of CT in the preoperative evaluation of myasthenic patients are presented.

  18. The Protective Role of HLA-DRB1(∗)13 in Autoimmune Diseases.

    PubMed

    Bettencourt, Andreia; Carvalho, Cláudia; Leal, Bárbara; Brás, Sandra; Lopes, Dina; Martins da Silva, Ana; Santos, Ernestina; Torres, Tiago; Almeida, Isabel; Farinha, Fátima; Barbosa, Paulo; Marinho, António; Selores, Manuela; Correia, João; Vasconcelos, Carlos; Costa, Paulo P; da Silva, Berta Martins

    2015-01-01

    Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1(∗)15 (OR = 2.17) and HLA-DRB1(∗)03 (OR = 1.81) alleles with MS, HLA-DRB1(∗)03 with SLE (OR = 2.49), HLA-DRB1(∗)01 (OR = 1.79) and HLA-DRB1(∗)04 (OR = 2.81) with RA, HLA-DRB1(∗)07 with Ps + PsA (OR = 1.79), HLA-DRB1(∗)01 (OR = 2.28) and HLA-DRB1(∗)08 (OR = 3.01) with SSc, and HLA-DRB1(∗)03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1(∗)13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1(∗)13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1(∗)13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1(∗)13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.

  19. Addison disease

    MedlinePlus

    ... amounts of some or all of its hormones ( hypopituitarism ) Autoimmune disorder that affects the nerves and the ... disease) Dermatitis herpetiformis Diabetes Graves disease Hyperthyroidism Hypoparathyroidism Hypopituitarism Immune response Myasthenia gravis Ovarian hypofunction Pernicious anemia ...

  20. A case of chronic inflammatory demyelinating polyneuropathy presented with unilateral ptosis.

    PubMed

    Izadi, Sadegh; Karamimagham, Sina; Poursadeghfard, Maryam

    2014-01-01

    Chronic Inflammatory Demyelinating Polyneuropathy is an autoimmune disease with progressive and relapsing courses. The main clinical presentations are diffuse deep tendon hyporeflexia or areflexia and symmetric proximal-distal muscles weakness. Myasthenia gravis is also an immune mediated disease with fluctuating ocular and bulbar symptoms and sometimes weakness. Although both myasthenia gravis and chronic inflammatory demyelinating polyneuropathy are immune mediated disorders, clinical presentations are obviously different in the two diseases. Herein, we will report a case of chronic inflammatory demyelinating polyneuropathy who presented with isolated unilateral ptosis. Initially, the patient was managed as ocular type of myasthenia gravis, but after progression to general limb weakness and areflexia, the diagnosis of chronic inflammatory demyelinating polyneuropathy was made. Although unilateral ptosis is a typical feature of myasthenia gravis, it may be seen as the first presentation of chronic inflammatory demyelinating polyneuropathy as well which mimics myasthenia gravis disease.

  1. In vivo Therapy with Monoclonal Anti-I-A Antibody Suppresses Immune Responses to Acetylcholine Receptor

    NASA Astrophysics Data System (ADS)

    Waldor, Matthew K.; Sriram, Subramaniam; McDevitt, Hugh O.; Steinman, Lawrence

    1983-05-01

    A monoclonal antibody to I-A gene products of the immune response gene complex attenuates both humoral and cellular responses to acetylcholine receptor and appears to suppress clinical manifestations of experimental autoimmune myasthenia gravis. This demonstrates that use of antibodies against immune response gene products that are associated with susceptibility to disease may be feasible for therapy in autoimmune conditions such as myasthenia gravis.

  2. 9 CFR 319.313 - Beef with gravy and gravy with beef.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    .... 319.313 Section 319.313 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF... INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Canned, Frozen, or Dehydrated Meat Food Products § 319.313 Beef with gravy and gravy with beef. “Beef with Gravy” and...

  3. 9 CFR 319.313 - Beef with gravy and gravy with beef.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    .... 319.313 Section 319.313 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF... INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Canned, Frozen, or Dehydrated Meat Food Products § 319.313 Beef with gravy and gravy with beef. “Beef with Gravy” and...

  4. 9 CFR 319.313 - Beef with gravy and gravy with beef.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    .... 319.313 Section 319.313 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF... INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Canned, Frozen, or Dehydrated Meat Food Products § 319.313 Beef with gravy and gravy with beef. “Beef with Gravy” and...

  5. 9 CFR 319.313 - Beef with gravy and gravy with beef.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Beef with gravy and gravy with beef. 319.313 Section 319.313 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND...

  6. 9 CFR 319.313 - Beef with gravy and gravy with beef.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... AGRICULTURE AGENCY ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Canned, Frozen, or Dehydrated Meat Food Products § 319.313 Beef with gravy and gravy with beef. “Beef with Gravy” and...

  7. Improved outcomes with surgery vs. medical therapy in non-thymomatous myesthenia gravis: a perspective on the results of a randomized trial

    PubMed Central

    Okusanya, Olugbenga T.; Hess, Nick; Christie, Neil; Luketich, James D.

    2016-01-01

    Myasthenia gravis can be a debilitating neurological disorder that affects thousands worldwide. Thymectomy has historically been considered in patients refractory to medical therapy or with concurrent thymoma. While retrospective data and propensity matched trials have favored thymectomy in order to decrease disease severity and disease associated morbidity, no randomized data existed to clearly delineate the benefit of this practice. The reviewed paper by Wolfe et al. represents the first high-level randomized prospective study investigating the role of thymectomy in patients with non-thymomatous myasthenia gravis. In a subset of antibody positive patients undergoing thymectomy within 5 years of disease onset, the study demonstrated a decrease in steroid use, hospitalization and overall disease severity compared to patients receiving best medical therapy alone. This work provides a sound evidence-based foundation to strongly consider thymectomy early in the disease process, and possibly for expanded indications. Additionally, the onus lies on surgeons to identify the most efficacious and least morbid approaches to these operations, whether they be open, minimally invasive, robotic, or otherwise. PMID:28149887

  8. [Validation of the ice pack test in ophthalmoparesis due to myasthenia gravis].

    PubMed

    Ramirez-Antunez, Ángel G; García-Ramos, Guillermo; Estañol-Vidal, Bruno; Juárez-Flores, Alejandra

    2013-11-01

    Introduccion. La miastenia grave es una enfermedad autoinmune de la union neuromuscular que se presenta clinicamente como debilidad fluctuante de los musculos estriados, como los de la region ocular (miastenia ocular). Objetivo. Demostrar que la sensibilidad y la especificidad de la prueba de hielo son altas en el diagnostico diferencial de la oftalmoparesia y ptosis palpebral por miastenia grave y miastenia ocular. Sujetos y metodos. Estudio observacional, analitico, no aleatorizado, de una muestra de 43 sujetos, 21 con miastenia grave y 22 controles. A todos los pacientes se les aplico un guante con hielo sobre sus parpados superiores afectados durante dos minutos, despues de los cuales se evaluo el grado de mejoria de la ptosis palpebral y la oftalmoparesia. Todos tenian estudio de estimulacion nerviosa repetitiva. Resultados. Se analizaron 36 pacientes, 18 con miastenia grave u ocular y 18 controles. Todos presentaron ptosis palpebral y solo 20 de ellos oftalmoparesia. La prueba de hielo para la oftalmoparesia mostro una sensibilidad del 83%, especificidad del 100%, valor predictivo positivo (VPP) del 100% y valor predictivo negativo (VPN) del 80% en el diagnostico de la miastenia grave. Para la ptosis palpebral, se determino una sensibilidad del 89%, especificidad del 100%, VPP del 100% y VPN del 90%. Para la estimulacion nerviosa repetitiva se calculo una sensibilidad del 61%, especificidad del 83%, VPP del 79% y VPN del 68%. Conclusion. La prueba de hielo es sencilla, segura, economica, rapida y fiable para utilizarse de rutina en pacientes con sospecha de ptosis u oftalmoparesia por miastenia grave, ya que tiene una alta validez, seguridad y reproducibilidad como prueba diagnostica.

  9. Anticholinesterase-Responsive Weakness in the Canine Similar to Myasthenia Gravis of Man.

    DTIC Science & Technology

    1976-01-01

    achalasia , organophosphate toxicity, and poly- neuritis. Edrop honium is the most widely employed facilitators ’ agent. 11 The main advantag e of e~ ro...The effects in the ease of Ib is relsort lasted approximatel y six hours. Achalasia in older dogs occurs due to degener— ‘the neostigmine lest is

  10. Identification and characterization of a new multigene family in the human MHC: A candidate autoimmune disease susceptibility element (3.8-1)

    SciTech Connect

    Harris, J.M.; Venditti, C.P.; Chorney, M.J.

    1994-09-01

    An association between idiopathic hemochromatosis (HFE) and the HLA-A3 locus has been previously well-established. In an attempt to identify potential HFE candidate genes, a genomic DNA fragment distal to the HLA-A9 breakpoint was used to screen a B cell cDNA library; a member (3.8-1) of a new multigene family, composed of five distinct genomic cross-reactive fragments, was identified. Clone 3.8-1 represents the 3{prime} end of 9.6 kb transcript which is expressed in multiple tissues including the spleen, thymus, lung and kidney. Sequencing and genome database analysis indicate that 3.8-1 is unique, with no homology to any known entries. The genomic residence of 3-8.1, defined by polymorphism analysis and physical mapping using YAC clones, appears to be absent from the genomes of higher primates, although four other cross-reactivities are maintained. The absence of this gene as well as other probes which map in the TNF to HLA-B interval, suggest that this portion of the human HMC, located between the Class I and Class III regions, arose in humans as the result of a post-speciation insertional event. The large size of the 3.8-1 gene and the possible categorization of 3.8-1 as a human-specific gene are significant given the genetic data that place an autoimmune susceptibility element for IDDM and myasthenia gravis in the precise region where this gene resides. In an attempt to isolate the 5{prime} end of this large transcript, we have constructed a cosmid contig which encompasses the genomic locus of this gene and are progressively isolating coding sequences by exon trapping.

  11. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota.

    PubMed Central

    Bartley, G B

    1994-01-01

    accompanied GO in approximately 4% and 1% of patients, respectively. Myasthenia gravis occurred in less than 1% of patients. Superior limbic keratoconjunctivitis was documented in less than 4% of patients. The median age at the time of diagnosis of GO was 43 years (range, 8 to 88). Among patients with hyperthyroidism, 61% developed ophthalmopathy within 1 year of the onset of thyrotoxicosis. Symptoms and signs for which statistically significant changes occurred between the initial and final examinations included lacrimation, pain or ocular discomfort, photophobia, eyelid retraction, lid lag, eyelid fullness, conjunctival injection, chemosis, and exophthalmos.(ABSTRACT TRUNCATED AT 400 WORDS) Images FIGURE 1 FIGURE 2 FIGURE 3 PMID:7886878

  12. [Autoimmune hepatitis and autoimmune cholangitis].

    PubMed

    Dienes, H P

    2005-01-01

    Autoimmune liver diseases encompass autoimmune hepatitis, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) as lesions of the biliary tract. The term autoimmune cholangitis has not been generally accepted, so it remains an entitiy waiting for precise definition. AIH is a chronic progressive necroinflammatory liver disease mostly occuring in female individuals and leading to ultimate autodestruction of the liver if not treated. Histopathology of the liver reflects the gerneral understanding of the underlying immune especially self reactive CD4 + T-helper cells mediated mechanisms in destruction of liver cells displaying a typical but by no means pathognomonic histopathological pattern. Since there are no specific and generally valid tests the diagnosis should be confirmed by a scoring system including histopathology. Variants of autoimmune hepatitis cover seronegative cases, acute onset autoimmune hepatitis and autoimmune hepatitis with centrilobular necrosis. Differential diagnosis of autoimmune hepatitis includes drug induced chronic hepatitis that may mimick autoimmune hepatitis by clinical course and serology. Histopathology may give helpful hints for the correct diagnosis. Autoimmune lesions of the biliary tract are PBC in the first line. The target antigen of the autoimmune response has been identified, natural history of the diseases is well known and histopathology is pathognomonic in about a third of the cases. In clinical practice liver biopsy is taken to exclude other etiologies when AMA is present in the serum, staging the disease at first diagnosis and to establish diagnosis in cases of AMA negativity. The autoimmune nature of PSC has been discussed in the literature ever since the first description and the answer in not settled yet. Histopathology is relevant for the diagnosis in excluding other etiologies and confirming the diagnosis of small duct PSC. The term autoimmune cholangitis has been used to designate AMA-negative PBC

  13. Autoimmune Diseases

    MedlinePlus

    ... Women - particularly African-American, Hispanic-American, and Native-American women - have a higher risk for some autoimmune diseases. There are more than 80 types of autoimmune diseases, and some have similar symptoms. This makes it hard for your health care provider to know if ...

  14. Management of disease-modifying treatments in neurological autoimmune diseases of the central nervous system

    PubMed Central

    Salmen, A; Gold, R; Chan, A

    2014-01-01

    sclerosis. Clinical and Experimental Immunology 2014, 175: 373–84. CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders. Clinical and Experimental Immunology 2014, 175: 385–96. Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clinical and Experimental Immunology 2014, 175: 397–407. Myasthenia gravis: an update for the clinician. Clinical and Experimental Immunology 2014, 175: 408–18. Cerebral vasculitis in adults: what are the steps in order to establish the diagnosis? Red flags and pitfalls. Clinical and Experimental Immunology 2014, 175: 419–24. Multiple sclerosis treatment and infectious issues: update 2013. Clinical and Experimental Immunology 2014, 175: 425–38. Diagnosis, pathogenesis and treatment of myositis: recent advances 2014, 175: 349–58. Neuromyelitis optica: clinical features, immunopathogenesis and treatment 2014, 176: 149–64. PMID:24358961

  15. Autoimmune disorders

    MedlinePlus

    ... that may be done to diagnose an autoimmune disorder include: Antinuclear antibody tests Autoantibody tests CBC Comprehensive metabolic panel C-reactive protein (CRP) Erythrocyte sedimentation rate (ESR) Urinalysis

  16. Autoimmune hepatitis

    MedlinePlus

    Lupoid hepatitis; Chronic acute liver disease ... This form of hepatitis is an autoimmune disease . The body's immune system cannot tell the difference between healthy body tissue and harmful, outside ...

  17. Autoimmune hepatitis.

    PubMed

    Heneghan, Michael A; Yeoman, Andrew D; Verma, Sumita; Smith, Alastair D; Longhi, Maria Serena

    2013-10-26

    Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.

  18. Autoimmune Diseases

    MedlinePlus

    ... of CAM are herbal products, chiropractic , acupuncture , and hypnosis . If you have an autoimmune disease, you might ... help you to feel your best. Meditation, self-hypnosis, and guided imagery, are simple relaxation techniques that ...

  19. Autoimmune encephalopathies

    PubMed Central

    Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep

    2014-01-01

    Over the last 10 years the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders, grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases. PMID:25315420

  20. The autoimmune diseases

    SciTech Connect

    Rose, N.R.; Mackay, I.R.

    1985-01-01

    This book contains 25 chapters. Some of the chapter titles are: Genetic Predisposition to Autoimmune Diseases; Systemic Lupus Erythematosus; Autoimmune Aspects of Rheumatoid Arthritis; Immunology of Insulin-Dependent Diabetes; and Adrenal Autoimmunity and Autoimmune Polyglandular Syndromes.

  1. Gravi- and photostimuli in moss protonema growth movements

    NASA Astrophysics Data System (ADS)

    Demkiv, O. T.; Kordyum, E. L.; Khorkavtsiv, Ya D.; Kardash, O. R.; Chaban, Ch. I.

    Moss protonemal growth direction is controlled by at least three factors, photo-, gravi- and autotropism. It is possible to experimentally separate these factors and to control selectively their morphological appearance. In darkness protonema grow negatively gravitropically, and unilateral illumination initiated positive phototropism. Red light suppressed auto- and gravitropism, blue light suppressed only gravitropism. Green light allowed both gravi- and autotropism. The effect of light on gravitropism might involve changes in starch synthesis.

  2. Sedenion unified theory of gravi-electromagnetism

    NASA Astrophysics Data System (ADS)

    Chanyal, B. C.

    2014-11-01

    In this paper, we represent 16-component sedenions, the generalization of octonions, which is noncommutative space-time algebra. The sedenions is neither a composition algebra nor a division algebra because it has zero divisors. Here we have formulated the sedenionic unified potential equations, unified fields equations and unified current equations of dyons and gravito-dyons. We have developed the sedenionic unified theory of dyons and gravito-dyons in terms of two eight-potentials leading to the structural symmetry between generalized electromagnetic fields of dyons and generalized gravito-Heavisidian fields of gravito-dyons. Thus we have obtained the sedenionic form of generalized Dirac-Maxwell's equations, unified work-energy theorem (Poynting theorem), generalized unified gravi-electromagnetic force and other quantum equations of dyons and gravito-dyons in simple, compact and consistent way incorporating the non-associativity and non-commutativity of sedenion variables.

  3. Autoimmune liver disease panel

    MedlinePlus

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cirrhosis. This group of tests helps your health care provider ...

  4. Autoimmune pancreatitis

    PubMed Central

    2016-01-01

    Autoimmune pancreatitis (AIP) is a rare, distinct and increasingly recognized form of pancreatitis which has autoimmune features. The international consensus diagnostic criteria (ICDC) for AIP recently described two subtypes; type 1[lymphoplasmacytic sclerosing pancreatitis (LPSP)] and type 2 [idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesion (GEL)]. Type 1 is the more common form of the disease worldwide and current understanding suggests that it is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). In contrast, type 2 AIP is a pancreas-specific disease not associated with IgG4 and mostly without the overt extra-pancreatic organ involvement seen in type 1. The pathogenesis of AIP is not completely understood and its clinical presentation is non-specific. It shares overlapping features with more sinister pathologies such as cancer of the pancreas, which continues to pose a diagnostic challenge for clinicians. The diagnostic criteria requires a variable combination of histopathological, imaging and serological features in the presence of typical extrapancreatic lesions and a predictable response to steroids. PMID:27294040

  5. [Multidisciplinary treatment for a patient with recurrent thymoma associated with myasthenia gravis (MG), pure red cell aplasia (PRCA), and hypogammaglobulinemia].

    PubMed

    Kawamura, M; Sawafuji, M; Hangai, N; Yamamoto, T; Kakizaki, T; Kobayashi, T; Kato, R; Kikuchi, K; Kobayashi, K

    1993-12-01

    The patient is 62-year-old female. When she was 43 years old, MG occurred. At age of 49 years thymoma was found and complete thymectomy (stage III) and postsurgical irradiation were performed. At age of 57 years pleural dissemination of the thymoma was found. Chemotherapy was effective but did not obtain total tumor cell kill. Though chemotherapy has been repeated for each tumor regrowth, the regimen used at first recurrence became ineffective and the interval between tumor regrowth became shorter. This year, when she is 62 years old, PRCA and hypogammaglobulinemia were accompanied with the forth tumor regrowth.

  6. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    PubMed Central

    Faria, Ana M. C.; Weiner, Howard L.

    2006-01-01

    Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-β) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy. PMID:17162357

  7. Neurophysiological Strategies for the Diagnosis of Disorders of the Neuromuscular Junction in Children

    ERIC Educational Resources Information Center

    Pitt, Matthew

    2008-01-01

    The disorders of the neuromuscular junction seen in children, the congenital myasthenic syndromes and autoimmune myasthenia gravis, are very rare. Their clinical symptoms and signs may be variable, most notably in the neonate and infant. They should enter the differential diagnosis of many different clinical presentations, such as "floppy infant"…

  8. Toxicology of Autoimmune Diseases

    PubMed Central

    Hultman, Per; Kono, Dwight H.

    2010-01-01

    Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely drugs and chemicals, can promote the development of autoimmunity, focusing on a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity some similarities do exist and a working model is proposed. PMID:20078109

  9. Perspectives on autoimmunity

    SciTech Connect

    Cohen, I.R.

    1987-01-01

    The contents of this book are: HLA and Autoimmunity; Self-Recognition and Symmetry in the Immune System; Immunology of Insulin Dependent Diabetes Mellitus; Multiple Sclerosis; Autoimmunity and Immune Pathological Aspects of Virus Disease; Analyses of the Idiotypes and Ligand Binding Characteristics of Human Monoclonal Autoantibodies to DNA: Do We Understand Better Systemic Lupus Erythematosus. Autoimmunity and Rheumatic Fever; Autoimmune Arthritis Induced by Immunization to Mycobacterial Antigens; and The Interaction Between Genetic Factors and Micro-Organisms in Ankylosing Spondylitis: Facts and Fiction.

  10. Autoimmune Hemolytic Anemia.

    PubMed

    Liebman, Howard A; Weitz, Ilene C

    2017-03-01

    Autoimmune hemolytic anemia is an acquired autoimmune disorder resulting in the production of antibodies directed against red blood cell antigens causing shortened erythrocyte survival. The disorders can present as a primary disorder (idiopathic) or secondary to other autoimmune disorders, malignancies, or infections. Treatment involves immune modulation with corticosteroids and other agents.

  11. Sexual dimorphism in autoimmunity

    PubMed Central

    Rubtsova, Kira; Marrack, Philippa; Rubtsov, Anatoly V.

    2015-01-01

    Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Autoimmunity is the third most common type of disease in the United States. Because there is no cure for autoimmunity, it is extremely important to study the mechanisms that trigger these diseases. Most autoimmune diseases predominantly affect females, indicating a strong sex bias. Various factors, including sex hormones, the presence or absence of a second X chromosome, and sex-specific gut microbiota can influence gene expression in a sex-specific way. These changes in gene expression may, in turn, lead to susceptibility or protection from autoimmunity, creating a sex bias for autoimmune diseases. In this Review we discuss recent findings in the field of sex-dependent regulation of gene expression and autoimmunity. PMID:25915581

  12. Sirolimus for Autoimmune Disease of Blood Cells

    ClinicalTrials.gov

    2017-03-16

    Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis

  13. Galectin-3 in autoimmunity and autoimmune diseases

    PubMed Central

    de Oliveira, Felipe L; Gatto, Mariele; Bassi, Nicola; Luisetto, Roberto; Ghirardello, Anna; Punzi, Leonardo

    2015-01-01

    Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell–cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte–macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases. PMID:26142116

  14. Galectin-3 in autoimmunity and autoimmune diseases.

    PubMed

    de Oliveira, Felipe L; Gatto, Mariele; Bassi, Nicola; Luisetto, Roberto; Ghirardello, Anna; Punzi, Leonardo; Doria, Andrea

    2015-08-01

    Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell-cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte-macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases.

  15. Environmental Basis of Autoimmunity.

    PubMed

    Floreani, Annarosa; Leung, Patrick S C; Gershwin, M Eric

    2016-06-01

    The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive.

  16. Metals and kidney autoimmunity.

    PubMed Central

    Bigazzi, P E

    1999-01-01

    The causes of autoimmune responses leading to human kidney pathology remain unknown. However, environmental agents such as microorganisms and/or xenobiotics are good candidates for that role. Metals, either present in the environment or administered for therapeutic reasons, are prototypical xenobiotics that cause decreases or enhancements of immune responses. In particular, exposure to gold and mercury may result in autoimmune responses to various self-antigens as well as autoimmune disease of the kidney and other tissues. Gold compounds, currently used in the treatment of patients with progressive polyarticular rheumatoid arthritis, can cause a nephrotic syndrome. Similarly, an immune-mediated membranous nephropathy frequently occurred when drugs containing mercury were commonly used. Recent epidemiologic studies have shown that occupational exposure to mercury does not usually result in autoimmunity. However, mercury induces antinuclear antibodies, sclerodermalike disease, lichen planus, or membranous nephropathy in some individuals. Laboratory investigations have confirmed that the administration of gold or mercury to experimental animals leads to autoimmune disease quite similar to that observed in human subjects exposed to these metals. In addition, studies of inbred mice and rats have revealed that a few strains are susceptible to the autoimmune effects of gold and mercury, whereas the majority of inbred strains are resistant. These findings have emphasized the importance of genetic (immunogenetic and pharmacogenetic) factors in the induction of metal-associated autoimmunity. (italic)In vitro(/italic) and (italic)in vivo(/italic) research of autoimmune disease caused by mercury and gold has already yielded valuable information and answered a number of important questions. At the same time it has raised new issues about possible immunostimulatory or immunosuppressive mechanisms of xenobiotic activity. Thus it is evident that investigations of metal

  17. [Syndrome overlap: autoimmune hepatitis and autoimmune cholangitis].

    PubMed

    Guerra Montero, Luis; Ortega Alvarez, Félix; Marquez Teves, Maguin; Asato Higa, Carmen; Sumire Umeres, Julia

    2016-01-01

    Autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangitis are chronic autoimmune liver disease, usually present separate, the cases where characteristics of two of the above is observed liver disease is commonly referred to as Overlap Syndromes (OS). Although there is no consensus on specific criteria for the diagnosis of OS identification of this association is important for initiating appropriate treatment and prevent its progression to cirrhosis or at least the complications of cirrhosis and death. We report the case of awoman aged 22 cirrhotic which debuted are edematous ascites, severe asthenia and jaundice compliant diagnostics SS criteria and initially present any response to treatment with ursodeoxycholic acid and oral corticosteroids, but ultimately finished performing a transplant orthotopic liver.

  18. The Autoimmune Ecology

    PubMed Central

    Anaya, Juan-Manuel; Ramirez-Santana, Carolina; Alzate, Maria A.; Molano-Gonzalez, Nicolas; Rojas-Villarraga, Adriana

    2016-01-01

    Autoimmune diseases (ADs) represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology), which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation). As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology). In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures – internal and external – across the lifespan, interacting with hereditary factors (both genetics and epigenetics) to favor or protect against autoimmunity and its outcomes. Herein, we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status (SES), gender and sex hormones, vitamin D, organic solvents, and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied. PMID:27199979

  19. Infection and autoimmunity.

    PubMed

    Cooke, Anne

    2009-01-01

    The development of some autoimmune diseases is increasing in the developed world faster than can be accounted for by genetic change. The development of these autoimmune diseases, such as Type 1 diabetes, is known to be influenced by both genetic and environmental factors. Environmental factors which have been considered to play a role include infectious agents such as viruses or bacteria. The search for a common initiating infection in the aetiology of Type 1 diabetes as proved thus far inconclusive. An alternative way of considering a role for infection is that infection may have historically prevented the development of autoimmune disease. In the developing world changes have occurred such that many chronic infections have been eliminated and this may have led to the emergence of autoimmune pathology. Evidence in support of this hypothesis is considered here and factors governing the development of autoimmunity compared with those which might have influenced the development of childhood leukaemia.

  20. Autoimmune hypophysitis: new developments.

    PubMed

    Takahashi, Yutaka

    2014-01-01

    Autoimmune hypophysitis, often referred to as lymphocytic hypophysitis, is defined as an inflammatory condition of the pituitary gland of autoimmune etiology that leads to pituitary dysfunction. However, the pathogenesis of autoimmune hypophysitis is still incompletely defined. Although pathogenic autoantibodies in autoimmune hypophysitis have not yet been reported, it has been suggested that several antibodies may be closely related to pathogenesis. Novel clinical entities that are associated with hypophysitis, such as IgG4-related hypophysitis and anti-PIT-1 antibody syndrome, have recently been reported. The findings demonstrate the heterogeneity of the disease and provide important clues for understanding the pathogenesis and definition of hypophysitis, as well as the significance of antipituitary antibodies. This review focuses on new developments in autoimmune hypophysitis.

  1. Drugs in autoimmune diseases.

    PubMed

    Herrmann, D B; Bicker, U

    1990-01-01

    Autoimmune diseases arise when autoimmunity or the loss of self tolerance results in tissue damages. Many mechanisms have been proposed for the origin of autoimmunity, including immunologic, viral, hormonal and genetic factors. All known parts of the immunological network are involved in causing immunopathologic symptoms. Therefore, more or less specific immunosuppressants are widely used in the treatment of autoimmune disorders which range from organ-specific, i.e. Hashimoto's thyroiditis, to non-organ-specific or systemic diseases, i.e. systemic lupus erythematosus. Unspecifically acting cytostatics do not only suppress autoimmune reactions but also create severe side-effects due to the impairment of immune responses against foreign antigens, leading, for example, to an increased risk of infections. Moreover, the genotoxic activity of cytostatics might induce malignancies. Corticosteroids are clinically well known and very active agents for the management of acute symptoms but different side-effects limit their use in the treatment of chronic diseases. Cyclosporin A has been an important step forward to a more specific prevention of organ transplant rejections and to the therapy of some autoimmune disorders. Modern approaches to immunosuppression include monoclonal antibodies directed against a variety of different determinants on immunocompetent cells. Ciamexone and Leflunomide which are in early clinical and preclinical development, respectively, might be interesting new drugs. Future immunopharmacologic drug research and development should lead to more specific, low molecular weight, orally active and chemically defined immunosuppressive compounds with good tolerability under long-term treatment of autoimmune diseases.

  2. Psoriasis and autoimmunity.

    PubMed

    Sticherling, Michael

    2016-12-01

    Psoriasis is one of the most common chronic inflammatory human skin diseases. Though clinically well characterized, the exact etiological and pathogenic mechanisms are still not known in detail. Current knowledge indicates distinct overlap to other inflammatory as well as autoimmune disorders. However, the one or more relevant autoantigens could not be characterized so-far. On the other side, several autoimmune diseases were shown to be associated with psoriasis. In addition, serological autoimmune phenomena, namely diverse circulating specific autoantibodies could be demonstrated in the past. A matter of current debate is if psoriasis is a primary autoimmune disease or secondarily evolving into autoimmunity as seen in other chronic inflammatory diseases. Related to this aspect is the concept of autoinflammation versus autoimmunity where psoriasis shares mechanisms of both entities. Though T-cells remain among the most important cellular players in the pathogenesis of psoriasis and current therapeutic strategies successfully target these cells or their products irrespective of these concepts, autoimmunity if relevant will add to the treatment armamentarium by using protective and prophylactic antigen-specific modalities.

  3. Pain in autoimmune disorders.

    PubMed

    Mifflin, Katherine A; Kerr, Bradley J

    2016-07-22

    Most autoimmune diseases are associated with pathological pain development. Autoimmune diseases with pathological pain include complex regional pain syndrome, rheumatoid arthritis, and Guillian-Barré syndrome to name a few. The present Review explores research linking the immune system to the development of pathological pain in autoimmune diseases. Pathological pain has been linked to T-cell activation and the release of cytokines from activated microglia in the dorsal horn of the spinal cord. New research on the role of autoantibodies in autoimmunity has generated insights into potential mechanisms of pain associated with autoimmune disease. Autoantibodies may act through various mechanisms in autoimmune disorders. These include the alteration of neuronal excitability via specific antigens such as the voltage-gated potassium channel complexes or by mediating bone destruction in rheumatoid arthritis. Although more research must be done to understand better the role of autoantibodies in autoimmune disease related pain, this may be a promising area of research for new analgesic therapeutic targets. © 2016 Wiley Periodicals, Inc.

  4. Immunometabolism and autoimmunity.

    PubMed

    Freitag, Jenny; Berod, Luciana; Kamradt, Thomas; Sparwasser, Tim

    2016-11-01

    A continuous increase in the prevalence of autoimmune diseases is to be expected in the aging societies worldwide. Autoimmune disorders not only cause severe disability and chronic pain, but also lead to considerable socio-economic costs. Given that the current treatment options are not curative, have substantial side effects and a high percentage of non-responders, innovative options to the existing therapeutic armament against autoimmune diseases are urgently required. Accumulating evidence suggests that changes in the metabolism of immune cells are associated with, and contribute to the pathogenesis of autoimmunity. Additionally, some autoimmune diseases share alterations in metabolic pathways, key metabolites or metabolic byproducts such as reactive oxygen species. Other examples for metabolic changes in autoimmune settings include modifications in amino acid and cholesterol levels or glucose catabolism. Thus, the emerging field of immunometabolism may hold the potential to discover new therapeutic targets. Here, we discuss recent findings describing metabolic changes in autoimmune arthritis, multiple sclerosis as well as type 1 diabetes, focusing on pathophysiological aspects.

  5. Autoimmunity in Immunodeficiency

    PubMed Central

    Todoric, Krista; Koontz, Jessica B.; Mattox, Daniel; Tarrant, Teresa K.

    2013-01-01

    Primary immunodeficiencies (PID) comprise a diverse group of clinical disorders with varied genetic defects. Paradoxically, a substantial proportion of PID patients develop autoimmune phenomena in addition to having increased susceptibility to infections from their impaired immunity. Although much of our understanding comes from data gathered through experimental models, there are several well-characterized PID that have improved our knowledge of the pathways that drive autoimmunity. The goals of this review will be to discuss these immunodeficiencies and to review the literature with respect to the proposed mechanisms for autoimmunity within each put forth to date. PMID:23591608

  6. Autoimmunity in picornavirus infections

    PubMed Central

    Massilamany, Chandirasegaran; Koenig, Andreas; Reddy, Jay; Huber, Sally

    2015-01-01

    Enteroviruses are small, non-enveloped, positive-sense single-strand RNA viruses, and are ubiquitously found throughout the world. These viruses usually cause asymptomatic or mild febrile illnesses, but have a propensity to induce severe diseases including type 1 diabetes and pancreatitis, paralysis and neuroinflammatory disease, myocarditis, or hepatitis. This pathogenicity may result from induction of autoimmunity to organ-specific antigens. While enterovirus-triggered autoimmunity can arise from multiple mechanisms including antigenic mimicry and release of sequestered antigens, the recent demonstration of T cells expressing dual T cell receptors arising as a natural consequence of Theiler's virus infection is the first demonstration of this autoimmune mechanism. PMID:26554915

  7. [Non-autoimmune thyroiditis].

    PubMed

    Rizzo, Leonardo F L; Mana, Daniela L; Bruno, Oscar D

    2014-01-01

    The term thyroiditis comprises a group of thyroid diseases characterized by the presence of inflammation, including autoimmune and non-autoimmune entities. It may manifest as an acute illness with severe thyroid pain (subacute thyroiditis and infectious thyroiditis), and conditions in which the inflammation is not clinically evident evolving without pain and presenting primarily thyroid dysfunction and/or goiter (drug-induced thyroiditis and Riedel thyroiditis). The aim of this review is to provide an updated approach on non-autoimmune thyroiditis and its clinical, diagnostic and therapeutic aspects.

  8. Protective Autoimmunity in Atherosclerosis

    PubMed Central

    Ley, Klaus

    2016-01-01

    Objective Atherosclerosis is an inflammatory disease of the arterial wall. It is accompanied by an autoimmune response against ApoB100, the core protein of LDL, which manifests as CD4 T cell and antibody responses. Approach and Results To assess the role of the autoimmune response in atherosclerosis, the nature of the CD4 T cell response against ApoB100 was studied with and without vaccination with MHC-II restricted ApoB100 peptides. The immunological basis of autoimmunity in atherosclerosis is discussed in the framework of theories of adaptive immunity. Older vaccination approaches are also discussed. Vaccinating Apoe−/− mice with MHC-II restricted ApoB100 peptides reduces atheroma burden in the aorta by ~40%. The protective mechanism likely includes secretion of IL-10. Conclusion Protective autoimmunity limits atherosclerosis in mice and suggests potential for developing preventative and therapeutic vaccines for humans. PMID:26821946

  9. Autoimmunity against laminins.

    PubMed

    Florea, Florina; Koch, Manuel; Hashimoto, Takashi; Sitaru, Cassian

    2016-09-01

    Laminins are ubiquitous constituents of the basement membranes with major architectural and functional role as supported by the fact that absence or mutations of laminins lead to either lethal or severely impairing phenotypes. Besides genetic defects, laminins are involved in a wide range of human diseases including cancer, infections, and inflammatory diseases, as well as autoimmune disorders. A growing body of evidence implicates several laminin chains as autoantigens in blistering skin diseases, collagenoses, vasculitis, or post-infectious autoimmunity. The current paper reviews the existing knowledge on autoimmunity against laminins referring to both experimental and clinical data, and on therapeutic implications of anti-laminin antibodies. Further investigation of relevant laminin epitopes in pathogenic autoimmunity would facilitate the development of appropriate diagnostic tools for thorough characterization of patients' antibody specificities and should decisively contribute to designing more specific therapeutic interventions.

  10. Understanding Autoimmune Diseases

    MedlinePlus

    ... Autoimmune Diseases Progress and Promise Key Words The Immune System Your immune system is the network of cells and tissues throughout ... having two parts: the acquired and the innate immune systems. The acquired (or adaptive) immune system develops as ...

  11. Autoimmunity and Immunodeficiency.

    PubMed

    Dosanjh, Amrita

    2015-11-01

    The references provided include data from evidence A and B studies based on the relevant populations. Because many primary immunodeficiencies associated with autoimmune diseases are rare, illustrative cases (evidence D) also are referenced. On the basis of level A evidence, immunoglobulin A deficiency is the most common primary immunodeficiency and is associated with defective mucosal immunity and autoimmune disease. On the basis of strong evidence (level A), Wiskott Aldrich syndrome presents early in life and is associated with autoimmune arthritis and anemia. On the basis of strong evidence in the literature, a number of primary immunodeficiencies are associated with defects in T regulatory cell number and development, cytokine aberrancies, and, as a consequence, production of autoantibodies. On the basis of strong evidence (level A) and case reports (level D), complement deficiency can be associated with autoimmune disease, most notably systemic lupus erythematosus.

  12. Vaccines, adjuvants and autoimmunity.

    PubMed

    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.

  13. Auto-immune disease.

    PubMed

    Panayi, G S

    1976-02-01

    Auto-immune disease may result from the interaction of the genetic load of the individual, modification of self-tissue antigens by environmental agents such as virus or drugs and abnormalities of the immunological system itself such as the loss of controlling or suppressor T cells with age. In the majority of people the outcome is tolerance, maintenance of normal tissue architecture and function. In the unfortunate few the outcome is auto-immune disease, that is, failure to recognize "self".

  14. Silica, Silicosis, and Autoimmunity

    PubMed Central

    Pollard, Kenneth Michael

    2016-01-01

    Inhalation of dust containing crystalline silica is associated with a number of acute and chronic diseases including systemic autoimmune diseases. Evidence for the link with autoimmune disease comes from epidemiological studies linking occupational exposure to crystalline silica dust with the systemic autoimmune diseases systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Although little is known regarding the mechanism by which silica exposure leads to systemic autoimmune disease, there is a voluminous literature on silica exposure and silicosis that may help identify immune processes that precede development of autoimmunity. The pathophysiology of silicosis consists of deposition of silica particles in the alveoli of the lung. Ingestion of these particles by macrophages initiates an inflammatory response, which stimulates fibroblasts to proliferate and produce collagen. Silica particles are encased by collagen leading to fibrosis and the nodular lesions characteristic of the disease. The steps in the development of silicosis, including acute and chronic inflammation and fibrosis, have different molecular and cellular requirements, suggesting that silica-induced inflammation and fibrosis may be mechanistically separate. Significantly, it is unclear whether silica-induced inflammation and fibrosis contribute similarly to the development of autoimmunity. Nonetheless, the findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production, pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, and autoantibodies and tissue damage. The variable frequency of these immunological features following silica exposure suggests substantial genetic involvement and gene/environment interaction in silica-induced autoimmunity. However, numerous questions remain unanswered. PMID:27014276

  15. Autoimmunity in 2013.

    PubMed

    Selmi, Carlo

    2014-08-01

    The peer-reviewed publications in the field of autoimmunity published in 2013 represented a significant proportion of immunology articles and grew since the previous year to indicate that more immune-mediated phenomena may recognize an autoimmune mechanism and illustrated by osteoarthritis and atherosclerosis. As a result, our understanding of the mechanisms of autoimmunity is becoming the paradigm for translational research in which the progress in disease pathogenesis for both tolerance breakdown and inflammation perpetuation is rapidly followed by new treatment approaches and clinical management changes. The similarities across the autoimmune disease spectrum outnumber differences, particularly when treatments are compared. Indeed, the therapeutics of autoimmune diseases are based on a growing armamentarium that currently includes monoclonal antibodies and small molecules which act by targeting molecular markers or intracellular mediators with high specificity. Among the over 100 conditions considered as autoimmune, the common grounds are well illustrated by the data reported for systemic lupus erythematosus and rheumatoid arthritis or by the plethora of studies on Th17 cells and biomarkers, particularly serum autoantibodies. Further, we are particularly intrigued by studies on the genomics, epigenetics, and microRNA at different stages of disease development or on the safe and effective use of abatacept acting on the costimulation of T and B cells in rheumatoid arthritis. We are convinced that the data published in 2013 represent a promising background for future developments that will exponentially impact the work of laboratory and clinical scientists over the next years.

  16. Vaccines and autoimmunity.

    PubMed

    De Martino, M; Chiappini, E; Galli, L

    2013-01-01

    Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the success of vaccines over the last two centuries, parents (and also some health care workers) gloss over the devastating consequences of diseases, which are now avoided thanks to vaccines, and direct their attention to possible negative effects of immunization. Three immunological objections are raised: vaccines cause antigenic overload, natural immunity is safer and better than vaccine-induced immunity, and vaccines induce autoimmunity. The last point is examined in this review. Theoretically, vaccines could trigger autoimmunity by means of cytokine production, anti-idiotypic network, expression of human histocompatibility leukocyte antigens, modification of surface antigens and induction of novel antigens, molecular mimicry, bystander activation, epitope spreading, and polyclonal activation of B cells. There is strong evidence that none of these mechanisms is really effective in causing autoimmune diseases. Vaccines are not a source of autoimmune diseases. By contrast, absolute evidence exists that infectious agents can trigger autoimmune mechanisms and that they do cause autoimmune diseases.

  17. Postoperative survival for patients with thymoma complicating myasthenia gravis—preliminary retrospective results of the ChART database

    PubMed Central

    Wang, Fangrui; Fu, Jianhua; Shen, Yi; Wei, Yucheng; Tan, Lijie; Zhang, Peng; Han, Yongtao; Chen, Chun; Zhang, Renquan; Li, Yin; Chen, Keneng; Chen, Hezhong; Liu, Yongyu; Cui, Youbing; Wang, Yun; Yu, Zhentao; Zhou, Xinming; Liu, Yangchun; Liu, Yuan; Gu, Zhitao

    2016-01-01

    Background It is so far not clear that how myasthenia gravis (MG) affected the prognosis of thymoma patients. The aim of this assay is to compare the postoperative survival between patients with thymoma only and those with both thymoma and MG. Methods The Chinese Alliance for Research in Thymomas (ChART) registry recruited patients with thymoma from 18 centers over the country on an intention to treat basis from 1992 to 2012. Two groups were formed according to whether the patient complicated MG. Demographic and clinical data were reviewed, patients were followed and their survival status were analyzed. Results There were 1,850 patients included in this study, including 421 with and 1,429 without MG. Complete thymectomy were done in 91.2% patients in MG group and 71.0% in non-MG group (P<0.05). There were more percentage of patients with the histology of thymoma AB, B1, or B2 (P<0.05) in MG group, and more percentage of patients with MG were in Masaoka stage I and II. The 5- and 10-year overall survival (OS) rates were both higher in MG group (93% vs. 88%; 83% vs. 81%, P=0.034) respectively. The survival rate was significantly higher in patients with MG when the Masaoka staging was 3/4 (P=0.003). Among patients with advanced stage thymoma (stage 3, 4a, 4b), the constituent ratios of 3, 4a, 4b were similar between MG and non-MG group. Histologically, however, there were significantly more proportion of AB/B1/B2/B3 in the MG group while there were more C in the non-MG group (P=0.000). Univariate analyses for all patients showed that MG, WHO classification, Masaoka stage, surgical approach, chemotherapy and radiotherapy and resectability were significant factors, and multivariate analysis showed WHO classification, Masaoka stage, and resectability were strong independent prognostic indicators. Conclusions Although MG is not an independent prognostic factor, the survival of patients with thymoma was superior when MG was present, especially in late Masaoka stage

  18. Pregnancy with autoimmune hepatitis

    PubMed Central

    Braga, António Costa; Vasconcelos, Carlos; Braga, Jorge

    2016-01-01

    Aim: The aim of this study was to review our experience with gestations in autoimmune hepatitis patients. Background: There are only limited data describing pregnancy in patients with autoimmune hepatitis. Patients and methods: Retrospective analysis of pregnancies with autoimmune hepatitis followed in Centro Hospitalar do Porto, Portugal in the last ten years. Results: We reported nine pregnancies in seven patients with autoimmune hepatitis. Two patients had documented liver cirrhosis prior to the pregnancy. In this study, 66.7% of patients were treated with azathioprine and 88.9% with prednisolone. Clinical improvements were observed in 11.1% of pregnancies and 22.2% exacerbations were diagnosed. There were six live births and two preterm deliveries (preterm delivery rate of 33%). We also report three first trimester miscarriages (early gestation miscarriage rate of 33%). There were no neonatal or maternal deaths. Conclusion: The favorable obstetric outcome is a realistic expectation in patients with autoimmune hepatitis. Tight monitoring and control of asymptomatic and unpredictable exacerbations, which are unrelated to the severity of the underlying disease, are essential to the prognosis of the current pregnancy. PMID:27458515

  19. Autoimmune gastritis: Pathologist's viewpoint.

    PubMed

    Coati, Irene; Fassan, Matteo; Farinati, Fabio; Graham, David Y; Genta, Robert M; Rugge, Massimo

    2015-11-14

    Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic (and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and (intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling.

  20. Autoimmune movement disorders.

    PubMed

    Mckeon, Andrew; Vincent, Angela

    2016-01-01

    Autoimmune movement disorders encapsulate a large and diverse group of neurologic disorders occurring either in isolation or accompanying more diffuse autoimmune encephalitic illnesses. The full range of movement phenomena has been described and, as they often occur in adults, many of the presentations can mimic neurodegenerative disorders, such as Huntington disease. Disorders may be ataxic, hypokinetic (parkinsonism), or hyperkinetic (myoclonus, chorea, tics, and other dyskinetic disorders). The autoantibody targets are diverse and include neuronal surface proteins such as leucine-rich, glioma-inactivated 1 (LGI1) and glycine receptors, as well as antibodies (such as intracellular antigens) that are markers of a central nervous system process mediated by CD8+ cytotoxic T cells. However, there are two conditions, stiff-person syndrome (also known as stiff-man syndrome) and progressive encephalomyelitis with rigidity and myoclonus (PERM), that are always autoimmune movement disorders. In some instances (such as Purkinje cell cytoplasmic antibody-1 (PCA-1) autoimmunity), antibodies detected in serum and cerebrospinal fluid can be indicative of a paraneoplastic cause, and may direct the cancer search. In other instances (such as 65kDa isoform of glutamic acid decarboxylase (GAD65) autoimmunity), a paraneoplastic cause is very unlikely, and early treatment with immunotherapy may promote improvement or recovery. Here we describe the different types of movement disorder and the clinical features and antibodies associated with them, and discuss treatment.

  1. Autoimmunity and Asbestos Exposure

    PubMed Central

    Pfau, Jean C.; Serve, Kinta M.; Noonan, Curtis W.

    2014-01-01

    Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA), a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a) a lack of statistical power due to relatively small or diffuse exposure cohorts, (b) exposure misclassification, (c) latency of clinical disease, (d) mild or subclinical entities that remain undetected or masked by other pathologies, or (e) effects that are specific to certain fiber types, so that analyses on mixed exposures do not reach statistical significance. This review summarizes epidemiological, animal model, and in vitro data related to asbestos exposures and autoimmunity. These combined data help build toward a better understanding of the fiber-associated factors contributing to immune dysfunction that may raise the risk of autoimmunity and the possible contribution to asbestos-related pulmonary disease. PMID:24876951

  2. A minimum number of autoimmune T cells to induce autoimmunity?

    PubMed

    Bosch, Angela J T; Bolinger, Beatrice; Keck, Simone; Stepanek, Ondrej; Ozga, Aleksandra J; Galati-Fournier, Virginie; Stein, Jens V; Palmer, Ed

    2017-03-12

    While autoimmune T cells are present in most individuals, only a minority of the population suffers from an autoimmune disease. To better appreciate the limits of T cell tolerance, we carried out experiments to determine how many autoimmune T cells are required to initiate an experimental autoimmune disease. Variable numbers of autoimmune OT-I T cells were transferred into RIP-OVA mice, which were injected with antigen-loaded DCs in a single footpad; this restricted T cell priming to a few OT-I T cells that are present in the draining popliteal lymph node. Using selective plane illumination microscopy (SPIM) we counted the number of OT-I T cells present in the popliteal lymph node at the time of priming. Analysis of our data suggests that a single autoimmune T cell cannot induce an experimental autoimmune disease, but a "quorum" of 2-5 autoimmune T cells clearly has this capacity.

  3. Autoimmune encephalitis update

    PubMed Central

    Dalmau, Josep; Rosenfeld, Myrna R.

    2014-01-01

    Cancer-associated immune-mediated disorders of the central nervous system are a heterogeneous group. These disorders include the classic paraneoplastic neurologic disorders and the more recently described autoimmune encephalitis associated with antibodies to neuronal cell-surface or synaptic receptors that occur with and without a cancer association. Autoimmune encephalitis is increasingly recognized as the cause of a variety of neuropsychiatric syndromes that can be severe and prolonged. In contrast to the classic paraneoplastic disorders that are poorly responsive to tumor treatment and immunotherapy, autoimmune encephalitis often responds to these treatments, and patients can have full or marked recoveries. As early treatment speeds recovery, reduces disability, and decreases relapses that can occur in about 20% of cases, it is important that the immune pathogenesis of these disorders is recognized. PMID:24637228

  4. Headache in autoimmune diseases.

    PubMed

    John, Seby; Hajj-Ali, Rula A

    2014-03-01

    Autoimmune diseases are a group of heterogeneous inflammatory disorders characterized by systemic or localized inflammation, leading to ischemia and tissue destruction. These include disorders like systemic lupus erythematosus and related diseases, systemic vasculitides, and central nervous system (CNS) vasculitis (primary or secondary). Headache is a very common manifestation of CNS involvement of these diseases. Although headache characteristics can be unspecific and often non-diagnostic, it is important to recognize because headache can be the first manifestation of CNS involvement. Prompt recognition and treatment is necessary not only to treat the headache, but also to help prevent serious neurological sequelae that frequently accompany autoimmune diseases. In this review, we discuss headache associated with autoimmune diseases along with important mimics.

  5. Epigenomics of autoimmune diseases.

    PubMed

    Gupta, Bhawna; Hawkins, R David

    2015-03-01

    Autoimmune diseases are complex disorders of largely unknown etiology. Genetic studies have identified a limited number of causal genes from a marginal number of individuals, and demonstrated a high degree of discordance in monozygotic twins. Studies have begun to reveal epigenetic contributions to these diseases, primarily through the study of DNA methylation, but chromatin and non-coding RNA changes are also emerging. Moving forward an integrative analysis of genomic, transcriptomic and epigenomic data, with the latter two coming from specific cell types, will provide an understanding that has been missed from genetics alone. We provide an overview of the current state of the field and vision for deriving the epigenomics of autoimmunity.

  6. [Autoimmune hemolytic anemia in children].

    PubMed

    Becheur, M; Bouslama, B; Slama, H; Toumi, N E H

    2015-01-01

    Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options.

  7. [A comparative analysis of the informative value of anti-AChR-antibody radioimmunoassay and laser correlation spectroscopy in myasthenia gravis].

    PubMed

    Alchinova, I B; Yakovenko, E N; Sidnev, D V; Dedaev, S Yu; Sanadze, A G; Karganov, M Yu

    2017-01-01

    Цель исследования. Сопоставление информативности традиционного подхода (радиоиммунологическое определение концентрации антител к ацетилхолиновому рецептору — АХР) с оценкой сдвигов метаболизма, выявляемых с помощью лазерной корреляционной спектроскопии при миастении. Материал и методы. Обследованы 77 пациентов с миастенией в возрасте от 12 до 80 лет. Тяжесть ее клинических проявлений оценивалась согласно Международной клинической классификации. Концентрацию антител к АХР определяли радиоиммунологическим методом. Повышенным титром являлось значение, превышающее 0,40 нмоль/л. Субфракционный состав биологических жидкостей регистрировали, используя лазерный корреляционный спектрометр. Результаты и заключение. В результате анализа гистограмм были выделены три информативные зоны: 6—15, 27—67 и 127—223 нм. У больных без нарушения витальных функций с нарастанием тяжести наблюдалось достоверное увеличение вклада в светорассеяние частиц первой зоны при снижении этого показателя в третьей зоне. Существенные различия, достигающие уровня статистической значимости в зонах 6 и 20 нм, обнаружены в спектрах сыворотки крови больных миастенией одинаковой степени тяжести с тимомой и без опухоли. Таким образом, открывается перспектива для динамического контроля эффективности терапии.

  8. [THE ENVIRONMENT AND AUTOIMMUNE DISEASES].

    PubMed

    Watad, Abdulla; Amital, Howard; Shoenfeld, Yehuda

    2015-05-01

    The immune system carefully distinguishes between self and non-self-components. Therefore, any small deviation of this balanced function may result in an autoimmune activity and harm against self-antigens (autoantigens). The link between autoimmune diseases and various heredity and environmental factors has been discussed in numerous studies. The infectious factor is still considered to be the most important environmental factor leading to the development of autoimmune disease. Recent studies associated new environmental factors to autoimmunity, such as excessive salt consumption. In this paper, we summarize the relationship between environmental factors and autoimmune diseases covering innovations in this field.

  9. Update on autoimmune hepatitis

    PubMed Central

    Teufel, Andreas; Galle, Peter R; Kanzler, Stephan

    2009-01-01

    Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features, hyperglobulinemia (IgG), and the presence of circulating autoantibodies, as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years, a couple of new insights into the genetic aspects, clinical course and treatment of AIH have been reported, which will be the focus of this review. In particular, we concentrate on genome-wide microsatellite analysis, a novel mouse model of AIH, the evaluation of a large AIH cohort for overlap syndromes, suggested novel criteria for the diagnosis of AIH, and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil. PMID:19266594

  10. Autoimmune Neuromuscular Disorders

    PubMed Central

    Kraker, Jessica; Živković, Saša A

    2011-01-01

    Autoimmune neuromuscular disorders affecting peripheral nerves, neuromuscular junction or muscle have a wide clinical spectrum with diverse pathogenetic mechanisms. Peripheral nervous system may be targeted in the context of complex immune reactions involving different cytokines, antigen-presenting cells, B cells and different types of T cells. Various immunomodulating and cytotoxic treatments block proliferation or activation of immune cells by different mechanisms attempting to control the response of the immune system and limit target organ injury. Most treatment protocols for autoimmune neuromuscular disorders are based on the use of corticosteroids, intravenous immunoglobulins and plasmapheresis, with cytotoxic agents mostly used as steroid-sparing medications. More recently, development of specific monoclonal antibodies targeting individual cell types allowed a different approach targeting specific immune pathways, but these new treatments are also associated with various adverse effects and their long-term efficacy is still unknown. PMID:22379454

  11. Immunology Research in Israel.

    DTIC Science & Technology

    1985-11-14

    experimental autoimmune I. Pecht (Department of Chemical myasthenia gravis (EAMG). These anti- " Immunology, Weizmann Institute) and his bodies block...of histocompatability tributlons that played a major role in antigens and was the first to show the the complete eradication of malaria from theta...were compared to School, Jerusalem) and J. Haimovich (De- conventional antibodies. The role of partment of Human Microbiology, Tel-Aviv monoclonal

  12. Complement in autoimmune diseases.

    PubMed

    Vignesh, Pandiarajan; Rawat, Amit; Sharma, Madhubala; Singh, Surjit

    2017-02-01

    The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli. However, all the 3 pathways converge on Complement C3. Cleavage of C3 and C5 successively leads to the production of the membrane attack complex which is final common effector. Excessive and uncontrolled activation of the complement has been implicated in the host of autoimmune diseases. But the complement has also been bemusedly described as the proverbial "double edged sword". On one hand, complement is the final effector of tissue injury in autoimmune diseases and on the other, deficiencies of some components of the complement can result in autoimmune diseases. Currently available tools such as enzyme based immunoassays for functional assessment of complement pathways, flow cytometry, next generation sequencing and proteomics-based approaches provide an exciting opportunity to study this ancient yet mysterious element of innate immunity.

  13. Cytokines and autoimmunity.

    PubMed Central

    Cavallo, M G; Pozzilli, P; Thorpe, R

    1994-01-01

    Although the immunopathology of most autoimmune diseases has been well defined, the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of systemic and organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of cytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases. PMID:8149655

  14. Paediatric Autoimmune Liver Disease.

    PubMed

    Liberal, Rodrigo; Vergani, Diego; Mieli-Vergani, Giorgina

    2015-01-01

    In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: 'classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the

  15. Akinesia, arthrogryposis, craniosynostosis: a presentation of neonatal myasthenia with fetal onset.

    PubMed

    Cantagrel, Sylvain; Maury, Laure; Yamamoto, Anne-Marie; Maheut, Josette; Toutain, Annick; Castelnau, Pierre

    2002-08-01

    Major akinesia with arthrogryposis and craniosynostosis at birth mimics irreversible disorders of the nervous system of pejorative outcome. In this context, the early detection of anti-acetylcholine fetal receptor antibodies in the mother may allow rapid diagnosis of transient neonatal myasthenia of favorable prognosis.

  16. Imaging of autoimmune biliary disease.

    PubMed

    Yeh, Melinda J; Kim, So Yeon; Jhaveri, Kartik S; Behr, Spencer C; Seo, Nieun; Yeh, Benjamin M

    2017-01-01

    Autoimmune biliary diseases are poorly understood but important to recognize. Initially, autoimmune biliary diseases are asymptomatic but may lead to progressive cholestasis with associated ductopenia, portal hypertension, cirrhosis, and eventually liver failure. The three main forms of autoimmune biliary disease are primary biliary cirrhosis, primary sclerosing cholangitis, and IgG4-associated cholangitis. Although some overlap may occur between the three main autoimmune diseases of the bile ducts, each disease typically affects a distinct demographic group and requires a disease-specific diagnostic workup. For all the autoimmune biliary diseases, imaging provides a means to monitor disease progression, assess for complications, and screen for the development of hepatobiliary malignancies that are known to affect patients with these diseases. Imaging is also useful to suggest or corroborate the diagnosis of primary sclerosing cholangitis and IgG4-associated cholangitis. We review the current literature and emphasize radiological findings and considerations for these autoimmune diseases of the bile ducts.

  17. Neuropathology of autoimmune encephalitides.

    PubMed

    Bauer, Jan; Bien, Christian G

    2016-01-01

    In recent years a large number of antibody-associated or antibody-defined encephalitides have been discovered. These conditions are often referred to as autoimmune encephalitides. The clinical features include prominent epileptic seizures, cognitive and psychiatric disturbance. These encephalitides can be divided in those with antibodies against intracellular antigens and those with antibodies against surface antigens. The discovery of new antibodies against targets on the surface of neurons is especially interesting since patients with such antibodies can be successfully treated immunologically. This chapter focuses on the pathology and the pathogenetic mechanisms involved in these encephalitides and discusses some of the questions that are raised in this exciting new field. It is important to realise, however, that because of the use of antibodies to diagnose the patients, and their improvement with treatment, there are relatively few biopsy or postmortem reports, limiting the neuropathological data and conclusions that can be drawn. For this reason we especially focus on the most frequent autoimmune encephalitides, those with antibodies to the NMDA receptor and with antibodies to the known protein components of the VGKC complex. Analysis of these encephalitides show completely different pathogenic mechanisms. In VGKC complex encephalitis, antibodies seem to bind to their target and activate complement, leading to destruction and loss of neurons. On the other hand, in NMDAR encephalitis, complement activation and neuronal degeneration seems to be largely absent. Instead, binding of antibodies leads to a decrease of NMDA receptors resulting in a hypofunction. This hypofunction offers an explanation for some of the clinical features such as psychosis and episodic memory impairment, but not for the frequent seizures. Thus, additional analysis of the few human brain specimens present and the use of specific animal models are needed to further understand the effects

  18. Warm autoimmune hemolytic anemia.

    PubMed

    Naik, Rakhi

    2015-06-01

    Warm autoimmune hemolytic anemia (AIHA) is defined as the destruction of circulating red blood cells (RBCs) in the setting of anti-RBC autoantibodies that optimally react at 37°C. The pathophysiology of disease involves phagocytosis of autoantibody-coated RBCs in the spleen and complement-mediated hemolysis. Thus far, treatment is aimed at decreasing autoantibody production with immunosuppression or reducing phagocytosis of affected cells in the spleen. The role of complement inhibitors in warm AIHA has not been explored. This article addresses the diagnosis, etiology, and treatment of warm AIHA and highlights the role of complement in disease pathology.

  19. Autoimmune diseases and myelodysplastic syndromes.

    PubMed

    Komrokji, Rami S; Kulasekararaj, Austin; Al Ali, Najla H; Kordasti, Shahram; Bart-Smith, Emily; Craig, Benjamin M; Padron, Eric; Zhang, Ling; Lancet, Jeffrey E; Pinilla-Ibarz, Javier; List, Alan F; Mufti, Ghulam J; Epling-Burnette, Pearlie K

    2016-05-01

    Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation.

  20. Pyrosequencing analysis of the microbiota of kusaya gravy obtained from Izu Islands.

    PubMed

    Fujii, Tateo; Kyoui, Daisuke; Takahashi, Hajime; Kuda, Takashi; Kimura, Bon; Washizu, Yukio; Emoto, Eiji; Hiramoto, Tadahiro

    2016-12-05

    Kusaya is a salted, dried fish product traditionally produced on the Izu Islands in Japan. Fish are added to kusaya gravy repeatedly and intermittently, and used over several hundred years, which makes unique microbiota and unique flavors. In this study, we performed a metagenomic analysis to compare the composition of the microbiota of kusaya gravy between different islands. Twenty samples obtained from a total of 13 manufacturers on three islands (Hachijojima, Niijima, and Oshima Islands) were analyzed. The statistical analysis revealed that the microbiota in kusaya gravy maintain a stable composition regardless of the production steps, and that the microbiota are characteristic to the particular islands. The bacterial taxa common to all of the samples were not necessarily the dominant ones. On the other hand, the genera Halanaerobium and Tissierella were found to be characteristic to the microbiota of one or two islands. Because these genera are known to be present in the natural environment, it is likely that the bacterial strains peculiar to an island had colonized kusaya gravy for many years. The results of this study revealed an influence of geographical conditions on the microbiota in fermented food.

  1. Effect of marination in gravy on the radio frequency and microwave processing properties of beef.

    PubMed

    Basaran-Akgul, Nese; Rasco, Barbara A

    2015-02-01

    Dielectric properties (the dielectric constant (ε') and the dielectric loss factor (ε″)) and the penetration depth of raw eye of round beef Semitendinosus muscle, raw beef marinated in gravy, raw beef cooked in gravy, and gravy alone were determined as a function of the temperature (20-130 °C) and frequency (27-1,800 MHz). Both ε' and ε″ values increased as the temperature increased at low frequencies (27 and 40 MHz). At high frequencies (915 and 1,800 MHz), ε' showed a 50 % decrease while ε″ increased nearly three fold with increasing temperature in the range from 20 to 130 °C. ε' increased gradually while ε″ increased five fold when the temperature increased from 20 to 130 °C. Both ε' and ε″ of all samples decreased with increase in frequency. Marinating the beef in gravy dramatically increased the ε″ values, particularly at the lower frequencies. Power penetration depth of all samples decreased with increase temperature and frequency. These results are expected to provide useful data for modeling dielectric heating processes of marinated muscle food.

  2. Mast Cell and Autoimmune Diseases

    PubMed Central

    Xu, Yunzhi; Chen, Guangjie

    2015-01-01

    Mast cells are important in innate immune system. They have been appreciated as potent contributors to allergic reaction. However, increasing evidence implicates the important role of mast cells in autoimmune disease like rheumatoid arthritis and multiple sclerosis. Here we review the current stage of knowledge about mast cells in autoimmune diseases. PMID:25944979

  3. Autoimmunity: alopecia areata.

    PubMed

    Hordinsky, Maria; Ericson, Marna

    2004-01-01

    Strong direct and indirect evidence supports an autoimmune etiology for alopecia areata. T lymphocytes that have been shown to be oligoclonal and autoreactive are predominantly present in the peribulbar inflammatory infiltrate. Alopecia areata frequently occurs in association with other autoimmune diseases, such as thyroiditis and vitiligo, and autoantibodies to follicular components have been detected. Finally, the use of immune modulating drugs, including corticosteroids and contact sensitizers such as dyphencyprone, can be beneficial in the management of this disease. Recent studies have demonstrated that alopecia areata scalp skin grafted onto nude mice with severe combined immunodeficiency grow hair and that infiltrating lymphocytes in the graft are lost. It is now also possible to induce alopecia areata in human scalp explants on these mice by injecting T lymphocytes with scalp homogenate. Neuropeptides produced by cutaneous nerves are known to modify immune reactivity and, in all likelihood, affect the alopecia areata process. Future studies may show that modulation of neuropeptide expression is associated with hair regrowth. Likewise, testing the efficacy of the newly developed immunomodulatory agents in patients with alopecia areata may lead to the introduction of novel therapies for this immune-mediated disease of the hair follicle.

  4. [Hydroxychloroquine for autoimmune diseases].

    PubMed

    Danza, Álvaro; Graña, Diego; Goñi, Mabel; Vargas, Andrea; Ruiz-Irastorza, Guillermo

    2016-02-01

    Hydroxychloroquine (HCQ) is by far the most frequently used antimalarial for the management of Systemic Autoimmune Diseases. It has immunomodulatory, hypolipidemic, hypoglycemic and antithrombotic properties and it diminishes the risk of malignancies. The most important mechanisms to explain the immunomodulatory actions are its ability to reduce inflammatory pathways and Toll-like receptors activation. The safety profile is favorable. In spite of its low frequency, retinal toxicity is potentially severe. In systemic lupus erythematous HCQ therapy reduces activity, the accrual of organ damage, risk of infections and thrombosis and improves the cardiometabolic profile. It contributes to induce lupus nephritis remission, spares steroid use and increases survival rates. In rheumatoid arthritis, it improves cardiometabolic risk and has a favorable effect in joint inflammation. In Sjögren's syndrome, an increased lacrimal quality as well as an improvement in objective and subjective inflammatory markers has been demonstrated with HCQ. In Antiphospholipid Syndrome, HCQ is effective in primary and secondary thrombosis prevention. The effectiveness of the drug in other systemic autoimmune diseases is less established. HCQ therapy may improve dermatological manifestations in Dermatomyositis and may have a positive effects in the treatment of Sarcoidosis and Still disease.

  5. [Autoimmune lymphoproliferative syndrome].

    PubMed

    Rodrigues, Vera; Conde, Marta; Figueiredo, António; Vasconcelos, Júlia; Dias, Alexandra

    2011-01-01

    The Autoimmune Lymphoproliferative Syndrome (ALPS) is an impairment of lymphocyte apoptosis expressed by generalized non-malignant lymphoproliferation, lymphadenopathy and/or splenomegaly. This article describes a seven and 14 year old males. The first one was admitted at 3 years of age with fever, bicytopenia and generalized lymphadenopathy. Hystopathological analysis of lymph nodes showed reactive follicular hyperplasia and marked paracortical expansion. He was readmitted three years later presenting herpes zoster and similar clinical features. High levels of IL-10 and increasing tendency of Fas-L in plasma and serum. The second child was admitted at 13 years of age presenting thigh and gluteus cellulitis, anemia and neutropenia. T lymphocytes aß+CD4-CD8- 3,1%. Hystopathological analysis of lymph nodes showed marked paracortical hyperplasia. Both children are treated with mycophenolate mofetil with good response. ALPS is an underestimated entity that must be considered in non malign lymphoproliferation, autoimmunity and expansion of an unusual population of a/ßCD3+CD4-CD8-(double-negative T cells>1%).

  6. [Autoimmune bullous skin disorders].

    PubMed

    Hertl, Michael; Niedermeier, Andrea; Borradori, Luca

    2010-09-01

    Autoimmune bullous skin disorders are rare, potentially fatal disorders of skin and mucous membranes which are associated with IgG or IgA autoantibodies against distinct adhesion molecules of the epidermis and dermal epidermal basement membrane zone, respectively. These autoantibodies lead to a loss of skin adhesion which shows up clinically as the formation of blisters or erosions. In pemphigus, loss of adhesion occurs within the epidermis while in the pemphigoids, linear IgA dermatosis, epidermolysis bullosa acquisita and dermatitis herpetiformis, loss of adhesion takes place within or underneath the basement membrane zone. The autoantigens of these disorders are largely identified and characterized. Making the diagnosis of autoimmune bullous skin diseases is based on histology and direct immunofluorescence of perilesional skin and the serological detection of autoantibodides by indirect immunofluorescence and recombinant autoantigens. Therapeutically, systemic treatment with glucocorticoids is combined with immunosuppressive adjuvants which allow for the fast reduction of systemic steroids. A prospective trial in pemphigus showed that adjuvant treatment with azathioprine, mycophenolate mofetil and cyclophosphamide, respectively, led to a significant reduction of the cummulative dose of systemic steroids until complete clinical remission was achieved. In bullous pemphigoid, topical treatment with clobetasol led to complete clinical remissions without major side effects seen when glucocorticoids were applied systemically. Therapeutic depletion of B cells by rituximab as a second line therapy has significantly improved the overall prognosis of pemphigus. Comparable controlled therapeutic trials have not yet been performed in dermatitis herpetiformis and epidermolysis bullosa acquisita.

  7. Prolactin and autoimmunity.

    PubMed

    Vera-Lastra, Olga; Jara, Luis J; Espinoza, Luis R

    2002-12-01

    Prolactin (PRL) is a versatile hormone that is produced by the anterior pituitary gland and various extrapituitary sites including immune cells. Furthermore, PRL has widespread influences on proliferation and differentiation of a variety of cells in the immune system and is, in effect, a cytokine. PRL-receptors (PRL-R) are distributed throughout the immune system and are included as members of the cytokine receptor superfamily. PRL-R signal transduction is mediated by a complex array of signaling molecules of which JAK2, Stat1 and Stat5 pathway have been well studied. In PRL-stimulated T cells, the transcription factor gene, interferon regulatory factor-1 provides a mechanism whereby PRL can regulate the immune response. The human PRL gene is situated on the short arm of chromosome 6 close to the major histocompatibility complex. Polymorphisms of the human PRL gene have implications for production of lymphocyte PRL in SLE. Mild and moderate hyperprolactinemia (HPRL) has been demonstrated in 20-30% of SLE patients and is associated with active disease. HPRL may have a role in lupus nephritis and central nervous system involvement of SLE patients. HPRL stimulated the production of autoantibodies. These evidences support the important role of PRL in autoimmunity and autoimmune diseases, mainly SLE.

  8. Electrosmog and autoimmune disease.

    PubMed

    Marshall, Trevor G; Heil, Trudy J Rumann

    2016-07-13

    Studies in mice have shown that environmental electromagnetic waves tend to suppress the murine immune system with a potency similar to NSAIDs, yet the nature of any Electrosmog effects upon humans remains controversial. Previously, we reported how the human Vitamin-D receptor (VDR) and its ligand, 1,25-dihydroxyvitamin-D (1,25-D), are associated with many chronic inflammatory and autoimmune diseases. We have shown how olmesartan, a drug marketed for mild hypertension, acts as a high-affinity partial agonist for the VDR, and that it seems to reverse disease activity resulting from VDR dysfunction. We here report that structural instability of the activated VDR becomes apparent when observing hydrogen bond behavior with molecular dynamics, revealing that the VDR pathway exhibits a susceptibility to Electrosmog. Further, we note that characteristic modes of instability lie in the microwave frequency range, which is currently populated by cellphone and WiFi communication signals, and that the susceptibility is ligand dependent. A case series of 64 patient-reported outcomes subsequent to use of a silver-threaded cap designed to protect the brain and brain stem from microwave Electrosmog resulted in 90 % reporting "definite" or "strong" changes in their disease symptoms. This is much higher than the 3-5 % rate reported for electromagnetic hypersensitivity in a healthy population and suggests that effective control of environmental Electrosmog immunomodulation may soon become necessary for successful therapy of autoimmune disease.

  9. Spontaneous germinal centers and autoimmunity.

    PubMed

    Domeier, Phillip P; Schell, Stephanie L; Rahman, Ziaur S M

    2017-02-01

    Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.

  10. Gene Therapy for Autoimmune Disease.

    PubMed

    Shu, Shang-An; Wang, Jinjun; Tao, Mi-Hua; Leung, Patrick S C

    2015-10-01

    Advances in understanding the immunological and molecular basis of autoimmune diseases have made gene therapy a promising approach to treat the affected patients. Gene therapy for autoimmune diseases aims to regulate the levels of proinflammatory cytokines or molecules and the infiltration of lymphocytes to the effected sites through successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain the immune tolerance to the relevant autoantigens and improve clinical outcomes for patients. Here, we summarize the recent progress in identifying genes responsible for autoimmune diseases and present examples where gene therapy has been applied as treatments or prevention in autoimmune diseases both in animal models and the clinical trials. Discussion on the advantages and pitfalls of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of autoimmune diseases.

  11. Mucormycosis in systemic autoimmune diseases.

    PubMed

    Royer, Mathieu; Puéchal, Xavier

    2014-07-01

    Mucormycosis is an emerging infection in systemic autoimmune diseases. All published cases of systemic autoimmune diseases complicated by mucormycosis were reviewed. The clinical features, diagnostic procedures and the main principles of treatment were analyzed. Twenty-four cases of mucormycosis have been reported in systemic auto-immune diseases, of which 83% in systemic lupus erythematosus, all occurring during immunosuppressants. In most cases, the infection was disseminated or rhinocerebral and it had mimicked a flare of the underlying connective tissue disease. A fatal outcome was reported in 58.3% of these patients. In conclusion, mucormycosis often mimics a flare of the underlying systemic disease and is associated with a high mortality rate. Systemic lupus erythematosus is by far the most common associated systemic autoimmune disease. A high degree of awareness is warranted to rapidly rule out infection, of which mucormycosis, in immunocompromised patients with systemic autoimmune disease before a disease flare is conclusively diagnosed.

  12. Autoimmunity in Common Variable Immunodeficiency

    PubMed Central

    Agarwal, Shradha; Cunningham-Rundles, Charlotte

    2010-01-01

    Common variable immunodeficiency (CVID) is the most common clinically significant primary immune defect. Although the hallmark of CVID is hypogammaglobulinemia, the intrinsic dysregulation of the immune system leads to defective T-cell activation and proliferation, as well as dendritic cell and cytokine defects. Although 70% to 80% of patients have had recurrent sinopulmonary infections, auto-immunity and inflammatory complications are also common. The most common autoimmune conditions are immune thrombocytopenic purpura and hemolytic anemia, but other autoimmune complications arise, including rheumatoid arthritis, pernicious anemia, primary biliary cirrhosis, thyroiditis, sicca syndrome, systemic lupus, and inflammatory bowel disease. Treatment of autoimmunity includes high-dose immunoglobulins, corticosteroids, selected immunosuppressants, and other immune modulators. This review focuses on autoimmune conditions associated with CVID, potential mechanisms of immune dysregulation, and therapeutic strategies. PMID:19671377

  13. Psychoneuroimmunology - psyche and autoimmunity.

    PubMed

    Ziemssen, Tjalf

    2012-01-01

    Psychoneuroimmunology is a relatively young field of research that investigates interactions between central nervous and immune system. The brain modulates the immune system by the endocrine and autonomic nervous system. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and autoimmune disease. For several diseases, the relevance of psychoneuroimmunological findings has already been demonstrated.

  14. Autoimmune premature ovarian failure

    PubMed Central

    2017-01-01

    Premature ovarian failure (POF), also termed as primary ovarian insufficiency (POI), is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS) in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system. PMID:28250725

  15. Autoimmune Encephalitis in Children

    PubMed Central

    Armangue, Thaís; Petit-Pedrol, Mar; Dalmau, Josep

    2013-01-01

    The causes of encephalitis are numerous, and extensive investigations for infectious agents and other etiologies are often negative. The discovery that many of these encephalitis are immune mediated has changed the approach to the diagnosis and treatment of these disorders. Moreover, the broad spectrum of symptoms including, psychosis, catatonia, alterations of behavior and memory, seizures, abnormal movements, and autonomic dysregulation usually requires a multidisciplinary treatment approach. This review focuses in several forms of encephalitis that occur in children, and for which an autoimmune etiology has been demonstrated (eg, anti-N-methyl-D-aspartate receptor encephalitis) or is strongly suspected (eg, Rasmussen encephalitis, limbic encephalitis, opsoclonus-myoclonus). The authors also review several disorders that may be immune mediated, such as the rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) syndrome and some encephalopathies with fever and status epilepticus. Recognition of novel immune-mediated encephalitis is important because some of these disorders are highly responsive to immunotherapy. PMID:22935553

  16. [Autoantibodies, tolerance and autoimmunity].

    PubMed

    Oppezzo, Pablo; Dighiero, Guillaume

    2003-07-01

    In 1900, the group from Metchnikoff suggested the concept of autoimmunization by demonstrating the presence of autoantibodies in normal conditions; which was opposed to the concept of horror autotoxicus raised by Ehrlich. Landsteiner's description of the transfusion compatibility rules and 50 year-later work from Burnett's and Medawar's groups lead to the clonal deletion theory as a general explanation of tolerance and autoimmunity. However, more recent work succeeded demonstrating that autoreactive B cells constitute a substantial part of the B-cell repertoire and that this autoreactive repertoire secretes the so-called natural autoantibodies (NAA) characterized by their broad reactivity mainly directed against very well conserved public epitopes. They fulfill the definition of an autoantibody since they are self-reactive, but they are not self-specific. As yet, NAA directed against determinants of polymorphism have not been reported. The presence of this repertoire in normal conditions challenges the clonal deletion theory as a unique explanation for self-tolerance. However, if we take into account that this autoreactive B-cell repertoire is not self-specific, this contradiction may not be a real one opposition. Indeed, the Lansteiner's rule that a subject belonging to group A will never produce anti-A antibodies and will always produce natural antibodies against the B-cell group, could never be challenged. Clonal deletion is probably accounting for this phenomenum. However, the serum of healthy adult individuals frequently exhibits low titers of anti-I antibodies, which is a precursor molecule of AB0 antigen system. The mechanism accounting for deletion of B cells directed against critical determinants like antigens A and B in the red blood cell system and allowing the production of autoantibodies against I remain elusive.

  17. Mechanisms of Action of Anticholinesterases and Oximes on Acetylcholine Receptors

    DTIC Science & Technology

    1988-07-23

    J.F. and D.B. Sanders. The management of patients with myasthenia gravis , in Myasthenia Gravis (E.X. Albuquerque and A.T. Eldefrawi, eds.), Chapman...Eldefrawi. Affinity of myasthenia drugs to acetylcholinesterase and acetylcholine receptor. Biochem. Med. 10:258-265 (1974). 9. Carpenter, D.O., L.A

  18. Current Pyridostigmine Bromide and Huperzine A Studies and Future Cholinesterase Screening Using the WRAIR Whole Blood Cholinesterase Assay

    DTIC Science & Technology

    2004-11-15

    with pyridostigmine bromide, its therapeutic advantage being to increase the muscle strength in myasthenia gravis patients by inhibiting...exposure in military and civilian populations and also monitoring therapeutic regimens for neurological diseases e.g., myasthenia gravis or...against the lethal effects of GD nerve agent poisoning. Given the extensive cumulative experience with the use of PB in patients with myasthenia

  19. Questions and Answers on Autoimmunity and Autoimmune Diseases

    MedlinePlus

    ... for Updates Join Our Email List For Email Marketing you can trust. Contact AARDA National Office 22100 ... Grassroots Fundraising Workplace Giving Special Events AARDA on Facebook Copyright © 2004 - 2017. American Autoimmune Related Diseases Association, ...

  20. Rheumatic symptoms in autoimmune thyroiditis.

    PubMed

    Tagoe, Clement E

    2015-02-01

    Autoimmune thyroiditis (ATD) is generally regarded as a classic example of single organ autoimmunity with a high association with endocrine thyroid disorders. However, it is closely associated with several autoimmune diseases including rheumatologic syndromes and has long been known to have several rheumatic manifestations particularly in association with hypothyroidism. More recently, it has also been implicated in rheumatologic syndromes in the absence of hypothyroidism or subclinical hypothyroidism. There is also an emerging body of evidence that ATD is highly linked to chronic generalized pain syndromes including fibromyalgia. This review examines the rheumatic symptoms of ATD described in the current literature and discusses the clinical relevance of ATD in general rheumatology.

  1. Epigenetic alterations underlying autoimmune diseases.

    PubMed

    Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein

    2016-01-01

    Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases.

  2. [Molecular diagnosis of autoimmune dermatoses].

    PubMed

    Hoffmann, K; Hertl, M; Sitaru, C

    2016-01-01

    Bullous autoimmune diseases are organ-specific disorders characterized by an autoantibody-mediated blistering of skin and mucous membranes. The detection of tissue-bound and serum autoantibodies is prerequisite for the diagnosis of autoimmune blistering diseases. The individual entities of this group may be difficult to differentiate on clinical grounds alone. An accurate diagnosis is however important for prognosis and therapy. A preliminary diagnostic step includes direct and indirect immunofluorescence microscopy, which provide information about the binding pattern and isotype of autoantibodies and allow the diagnosis of the autoimmune blistering disease. Subsequent characterization of the molecular specificity of autoantibodies is necessary for the exact classification of autoimmune bullous dermatoses. The quantitative measurement of autoantibodies against structural proteins of the skin may be often used to assess disease severity at follow-up.

  3. SIALIC ACIDS AND AUTOIMMUNE DISEASE

    PubMed Central

    Mahajan, Vinay S.; Pillai, Shiv

    2016-01-01

    summary An important underlying mechanism that contributes to autoimmunity is the loss of inhibitory signaling in the immune system. Sialic acid-recognizing Ig superfamily lectins or Siglecs are a family of cell surface proteins largely expressed in hematopoietic cells. The majority of Siglecs are inhibitory receptors expressed in immune cells that bind to sialic acid containing ligands and recruit SH2-domain containing tyrosine phosphatases to their cytoplasmic tails. They deliver inhibitory signals that can contribute to the constraining of immune cells and thus protect the host from autoimmunity. The inhibitory functions of CD22/Siglec-2 and Siglec-G and their contributions to tolerance and autoimmunity, primarily in the B lymphocyte context, are considered in some detail in this review. The relevance to autoimmunity and unregulated inflammation of modified sialic acids, enzymes that modify sialic acid, and other sialic acid binding proteins are also reviewed. PMID:26683151

  4. Functional connectivity under optogenetic control allows modeling of human neuromuscular disease

    PubMed Central

    Steinbeck, Julius A.; Jaiswal, Manoj K.; Calder, Elizabeth L; Kishinevsky, Sarah; Weishaupt, Andreas; Toyka, Klaus V.; Goldstein, Peter A.; Studer, Lorenz

    2015-01-01

    Summary Capturing the full potential of human pluripotent stem cell (PSC)-derived neurons in disease modeling and regenerative medicine requires analysis in complex functional systems. Here we establish optogenetic control in human PSC-derived spinal motorneurons and show that co-culture of these cells with human myoblast-derived skeletal muscle builds a functional all-human neuromuscular junction that can be triggered to twitch upon light stimulation. To model neuromuscular disease we incubated these co-cultures with IgG from myasthenia gravis patients and active complement. Myasthenia gravis is an autoimmune disorder that selectively targets neuromuscular junctions. We saw a reversible reduction in the amplitude of muscle contractions, representing a surrogate marker for the characteristic loss of muscle strength seen in this disease. The ability to recapitulate key aspects of disease pathology and its symptomatic treatment suggests that this neuromuscular junction assay has significant potential for modeling of neuromuscular disease and regeneration. PMID:26549107

  5. [Sexuality and auto-immunity].

    PubMed

    Abraham, Georges; Vlatkovic, Dejan

    2010-03-24

    The idea that it might be a link between auto-immune affections and sexual disturbances could appear a vain purpose at a first glance. Nevertheless, as we start from a new point of view, it is understandable that we focus on a possible common tendency to develop self-aggression and self-destruction. Similarities which could play a role in the development of an auto-immune disease and of a sexual dixturbance as well.

  6. Xenobiotic Exposure and Autoimmune Hepatitis

    PubMed Central

    Gilbert, Kathleen M.

    2010-01-01

    Although genetics contributes to the development of autoimmune diseases, it is clear that “environmental” factors are also required. These factors are thought to encompass exposure to certain drugs and environmental pollutants. This paper examines the mechanisms that normally maintain immune unresponsiveness in the liver and discusses how exposure to certain xenobiotics such as trichloroethylene may disrupt those mechanisms and promote autoimmune hepatitis. PMID:21253536

  7. Autoimmune NMDA receptor encephalitis.

    PubMed

    Lazar-Molnar, Eszter; Tebo, Anne E

    2015-01-01

    Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune disease of the central nervous system (CNS) with prominent neurologic and psychiatric features at disease onset. The disease is associated with the production of autoantibodies to NMDAR, a protein involved in memory function and synaptic plasticity. Affected patients develop a multistage progressive illness with symptoms ranging from memory deficits, seizures and psychosis, to potentially lethal catatonia, and autonomic and breathing instability. The outcome can be much improved with accurate diagnosis and early treatment using adequate immunosuppressive therapy. However, since the neurological and psychiatric symptoms as well as the clinical examination results can be non-specific, the disease is probably under-recognized. Reliable and accurate clinical testing for the identification of NMDAR autoantibodies is crucial for diagnosis, timely treatment selection, and monitoring. Recently, a cell-based indirect immunofluorescent antibody test for the detection of IgG antibodies to NMDAR has become available for diagnostic use. This review highlights the progress and challenges of laboratory testing in the evaluation and management anti-NMDAR encephalitis, and perspectives for the future.

  8. Diagnosis of autoimmune pancreatitis.

    PubMed

    Matsubayashi, Hiroyuki; Kakushima, Naomi; Takizawa, Kohei; Tanaka, Masaki; Imai, Kenichiro; Hotta, Kinichi; Ono, Hiroyuki

    2014-11-28

    Autoimmune pancreatitis (AIP) is a distinct form of chronic pancreatitis that is increasingly being reported. The presentation and clinical image findings of AIP sometimes resemble those of several pancreatic malignancies, but the therapeutic strategy differs appreciably. Therefore, accurate diagnosis is necessary for cases of AIP. To date, AIP is classified into two distinct subtypes from the viewpoints of etiology, serum markers, histology, other organ involvements, and frequency of relapse: type 1 is related to IgG4 (lymphoplasmacytic sclerosing pancreatitis) and type 2 is related to a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis). Both types of AIP are characterized by focal or diffuse pancreatic enlargement accompanied with a narrowing of the main pancreatic duct, and both show dramatic responses to corticosteroid. Unlike type 2, type 1 is characteristically associated with increasing levels of serum IgG4 and positive serum autoantibodies, abundant infiltration of IgG4-positive plasmacytes, frequent extrapancreatic lesions, and relapse. These findings have led several countries to propose diagnostic criteria for AIP, which consist of essentially similar diagnostic items; however, several differences exist for each country, mainly due to differences in the definition of AIP and the modalities used to diagnose this disease. An attempt to unite the diagnostic criteria worldwide was made with the publication in 2011 of the international consensus diagnostic criteria for AIP, established at the 2010 Congress of the International Association of Pancreatology (IAP).

  9. Gravi-sensing microorganisms as model systems for gravity sensing in eukaryotes

    NASA Astrophysics Data System (ADS)

    Streb, C.; Richter, P.; Lebert, M.; Häder, D.-P.

    2001-08-01

    Gravi-sensing in single cells and multicellular organisms is a very active field of investigation. Similarities between gravity sensing mechanisms in uni- and multicellular eukaryotes make single cells ideal model systems for the understanding of gravity responses on the cellular and molecular level with far fetching significance for other systems. This article gives a short overview about gravi-sensing in plants (Arabidopsis, Chara) as well as the ciliates Loxodes and Paramecium and concentrates on gravitaxis research in the single cellular flagellate, Euglena gracilis. Experiments revealed the involvement of cAMP, Ca2+ specific mechanosensitive channels and membrane potential in the signal transduction chain of gravitaxis. Future perspectives for the use of motile, photosynthetic and other unicellular microorganisms for space applications e.g. for oxygen supply in life support systems or research on the origin of life are discussed.

  10. Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Thyroid Autoimmunity

    PubMed Central

    Watad, Abdulla; David, Paula; Brown, Stav; Shoenfeld, Yehuda

    2017-01-01

    The autoimmune/inflammatory syndrome induced by adjuvants (ASIA), presented by Shoenfeld and Agmon-Levin in 2011, is an entity that incorporates diverse autoimmune conditions induced by the exposure to various adjuvants. Adjuvants are agents that entail the capability to induce immune reactions. Adjuvants are found in many vaccines and used mainly to increase the response to vaccination in the general population. Silicone has also been reported to be able to induce diverse immune reactions. Clinical cases and series of heterogeneous autoimmune conditions including systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis have been reported to be induced by several adjuvants. However, only a small number of cases of autoimmune thyroid disorder have been included under the umbrella of ASIA syndrome. Indeed, clinical cases of Hashimoto’s thyroiditis and/or subacute thyroiditis were observed after the exposure to vaccines as well as silicone implantation. In our review, we aimed to summarize the current knowledge on ASIA syndrome presented as endocrinopathies, focusing on autoimmune thyroid disorders associated with the various adjuvants. PMID:28167927

  11. Occupational exposures and autoimmune diseases.

    PubMed

    Cooper, Glinda S; Miller, Frederick W; Germolec, Dori R

    2002-02-01

    Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely.

  12. Free radical theory of autoimmunity

    PubMed Central

    Kannan, Subburaj

    2006-01-01

    Background Despite great advances in clinical oncology, the molecular mechanisms underlying the failure of chemotherapeutic intervention in treating lymphoproliferative and related disorders are not well understood. Hypothesis A hypothetical scheme to explain the damage induced by chemotherapy and associated chronic oxidative stress is proposed on the basis of published literature, experimental data and anecdotal observations. Brief accounts of multidrug resistance, lymphoid malignancy, the cellular and molecular basis of autoimmunity and chronic oxidative stress are assembled to form a basis for the hypothesis and to indicate the likelihood that it is valid in vivo. Conclusion The argument set forward in this article suggests a possible mechanism for the development of autoimmunity. According to this view, the various sorts of damage induced by chemotherapy have a role in the pattern of drug resistance, which is associated with the initiation of autoimmunity. PMID:16759382

  13. Multiple autoimmune syndrome with celiac disease.

    PubMed

    Harpreet, Singh; Deepak, Jain; Kiran, B

    2016-01-01

    Multiple autoimmune syndrome (MAS) is a condition characterised by three or more autoimmune disorders in a same individual. Familial, immunologic and infectious factors are implicated in the development of MAS. Here we report a case of a 32-year-old woman with co-existence of four auto-immune diseases, namely autoimmune hypothyroidism, Sjögren's syndrome, systemic lupus erythematosus (SLE) and celiac disease which leads to the final diagnosis of multiple autoimmune syndrome type 3 with celiac disease. Patients with single autoimmune disorder are at 25% risk of developing other autoimmune disorders. The present case emphasises to clinicians that there is a need for continued surveillance for the development of new autoimmune disease in predisposed patients.

  14. Unbalanced Immune System: Immunodeficiencies and Autoimmunity

    PubMed Central

    Giardino, Giuliana; Gallo, Vera; Prencipe, Rosaria; Gaudino, Giovanni; Romano, Roberta; De Cataldis, Marco; Lorello, Paola; Palamaro, Loredana; Di Giacomo, Chiara; Capalbo, Donatella; Cirillo, Emilia; D’Assante, Roberta; Pignata, Claudio

    2016-01-01

    Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained. PMID:27766253

  15. Multiple autoimmune syndrome with celiac disease

    PubMed Central

    Harpreet, Singh; Kiran, B.

    2016-01-01

    Multiple autoimmune syndrome (MAS) is a condition characterised by three or more autoimmune disorders in a same individual. Familial, immunologic and infectious factors are implicated in the development of MAS. Here we report a case of a 32-year-old woman with co-existence of four auto-immune diseases, namely autoimmune hypothyroidism, Sjögren’s syndrome, systemic lupus erythematosus (SLE) and celiac disease which leads to the final diagnosis of multiple autoimmune syndrome type 3 with celiac disease. Patients with single autoimmune disorder are at 25% risk of developing other autoimmune disorders. The present case emphasises to clinicians that there is a need for continued surveillance for the development of new autoimmune disease in predisposed patients. PMID:28115785

  16. The genetics and epigenetics of autoimmune diseases

    PubMed Central

    Hewagama, Anura; Richardson, Bruce

    2010-01-01

    Self tolerance loss is fundamental to autoimmunity. While understanding of immune regulation is expanding rapidly, the mechanisms causing loss of tolerance in most autoimmune diseases remain elusive. Autoimmunity is believed to develop when genetically predisposed individuals encounter environmental agents that trigger the disease. Recent advances in the genetic and environmental contributions to autoimmunity suggest that interactions between genetic elements and epigenetic changes caused by environmental agents may be responsible for inducing autoimmune disease. Genetic loci predisposing to autoimmunity are being identified through multi-center consortiums, and the number of validated genes is growing rapidly. Recent reports also indicate that the environment can contribute to autoimmunity by modifying gene expression through epigenetic mechanisms. This article will review current understanding of the genetics and epigenetics of lupus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, using systemic lupus erythematosus as the primary example. Other autoimmune diseases may have a similar foundation. PMID:19349147

  17. The genetics and epigenetics of autoimmune diseases.

    PubMed

    Hewagama, Anura; Richardson, Bruce

    2009-08-01

    Self tolerance loss is fundamental to autoimmunity. While understanding of immune regulation is expanding rapidly, the mechanisms causing loss of tolerance in most autoimmune diseases remain elusive. Autoimmunity is believed to develop when genetically predisposed individuals encounter environmental agents that trigger the disease. Recent advances in the genetic and environmental contributions to autoimmunity suggest that interactions between genetic elements and epigenetic changes caused by environmental agents may be responsible for inducing autoimmune disease. Genetic loci predisposing to autoimmunity are being identified through multi-center consortiums, and the number of validated genes is growing rapidly. Recent reports also indicate that the environment can contribute to autoimmunity by modifying gene expression through epigenetic mechanisms. This article will review current understanding of the genetics and epigenetics of lupus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, using systemic lupus erythematosus as the primary example. Other autoimmune diseases may have a similar foundation.

  18. Vascular CD44 Expression and Breast Cancer Angiogenesis and Metastasis

    DTIC Science & Technology

    1999-09-01

    space is thus vital to understanding mechanisms of thymic atrophy. We have analyzed 87 normal and 31 myasthenia gravis thymus tissues from newborn to 78...Perivascular space of both normal adult and myasthenia gravis thymus contains mature single positive (CD la, CD4+ or CD8÷) T lymphocytes that express CD45RO...immune system that is not directly involved in thymopoiesis. Keywords: thymus , aging, perivascular space, myasthenia gravis , lymphocyte homing 3

  19. Human Response to Pyridostigmine Bromide.

    DTIC Science & Technology

    1984-03-01

    of myasthenia gravis for more than thirty years. The drug has also been widely used in surgical patients for the reversal of neuromuscular blockade...are generally related to overdosage; in treatment of myasthenia gravis , dosage must be adjusted to achieve optimal %. therapeutic effects with minimal...at Low doses, i.e. 30 mg at 8 hour intervals. 2 S6_ F--. -- -- -- -:" Y 6 TABLE OF CONTENTS II Page 5 TREATMENT OF MYASTHENIA GRAVIS 50 REVERSAL OF

  20. PubMed Central

    Breton, L.; Gosselin, Y.; Couture, L.

    1981-01-01

    Myasthenia gravis in a young dog Myasthenia gravis is a rare disease in dogs and cats. This article presents a case of myasthenia gravis affecting a young dog. The clinical signs are presented and there is a description of the typical attitude of the animal affected by this particular disease. The way to confirm the diagnosis is described and there is a discussion of the different aspects of the disease. PMID:7343070