Tumours of non-endocrine origin may exert deleterious effects by elaborating active principles which disturb body regulation. Systemic manifestations are fairly common with neoplasms of the lung, kidney, gastro-intestinal tract and thymus. The secretion of these tumours may have a known chemical structure (serotonin), may present hormone-like action (parathormone, antidiuretic hormone, insulinoid), or have well-defined biological properties (erythropoietin, gastrin-like principle). Tumours may stimulate endocrine glands by an unknown mechanism, producing disorders such as Cushing's syndrome, hypercalcemia, gynecomastia and hypoglycemia. Thymomas may be associated with autoimmune diseases. Tumours may extensively utilize or excrete some metabolite (glucose) or electrolyte (Na or K). Awareness of the systemic effects of various neoplasms may lead to an early diagnosis and proper treatment of these manifestations.
Sullivan, James D.; Rona, George
A non-human mammalian model of an autoimmune disorder co-expresses a major histocompatibility (MHC) class II-restricted T cell receptor (TCR) and a selected peptide that binds to the TCR. The selected peptide is selectively expressed by MHC class II posit...
A. J. Caton
Although many autoimmune disorders do not have a strong genetic basis, their treatment may nevertheless be improved by gene therapies. Most strategies seek to transfer genes encoding immunomodulatory products that will alter host immune responses in a beneficial manner. Used in this fashion, genes serve as biological delivery vehicles for the products they encode. By this means gene therapy overcomes
C. H. Evans; S. C. Ghivizzani; T. J. Oligino; P. D. Robbins
Celiac sprue (CS) is a gluten-sensitive enteropathy with many autoimmune features. CS involves multiple organs through immune and nonimmune processes, and is frequently associated with other autoimmune disorders. This article reviews the co-occurrence of CS with autoimmune disorders of the cutaneous, nervous, endocrine, musculoskeletal, gastrointestinal and cardiovascular systems. The types of autoimmune disorders associated with CS and the prevalence of CS in other autoimmune disorders are also discussed. A brief review of the literature on the potential mechanisms behind these associations and the therapeutic effects of a gluten-free diet for autoimmune comorbidities in CS is also provided. PMID:20477645
Rashtak, Shadi; Marietta, Eric V; Murray, Joseph A
Autoimmune bullous skin diseases, such as pemphigus vulgaris (PV) and bullous pemphigoid (BP), are severe, frequently life-threatening skin disorders. Immunologically, they are characterized by the presence of serum autoantibodies (auto-Ab) targeting distinct adhesion molecules of the epidermis or dermoepidermal basement membrane zone. Antibody (Ab) binding interferes with the adhesive function of these molecules, leading to detachment and subsequently blister formation.
Knowledge of immunity enables us to predict that the reactions set in response to infection with helminth would prevent concomitant disease driven by an opposing spectrum of immune events. In another way, the immune response generated to combat the helminth infection could counteract the immunopathological reactions that drive autoimmune diseases. Rodent model systems recapitulate many aspects of human autoimmune diseases and have been enormously useful in defining mechanisms of immunopathology after infection. From this theoretical perspective, many researchers have proved that infection with a variety of helminth can ameliorate disease in murine model systems. Thus, helminth-evoked Th2 events were shown to improve disorders in which Th1 events predominated. This raised the question, 'Can this information be translated into therapies for autoimmune diseases in humans via actual infection, cell delivery or drug intervention?' In this review, we will present some experimental trails to treat autoimmune disorders through establishment of some parasitic infections. PMID:21797885
El-Malky, M; Nabih, N; Heder, M; Saudy, N; El-Mahdy, M
Abnormal autoimmune activity has been implicated in a number of neuropsychiatric disorders. In this review, the authors discuss a newly recognized class of synaptic autoimmune encephalitides as well as behavioral and cognitive manifestations of systemic autoimmune diseases.
Kayser, Matthew S.; Dalmau, Josep
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) is a group of disorders recently recognized as a clinical entity. A case of PANDAS is described here, which remitted after 1 month of treatment. Recent Group A beta-hemolytic streptococcus infection should be considered in a child who presents with a sudden explosive onset of tics or obsessive compulsive symptoms. PMID:23372243
Maini, Baljeet; Bathla, Manish; Dhanjal, Gurdeep S; Sharma, Prem D
Systemic autoimmune disorders affect multiple organ systems. Brain involvement commonly causes seizures, which may be the presenting symptom. Systemic lupus erythematosus, Sjorgren's syndrome, Wegener's granulomatosis, sarcoidsosis, celiac disease, Crohn's disease, Behcet's, and Hashimoto's encephalopathy are reviewed. Mechanisms underlying CNS pathology in systemic autoimmune disorders—and specifically factors predisposing these patients—are discussed, including vascular disease (e.g., prothrombotic state, anticardiolipin antibody, emboli, vasculitis), antineuronal antibodies, immune complexes, cytokines, metabolic disorders, infection, and therapy. Diagnostic and therapeutic strategies must be individualized for both the disorder and the patient. Systemic autoimmune disorders affect multiple organ systems and frequently involve the central and peripheral nervous systems. Seizures are among the most common neurological manifestation and occasionally can be the presenting symptom. There are many causes of seizures in systemic autoimmune disorders (Table 1), and the first clinical challenge is to determine not only the cause but also the significance of seizures. In some cases, they are clues to metabolic or infectious disorders or medication toxicity; in other cases, seizures herald a life-threatening progression of the underlying illness.
Devinsky, Orrin; Schein, Adam; Najjar, Souhel
Even though autoimmune thyroiditis is considered as the most emblematic type of organ-specific autoimmune disorder of autoimmunity, autoimmune thyroid diseases can be associated with other autoimmune endocrine failures or non-endocrine diseases (namely vitiligo, pernicious anemia, myasthenia gravis, autoimmune gastritis, celiac disease, hepatitis). Thyroid disorders, which are the most frequent expression of adult polyendocrine syndrome type 2, occur concomitantly with or secondarily to insulinodependent diabetes, premature ovarian failure, Addison's disease (Schmidt syndrome, or Carpenter syndrome if associated with diabetes). Testicular failure and hypoparathyroidism are unusual. The disease is polygenic and multifactorial. Disorders of thyroid autoimmunity are, surprisingly, very rare in polyendocrine syndrome type 1 (or APECED) beginning during childhood. They are related to mutations of the AIRE gene that encodes for a transcriptional factor implicated in central and peripheral immune tolerance. Hypothyroidism can also be observed in the very rare IPEX and POEMS syndromes. PMID:23624130
Wémeau, Jean-Louis; Proust-Lemoine, Emmanuelle; Ryndak, Amélie; Vanhove, Laura
Most of the recently identified autoimmunity loci are shared among multiple autoimmune diseases. The pattern of genetic association with autoimmune phenotypes varies, suggesting that certain subgroups of autoimmune diseases are likely to share etiological similarities and underlying mechanisms of disease. In this review, we summarize the major findings from recent studies that have sought to refine genotype-phenotype associations in autoimmune disease by identifying both shared and distinct autoimmunity loci. More specifically, we focus on information from recent genome-wide association studies of rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and inflammatory bowel disease. Additional work in this area is warranted given both the opportunity it provides to elucidate pathogenic mechanisms in autoimmunity and its potential to inform the development of improved diagnostic and therapeutic tools for this group on complex human disorders.
A 10-year-old boy with acute onset cranial diabetes insipidus and multiple autoimmune disorders had evolving panhypopituitarism, thought to be due to autoimmune hypophysitis. Over 18 months, a dramatic clinical course with progressive hypopituitarism and development of type 1 diabetes mellitus was evident. Serial brain imaging showed changes suggestive of germinoma. PMID:23586429
Jevalikar, Ganesh; Wong, Sze Choong; Zacharin, Margaret
Patients undergoing autologous hemato- poietic stem cell transplantation (auto- HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. There- fore, we undertook a retrospective analy- sis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occur- rence of a second
Yvonne Loh; Yu Oyama; Laisvyde Statkute; Kathleen Quigley; Kimberly Yaung; Elizabeth Gonda; Walter Barr; Borko Jovanovic; Robert Craig; Dusan Stefoski; Bruce Cohen; Richard K. Burt
Objective Clinic-based studies of immune function, as well as comorbidity of autoimmune diseases, bipolar disorder, and schizophrenia, suggest a possible autoimmune etiology. Studies of non-affective psychosis and schizophrenia suggest common etiologies. The objective was to determine the degree to which 30 different autoimmune diseases are antecedent risk factors for bipolar disorder, schizophrenia, and non-affective psychosis. Methods A cohort of 3.57 million births in Denmark was linked to the Psychiatric Case Register and the National Hospital Register. There were 20,317 cases of schizophrenia, 39,076 cases of non-affective psychosis, and 9,920 cases of bipolar disorder. Results As in prior studies, there were a range of autoimmune diseases which predicted raised risk of schizophrenia in individuals who had a history of autoimmune diseases, and also raised risk in persons whose first-degree relatives had an onset of autoimmune disease prior to onset of schizophrenia in the case. These relationships also existed for the broader category of non-affective psychosis. Only pernicious anemia in the family was associated with raised risk for bipolar disorder (relative risk: 1.7), suggesting a small role for genetic linkage. A history of Guillain-Barré syndrome, Crohn’s disease, and autoimmune hepatitis in the individual was associated with raised risk of bipolar disorder. Conclusions The familial relationship of schizophrenia to a range of autoimmune diseases extends to non-affective psychosis, but not to bipolar disorder. The data suggest that autoimmune processes precede onset of schizophrenia, but also non-affective psychosis and bipolar disorder.
Eaton, William W; Pedersen, Marianne G; Nielsen, Philip R; Mortensen, Preben Bo
Autoimmune blistering diseases are associated with autoantibodies to desmosomal (pemphigus group) or hemidesmosomal proteins\\u000a (autoimmune subepidermal blistering disorders) that are essential for the structural integrity of the epidermis and dermoepidermal\\u000a junction. Treatment is usually based on systemic glucocorticosteroids, which are often combined with additional immunosuppressants\\u000a such as azathioprine and mycophenolate mofetil or immunomodulators including dapsone, antibiotics, and intravenous immunoglobulins.\\u000a These
Enno Schmidt; Eva-Bettina Bröcker; Matthias Goebeler
Autism is an age-dependent neurologic disorder that is often associated with autoimmune disorders in the patients' relatives. To evaluate the frequency of autoimmune disorders, as well as various prenatal and postnatal events in autism, we surveyed the families of 61 autistic patients and 46 healthy controls using questionnaires. The mean number of autoimmune disorders was greater in families with autism;
Anne M. Comi; Andrew W. Zimmerman; Virginia H. Frye; Paul A. Law; Joseph N. Peeden
Patients with hepatitis C virus (HCV) chronic infection may develop a great number of extrahepatic manifestations. Among these latter, mixed cryoglobulinemia (MC) represents the prototype of HCV-associated autoimmune-lymphoproliferative disorders. Other rheumatological manifestations of HCV chronic infection are Siögren syndrome, arthritis and CREST syndrome. Thyroid autoimmmune disorders are among the most frequent manifestations of HCV chronic infections and are clinically relevant because of the association with thyroid dysfunctions and hypothyroidism. Autoimmune cytopenia is also reported in association with HCV infection. This paper reviews the association of HCV chronic infection with the above mentioned pathologies, and their immunopathogenesis. PMID:24045529
Ferrari, S M; Fallahi, P; Mancusi, C; Colaci, M; Manfredi, A; Ferri, C; Antonelli, A
Summary Recent research on Anorexia Nervosa (AN) and Bulimia Nervosa (BN) has shown an increasing understanding of the biological and physiological abnormalities that underlie the development of an eating disorder. Cultural pressures, individual and family experiences, along with physiological and genetic systems all appear to contribute to the onset of these disorders. There is significant evidence for genetic factors in
Various case series of patients with autoimmune demyelinating disease affecting both the central and peripheral nervous system (CNS and PNS), either sequentially or simultaneously, have been reported for decades, but their frequency is considerably lower than that of the "classical" neurological autoimmune diseases affecting only either CNS or PNS, such as multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP) or Guillain-Barré-Syndrome (GBS), and attempts to define or even recognize the former as a clinical entity have remained elusive. Frequently, demyelination started with CNS involvement with subsequent PNS pathology, in some cases with a relapsing-remitting course. Three potential mechanisms for the autoimmune etiology of these conditions can be discussed: (I) They could be caused by a common autoimmunological reactivity against myelin antigens or epitopes present in both the central and peripheral nervous system; (II) They could be due to a higher general susceptibility to autoimmune disease, which in some cases may have been caused or exacerbated by immunomodulatory treatment, e.g. b-interferon; (III) Their co-occurrence might be coincidental. Another example of an autoimmune disease variably involving the central or peripheral nervous system or both is the overlapping and continuous clinical spectrum of Fisher syndrome (FS), as a variant of GBS, and Bickerstaff brainstem encephalitis (BBE). Recent data from larger patient cohorts with demonstration of common autoantibodies, antecedent infections, and results of detailed clinical, neuroimaging and neurophysiological investigations suggest that these three conditions are not separate disorders, but rather form a continuous spectrum with variable central and peripheral nervous system involvement. We herein review clinical and paraclinical data and therapeutic options of these disorders and discuss potential underlying common vs. divergent immunopathogenic mechanisms. PMID:21619947
Kamm, Christoph; Zettl, Uwe K
BACKGROUND: We conducted a study in order to determine the usefulness and diagnostic value of International Autoimmune Hepatitis Group (IAHG) score in non-autoimmune hepatitis (AIH) hepatic disorders as well as in AIH\\/overlap syndromes and in cases with coexistence of AIH and other liver diseases. METHODS: We applied the IAHG score in 423 patients with liver diseases excluding patients with AIH,
Panagiotis A Papamichalis; Kalliopi Zachou; George K Koukoulis; Aikaterini Veloni; Efthimia G Karacosta; Lampros Kypri; Ioannis Mamaloudis; Stella Gabeta; Eirini I Rigopoulou; Ansgar W Lohse; George N Dalekos
Abstract Question I have heard about children who have tic disorders that seem to be exacerbated by group A ?-hemolytic streptococcal infection. Should children presenting with this phenomenon receive treatment with antibiotics, receive prophylactic treatment, or use immunomodulators to treat the symptoms? Answer Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) constitute a condition that includes neuropsychiatric symptoms, mainly obsessive-compulsive disorder or tic disorders, temporally associated with an immune-mediated response to streptococcal infections. The actual existence of PANDAS as a unique clinical entity is still up for debate, as a temporal association between group A ?-hemolytic streptococcal infections and symptom exacerbations has been difficult to prove thus far. Based on only a few studies, positive results have been found using antibiotic prophylaxis and immunomodulatory therapy in children with PANDAS. At this time, however, evidence does not support a recommendation for long-term antibiotic prophylaxis or immunomodulatory therapy.
Tan, Jason; Smith, Christine H.; Goldman, Ran D.
Parkinson's disease (PD) is a motor disease including disorders of mobility, fine tremor, rigidity and posture caused by a relentless deterioration of dopaminergic cells in the substantia nigra (SN). Disorders of affect and a range of other symptoms including fatigue, cognitive dysfunction and mental confusion, sleep disorder and addictions are also seen as other CNS sites are also affected. Idiopathic and genetic causes together with inflammatory and degenerative disorders of ageing have been postulated as contributing to PD. Autoimmunity affecting certain vasoactive neuropeptides (VNs) has been postulated as contributing to certain fatigue-related conditions in humans and may be consistent with compromise of receptors associated with VNs and including receptors for vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Pro-inflammatory responses are seen in PD patients consistent with apoptotic neurodegeneration. Involvement of the Th1 directed cytokine interferon-gamma has been demonstrated and Th2 directed cytokines such as IL-10 protect against inflammation-mediated degeneration of dopaminergic neurons in the SN. Nitric-oxide dysregulation is also postulated in PD by fostering dopamine depletion via nitric-oxide synthase (iNOS). Both PACAP and VIP have neuroprotective effects in PD models by inhibiting the production of inflammatory mediators. PACAP specifically protects against the neurotoxicity induced by rotenone as well as protecting against oxidative stress-induced apoptosis. These findings suggest that a defect in VN function may act adversely on SN cells and hence contribute to a clinical presentation consistent with PD. The conclusion drawn from these findings is that PD may be an autoimmune disorder of VNs, specifically PACAP and VIP. Possibly unusual or anatomically specific receptors for these VNs may be involved. If proven, this hypothesis would have significant implications for immunological and pharmacological treatment and prevention of PD. PMID:17562359
Staines, Donald R
Demyelinating diseases with presumed autoimmune pathogenesis are characterised by direct or indirect immune-mediated damage to myelin sheaths, which normally surround nerve fibres to ensure proper electrical nerve conduction. Parenteral administration of polyclonal IgG purified from multi-donor human plasma pools may beneficially modulate these misguided immune reactions via several mechanisms that are outlined in this review. Convincing therapeutic evidence from controlled trials now exists for certain disorders of the peripheral nervous system, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. In addition, there is evidence for potential therapeutic benefits of IgG in patients with chronic inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis and neuromyelitis optica. This review introduces these disorders, briefly summarises the established treatment options, and discusses therapeutic evidence for the use of polyclonal immunoglobulins with a particular emphasis on recent clinical trials and meta-analyses. PMID:23791035
Buttmann, Mathias; Kaveri, Srini; Hartung, Hans-Peter
Background & Aims: The relationship between celiac disease and many autoimmune disorders has been explained by the sharing of a common genetic factor. In a multicenter national study, we examined the relationship between the prevalence of autoimmune disorders in celiac disease and the duration of exposure to gluten. Methods: Over a 6-month period, 909 patients with celiac disease (group A;
Alessandro Ventura; Giuseppe Magazzù; Luigi Greco
Important progress has been made in our understanding of the cellular and molecular processes underlying the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus guidelines for the treatment of the autoimmune NMT disorders. References retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts and a patient representative. The proposed practical treatment guidelines are agreed upon by the Task Force: (i) Anticholinesterase drugs should be the first drug to be given in the management of MG (good practice point). (ii) Plasma exchange is recommended as a short-term treatment in MG, especially in severe cases to induce remission and in preparation for surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and plasma exchange are equally effective for the treatment of MG exacerbations (level A Recommendation). (iv) For patients with non-thymomatous autoimmune MG, thymectomy (TE) is recommended as an option to increase the probability of remission or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is indicated irrespective of the severity of MG (level A recommendation). (vi) Oral corticosteroids is a first choice drug when immunosuppressive drugs are necessary in MG (good practice point). (vii) In patients where long-term immunosuppression is necessary, azathioprine is recommended together with steroids to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (level A recommendation). (viii) 3,4-diaminopyridine is recommended as symptomatic treatment and IvIg has a positive short-term effect in LEMS (good practice point). (ix) All neuromyotonia patients should be treated symptomatically with an anti-epileptic drug that reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive management of paraneoplastic neuromyotonia and LEMS is treatment of the underlying tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and NMT it is reasonable to adopt treatment procedures by analogy with MG (good practice point). PMID:16834699
Skeie, G O; Apostolski, S; Evoli, A; Gilhus, N E; Hart, I K; Harms, L; Hilton-Jones, D; Melms, A; Verschuuren, J; Horge, H W
As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 [ANNA-1] is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltage-gated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 [antiYo]). Positron-emission tomography-computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-d-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared. PMID:23983888
As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 [ANNA-1] is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltage-gated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 [antiYo]). Positron-emission tomography–computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-d-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared.
The lack of complete concordance of autoimmune disease in identical twins suggests that nongenetic factors play a major role in determining disease susceptibility. In this review, we consider how epigenetic mechanisms could affect the immune system and effector mechanisms in autoimmunity and/or the target organ of autoimmunity and thus affect the development of autoimmune diseases. We also consider the types of stimuli that lead to epigenetic modifications and how these relate to the epidemiology of autoimmune diseases and the biological pathways operative in different autoimmune diseases. Increasing our knowledge of these epigenetic mechanisms and processes will increase the prospects for controlling or preventing autoimmune diseases in the future through the use of drugs that target the epigenetic pathways.
Greer, Judith M; McCombe, Pamela A
Various case series of patients with autoimmune demyelinating disease affecting both the central and peripheral nervous system (CNS and PNS), either sequentially or simultaneously, have been reported for decades, but their frequency is considerably lower than that of the “classical” neurological autoimmune diseases affecting only either CNS or PNS, such as multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP) or
Christoph Kamm; Uwe K. Zettl
Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals.
Carl, Philip L; Temple, Brenda RS; Cohen, Philip L
Advances in understanding the pathogenesis of rheumatic diseases have led to the discovery of mechanisms of inflammation and\\u000a autoimmunity and have made possible the invention of new target-specific drugs. Biologic drugs, designed to inhibit specific\\u000a components of the immune system, such as cytokines, cytokine gene expression, and their complex interactions, have revolutionized\\u000a the treatment options in pediatric rheumatology. Only three
Luciana Breda; Marianna Del Torto; Sara De Sanctis; Francesco Chiarelli
Cooccurrences of chronic lymphocytic thyroiditis (CLT) and thyroid cancer (DTC) have been repeatedly reported. Both CLT and DTC, mainly papillary thyroid carcinoma (PTC), share some epidemiological and molecular features. In fact, thyroid lymphocytic inflammatory reaction has been observed in association with PTC at variable frequency, although the precise relationship between the two diseases is still debated. It also remains a matter of debate whether the association with a CLT or even an autoimmune disorder could influence the prognosis of PTC. A better understanding about clinical implications of autoimmunity in concurrent thyroid cancer could raise new insights of thyroid cancer immunotherapy. In addition, elucidating the molecular mechanisms involved in autoimmune disease and concurrent cancer allowed us to identify new therapeutic strategies against thyroid cancer. The objective of this article was to review recent literature on the association of these disorders and its potential significance. PMID:21403889
Cunha, L L; Ferreira, R C; Marcello, M A; Vassallo, J; Ward, L S
The present invention provides compositions and methods for preventing and treating gastrointestinal disorders by administering to a subject an effective amount of secretin either alone or in combination with an effective amount of oxytocin. The invention also provides compositions and methods for preventing and treating central nervous system disorders by administering to a subject an effective amount of secretin in combination with an effective amount of oxytocin. The invention further provides compositions and methods for treating and preventing a variety of autoimmune diseases by administering to a subject an effective amount of secretin in combination with an effective amount of oxytocin. Additionally, the invention provides compositions and methods for preventing and treating pain by administering to a subject using a combination of an effective amount of secretin and an effective amount of oxytocin. The invention also provides kits for use in treating and/or preventing gastrointestinal disorders, central nervous system disorders, autoimmune diseases and pain comprising a combination of secretin and oxytocin.
IMPORTANCE Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. OBJECTIVE To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. DESIGN Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. SETTING Individual data drawn from Danish longitudinal registers. PARTICIPANTS A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91?637 people having hospital contacts for mood disorders. MAIN OUTCOMES AND MEASURES The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. RESULTS A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60-1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. CONCLUSIONS AND RELEVANCE Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients. PMID:23760347
Benros, Michael E; Waltoft, Berit L; Nordentoft, Merete; Ostergaard, Søren D; Eaton, William W; Krogh, Jesper; Mortensen, Preben B
Obsessive-compulsive disorder (OCD) and related conditions including Tourette's disorder (TD) are chronic, relapsing disorders of unknown etiology associated with marked impairment and disability. Associated immune dysfunction has been reported and debated in the literature since the late 80s. The immunologic culprit receiving the most interest has been Group A Streptococcus (GAS), which began to receive attention as a potential cause of neuropsychiatric symptoms, following the investigation of the symptoms reported in Sydenham's chorea (SC) and rheumatic fever, such as motor tics, vocal tics, and both obsessive-compulsive and attention deficit/hyperactivity symptoms. Young children have been described as having a sudden onset of these neuropsychiatric symptoms temporally associated with GAS, but without supporting evidence of rheumatic fever. This presentation of OCD and tics has been termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS). Of note, SC, OCD, and TD often begin in early childhood and share common anatomic areas--the basal ganglia of the brain and the related cortical and thalamic sites--adding support to the possibility that these disorders might share a common immunologic and/or genetic vulnerability. Relevant manuscripts were identified through searches of the PsycINFO and MedLine databases using the following keywords: OCD, immune, PANDAS, Sydenham chorea, Tourette's disorder Group A Streptococcus. Articles were also identified through reference lists from research articles and other materials on childhood OCD, PANDAS, and TD between 1966 and December 2010. Considering the overlap of clinical and neuroanatomic findings among these disorders, this review explores evidence regarding the immunobiology as well as the relevant clinical and therapeutic aspects of TD, OCD, and PANDAS. PMID:20807070
Murphy, Tanya K; Kurlan, Roger; Leckman, James
Bipolar disorder (also called manic-depressive illness) is one of the major mood disorders. The term manic-depressive illness was introduced by Emil Kraepelin (1856-1926) in the late nineteenth century.1 It is in most patients a chronic illness with recurrent manic and depressive episodes, usually alternated with periods with normal mood between the episodes. A manic episode is characterised by an elevated,
R. C. Padmos
Uveitis is a complex multifactorial autoimmune disease of the eye characterized by inflammation of the uvea and retina, degeneration of the retina, and blindness in genetically predisposed patients. Using the rat model of experimental autoimmune uveitis (EAU), we previously identified three quantitative trait loci (QTL) associated with EAU on rat chromosomes 4, 12, and 10 (Eau1, Eau2, and Eau3). The primary goal of the current study is to delineate additional non-MHC chromosomal regions that control susceptibility to EAU, and to identify any QTLs that overlap with the QTLs of other autoimmune diseases. Using a set of informative microsatellite markers and F2 generations of resistant and susceptible MHC class II-matched rat strains (F344 and LEW), we have identified several new significant or suggestive QTLs on rat chromosomes 2, 3, 7, 10, and 19 that control susceptibility to EAU. A protective allele was identified in the susceptible LEW strain in the Eau5 locus at D7Wox18, and epistatic interactions between QTLs were found to influence the severity of disease. The newly identified regions (Eau4 through Eau9) colocalize with the genetic determinants of other autoimmune disease models, and to disease-regulating syntenic regions identified in autoimmune patients on human chromosomes 4q21-31, 5q31-33, 16q22-24, 17p11-q12, 20q11-13, and 22q12-13. Our results suggest that uveitis shares some of the pathogenic mechanisms associated with other autoimmune diseases, and lends support to the “common gene, common pathway” hypothesis for autoimmune disorders.
Mattapallil, Mary J.; Sahin, Azize; Silver, Phyllis B.; Sun, Shu-Hui; Chan, Chi-Chao; Remmers, Elaine F.; Hejtmancik, J. Fielding; Caspi, Rachel R.
While knowledge of the aetiology of psychiatric disorders is complex and has not been fully elucidated, recently it has been noted that a sizeable proportion of psychiatric patients have coexisting immunological health conditions. It is debatable whether inflammatory factors plays a role in the aetiology of the psychiatric conditions, or if psychiatric conditions predispose to immune dysfunction. However, previous work has given weight to the theory that the immune system has important neuromodulatory roles in the brain, and disturbances in this system can lead to psychiatric manifestations. Epidemiological evidence is needed to explore the strength of the correlation between immune conditions and psychiatric disorders, and this audit attempts to investigate this potential association using the psychiatric patient databaseof Bedford East Community Mental Health Team (Bedfordshire, UK). In this audit, the patient information was analysed to obtain prevalence data for an array of autoimmune conditions. This was then compared to the expected prevalence of the same autoimmune conditions. The results showed that patients with each psychiatric condition had a higher than expected prevalence of autoimmune conditions overall. The most striking discrepancy was that the percentage of patients with coexisting hypothyroidism was higher than expected in almost every psychiatric condition recorded. Other patterns in prevalence of autoimmune conditions were also noted. A causative link between psychiatric and autoimmune diseases is still questionable, and this issue needs to be researched further in terms of prevalence data and aetiological evidence. There are significant implications for clinical practice if a greater incidence of autoimmune conditions among psychiatric patients is proven. This includes screening opportunities and risk assessments, as well as potential for new pharmacological therapies based around immune regulation. PMID:23995199
Vaja, Rakhee; Agius, Mark; Zaman, Rashid
Some autoimmune disorders are increas- ingly recognized as risk factors for non- Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self- reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence
Karin Ekstrom Smedby; Claire M. Vajdic; Michael Falster; Eric A. Engels; Otoniel Martõ ´ nez-Maza; Jennifer Turner; Henrik Hjalgrim; Paolo Vineis; Adele Seniori Costantini; Paige M. Bracci; Elizabeth A. Holly; John J. Spinelli; Tongzhang Zheng; Brian C.-H. Chiu; Marc Maynadie; Paul Brennan; Scott Davis; James R. Cerhan; Elizabeth C. Breen; Andrew E. Grulich; Wendy Cozen
Thymoma-associated multi-organ autoimmunity is a rare, autoimmune disease that causes colitis, liver dysfunction and cutaneous graft-versus-host (GVH)-like skin damage. This paraneoplastic autoimmune disorder may be due to inadequate T cell selection in the tumour environment of the thymus. Although sporadic case reports have revealed its clinical features, little is known about its pathological mechanism. By comparing the skin-infiltrating T cell subsets with those of GVH disease (GVHD) and other inflammatory skin diseases, we sought to elucidate the pathological mechanism of thymoma-associated multi-organ autoimmunity. Histopathological and immunohistochemical analysis of skin biopsies was performed for three patients with thymoma-associated multi-organ autoimmunity. Histopathological findings of thymoma-associated multi-organ autoimmunity were indistinguishable from those of patients with acute GVHD, although the aetiologies of these diseases are completely different. The frequency of regulatory T cells (T(regs)) is reduced in cutaneous lesions and CD8+ cytotoxic T lymphocytes that massively infiltrate into the epidermis of patients with thymoma-associated multi-organ autoimmunity. Additionally, the ratio of T helper type 17 (Th17) cells to CD4+ cells in patients with thymoma-associated multi-organ autoimmunity and acute GVHD was higher than that in healthy controls, but similar to that in psoriasis vulgaris patients. Similarity of the skin-infiltrating T cell subsets with those of acute GVHD suggested that skin damage in patients with thymoma-associated multi-organ autoimmunity might be induced by self-reactive cytotoxic T lymphocytes under the diminished suppressive capacity of T(regs). PMID:21985362
Hanafusa, T; Azukizawa, H; Kitaba, S; Murota, H; Umegaki, N; Terao, M; Sano, S; Nakagiri, T; Okumura, M; Katayama, I
Background: A growing body of evidence suggests that styles of adaptation, assessed with the Serial Color-Word Test (S-CWT, a 5-trials Stroop task), are able to differentiate several mental and psychosomatic disorders. Recent findings have confirmed a very high rate of cases of autoimmune thyroiditis (so called Hashimoto disease) among bipolar patients, suggesting an etio-pathogenetic relatedness between the two ailments. Based
I. Alex Rubino; Giacomo Salvadore; Alberto Siracusano; Enrico Fidotti; Paolo Zuppi
This study evaluated neurocognitive functioning in 26 youth with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and primarily obsessive-compulsive disorder (OCD) symptoms. Marked impairment in visuospatial recall memory (as assessed using the Rey-Osterrieth Complex Figure Test) was observed in spite of average to above-average performance on academic and other neurocognitive measures. Group A beta-hemolytic Streptococcus titer elevations were associated with worse performance on tasks of neurocognitive and executive ability (Stroop Color-Word Interference Test), visuospatial memory, and fine motor speed (finger tapping) as well as elevated obsessive-compulsive symptom severity. PMID:22231309
Lewin, Adam B; Storch, Eric A; Mutch, P Jane; Murphy, Tanya K
Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies, accompanied by olfactory regional alterations in neuroimaging. Some evidence suggests that olfactory gene receptors have additional functions in the brain, related to their direct anatomical connection to the limbic system. For example, odor sensing may explain HLA-dissimilar mate selection in humans and animals. Recently, a large cluster of the olfactory receptor (OR) genes was mapped in proximity to the HLA locus on chromosome 6. The HLA and linked OR genes are clustered in haplotypes and are highly polymorphic. This finding may constitute an association among autoimmunity, psychiatric disorders and smell impairment. In this review, we examine the anatomic, genetic and clinical clues that may support an association among these conditions. PMID:19127459
Ortega-Hernandez, Oscar-Danilo; Kivity, Shaye; Shoenfeld, Yehuda
The nature of autoimmune polyglandular syndrome type 2 (APS-2) has been based on the presence of lymphocyte infiltration in\\u000a the affected gland, organ-specific antibodies (Abs) in the serum, cellular immune defects, and an association with the human\\u000a leukocyte antigen (HLA)-DR\\/DQ genes or immune-response genes. Autoantibodies to the various endocrine and non-endocrine tissues\\u000a not only offer a diagnostic clue to the
George J. Kahaly; Manuela Dittmar
Posttranslational modification (PTM) of antigen is a way to break T-cell tolerance to self-antigens and promote autoimmunity. However, the precise mechanisms by which modifications would facilitate autoimmune T-cell responses and how they relate to particular autoimmune-associated MHC molecules remain elusive. Celiac disease is a T-cell mediated enteropathy with a strong HLA association where the immune response is directed mainly against deamidated cereal gluten peptides that have been modified by the enzyme transglutaminase 2. The disease is further characterized by autoantibodies to transglutaminase 2 that have extraordinary high disease specificity and sensitivity. There have been important advances in the knowledge of celiac disease pathogenesis, and these insights may be applicable to other autoimmune disorders where posttranslational modification plays a role. This insight gives clues for understanding the involvement of PTMs in other autoimmune diseases.
Sollid, Ludvig M.; Jabri, Bana
Lyme disease (LD) is a complex, multisystemic illness. As the most common vector- borne disease in the United States, LD is caused by bacterial spirochete Borrelia burgdorferi sensu stricto, with potential coinfections from agents of anaplasmosis, babesiosis, and ehrlichiosis. Persistent symptoms and clinical signs reflect multiorgan involvement with episodes of active disease and periods of remission, not sparing the coveted central nervous system. The capability of microorganisms to cause and exacerbate various neuropsychiatric pathology is also seen in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), a recently described disorder attributed to bacterium Streptococcus pyogenes of group A beta-hemolytic streptococcus in which neurologic tics and obsessive-compulsive disorders are sequelae of the infection. In the current overview, LD and PANDAS are juxtaposed through a review of their respective infectious etiologies, clinical presentations, mechanisms of disease development, courses of illness, and treatment options. Future directions related to immunoneuropsychiatry are also discussed.
Rhee, Hanna; Cameron, Daniel J
Children with obsessive compulsive disorder or tic disorders that are associated with streptococcal infections (Group A beta-hemolytic) in the oro-pharyngeal region are given the diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Tonsillectomy has been reported to resolve the neuro-psychiatric symptoms in these children. We have a case of a 9-year-old boy who was seen in our clinic with multiple recurrent streptococcal infections of the oro-pharyngeal cavity. He also exhibited neuro-psychiatric symptoms including agitation, hyperactivity, and tics. These symptoms followed his recurrent infections. Tonsillectomy was performed and in one year follow-up the patient did not have any recurrent streptococcal infections, and his neuro-psychiatric symptoms resolved completely. Guidelines for medical and surgical management of recurrent strep infections in the face of PANDAS are reviewed. PMID:21466900
Alexander, Alan A Z; Patel, Nitin J; Southammakosane, Cathy A; Mortensen, Melissa M
|A multicenter study of 308 children with Autism Spectrum Disorder (ASD) was conducted through the Collaborative Programs of Excellence in Autism (CPEA), sponsored by the National Institute of Child Health and Human Development, to compare the family history of autoimmune disorders in children with ASD with and without a history of regression. A…
Molloy, Cynthia A.; Morrow, Ardythe L.; Meinzen-Derr, Jareen; Dawson, Geraldine; Bernier, Raphael; Dunn, Michelle; Hyman, Susan L.; McMahon, William M.; Goudie-Nice, Julie; Hepburn, Susan; Minshew, Nancy; Rogers, Sally; Sigman, Marian; Spence, M. Anne; Tager-Flusberg, Helen; Volkmar, Fred R.; Lord, Catherine
Lymphoproliferative disorders (LPDs) may involve intrathoracic organs in patients with autoimmune disease, but little is known about the radiologic manifestations of autoimmune disease-associated LPDs (ALPDs) of the lungs. The purpose of our work was to identify the radiologic characteristics of pulmonary involvement in ALPDs. A comprehensive search for PubMed database was conducted with the combination of MeSH words. All articles which had original images or description on radiologic findings were included in this analysis. Also, CT images of eight patients with biopsy-proven lymphoproliferative disorder observed from our institution were added. Overall, 44 cases of ALPD were identified, and consisted of 24 cases of bronchus-associated lymphoid tissue lymphoma (BALToma), eight cases of non-Hodgkin's lymphoma (NHL), six cases of lymphoid interstitial pneumonia (LIP), two cases of nodular lymphoid hyperplasia, two cases of unclassified lymphoproliferative disorder, and one case each of lymphomatoid granulomatosis and hyperblastic BALT. Multiple nodules (n?=?14, 32 %) and single mass (n?=?8, 18 %) were the predominant radiologic manifestations. The imaging findings conformed to previously described findings of BALToma, NHL, or LIP. Data suggest that BALToma, NHL, and LIP are the predominant ALPDs of the lung, and ALPD generally shared common radiologic features with sporadic LPDs. Familiarity with ALPDs and their imaging findings may enable radiologists or clinicians to include the disease as a potential differential diagnosis and thus, to prompt early biopsy followed by appropriate treatment. PMID:23728499
Lee, Geewon; Lee, Ho Yun; Lee, Kyung Soo; Lee, Kyung Jong; Cha, Hoon-Suk; Han, Joungho; Chung, Man Pyo
This paper discusses concepts and terminology of some aspects of the autoimmune and rheumatic disorders as related to medical reference work. Details of anatomic, biochemical, and pathologic processes are not discussed. Knowledge of the specific terminology involved in this area may help to ensure a good approach to developing prudent strategies for database searching of the medical literature and, therefore, is reviewed. MeSH thesaurus terms are shown and textword synonyms are presented that provide tools for thorough searching techniques. Commonly used medical jargon as well as older terminology for this area is also explained. Examples of specific search strategies are illustrated. PMID:14711045
Fikar, Charles R
Interferons (IFNs) are now known to exert a multitude of immunological functions on both the innate and adaptive immunity. Given their pleiotropic effects on the immune system, it is conceivable that excess type I IFN or aberrant regulation of its signaling could contribute to autoimmunity. Several lines of evidence link IFNs to autoimmune disorders, in particular to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Expression of a spectrum of genes that constitutes an "IFN signature" is the most significant observation indicating that IFNs may be dominant among the pathogenic mediators involved in some autoimmune diseases. A family of IFN-inducible genes, designated HIN-200 in the human and IFI-200 in the murine species, encodes evolutionary related human (IFI16, MNDA, AIM2, IFIX) and murine proteins (Ifi202 a, Ifi202b, Ifi203, Ifi204, Ifi205/D3). Physiological IFI16 expression was found in cells of the immune system, in endothelial cells, and in stratified squamous epithelia, such as skin. The presence of anti-IFI16 antibodies was reported in SLE and primary/secondary Sjögren's syndrome. More recently, we reported that anti-IFI16 autoantibodies differentiate limited cutaneous systemic sclerosis (lcSSc) from diffuse systemic sclerosis (dcSSc). Molecular studies performed in primary endothelial cells overexpressing IFI16 demonstrated that it may be involved in the early steps of inflammation by modulating endothelial cell function, such as expression of adhesion molecules and chemokine production, cell growth, and apoptosis. Moreover, here we report that IFI16 expression is induced by proinflammatory cytokines. In this article the role of the IFI16 protein and its corresponding autoantibodies in the etiopathogenesis of systemic autoimmune diseases, in which chronic inflammation is involved, are discussed. PMID:17911419
Mondini, Michele; Vidali, Matteo; Airò, Paolo; De Andrea, Marco; Riboldi, Piersandro; Meroni, Pier Luigi; Gariglio, Marisa; Landolfo, Santo
Prevailing approaches to manage autoimmune thrombotic disorders, such as heparin-induced thrombocytopenia, antiphospholipid syndrome and thrombotic thrombocytopenic purpura, include immunosuppression and systemic anticoagulation, though neither provides optimal outcome for many patients. A different approach is suggested by the concurrence of autoantibodies and their antigenic targets in the absence of clinical disease, such as platelet factor 4 in heparin-induced thrombocytopenia and ?(2)-glycoprotein-I (?(2)GPI) in antiphospholipid syndrome. The presence of autoantibodies in the absence of disease suggests that conformational changes or other alterations in endogenous protein autoantigens are required for recognition by pathogenic autoantibodies. In thrombotic thrombocytopenic purpura, the clinical impact of ADAMTS13 deficiency caused by autoantibodies likely depends on the balance between residual antigen, that is, enzyme activity, and demand imposed by local genesis of ultralarge multimers of von Willebrand factor. A corollary of these concepts is that disrupting platelet factor 4 and ?(2)GPI conformation (or ultralarge multimer of von Willebrand factor oligomerization or function) might provide a disease-targeted approach to prevent thrombosis without systemic anticoagulation or immunosuppression. Validation of this approach requires a deeper understanding of how seemingly normal host proteins become antigenic or undergo changes that increase antibody avidity, and how they can be altered to retain adaptive functions while shedding epitopes prone to elicit harmful autoimmunity. PMID:22966172
Cines, Douglas B; McCrae, Keith R; Zheng, X Long; Sachais, Bruce S; Luning Prak, Eline T; Siegel, Don L
Dendritic cells (DC), considered as immunological sentinels of the organism since they are antigen presenting cells, create the link between innate and adaptive immunity. DC include myeloid dendritic cells (MDC) and plasmacytoid dendritic cells (PDC). The presence of PDC, cells capable of producing large quantities of interferon alpha (IFN-?) in response to pathogenic agents or danger signals, seem to be tightly related to pathological conditions. Thereby, PDC have been observed in inflammatory immunoallergic dermatological disorders, in malignant cutaneous tumours and in cutaneous lesions of infectious origin. They seem to play a crucial role in the initiation of the pathological process of autoimmune diseases such as lupus or psoriasis. Their function within a tumour context is not as well known and is controversial. They could have a tolerogenic role towards tumour cells in the absence of activator but they also have the capacity to become activated in response to Toll-like receptor (TLR) ligands and could therefore be usefull for therapeutic purposes.
Charles, Julie; Chaperot, Laurence; Salameire, Dimitri; Di Domizio, Jeremy; Aspord, Caroline; Gressin, Remy; Jacob, Marie-Christine; Richard, Marie-Jeanne; Beani, Jean-Claude; Plumas, Joel; Leccia, Marie-Therese
Abstract Objective The objectives of this study were to identify unique clinical characteristics of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) compared with a control group of children with non-PANDAS obsessive-compulsive disorder (OCD) with respect to ancillary symptoms, types of obsessions and compulsions, symptom severity, and co-morbid DSM-IV diagnoses. Method Classification of PANDAS was based on review of pediatric and psychiatric records using the criteria developed by Swedo and colleagues. Children aged 6–14 with PANDAS (n?=?21) and non-PANDAS OCD (n?=?18) were assessed by blind independent evaluators using the PANDAS Questionnaire, Children's Yale-Brown Obsessive Compulsive Scale, Yale Global Tic Severity Scale, and Anxiety Disorders Interview Schedule for DSM-IV. Results PANDAS children were significantly more likely to present with separation anxiety, urinary urgency, hyperactivity, impulsivity, deterioration in handwriting, and decline in school performance during their initial episode of neuropsychiatric illness compared with children with OCD. Total tics and vocal tics were more severe in PANDAS children. Separation anxiety disorder and social phobia were more prevalent in non-PANDAS OCD children. Children with non-PANDAS OCD were significantly more likely to include others in their rituals. There were no significant differences between groups on demographics or severity of OCD. Conclusions Distinguishing clinical characteristics in PANDAS, which included urinary urgency, hyperactivity, impulsivity, and deterioration in handwriting, are linked to basal ganglia functions. These clinical characteristics will aid in the differentiation of PANDAS children for research and clinical purposes and ultimately advance our understanding and treatment of this disorder.
Victor, Andrea M.; Pipal, Allison J.; Williams, Kyle A.
Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham’s chorea (SC)—the prototypical post-streptococcal neuropsychiatric disorder—and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo’s criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo’s criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders.
Macerollo, Antonella; Martino, Davide
Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham's chorea (SC)-the prototypical post-streptococcal neuropsychiatric disorder-and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo's criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo's criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders. PMID:24106651
Macerollo, Antonella; Martino, Davide
Summary High-dose intravenous immunoglobulin (hdIVIg) is being used increasingly for dermatological indications. Its mode of action is via a number of proposed mechanisms and it is not associated with the many side-effects of steroids and other immunosuppressive agents. The evidence for using hdIVIg in the treatment of autoimmune bullous disorders is based on uncontrolled trials and case reports. However, there
In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4(+)HLA-DR(+), CD8(+) T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-?/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection. PMID:23936564
Coelho-Dos-Reis, Jordana Grazziela Alves; Passos, Livia; Duarte, Mariana Costa; Araújo, Marcelo Grossi; Campi-Azevedo, Ana Carolina; Teixeira-Carvalho, Andréa; Peruhype-Magalhães, Vanessa; Trindade, Bruno Caetano; Dos Santos Dias, Raquel; Martins, Marina Lobato; Carneiro-Proietti, Anna Barbara de Freitas; Guedes, Antônio Carlos; Gonçalves, Denise Utsch; Martins-Filho, Olindo Assis
In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4+HLA-DR+, CD8+ T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-?/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection.
Duarte, Mariana Costa; Araujo, Marcelo Grossi; Campi-Azevedo, Ana Carolina; Teixeira-Carvalho, Andrea; Peruhype-Magalhaes, Vanessa; Trindade, Bruno Caetano; dos Santos Dias, Raquel; Martins, Marina Lobato; Carneiro-Proietti, Anna Barbara de Freitas; Guedes, Antonio Carlos; Goncalves, Denise Utsch; Martins-Filho, Olindo Assis
Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29?423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.
Vajdic, Claire M.; Falster, Michael; Engels, Eric A.; Martinez-Maza, Otoniel; Turner, Jennifer; Hjalgrim, Henrik; Vineis, Paolo; Seniori Costantini, Adele; Bracci, Paige M.; Holly, Elizabeth A.; Willett, Eleanor; Spinelli, John J.; La Vecchia, Carlo; Zheng, Tongzhang; Becker, Nikolaus; De Sanjose, Silvia; Chiu, Brian C.-H.; Dal Maso, Luigino; Cocco, Pierluigi; Maynadie, Marc; Foretova, Lenka; Staines, Anthony; Brennan, Paul; Davis, Scott; Severson, Richard; Cerhan, James R.; Breen, Elizabeth C.; Birmann, Brenda; Grulich, Andrew E.; Cozen, Wendy
It is believed that in utero environmental factors contribute to autism spectrum disorder (ASD). The goal of this study was to demonstrate, using the largest cohort reported so far, that mothers of an ASD child have an elevated frequency of anti-brain antibodies and to assess whether brain reactivity is associated with an autoimmune diathesis of the mother. We screened plasma of 2431 mothers of an ASD child from Simon Simplex Collection and plasma of 653 unselected women of child-bearing age for anti-brain antibodies using immunohistology on mouse brain. Positive and negative plasma from mothers with an ASD child were analyzed for anti-nuclear antibodies and for autoimmune disorders. Mothers of an ASD child were four times more likely to harbor anti-brain antibodies than unselected women of child-bearing age (10.5 vs 2.6%). A second cohort from The Autism Genetic Resource Exchange with multiplex families displayed an 8.8% prevalence of anti-brain antibodies in the mothers of these families. Fifty-three percent of these mothers with anti-brain antibodies also exhibited anti-nuclear autoantibodies compared with 13.4% of mothers of an ASD child without anti-brain antibodies and 15% of control women of child-bearing age. The analysis of ASD mothers with brain-reactive antibodies also revealed an increased prevalence of autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus. This study provides robust evidence that brain-reactive antibodies are increased in mothers of an ASD child and may be associated with autoimmunity. The current study serves as a benchmark and justification for studying the potential pathogenicity of these antibodies on the developing brain. The detailed characterization of the specificity of these antibodies will provide practical benefits for the management and prevention of this disorder. PMID:23958959
Brimberg, L; Sadiq, A; Gregersen, P K; Diamond, B
This study was purposed to investigate the clinical characteristics of B-cell chronic lymphoproliferative disorders (B-CLPD) complicated by autoimmune hemolytic anemia (AIHA) so as to improve the understanding of this disease. The clinical characteristics, laboratory data, therapy and outcome of 14 patients suffering from B-CLPD complicated by AIHA were restrospectively analyzed in Wuxi People Hospital and the First Affiliated Hospital of Nanjing Medical University from 2000 to 2012. The results showed that 9 cases of the 14 patients were patients with chronic lymplocytic leukemia (CLL), 5 cases were patients with lymphoma, at time of hemolysis the median level of hemoglobine was 61 (33 - 84)g/L, the median ratio of reticulocytes was 12.0 (3.1 - 35.0)%, the positive rate of Coombs test was 100%. 1 case received corticosteroid alone, 5 cases were treated with chemotherapy combined with corticosteroid, 8 cases were treated with immunochemotherapy rituximab combined with corticosteroid. Overall response rate was 100%, in which CR was 78.6% (11/14), PR was 21.4% (3/14). The follow-up for these patients were performed to now, 35.7% (5/14) patients relapsed with hemolysis again, but they showed therapeutic response to treatment with above-menthoned therapy. From patients treated with rituximab alone, only 1 patient relapsed. Among 14 patients, 6 cases died, 1 case was lost, the other cases are still alive. It is concluded that the AIHA is the commonest complication of B-CLPD, it can be observed at different stages of B-CLPD, the treatment with corticosteroids can give well therapeutic effect for these patients, but the long time CR is lower, the rituximab has been confirmed to be effective for B-CLPD complicated by AIHA. PMID:23815912
Zhuang, Yun; Fan, Lei; Shen, Yun-Feng; Xu, Wei; Li, Jian-Yong
Induced apoptosis of autoreactive T-lymphocyte precursors in the thymus is crucial for the prevention of autoimmune disorders. IGF-I and prolactin, which are lymphocyte growth factors, may have the potential to suppress apoptosis in thymocytes and thus encourage autoimmunity; conversely, dietary fish oil rich in omega-3 fats appears to upregulate apoptosis in lymphocytes. Since whole-food vegan diets may downregulate systemic IGF-I
M. F. McCarty
Aims\\/hypothesis Thyroid autoimmunity clusters with other endocrine and non-endocrine forms of autoimmunity. The aim of this study was to determine\\u000a the chronological appearance of thyroid autoantibodies in relation to other forms of autoimmunity in at-risk children.\\u000a \\u000a \\u000a \\u000a Methods The BABYDIAB study follows children of parents with type 1 diabetes. Children born in Germany between 1989 and 2000 were recruited\\u000a at birth and followed
E. Bonifacio; A. Mayr; A. Knopff; A.-G. Ziegler
Signal transducer and activator of transcription 4 (STAT4) has been recently identified as a susceptibility gene for multiple autoimmune diseases. Here we performed a comprehensive analysis of the association between STAT4 and several different autoimmune disorders to identify potential common inflammatory principles behind this association. Our meta-analysis revealed that the STAT4 rs7574865 polymorphism is associated with four autoimmune diseases with systemic pathology, including systemic lupus erythematosus (OR = 1.52; 95% CI = 1.48 - 1.56, P<1.0 × 10(-16)), rheumatoid arthritis (OR = 1.27; 95% CI = 1.21 - 1.33, P < 1.00 × 10(-16)), systemic sclerosis (OR = 1.38; 95% CI = 1.27 - 1.50, P < 1.44 × 10(-14)), and primary Sjogren's syndrome (OR = 1.32; 95% CI = 1.01 - 1.73, P = 4.40 × 10(-2)), while no association was found with type I diabetes, juvenile idiopathic arthritis, ulcerative colitis and Crohn's disease. Furthermore, the stratified meta-analysis also demonstrate that the STAT4 rs7574865 polymorphism is associated with the presence of autoantibodies with systemic reactivity (anti-ds-DNA antibodies) in SLE patients (OR = 1.37; 95% CI = 1.21 - 1.56, P = 1.12 × 10(-6)). However, no such specific association was seen in RA with regard to the presence of non-systemically reacting antibodies, including rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Taken together, these results suggest that STAT4 polymorphisms are associated with autoimmune diseases which are characterized by a systemic pathology and anti-dsDNA antibody. PMID:23628400
Zheng, Junfeng; Yin, Junping; Huang, Renliang; Petersen, Frank; Yu, Xinhua
We investigated the effects of the neuroprotective drug cerebrolysin on the autoimmune parameters (FasL, Fas and metallotionein-1) in 20 newborns with perinatal ischemic CNS damage and 20 healthy newborns. The treatment with cerebrolysin in dosage of 0,1 ml per 1 kg of body mass, 10 injections every other day, resulted in the normalization (p<0,001) of the T-lymphocyte apoptosis (the increase of Fas and decrease of FasL) and activation of antioxidant protection through the increase of metallotionein-1 expression. The normalization of the autoimmunity was found to reduce edema and improve the circulation of the brain sites affected with ischemia. PMID:19008804
Serkina, E V; Gromova, O A; Torshin, I Iu; Sotnikova, N Iu; Nikonov, A A
The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto's) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves' disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF ?1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF ?2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS. PMID:22342295
Bakalov, Vladimir K; Gutin, Liat; Cheng, Clara M; Zhou, Jian; Sheth, Puja; Shah, Kavita; Arepalli, Sruthi; Vanderhoof, Vien; Nelson, Lawrence M; Bondy, Carolyn A
Autoimmune pancreatitis (AIP) is a rare, heterogeneous, fibroinflammatory disorder of the pancreas. It has gained increasing recognition due to a presentation that can mimic difficult to treat disorders such as pancreatic cancer, cholangiocarcinoma and primary sclerosing cholangitis. In contrast, autoimmune pancreatitis is a benign disease that is very responsive to therapy with corticosteroids. There are two types of AIP. Type 1 disease is the most common worldwide and is associated with extrapancreatic manifestations and elevated levels of IgG4-positive cells. Type 2 AIP is characterized by a paucity of IgG4-positive cells, and is more difficult to diagnose. This review provides an update on the diagnosis, pathophysiology and treatment of AIP, with special emphasis on the two subtypes.
Ketwaroo, Gyanprakash A; Sheth, Sunil
Several autoimmune diseases are particularly important to oral health and nutrition because of their direct impact on the\\u000a oral mucosa, masticatory apparatus, salivary glands, teeth and supporting structures, oral pain, or mechanical ability to\\u000a chew. For some disorders, the earliest signs of systemic illness are found in the oral cavity, and these remain as significant\\u000a manifestations of the primary immune
David A. Sirois; Riva Touger-Decker
This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD. PMID:16685179
Valicenti-McDermott, Maria; McVicar, Kathryn; Rapin, Isabelle; Wershil, Barry K; Cohen, Herbert; Shinnar, Shlomo
Clustering of Autoimmune Diseases (CAD) is now emerging as a novel clinical entity within monogenic immune defects with a high familial occurrence. Aim of this study is to evaluate the regulatory mechanisms governing cell survival, paying a particular attention to Fas-induced apoptosis, in a cohort of 23 children affected with CAD. In 14 patients, Fas stimulation failed to induce cell apoptosis and in 1 case it was associated with Fas gene mutation. Our study highlights the importance to evaluate cell apoptosis in the group of children with CAD, which, with this regard, represents a distinct clinical entity.
Background Soluble CD200 (sCD200) is a novel immuno-effective molecule, which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was present in serum and blister fluid in a patient with bullous pemphigoid and a patient with toxic epidermal necrolysis. We therefore planned this study to evaluate the sCD200 levels of autoimmune and inflammatory skin disorder patients and to compare them with that of healthy controls. Material and Methods Our study included 30 consecutive patients with psoriasis vulgaris, 15 with pemphigus vulgaris, and 15 healthy controls. Clinical examination and laboratory tests were performed on the same day. Psoriasis patients were also assessed with the Psoriasis Area and Severity Index (PASI) and pemphigus patients were assessed using the Pemphigus Disease Area Index (PDAI). Levels of sCD200 in the serum samples were quantified using ELISA kits. Results The serum sCD200 level was observed to be statistically significantly higher in patients with psoriasis vulgaris (96.7±15.8) compared to patients with pemphigus vulgaris (76.2±14.6), (p<0.001) and healthy controls (26.8±7.0) (p<0.001). The serum sCD200 levels were observed to be statistically significantly higher in patients with pemphigus vulgaris compared with that in healthy controls (p<0.001). In addition, there was a statistically significant correlation between serum sCD200 levels and PDAI (r=0.987, p=0.001). Nevertheless, there was no statistically significant correlation between serum sCD200 levels and PASI (r=0.154, p=0.407). Conclusions sCD200 might play a role in immune response in the pathogenesis of autoimmune and inflammatory skin disorders. However, it remains to be fully elucidated how sCD200 can orchestrate inflammatory response in psoriasis and pemphigus. PMID:24157657
Akman-Karaka?, Ay?e; Yalcin, Arzu Didem; Koç, Saliha; Gumuslu, Saadet; Senol, Ye?im Yi?iter; Ozkesici, Birgül; Genç, Gizem Esra; Ergun, Erkan; Ongut, Gozde; Yilmaz, Ertan; Uzun, Soner; Alpsoy, Erkan
Thyroid disorders are common in chronic kidney disease. The aim of this study was to examine the role of renal anemia on thyroid function, morphology and autoimmunity in clinically euthyroid patients on chronic hemodialysis (HD). Prospective study during 12 months period included 40 stable patients on chronic HD treatment. Patients were divided into two groups according to the serum hemoglobin level (group A Hgb > 125 g / L and group B Hgb < 125 g / L). Blood samples were taken for determination total and free thyroid hormones, thyroid antibodies and standard biochemical tests. Thyroid ultrasonography was performed with a 7.5 MHz transducer, 50 mm linear transducer. Thyroid volume was calculated, echostructure assessed and presence of nodular changes. In group A, was found significantly lower levels of total T3 (1.29 +/- 0469 vs. 1.55 +/- 0352, p < 0.1); higher prevalence of low T3 syndrome (17.24% (n = 5) vs. 0.00 (n = 0), p < 0.05); ultrasound findings suggestive for Hashimoto thyroiditis (13.79 (n = 4) vs. 0.00% (n = 0), p < 0.05) and multinodular goiter (13.79% (n = 4) vs. 0.00% (n = 0), p < 0.05). We found no statistically significant difference in the mean values of of thyroid antibodies levels, as well as in their percentage representation among groups. Morphological, functional and autoimmune disorders of thyroid gland are more common in patients on HD with Hgb level < 125 g/L. These findings suggest a role of renal anemia in the pathogenesis of these, and need for periodical screening of thyroid function, morphology, and titer of thyroid antibodies in patients HD, as well as more effective diagnosis and more aggressive treatment of renal anemia. PMID:21950230
Jusufovic, Selma; Hodzic, Emir; Halilcevic, Alma
Background Soluble CD200 (sCD200) is a novel immuno-effective molecule, which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was present in serum and blister fluid in a patient with bullous pemphigoid and a patient with toxic epidermal necrolysis. We therefore planned this study to evaluate the sCD200 levels of autoimmune and inflammatory skin disorder patients and to compare them with that of healthy controls. Maleral/Methods Our study included 30 consecutive patients with psoriasis vulgaris, 15 with pemphigus vulgaris, and 15 healthy controls. Clinical examination and laboratory tests were performed on the same day. Psoriasis patients were also assessed with the Psoriasis Area and Severity Index (PASI) and pemphigus patients were assessed using the Pemphigus Disease Area Index (PDAI). Levels of sCD200 in the serum samples were quantified using ELISA kits. Results The serum sCD200 level was observed to be statistically significantly higher in patients with psoriasis vulgaris (96.7±15.8) compared to patients with pemphigus vulgaris (76.2±14.6), (p<0.001) and healthy controls (26.8±7.0) (p<0.001). The serum sCD200 levels were observed to be statistically significantly higher in patients with pemphigus vulgaris compared with that in healthy controls (p<0.001). In addition, there was a statistically significant correlation between serum sCD200 levels and PDAI (r=0.987, p=0.001). Nevertheless, there was no statistically significant correlation between serum sCD200 levels and PASI (r=0.154, p=0.407). Conclusions sCD200 might play a role in immune response in the pathogenesis of autoimmune and inflammatory skin disorders. However, it remains to be fully elucidated how sCD200 can orchestrate inflammatory response in psoriasis and pemphigus.
Akman-Karakas, Ayse; Yalcin, Arzu Didem; Koc, Saliha; Gumuslu, Saadet; Senol, Yesim Yigiter; Ozkesici, Birgul; Genc, Gizem Esra; Ergun, Erkan; Ongut, Gozde; Yilmaz, Ertan; Uzun, Soner; Alpsoy, Erkan
B cell-directed therapies are promising treatments for autoimmune disorders. Besides targeting CD20, newer B cell-directed therapies are in development that target other B cell surface molecules and differentiation factors. An increasing number of B cell-directed therapies are in development for the treatment of autoimmune disorders. Like rituximab, which is approved as a treatment for rheumatoid arthritis (RA), many of these newer agents deplete B cells or target pathways essential for B cell development and function; however, many questions remain about their optimal use in the clinic and about the role of B cells in disease pathogenesis. Other therapies besides rituximab that target CD20 are the furthest along in development. Besides targeting CD20, the newer B cell-directed therapies target CD22, CD19, CD40-CD40L, B cell activating factor belonging to the TNF family (BAFF) and A proliferation-inducing ligand (APRIL). Rituximab is being tested in an ever-increasing number of autoimmune disorders and clinical studies of rituximab combined with other biological therapies are being pursued for the treatment of rheumatoid arthritis (RA). B cell-directed therapies are being tested in clinical trials for a variety of autoimmune disorders including RA, systemic lupus erythematosus (SLE), Sjögren's syndrome, vasculitis, multiple sclerosis (MS), Graves' disease, idiopathic thrombocytopenia (ITP), the inflammatory myopathies (dermatomyositis and polymyositis) and the blistering skin diseases pemphigus and bullous pemphigoid. Despite the plethora of clinical studies related to B cell-directed therapies and wealth of new information from these trials, much still remains to be discovered about the pathophysiological role of B cells in autoimmune disorders. PMID:19604259
Levesque, M C
Aims\\/hypothesis The regenerative process in the pancreas is of particular interest, since insulin-producing beta cells are lost in diabetes.\\u000a Differentiation of new beta cells from pancreatic non-endocrine cells has been reported in vivo and in vitro, a finding that\\u000a implies the existence of pancreatic stem\\/progenitor cells. However, while tissue-specific stem cells are well documented in\\u000a skin, intestine and testis, pancreatic stem
R. Kikugawa; H. Katsuta; T. Akashi; S. Yatoh; G. C. Weir; A. Sharma; S. Bonner-Weir
Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II). PMID:15056005
Jönsson, Stig; Andersson, Gunnar; Fex, Tomas; Fristedt, Tomas; Hedlund, Gunnar; Jansson, Karl; Abramo, Lisbeth; Fritzson, Ingela; Pekarski, Olga; Runström, Anna; Sandin, Helena; Thuvesson, Ingela; Björk, Anders
Autoimmune thyroid diseases (AITD) are the far most common autoimmune disorders, their prevalence in Western countries exceeding 5% of the general population. In the large majority of individual cases the clinical impact of AITD is not severe, however, their widespread diffusion renders them a significant health problem. AITD are heterogeneous in their clinical presentation: the two main forms are autoimmune
Marcello Bagnasco; Irene Bossert; Giampaola Pesce
Autoimmune encephalitis is a heterogeneous group of disorders characterized by cognitive and behavioral decline due to an immune reaction against neuronal antigens. There is increasing evidence that autoimmune encephalitis represents a significant subgroup of encephalitis in children, which are defined by the presence of antibodies against important proteins involved in neurotransmission. The distinction between the different causes of autoimmune encephalitis is important for the patient, as there is a marked difference in therapeutic response; specifically, autoimmune encephalitis associated with the classical onconeuronal antibody is unresponsive to treatment, while autoimmune encephalitis in association with antibodies against surface proteins may respond to immunomodulation. Autoimmune encephalitis may be classified into forms with prevalent involvement of the grey matter (polioencephalitis), white matter (leucoencephalitis), or endothelial cells (vasculitis). The subject of this review includes polioencephalitis, which encompasses syndromes in which there is a loss and/or alteration of neuronal function and in which autoantibodies can be detected in the serum or CSF. PMID:23685381
Background: We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups.Methods: The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating
Ralph W Kupka; Willem A Nolen; Robert M Post; Susan L McElroy; Lori L Altshuler; Kirk D Denicoff; Mark A Frye; Paul E Keck Jr; Gabriele S Leverich; A. John Rush; Trisha Suppes; Chad Pollio; Hemmo A Drexhage
Systemic sclerosis (SSc) with involvement of vital organs has up to 50% 5-year mortality and no treatment is known which changes the natural history. Although components of vascular, immunological and fibrotic processes are involved, drugs such as cyclophosphamide (CY), an alkylating agent and a potent immunosuppressive, have been partially effective in uncontrolled studies. The dose of such agents is limited by the inevitable toxicity on the bone marrow, but this threshold may be superseded by first removing the patient's own haematopoietic stem cells, followed by reconstitution of the marrow after high-dose myeloablative CY or other therapy. This autologous haematopoietic stem cell transplantation (HSCT) technique has been applied to approximately 650 patients with severe autoimmune diseases worldwide, > 100 of whom had SSc. Of these, 75 are included in the Basle registry. Around 70% of patients responded with a significant (> 25%) improvement of the thickened skin and stabilisation of vital organ involvement. Approximately a third achieved a durable remission. The treatment-related mortality was 8.5%. Based on these encouraging Phase I/II study results, several multi-centre, international, prospective randomised Phase III trials are running or being planned. The preliminary data suggest that through such a jolt of heavy immunosuppression, the dysregulated autoaggressive immune system may be re-regulated. It is hypothesised that this results in fewer autoinflammatory and unwanted stimulatory signals to other systems such as vascular endothelium and fibroblasts, and these mechanisms are currently under study. PMID:14519069
Tyndall, Alan; Matucci-Cerinic, Marco
The stiff-person syndrome, a rare and disabling disorder, is characterized by muscle rigidity and episodic spasms that involve axial and limb musculature. Continuous contrac- tion of agonist and antagonist muscles caused by involun- tary motor-unit firing at rest are the hallmark clinical and electrophysiologic signs of the disease. Except for global muscle stiffness, results of neurologic examination are usu- ally
Lucien M. Levy; Marinos C. Dalakas; Mary Kay Floeter
Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory.Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary
Donald R Staines
The possibility of three or more autoimmune diseases occurring in the same patient cannot be fortuitous and suggests a pathogenic relationship between each of them. In the light of 4 personal cases, the authors have recorded 87 reports of such associations in the literature, an analysis of which leads them to propose a classification of three types of multiple autoimmune syndrome. The grouping of these syndromes under a single heading should make the research and analysis of these morbid associations easier. Moreover, the classification adopted by the authors allows a more precise definition of patients with at least two autoimmune diseases and so helps to recognize the onset of a third autoimmune disease at a later date. Multiple autoimmune syndromes can be classified in 3 groups according to the prevalence of their associations one with another. Type I comprises myasthenia, thymoma, polymyositis and giant cell myocarditis, this association having a single pathogenic mechanism. Type II includes the Sjögren's syndrome, rhumatoid arthritis, primary biliary cirrhosis, scleroderma and autoimmune thyroid disorders. Type III groups together 10 autoimmune diseases (autoimmune thyroid disease, myasthenia and/or thymoma, Sjögren's syndrome, pernicious anaemia, idiopathic thrombocytopaenic purpura, Addison's disease, insulin-dependent diabetes, vitiligo, autoimmune haemolytic anaemia, systemic lupus erythematosus) for which a genetic predisposition (phenotype HLA B8 and/or DR3 or DR5) seems to be an important factor. PMID:3059902
Humbert, P; Dupond, J L
We report a man with chronic fatigue, multiple autoimmune disorders, and a muscle biopsy consistent with macrophagic myofasciitis.\\u000a This rare and recently described muscle disorder is seen in patients exposed to vaccinations with aluminum hydroxide adjuvant.\\u000a This case highlights the relationship between macrophagic myofasciitis and autoimmunity.
Brett J. Theeler; Novae B. Simper; John P. Ney
The risk of some female predominant autoimmune diseases (ADs) has previously been shown to be higher in women who experience hyperemesis, gestational hypertensive disorders and idiopathic pregnancy losses. This study assessed the association between such pregnancy-related experiences and the subsequent risk of female predominant and other ADs. Our study cohort comprised 1.6 million Danish women born since 1955 for whom we had information about hyperemesis, gestational hypertensive disorders and pregnancy losses and subsequent hospital contacts for 31 ADs between 1982 and 2008. Ratios of first hospitalization rates (RRs) with 95% confidence intervals (CIs) were calculated using Poisson regression, adjusting for age, birth cohort, calendar period, marital status and childbirths. During 27.0 million person-years of follow-up 51,732 women were hospitalized with one or more ADs. Overall, compared with women without the specific pregnancy experiences, the risk of any AD was significantly increased for women with hyperemesis (RR = 1.41; 95% CI 1.30-1.51), gestational hypertensive disorders (1.21; 1.16-1.26), spontaneous abortions (1.10; 1.07-1.14), missed abortions (1.09; 1.04-1.13), stillbirths (1.25; 1.12-1.40), ectopic pregnancies (1.08; 1.02-1.14) and induced abortions (1.07; 1.04-1.09). Associations with female predominant ADs (i.e., ADs with a female:male ratio >2:1) were strongest in the first five years after the studied pregnancy experiences, but overall there was little difference between the RRs for groups of female predominant ADs and other ADs. Strong and potentially biological associations were observed for a number of specific ADs; including systemic lupus erythematosus, Graves' disease, type 1 diabetes mellitus and pernicious anemia, and for some specific ADs associations persisted even more than five years after the abnormal pregnancy experience. Abnormal pregnancies are associated with increased risk of certain ADs, possibly because of underlying immunologic or hormonal factors that predispose to both adverse pregnancy experiences and AD development. PMID:22226784
Jørgensen, Kristian Tore; Nielsen, Nete Munk; Pedersen, Bo Vestergaard; Jacobsen, Søren; Frisch, Morten
... Summary – Sept. 25, 2013 Bone Marrow or Blood Stem Cell Transplants in Children With Severe Forms of Autoimmune ... an HSCT may help your child. Understanding Hematopoietic Stem Cell Transplants What are hematopoietic stem cells? Hematopoietic stem ...
Autoimmune keratitis can present with a number of clinical profiles and with a number of underlying autoimmune systemic diseases.\\u000a Autoimmune keratitis should be suspected in all cases of unexplained stromal ulceration and should be closely monitored for\\u000a rate of progression if autoimmune keratitis is identified. Rapidly progressive ulcerative disease needs prompt and appropriate\\u000a immunosuppression.\\u000a \\u000a Most patients with collagen vascular stromal
John D. Gottsch
Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders. PMID:19668249
Yaddanapudi, K; Hornig, M; Serge, R; De Miranda, J; Baghban, A; Villar, G; Lipkin, W I
Chronic and complex autoimmune diseases, currently treated palliatively with immunosuppressives, require multi-targeted therapy for greater effectiveness. The naturally occurring polyphenol curcumin has emerged as a powerful "nutraceutical" that interacts with multiple targets to regress diseases safely and inexpensively. Up to 8 g/day of curcumin for 18 months was non-toxic to humans. However, curcumin's utility is limited by its aqueous insolubility. We have demonstrated a heat-mediated 12-fold increase in curcumin's aqueous solubility. Here, we show by SDS-PAGE and surface plasmon resonance that heat-solubilized curcumin binds to proteins. Based on this binding we hypothesized that heat-solubilized curcumin or turmeric would prevent autoantibody targeting of cognate autoantigens. Heat-solubilized curcumin/turmeric significantly decreased binding of autoantibodies from Sjögren's syndrome (up to 43/70%, respectively) and systemic lupus erythematosus (up to 52/70%, respectively) patients as well as an animal model of Sjögren's syndrome (up to 50/60%, respectively) to their cognate antigens. However, inhibition was not specific to autoimmunity. Heat-solubilized curcumin/turmeric also inhibited binding of commercial polyclonal anti-spectrin to spectrin (50/56%, respectively). Thus, we suggest that the multifaceted heat-solubilized curcumin can ameliorate autoimmune disorders. In addition, the non-toxic curcumin could serve as a new protein stain in SDS-PAGE even though it is less sensitive than the Coomassie system which involves toxic chemicals. PMID:20146265
Kurien, Biji T; D'Souza, Anil; Scofield, R Hal
In common with several other autoimmune diseases, there is a marked female preponderance in both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Whether this is due to gender differences relating specifically to the liver or more generally to the female constitution is unknown. The clinical expression of these disorders provides few clues to explain their predilection for females. Sexual
Ian G McFarlane; Michael A Heneghan
The NOD-like receptor (NLR) family members are cytosolic sensors of microbial components and danger signals. A subset of NLRs control inflammasome assembly that results in caspase-1 activation and, in turn, IL-1? and IL-18 production. Excessive inflammasome activation can cause autoinflammatory disorders, including the hereditary periodic fevers. Autoinflammatory and autoimmune diseases form a disease spectrum of aberrant, immune-mediated inflammation against self, through innate and adaptive immunity. However, the role of inflammasomes in autoimmune disease is less clear than in autoinflammation, despite the numerous effects IL-1? and IL-18 can have on shaping adaptive immunity. We summarize the role of inflammasomes in autoimmune disorders, highlight the need for a better understanding of inflammasomes in these conditions and offer suggestions for future research directions.
Shaw, Patrick J.; McDermott, Michael F.; Kanneganti, Thirumala-Devi
Biermer's disease is an autoimmune atrophic gastritis of the fundus predominantly responsible for a malabsorption of vitamin B12. Despite its association with several autoimmune disorders, few observations have reported an association with autoimmune hemolytic anemia (AIHA). We report a case of Biermer's disease associated with AIHA in a patient of 66 years old. PMID:22796620
Nafil, Hatim; Tazi, Illias; Mahmal, Lahoucine
\\u000a Lymphocytic hypophysitis (LYH) is an autoimmune disease characterized by selective destruction of pituitary hormone-secreting\\u000a cells due to an autoimmune aggression to pituitary gland. Moreover, the organ-specific disease of the neurohypophyseal system\\u000a is characterized by selective immune attack to hypothalamic vasopressin-secreting cells often accompanied by lymphocytic-infundibulo\\u000a neurohypophysitis (autoimmune inflammatory process involving the infundibulum stem and the posterior lobe). Even though LYH
Annamaria De Bellis; Antonio Bizzarro; Antonio Bellastella
Patients with autoimmune urticaria show a higher rate of seropositivity for other autoantibodies and often have a history of autoimmune conditions. They also tend to have more severe symptoms and to have a poor response to conventional antihistamine treatment. Autoimmune hepatitis is a chronic inflammatory disorder in which progressive liver injury is thought to be the result of a T-cell-mediated immunologic attack against liver cells in genetically predisposed individuals. While the association between autoimmune urticaria and other autoimmune disorders such as thyroid disease is well known, there has been no reported case of autoimmune urticaria concomitant with autoimmune hepatitis. We report a case of autoimmune urticaria concurrent with autoimmune hepatitis, which was successfully treated with cyclosporine.
Ju, Hye Young; Kim, Hei Sung; Kim, Hyung Ok
We study the association between three Vitamin D receptor gene polymorphisms (rs10735810, rs1544410, rs731236) and susceptibility\\u000a to thyroid autoimmune diseases. Seventy-six affected subjects, belonging to a large family, as well as one hundred unrelated\\u000a Tunisian patients and one hundred healthy Tunisian controls were genotyped. A family-based association test and a standard\\u000a chi-square test were used to assess association in family
Abdellatif Maalej; Elisabeth Petit-Teixeira; Ghazi Chabchoub; Mariam Ben Hamad; Ahmed Rebai; Nadir R. Farid; Francois Cornelis; Hammadi Ayadi
Systemic autoimmune diseases are generally treated with immunosuppressive agents. In some instances immunomodulatory agents have shown promise in the treatment of certain types of autoimmune disorders. The in vitro and/or in vivo effects of some of these agents (glutaurine, ketoconazole, gutimine and its derivative) are demonstrated. Glutaurine exerts moderate immunostimulating activity, but fails to influence the clinical course of systemic lupus erythematosus. Although ketoconazole suppresses immune responses in vitro, it does not influence cellular reactivity of patients in vivo. The immunostimulatory activity of gutimine and its derivative (T 001) have been demonstrated in vitro, and need to be tested also in vivo. PMID:3452243
Gergely, P; Láng, I; Gonzalez-Cabello, R; Fehér, J
Much progress has been made in the field of haemopoietic stem cell transplants (HSCTs) for severe autoimmune disorders. Theoretical considerations, animal data and anecdotal evidence suggested some time ago that intensive immunoablation followed by autologous HSCT could restore normal immune reactivity in patients with severe autoimmune disorders. Based on a concept statement issued in 1995, two European societies, the European
A Gratwohl; J Passweg; I Gerber; A Tyndall
Antilactoferrin antibodies have been reported in patients with several autoimmune disorders, including primary biliary cirrhosis, autoimmune hepatitis and autoimmune cholangitis. We investigated the prevalence and the clinical significance of such autoreactivity in patients with autoimmune and viral chronic liver disease. Sera from 39 patients with autoimmune hepatitis, 51 with primary biliary cirrhosis, 17 with autoimmune cholangitis, 24 with primary sclerosing cholangitis and 28 with HCV-related chronic hepatitis were studied. Positivity for antilactoferrin antibodies was evaluated by Western immunoblotting with purified human lactoferrin. Antilactoferrin antibodies were detected more often in autoimmune liver disorders (25% autoimmune hepatitis, 25% primary biliary cirrhosis, 35% autoimmune cholangitis, 29% primary sclerosing cholangitis) than in HCV-related chronic hepatitis (3·5%, P < 0·02 versus all). Positivity for antilactoferrin antibodies was not associated with a particular clinical or biochemical profile of the underlying liver disease. No correlation was observed between antilactoferrin reactivity and perinuclear antineutrophil cytoplasmic antibodies. Antilactoferrin antibodies are present significantly more often in autoimmune than in viral liver disorders, but they cannot be considered the serological marker of a specific autoimmune liver disease.
Muratori, L; Muratori, P; Zauli, D; Grassi, A; Pappas, G; Rodrigo, L; Cassani, F; Lenzi, M; Bianchi, F B
Liver transplantation (LT) is an effective treatment for patients with end-stage autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Indications for LT for these diseases do not differ substantially from those used for other acute or chronic liver diseases. Despite the good outcomes reported, the recurrence of autoimmune liver disease is relatively common in the allograft. In addition, it has become apparent that autoimmunity and autoimmune liver disease can arise de novo after transplantation for nonautoimmune liver disorders. An awareness of the existence of recurrent autoimmune liver diseases and de novo autoimmune hepatitis after LT has important clinical implications because their management differs from the standard antirejection treatment and is similar to the management of classic autoimmune liver diseases in the native liver. Liver Transpl 19:1065-1077, 2013. © 2013 AASLD. PMID:23873751
Liberal, Rodrigo; Zen, Yoh; Mieli-Vergani, Giorgina; Vergani, Diego
The complement system is a component of the innate immune system. Its main function was initially believed to be limited to the recognition and elimination of pathogens through direct killing or stimulation of phagocytosis. However, in recent years, the immunoregulatory functions of the complement system were demonstrated and it was determined that the complement proteins play an important role in modulating adaptive immunity and in bridging innate and adaptive responses. When the delicate mechanisms that regulate this sophisticated enzymatic system are unbalanced, the complement system may cause damage, mediating tissue inflammation. Dysregulation of the complement system has been involved in the pathogenesis and clinical manifestations of several autoimmune diseases, such as systemic lupus erythematosus, vasculitides, Sjögren's syndrome, antiphospholipid syndrome, systemic sclerosis, dermatomyositis, and rheumatoid arthritis. Complement deficiencies have been associated with an increased risk to develop autoimmune disorders. Because of its functions, the complement system is an attractive therapeutic target for a wide range of diseases. Up to date, several compounds interfering with the complement cascade have been studied in experimental models for autoimmune diseases. The main therapeutic strategies are inhibition of complement activation components, inhibition of complement receptors, and inhibition of membrane attack complex. At present, none of the available agents was proven to be both safe and effective for treatment of autoimmune diseases in humans. Nonetheless, data from preclinical studies and initial clinical trials suggest that the modulation of the complement system could constitute a viable strategy for the treatment of autoimmune conditions in the decades to come. PMID:23615835
Ballanti, Eleonora; Perricone, Carlo; Greco, Elisabetta; Ballanti, Marta; Di Muzio, Gioia; Chimenti, Maria Sole; Perricone, Roberto
Differentiation of pancreatic ?-cells is regulated by a wide range of signalling pathways. The aim of our current work was to evaluate the effect of the Jak/Stat signalling pathway on the differentiation of human non-endocrine pancreatic cells into insulin-producing cells. Activation of the Jak/Stat signalling pathway by leukaemia inhibitory factor (LIF) stimulated differentiation of C-peptide-negative human non-endocrine pancreatic cells into insulin-producing cells in 6.3 ± 2.0 % cells (N = 5) and induced expression of pro-endocrine transcription factor neurogenin 3, Notch signalling pathway suppressor HES6 and stimulator of ?-cell neogenesis REG3A. The expression of the REG3A gene and increased rate of differentiation into insulin-producing cells (10.2 ± 2.1 %) were further stimulated by a combination of LIF with nicotinamide and dexamethasone. Glucose-stimulated (5 vs. 20 mM) C-peptide secretion confirmed proper insulin secretory function of trans-differentiated insulin-producing cells (0.51 vs. 2.03 pmol C-peptide/?g DNA, P < 0.05). Our results indicate that Jak/Stat signalling critically contributes to trans-differentiation of non-endocrine pancreatic cells into functional insulin-producing cells. The positive effect of the Jak/Stat signalling pathway on trans-differentiation is mediated by the key genes that activate differentiation of pancreatic ?-cells. PMID:22849859
Koblas, T; Leontovy?, I; Zacharovová, K; Berková, Z; K?íž, J; Girman, P; Saudek, F
Autoimmune pancreatitis is becoming a more widely recognized form of pancreatitis that can mimic pancreatic or biliary malignancy. The combination of serological, histological and radiographic findings makes it unique among pancreatic diseases. The presence of autoantibodies, IgG4 and a lymphoplasmacytic infiltrate reflect its autoimmune etiology. The dramatic response to steroids is also a distinguishing feature and differentiates it from other pancreatic diseases. PMID:20477698
Barth, Erin; Savides, Thomas J
Autoimmune hepatitis is a systemic disease, difficult to diagnose due the high variability of the clinical presentation and some non specific histological features. The recent identification of additional autoantibodies used as serological markers, as well as simplified diagnostic criteria should help the primary care physician to advance with the diagnostic process. These progresses are crucial as undiagnosed and therefore untreated autoimmune hepatitis has a poor prognosis, whereas immunosuppressive therapy leads to remission in a majority of cases. PMID:23667973
Luong Ba, Kim; Juillerat, Pascal; Ducommun, Julien
The present invention provides compositions and methods for preventing and treating gastrointestinal disorders by administering to a subject an effective amount of secretin either alone or in combination with an effective amount of oxytocin. The invention...
M. G. Welch D. A. Ruggiero M. Anwar
Objective To examine the risk of neurological and autoimmune disorders of special interest in people vaccinated against pandemic influenza A (H1N1) with Pandemrix (GlaxoSmithKline, Middlesex, UK) compared with unvaccinated people over 8-10 months. Design Retrospective cohort study linking individualised data on pandemic vaccinations to an inpatient and specialist database on healthcare utilisation in Stockholm county for follow-up during and after the pandemic period. Setting Stockholm county, Sweden. Population All people registered in Stockholm county on 1 October 2009 and who had lived in this region since 1 January 1998; 1?024?019 were vaccinated against H1N1 and 921?005 remained unvaccinated. Main outcome measures Neurological and autoimmune diagnoses according to the European Medicines Agency strategy for monitoring of adverse events of special interest defined using ICD-10 codes for Guillain-Barré syndrome, Bell’s palsy, multiple sclerosis, polyneuropathy, anaesthesia or hypoaesthesia, paraesthesia, narcolepsy (added), and autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes; and short term mortality according to vaccination status. Results Excess risks among vaccinated compared with unvaccinated people were of low magnitude for Bell’s palsy (hazard ratio 1.25, 95% confidence interval 1.06 to 1.48) and paraesthesia (1.11, 1.00 to 1.23) after adjustment for age, sex, socioeconomic status, and healthcare utilisation. Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged. The risks of paraesthesia and inflammatory bowel disease among those vaccinated in the early phase (within 45 days from 1 October 2009) of the vaccination campaign were significantly increased; the risk being increased within the first six weeks after vaccination. Those vaccinated in the early phase were at a slightly reduced risk of death than those who were unvaccinated (0.94, 0.91 to 0.98), whereas those vaccinated in the late phase had an overall reduced mortality (0.68, 0.64 to 0.71). These associations could be real or explained, partly or entirely, by residual confounding. Conclusions Results for the safety of Pandemrix over 8-10 months of follow-up were reassuring —notably, no change in the risk for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, or rheumatoid arthritis. Relative risks were significantly increased for Bell’s palsy, paraesthesia, and inflammatory bowel disease after vaccination, predominantly in the early phase of the vaccination campaign. Small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions.
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.
Rose, N.R.; Mackay, I.R.
In vitro lymphocyte function of 13 patients with selective IgA deficiency was studied. IgG, IgA and IgM secretion by pokeweed mitogen-stimulated peripheral blood lymphocytes from normal donors and IgA deficient patients was measured by an enzyme-linked immunosorbent assay. Addition of concanavalin A or hydrocortisone and co-cultures of B and T cell enriched populations from patients and normal donors, allowed us to investigate B cell Ig production and T cell regulatory abnormalities. IgA production by these patients' B cells was either absent or very low, as compared to their total Ig production, even in the presence of optimal T cell help. Several T cell immunoregulatory abnormalities were seen in different patients. A moderate increase in suppressor activity selective for IgA production was observed in some, but does not appear to play a major role in the pathogenesis of the IgA deficiency. In others, with associated autoimmune phenomena, a decrease in suppressor T cell function was found.
De la Concha, E G; Subiza, J L; Fontan, G; Pascual-Salcedo, D; Sequi, J; Bootello, A
Summary Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP)
Donald R. Staines
|Previous clinical and genetic studies have suggested autism spectrum disorders (ASDs) is associated with immunological abnormalities involving cytokines, immunoglobulins, inflammation, and cellular immunity, but epidemiological reports are still limited. Patients with ASDs were identified in the National Health Insurance Database from 1996 to…
Chen, Mu-Hong; Su, Tung-Ping; Chen, Ying-Sheue; Hsu, Ju-Wei; Huang, Kai-Lin; Chang, Wen-Han; Chen, Tzeng-Ji; Bai, Ya-Mei
Autoimmune hepatitis (AIH) is a distinct form of acute and chronic inflammatory liver disease in which immune reactions against host antigens are found to be the major pathological mechanism. If left untreated it carries an unfavourable prognosis, and the diagnosis should be made as soon as possible. The diagnostic approach has been greatly facilitated by the establishment of a panel
Karl-Hermann Meyer zum Büschenfelde; Hans-Peter Dienes
Autoantibodies to neuronal tissue are becoming increasingly more important in the evaluation and classification of several neurological diseases, e.g. neuromyelitis optica, paraneoplastic syndromes of the central nervous system (CNS), stiff person syndrome or autoimmune epilepsy. As these disorders are rare, no evidence-based recommendations for therapy are available. Currently, immunomodulating or immunosuppressive drugs are administered in most cases. In paraneoplastic syndromes treatment of the underlying cancer is of considerable importance. This overview summarizes current experiences and recommendations in the treatment of autoimmune neurological disorders. PMID:23568167
Borisow, N; Prüss, H; Paul, F
Background. About 10% of pregnancies are complicated by previously unknown impairment of glucose metabolism, which is defined as gestational diabetes. There are little data available on prevalence of thyroid disorders in patients affected by gestational diabetes, and about their postgestational thyroid function and autoimmunity. We therefore investigated pancreatic and thyroid autoimmunity in gestational diabetic patients and in women who had had a previous gestational diabetic pregnancy. Methods. We investigated 126 pregnant women at the time of a 100-g oral glucose tolerance test: 91 were classified as gestational diabetics, and 35 were negative (controls). We also studied 69 women who had delivered a baby 18–120 months prior to this investigation and who were classified at that time gestational diabetics (38 women) or normally pregnant (31 women; controls). Results. Our data show no differences for both thyroid function and prevalence of autoimmune disorders during pregnancy; however, a significant increase in thyroid autoimmunity was seen in women previously affected by gestational diabetes. This increased prevalence of thyroid autoimmunity was not associated with the development of impaired glucose metabolism after pregnancy. Conclusions. Our data suggest that maternal hyperglycemia is a risk factor for the development of thyroid autoimmunity, a conclusion that should now be confirmed in a larger cohort of patients.
Vitacolonna, Ester; Lapolla, Annunziata; Di Nenno, Barbara; Passante, Annalisa; Bucci, Ines; Giuliani, Cesidio; Cerrone, Dominique; Capani, Fabio; Monaco, Fabrizio; Napolitano, Giorgio
Psoriasis is a common inflammatory and hyperproliferative skin disease. Recent studies have reported that common genetic factors may underlie both skin and immune-mediated disorders. We hypothesized that such genes may be involved in susceptibility to psoriasis, and undertook an association analysis of 22 candidate genes in a set of French high-risk psoriasis families. One hundred fifty-three single-nucleotide polymorphisms (SNPs) were
Tiphaine Oudot; Fabienne Lesueur; Mickaël Guedj; Rafael de Cid; Steven McGinn; Simon Heath; Mario Foglio; Bernard Prum; Mark Lathrop; Jean-François Prud'homme; Judith Fischer
Association between pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections disease and tumor necrosis factor-? gene-308 g/a, -850 c/t polymorphisms in 4-12-year-old children in Adana/Turkey
OBJECTIVES: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a newly defined disease in neuropsychiatry and occurs with an autoimmune mechanism after Group A Beta Hemolytic Streptococcus (GABHS) infection. Tumor necrosis factor (TNF), encoded by TNF-? gene has an important role in the apoptotic mechanisms of autoimmune diseases. Recently, TNF-? polymorphisms and autoimmune/psychiatric disorders have been reported to be related. In this regard, we focused on to investigate a possible relation between the TNF-? gene promoter region?308 G/A and ? 850 C/T polymorphisms and PANDAS. MATERIALS AND METHODS: In this study, ages of PANDAS patient and control groups were ranging from 4 years to 12-year-old. Patient group includes childhood onset PANDAS patients (n = 42) and control group includes healthy children (n = 58). Diagnoses have been carried out according to Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria with Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale Moreover, PANDAS criteria established by the American National Psychiatry Institute have been employed for diagnoses. For identifying polymorphisms; Polymerase Chain Reaction, Restriction Fragment Length Polymorphism and Polyacrylamid Gel Electrophoresis were used. RESULTS AND DISCUSSION: For ?308 polymorphism, 37 of 42 PANDAS patients’ results and for ?850 C/T polymorphism, 38 of 42 PANDAS patients’ results were obtained. According to our statistical analysis there is a positive relationship between PANDAS patients for ?308 G/A polymorphism but not for ?850 C/T polymorphism. There is no positive relationship between ?308 G/A polymorphism and antistrep-tolysin O (ASO) titers and no relationship between ?850 C/T polymorphism and ASO titers. We found, however, positive relationship between genders of patients (boys) and the disease. According to our results, we propose that the AA polymorphism of ?308 G/A polymorphism can be used as a molecular indicator for PANDAS.
Luleyap, H. Umit; Onatoglu, Dilge; Yilmaz, M. Bertan; Alptekin, Davut; Tahiroglu, Aysegul Y.; Cetiner, Salih; Pazarbasi, Ayfer; Unal, Ilker; Avci, Ayse; Comertpay, Gamze
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autoimmune disorder. The clinical spectrum of symptoms is diverse; the diagnosis relying on the presence of at least two out of the three main conditions defining the syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. PMID:23277800
Sonal, Choudhary; Michael, McLeod; Daniele, Torchia; Paolo, Romanelli
Autoimmune hepatitis (AIH) is a rare disease, characterized by female predominance, hypergammaglobulinemia, autoantibodies, association with HLA DR3 and HLA DR4 and a good response to immunosuppression. Different subtypes of AIH may be distinguished, based on differences in the autoantibody patterns. AIH type 1 is characterized by anti-nuclear (ANA) and\\/or anti-smooth muscular (SMA) autoantibodies. AIH type 2 is characterized by liver\\/kidney
Petra Obermayer-Straub; Christian P. Strassburg; Michael P. Manns
Autoimmune hepatitis (AIH) is an inflammatory liver disease affecting mainly females and characterised histologically by interface\\u000a hepatitis, biochemically by elevated transaminase levels and serologically by the presence of autoantibodies and increased\\u000a levels of immunoglobulin G. AIH responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is\\u000a made. Seropositivity for smooth muscle and\\/or anti-nuclear antibody defines type 1
Diego Vergani; Maria Serena Longhi; Dimitrios P. Bogdanos; Yun Ma; Giorgina Mieli-Vergani
The polyglandular autoimmune syndrome (PGAS) is characterized by the association of two or more endocrine disorders that are mediated by autoimmune mechanisms and usually lead to a hypofunctional state. In this review we classify the various types of PGAS and discuss their clinical features and the pathophysiologic autoimmune mechanisms that are thought to play an important role. Circulating organ- and cell-specific autoantibodies are frequently detected in patients with the syndrome and may be a marker of future organ failure. PGAS should be considered in patients with one or more of the disorders constituting the syndrome; this should facilitate early diagnosis and perhaps even prevention of other components of the disease. Early recognition and replacement therapy can be life-saving, particularly when there is adrenal or thyroid insufficiency.
Meyerson, J; Lechuga-Gomez, E E; Bigazzi, P E; Walfish, P G
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
Jozsef Pal; Csilla Rozsa; Samuel Komoly; Zsolt Illes
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.
Armangue, Thais; Petit-Pedrol, Mar; Dalmau, Josep
We have previously found that conventional allogeneic bone marrow transplantation (allo BMT) can be used to treat various\\u000a spontaneously developed autoimmune diseases in mice. In addition, we have found that autoimmune diseases can be transferred\\u000a into the normal mice by conventional BMT from autoimmune-prone mice. Based on these findings, we have proposed that autoimmune\\u000a diseases are “stem cell disorders.” To
Objective To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. Design Observational, retrospective case series. Setting Mayo Clinic Health System. Patients Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. Intervention Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide. Main Outcome Measure Seizure frequency. Results After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone. Conclusion When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.
Quek, Amy M. L.; Britton, Jeffrey W.; McKeon, Andrew; So, Elson; Lennon, Vanda A.; Shin, Cheolsu; Klein, Christopher J.; Watson, Robert E.; Kotsenas, Amy L.; Lagerlund, Terrence D.; Cascino, Gregory D.; Worrell, Gregory A.; Wirrell, Elaine C.; Nickels, Katherine C.; Aksamit, Allen J.; Noe, Katherine H.; Pittock, Sean J.
Recent evidences suggest that the apoptotic pathway plays a central role in tolerazing T-cells to tissue-specific self-antigen,\\u000a and may drive the age-related autoimmune phenomenon. Primary Sjögren’s syndrome (SS) is an autoimmune disorder characterized\\u000a by lymphocytic infiltrates and destruction of the exocrine glands, and systemic production of autoantibodies to the ribonucleoprotein\\u000a (RNP) particles SS-A\\/Ro and SS-B\\/La. It can be considered that
Yoshio Hayashi; Naozumi Ishimaru
Background There is increasing evidence of the importance of copy number variants (CNV) in genetic diversity among individuals and populations, as well as in some common genetic diseases. We previously characterized a common 32-kb insertion/deletion variant of the PSORS4 locus at chromosome 1q21 that harbours the LCE3C and LCE3B genes. This variant allele (LCE3C_LCE3B-del) is common in patients with psoriasis and other autoimmune disorders from certain ethnic groups. Results Using array-CGH (Agilent 244 K) in samples from the HapMap and Human Genome Diversity Panel (HGDP) collections, we identified 54 regions showing population differences in comparison to Africans. We provided here a comprehensive population-genetic analysis of one of these regions, which involves the 32-kb deletion of the PSORS4 locus. By a PCR-based genotyping assay we characterised the profiles of the LCE3C_LCE3B-del and the linkage disequilibrium (LD) pattern between the variant allele and the tag SNP rs4112788. Our results show that most populations tend to have a higher frequency of the deleted allele than Sub-Saharan Africans. Furthermore, we found strong LD between rs4112788G and LCE3C_LCE3B-del in most non-African populations (r2 >0.8), in contrast to the low concordance between loci (r2 <0.3) in the African populations. Conclusions These results are another example of population variability in terms of biomedical interesting CNV. The frequency distribution of the LCE3C_LCE3B-del allele and the LD pattern across populations suggest that the differences between ethnic groups might not be due to natural selection, but the consequence of genetic drift caused by the strong bottleneck that occurred during “out of Africa” expansion.
Methods, compositions and kits for treating psoriasis and other autoimmune diseases in human or animal subjects. The disclosed methods generally comprise administering to the subject a therapeutically effective amount of a naturally occurring or synthetic...
G. D. Weinstein J. E. Murase R. R. Voskuhl
Netrin-1 is a chemotropic factor that plays an important role as a survival factor in the adult nervous system. To investigate whether netrin-1 is involved in autoimmune injury of the peripheral nervous system (PNS), the temporal expression of netrin-1 protein was analyzed in the sciatic nerves of Lewis rats with experimental autoimmune neuritis (EAN). Western blot analysis revealed a significant increase in the level of netrin-1 protein in the sciatic nerves of rats on days 11 to 24 post-immunization (p.i.) compared to controls; netrin-1 expression declined by day 30 p.i. Immunohistochemistry revealed that netrin-1 protein was expressed weakly in Schwann cells and vessels in the sciatic nerves of normal and CFA-immunized control rats. In the sciatic nerves of EAN-affected rats, netrin-1 immunoreactivity was increased mainly in the cell membrane and extracellular matrix of OX42-positive macrophages and S100-positive Schwann cells at the peak and recovery phases of EAN. Moreover, the putative netrin-1 receptor, deleted in colorectal cancer (DCC), was expressed mainly in axons, some macrophages, and Schwann cells in EAN-affected sciatic nerves, although the level of protein expression did not change significantly over the course of EAN. We suggest that a significant increase in netrin-1 expression contributes to host cell survival and axon regeneration to counter autoimmune injury and inflammation, which may play a role in recovery from EAN-induced paralysis. PMID:16337279
Moon, Changjong; Kim, Heechul; Ahn, Meejung; Jin, Jae-Kwang; Wang, Hongbing; Matsumoto, Yoh; Shin, Taekyun
Autoimmune diseases occur more in women than in men, and this may be attributable to the role of estrogens. Androgens promote autoimmune diseases with a profile of type 1 cytokines, such as rheumatoid arthritis, whereas estrogens promote autoimmune diseases with a type 2 cytokine profile, like systemic lupus erythematosus. Both androgens and estrogens regulate the Th1\\/Th2 balance. Type 1 autoimmune
Delia Almeida González; Buenaventura Brito Díaz; María del Cristo Rodríguez Pérez; Ana González Hernández; B. Nicolás Díaz Chico; Antonio Cabrera de León
A number of confounding factors can be identified from the search for autoimmune mechanisms over the last 2 decades that may be relevant for future studies. (1) An apparently homogeneous clinical disorder may represent more than one disease process and thereby imply antibody/antigen heterogeneity as, for example, in MG with and without detectable anti-AChR antibodies. In some cases, physiologic studies allow the different forms of the disease to be distinguished as in AIDP and acute inflammatory axonal polyneuropathy. (2) A homogeneous disorder (e.g., LEMS) may have at least two different triggering mechanisms (SCLC and an unknown stimulus). (3) Antigen density may be too low to be detected by the immunohistologic techniques available, as initially occurred in MG and LEMS. (4) Autoantibodies may be detected that are irrelevant to the primary disease, such as anti-striated muscle antibodies in MG. (5) Poor antibody cross-reactivity between species may mean that the pathogenic antibody is undetected in binding assays or in experimental passive transfer studies. For example, anti-AChR antibody in MG shows less than 5% reactivity with Torpedo AChR. (6) A poor regenerative capacity of the target antigen may mean that reduction of circulating autoantibodies by either plasma exchange or ISD treatment is not associated with detectable clinical improvement, as may be the case in SSN in which DRG cells appear to be the target. TABLE 5 summarizes the extent to which the data reviewed have established a role for pathogenic antibodies in the light of the postulates for autoimmunity set out earlier and ranks the disorders accordingly. Only in MG with detectable anti-AChR antibody are all the postulates met, including definition of the antigen, experimental passive transfer by the IgG fraction of MG sera, active immunization of experimental animals, and propagation. In both LEMS and the IgM kappa anti-MAG demyelinating neuropathy the antigen is known, although better characterized in LEMS; the epitopes are not yet defined in either. Data relating to passive transfer are more extensive in LEMS, however; systemic passive transfer of anti-MAG has not yet been reported. In neither condition is an animal model available. In the demyelinating neuropathies, the case for autoimmunity is less complete. Neither in AIDP nor in CIDP is the antigen known, and thus the relevance of the different EAN disorders is uncertain. Current evidence thus rests on the demonstration of serum IgM antibodies that react with peripheral nerve myelin and fix complement and on the intraneural passive transfer studies.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2849891
In the last 15 years, the estimated prevalence of autoimmune diseases increased from about 4 to 9.4%. Autoimmune co-morbidity (i.e., the association between two or more autoimmune diseases in the same patient) is present in 0.4-0.5% of the worldwide population, more frequently in patients with multiple sclerosis, rheumatoid arthritis, autoimmune thyroid disease, type 1 diabetes, inflammatory bowel disease and vitiligo. The most common associations between autoimmune diseases define two clusters: the multiple autoimmune syndromes and overlap syndromes. This review highlights the importance of multiple antibody assays in the diagnosis of multiple autoimmune and overlap syndromes and summarizes the general conditions of autoantibody detection using the model of the five W's: why, who, what, when and where. These conditions represent a new challenge for clinical and laboratory autoimmunologists, who, in a multidisciplinary arena, cooperate in investigating and treating multiple autoimmune disorders. PMID:23606120
Tozzoli, Renato; Sorrentino, Maria Concetta; Bizzaro, Nicola
ABSTRACT In an autoimmune disease, the immune system attacks and harms the body's own tissues. The systemic autoimmune diseases include collagen vascular diseases, the systemic vasculitides, Wegener granulomatosis, and Churg-Strauss syndrome. These disorders can involve any part of the gastrointestinal tract, hepatobiliary system and pancreas. They can cause a variety of gastrointestinal manifestations that are influenced by the pathophysiologic characteristics of the underlying disease process. There is a wide variation of gastrointestinal manifestations from these autoimmune disorders including, but not limited to: oral ulcers, dysphagia, gastroesophageal reflux disease, abdominal pain, constipation, diarrhea, fecal incontinence, pseudo-obstruction, perforation and gastrointestinal bleeding. Clinical workup should be initiated by the patient's subjective complaints. In this review, we analyze the effects of autoimmune diseases on the gastrointestinal tract.
COJOCARU, M.; COJOCARU, Inimioara Mihaela; SILOSI, Isabela; VRABIE, Camelia Doina
Common variable immunodeficiency (CVID) is a humoral immunodeficiency whose primary diagnostic features include hypogammaglobulinemia involving two or more immunoglobulin isotypes and impaired functional antibody responses in the majority of patients. While increased susceptibility to respiratory and other infections is a common thread that binds a large cross-section of CVID patients, the presence of autoimmune complications in this immunologically and clinically heterogeneous disorder is recognized in up to two-thirds of patients. Among the autoimmune manifestations reported in CVID (20–50%; Chapel et al., 2008; Cunningham-Rundles, 2008), autoimmune cytopenias are by far the most common occurring variably in 4–20% (Michel et al., 2004; Chapel et al., 2008) of these patients who have some form of autoimmunity. Association of autoimmune cytopenias with granulomatous disease and splenomegaly has been reported. The spectrum of autoimmune cytopenias includes thrombocytopenia, anemia, and neutropenia. While it may seem paradoxical “prima facie” that autoimmunity is present in patients with primary immune deficiencies, in reality, it could be considered two sides of the same coin, each reflecting a different but inter-connected facet of immune dysregulation. The expansion of CD21 low B cells in CVID patients with autoimmune cytopenias and other autoimmune features has also been previously reported. It has been demonstrated that this unique subset of B cells is enriched for autoreactive germline antibodies. Further, a correlation has been observed between various B cell subsets, such as class-switched memory B cells and plasmablasts, and autoimmunity in CVID. This review attempts to explore the most recent concepts and highlights, along with treatment of autoimmune hematological manifestations of CVID.
Podjasek, Jenna C.; Abraham, Roshini S.
MRL/Mp-Fas (lpr) (MRL-lpr) mice develop a systemic autoimmune disease and are considered to be a good model for systemic lupus erythematosus in humans. We have recently shown that mice lacking B and T lymphocyte attenuator (BTLA), an inhibitory co-receptor expressed mainly on lymphocytes, on a 129SvEv background spontaneously develop lymphocytic infiltration in multiple organs and an autoimmune hepatitis (AIH)-like disease. In this study, we investigated the role of BTLA in the pathogenesis of autoimmune diseases in MRL-lpr mice. We found that BTLA-deficient (BTLA(-/-)) MRL-lpr/lpr mice developed severe lymphocytic infiltration in salivary glands, lungs, pancreas, kidneys and joints as compared with BTLA-sufficient (BTLA(+/+)) MRL-lpr/lpr mice. In addition, although AIH-like disease was not found in BTLA(+/+) MRL-lpr/lpr mice, AIH-like disease was exacerbated in BTLA(-/-) MRL-lpr/lpr mice as compared with that in BTLA(-/-) 129SvEv mice. These results suggest that BTLA plays a protective role in autoimmune diseases in MRL-lpr mice and that AIH-like disease develops in BTLA(-/-) mice even in the absence of Fas-dependent signaling. PMID:21521881
Oya, Yoshihiro; Watanabe, Norihiko; Kobayashi, Yoshihisa; Owada, Takayoshi; Oki, Mie; Ikeda, Kei; Suto, Akira; Kagami, Shin-ichiro; Hirose, Koichi; Kishimoto, Takashi; Nakajima, Hiroshi
Variant forms of autoimmune hepatitis have features that are intermixed with another disorder (overlap syndrome) or findings\\u000a that are inconsistent with or insufficient for a confident diagnosis of classic disease (outlier syndrome). Diagnostic criteria\\u000a have not been codified, but application of a modified scoring system provides a template that can be combined with clinical\\u000a findings to ensure uniform evaluation and
Albert J. Czaja
This progress report is organized around the four major themes identified in the 2002 Autoimmune Diseases Coordinating Committee (ADCC) Autoimmune Diseases Research Plan: (1) Epidemiology and Burden of Autoimmune Diseases; (2) Etiology of Autoimmune Disea...
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.
Hultman, Per; Kono, Dwight H.
... autoimmune disease is inflammation, which can cause redness, heat, pain, and swelling. How an autoimmune disease affects ... thyroid hormone. This causes such symptoms as nervousness, heat intolerance, heart palpitations, and unexplained weight loss. Immune ...
Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases
High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients
Richard A Nash; Roger Dansey; Jan Storek; George E Georges; James D Bowen; Leona A Holmberg; George H Kraft; Maureen D Mayes; Kevin T McDonagh; Chien-Shing Chen; John DiPersio; C. Fred LeMaistre; Steven Pavletic; Keith M Sullivan; Julie Sunderhaus; Daniel E Furst; Peter A McSweeney
The association of immune dysfunction in patients with human immunodeficiency virus (HIV) infection and AIDS and the development of autoimmune diseases is intriguing. Yet, the spectrum of reported autoimmune phenomena in these patients is increasing. An infectious trigger for immune activation is one of the postulated mechanisms and derives from molecular mimicry. During frank loss of immunocompetence, autoimmune diseases that
Gisele Zandman-Goddard; Yehuda Shoenfeld
Alopecia areata (AA) frequently occur in association with other autoimmune diseases such as thyroid disorders, anemias and other skin disorders with autoimmune etiology. Despite numerous studies related to individual disease associations in alopecia areata, there is paucity of literature regarding comprehensive studies on concomitant cutaneous and systemic diseases. The present study has been designed to determine if there is a significant association between alopecia areata and other autoimmune diseases. This study covers 71 patients with the diagnosis of alopecia areata as the case group and 71 patients with no evidence of alopecia areata as the control group. Among the cutaneous diseases associated with AA, atopic dermatitis (AD) showed maximum frequency with an O/E ratio of 2.5, which indicates that it is two to three times more common in patients with alopecia areata. In our study, thyroid disorders showed the highest frequency with on O/E ratio of 3.2 and a P value of 0.01, which is statistically highly significant. Among the thyroid disorders, hypothyroidism was the most frequent association (14.1%) in our study. Since systemic involvement is not infrequent in patients with alopecia areata, it is imperative to screen these patients for associated disorders, particularly atopy, thyroid diseases, anemias and other autoimmune disorders, especially if alopecia areata is chronic, recurrent and extensive.
Thomas, Emy Abi; Kadyan, R S
Systemic autoimmune diseases that are resistant to conventional treatment cause considerable morbidity and mortality. Although\\u000a aggressive new approaches to treating autoimmune diseases have been developed over the past decade, there are still patients\\u000a with a severe, progressive, and life-threatening course. Based on animal studies and experience in the treatment of hematological\\u000a disorders with preexisting autoimmune disease, hematopoietic stem cell transplantation
Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune disorders affecting approximately 5% of the overall population. An aberrant interaction between abnormal thyrocytes, abnormal antigen-presenting cells and abnormal T cells forms the basis for the atypical autoimmune reaction targeting thyroid antigens. It was proposed that nongenetic (environmental and hormonal) factors play a crucial etiological role in AITD development, through
Alicia Juana Klecha; María Laura Barreiro Arcos; Luciana Frick; Ana María Genaro; Graciela Cremaschi
Lymphoproliferative disorders and autoimmune diseases have some common aspects in their clinical appearance. We reviewed 940 patient charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 421 non-Hodgkin's lymphoma (NHL) patients (230 males, 191 females), 32 (7.6%) had an autoimmune disease (26 females, six males, mean age 48.3 years). The most common diagnosis was Sjögren's syndrome. The other cases were autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), other musculoskeletal disorders (2), rheumatoid arthritis (1), vasculitis (1), undifferentiated collagenosis (1), colitis ulcerosa (1), autoimmune hepatitis (1), Addison's disease (1), and autoimmune hemolytic anemia (1). Of 519 Hodgkin's lymphoma patients (308 males, 211 females), an associated autoimmune disease occurred in 45 (8.6%) (25 females, 20 males, mean age 39.2 years). In 31 cases, we found autoimmune thyroid disorders, then came glomerulonephritis (3), immune thrombocytopenia (3), insulin-dependent diabetes mellitus (2), autoimmune hemolytic anemia (1), seronegative spondylarthritis (1), systemic lupus erythematosus (1), mixed connective tissue disease (1), scleroderma (1), and vasculitis (1). We also analyzed histology, choice of treatment, and sequence of appearance of the disease types. We found a difference between NHL and Hodgkin's lymphoma patients, since in NHL autoimmunity - mostly from Sjögren's syndrome - preceded the lymphoma diagnosis (70%), but in Hodgkin's the autoimmunity developed mainly after the treatment of malignancy. The relatively high prevalence of autoimmune diseases in malignant lymphomas has several explanations. Clinicians have to consider autoimmunity when treating lymphoproliferative disorders. PMID:12426661
Váróczy, László; Gergely, Lajos; Zeher, Margit; Szegedi, Gyula; Illés, Arpád
The clinical course of chronic lymphocytic leukemia (CLL) may be complicated at any time by autoimmune phenomena.The most common ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Pure red cell aplasia (PRCA) and autoimmune agranulocytosis (AG) are, indeed, more rarely seen. However, they are probably underestimated due to the possible misleading presence of cytopenias secondary to leukemic bone marrow involvement or to chemotherapy cytotoxicity. The source of autoantibodies is still uncertain, despite the most convincing data are in favor of the involvement of resting normal B-cells. In general, excluding the specific treatment of underlying CLL, the managementof these complications is not different from that of idiopathic autoimmune cytopenias or of those associated to other causes. Among different therapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective. PMID:23690826
D'Arena, Giovanni; Guariglia, Roberto; La Rocca, Francesco; Trino, Stefania; Condelli, Valentina; De Martino, Laura; De Feo, Vincenzo; Musto, Pellegrino
Autism Spectrum Disorder; Obsessive Compulsive Disorder; Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal In; Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS); Global Developmental Delay
Onychomycosis is the most common nail disorder in adults. Predisposing factors are immunosuppression, poor peripheral circulation, diabetes mellitus, increasing age, nail trauma, and tinea pedis. Autoimmune patients, who carry many of these predisposing factors, have never been studied. Autoimmune patients, with underlying autoimmune skin diseases; pemphigus, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, dermatomyositis and cutaneous vasculitis, as well as having abnormal-appearing nail(s) with suspicion of fungal nail infection were included. Clinical information was obtained. The causative organisms were identified by potassium hydroxide preparation and cultured. Duration of onychomycosis in autoimmune patients was twice longer than in non-autoimmune patients. Of those with mycological proven onychomycosis, the autoimmune patients had significantly more affected nails (p < 0.05; chi2, two-sided) compared to the non-autoimmune patients but there was no difference in the affected fingernails or toenails and clinical type of onychomycosis. Candida spp was the most frequently found in autoimmune subjects compared to dermatophytes, Trichophyton rubrum. However, dermatophytes especially Trichophyton rubrum was the most common causative organism in non-autoimmune samples, followed by Candida spp. The causative organisms were more frequently discovered in autoimmune patients, whether by potassium hydroxide (KOH) or culture, than in non-autoimmune patients (p < 0.05; chi2, two-sided). PMID:14696780
Boonchai, Waranya; Kulthanan, Kanokvalai; Maungprasat, Chanai; Suthipinittham, Puan
The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals. PMID:23643663
Palma, Alessia; Gianchecchi, Elena; Palombi, Melania; Luciano, Rosa; Di Carlo, Pierluigi; Crinò, Antonino; Cappa, Marco; Fierabracci, Alessandra
Allergic and autoimmune diseases have been considered to be at the opposite sides of the spectrum of the immune response. Autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis and type 1 insulin-dependent diabetes mellitus, are considered T helper 1 (Th1)-mediated diseases, and allergic disorders, such as asthma, food allergy or rhinitis, are considered to be Th2-mediated. In this Opinion,
Rosetta Pedotti; Jason J. De Voss; Lawrence Steinman; Stephen J. Galli
BMT can both transmit and eliminate autoimmune diseases, and hence it has been suggested as an optional treatment for severe autoimmune conditions. In this communication we deal with the question of whether chronic GVHD is an autoimmune disease in itself, review the literature reports of autoimmune diseases following BMT in humans, and describe the autoimmune nature of the post-BMT state.
Y Sherer; Y Shoenfeld
Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune disorders. In this report, we describe antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease have important treatment implications for patients with CGD. PMID:18823651
De Ravin, Suk See; Naumann, Nora; Cowen, Edward W; Friend, Julia; Hilligoss, Dianne; Marquesen, Martha; Balow, James E; Barron, Karyl S; Turner, Maria L; Gallin, John I; Malech, Harry L
Background Generalized vitiligo is an autoimmune disease of skin pigmentation that is associated with increased prevalence of other autoimmune diseases, particularly autoimmune thyroid disease (AITD; principally Hashimoto's disease and Graves' disease), both in vitiligo patients and their close relatives, suggesting a heritable predisposition involving, in part, shared susceptibility genes. Summary This review summarizes current knowledge of vitiligo epidemiology and genetics, highlighting recent findings from genome-wide approaches to disease gene identification, emphasizing susceptibility loci shared with other autoimmune diseases, particularly AITD, as well as some important differences. Conclusions Inherited susceptibility to generalized vitiligo involves a number of specific genes, many of which are shared with other autoimmune diseases that are epidemiologically associated with vitiligo, including AITD, confirming a longstanding hypothesis about the genetic basis of these disorders. These genes provide potential therapeutic targets for novel approaches to treatment as well as for approaches to presymptomatic diagnosis and disease prevention in individuals with inherited susceptibility to this group of autoimmune diseases.
The sense of smell is an ancient sensory modality vital for sampling and perceiving the chemical composition of surrounding environments. Olfaction involves a pathway of biochemical and electrophysiological processes, which allows the conversion of molecular information into sensations. Disturbances in the olfactory function have been investigated mainly in neurological/neurodegenerative disorders such as Alzheimer's and Parkinson's diseases; impaired sense of smell has been associated with depressed mood. Only recently, smell capability was tested in other diseases, particularly autoimmune diseases. Shoenfeld and colleagues opened this chapter showing that patients affected with systemic lupus erythematosus (SLE) have disturbances in their olfactory functions and revealed its association with neuropsychiatric manifestations of the disease. This evidence was confirmed in experimental models and replicated in other SLE populations. The connection between autoimmunity and the sense of smell was lately emphasized by studies on patients with Sjögren's syndrome and in patients with other autoimmune/immune-mediated diseases, such as polydermatomyositis, recurrent spontaneous abortion, and hereditary angioedema. Genetic susceptibility and hormonal and environmental factors may play a role in these conditions. Olfactory receptor gene clusters are located in proximity to key locus of susceptibility for autoimmune diseases such as the major histocompatibility complex, suggesting not only a physic linkage, but a functional association. Nonetheless, gender- and hormone-mediated effects are fundamental in the development of autoimmune diseases. The different connections between smell and autoimmunity, genes and hormones may suggest that this is another tessera of a mosaic which is waiting the answer of Oedipus. PMID:23233263
Perricone, Carlo; Shoenfeld, Netta; Agmon-Levin, Nancy; de Carolis, Caterina; Perricone, Roberto; Shoenfeld, Yehuda
Patients with systemic autoimmune disorders produce autoantibodies against sequence-specific conformational RNA epitopes on U1 snRNA, 28S rRNA, and transfer RNAs. The molecular basis for immunological reactivity with these highly abundant and stable RNAs is not understood. Here, we report the existence of discrete RNA epitopes in messenger RNAs that are generally less abundant and less stable than snRNAs and tRNAs. An iterative selection and amplification procedure using pooled autoimmune patient sera identified immunoreactive mRNA species. Following deconvolution of the pools to identify the reactive sera, several mRNAs recognized by these autoantibodies were cloned and sequenced. Detailed analysis using one particular serum indicated reactivity against the messages encoding alternative splicing factor (ASF/SF2) and calmodulin. Deletion and site-directed mutagenesis determined that an epitope recognized by this serum is located in a 17-base stem-loop structure common to both messages. This serum was then used to immunoprecipitate native mRNAs encoding ASF/SF2 and calmodulin from total HeLa cell RNA. Our results demonstrate that despite its low abundance and instability, messenger RNA is capable of reacting with autoantibodies generated during an autoimmune response. These data are consistent with direct presentation as a model to explain the generation of RNA conformation-specific autoantibodies.
Lipes, Barbara D; Keene, Jack D
The HPA axis is fundamental for long-term survival and protection from the ravages of autoimmune disease. Continuing investigations suggest that the hypothesis linking susceptibility to autoimmune dissease and a hyporesponsive HPA axis is somewhat simplistic. Instead, data from a number of different human diseases and from preclinical studies in a variety of models have suggested a more complicated picture. Alterations
Autoimmune pancreatitis (AIP) is recognized as a distinct clinical entity, identified as a chronic inflammatory process of the pancreas in which the autoimmune mechanism is involved. Clinically and histologically, AIP has two subsets: type 1 – lymphoplasmatic sclerosing pancreatitis with abundant infiltration of the pancreas and other affected organs with immunoglobulin G4-positive plasma cells, and type 2 – duct centric
I. Novotný; J. Lata; H. Nechutová
The high percentage of disease-discordant pairs of monozygotic twins demonstrates the central role of environmental factors in the etiology of autoimmune diseases. Efforts were first focussed on the search for triggering factors. The study of animal models has clearly shown that infections may trigger autoimmune diseases, as in the case of Coxsackie B4 virus in type I diabetes and the
Autoimmune diseases occur more in women than in men, and this may be attributable to the role of estrogens. Androgens promote autoimmune diseases with a profile of type 1 cytokines, such as rheumatoid arthritis, whereas estrogens promote autoimmune diseases with a type 2 cytokine profile, like systemic lupus erythematosus. Both androgens and estrogens regulate the Th1/Th2 balance. Type 1 autoimmune diseases are improved when decrease type 1 cytokines (i.e. during fasting), or when there is a rise in type 2 cytokines (increased estrogens, as in pregnancy). Type 2 autoimmune diseases improve when type 2 cytokines are diminished (decreased estrogen, as in post-partum period) or when type 1 response is stimulated. PMID:20637236
González, Delia Almeida; Díaz, Buenaventura Brito; Rodríguez Pérez, María del Cristo; Hernández, Ana González; Chico, B Nicolás Díaz; de León, Antonio Cabrera
For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a
OP Kristiansen; ZM Larsen; F Pociot
Background: Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging. Aim: We aimed to provide clinical and mutational data
Elizaveta M. Orlova; Anna M. Bukina; Elvira S. Kuznetsova; Maria A. Kareva; Ekaterina U. Zakharova; Valentina A. Peterkova; Ivan I. Dedov
Autoimmune polyglandular syndromes are conditions characterized by the association of two or more organ-specific disorders. On the basis of the clinical picture, they are divided into four different types. If undiagnosed and untreated, autoimmune polyglandular syndromes may pose a serious risk to patients. We report here a case of a pregnant woman with autoimmune polyglandular syndrome type 2. She was diagnosed with Addison's disease 11 months before the onset of the pregnancy and until the end of the first trimester the disease was effectively controlled by hydrocortisone and fludrocortisone treatment. In the tenth week of gestation, the patient developed Graves' disease and the treatment with propylthiouracil was started treatment leading to the unmasking of adrenal insufficiency, which required titration of hydrocortisone dose. Our study shows that autoimmune polyglandular syndromes should be considered in every pregnant woman with any autoimmune endocrine disease and that the treatment of these syndromes during gestation may be challenging. PMID:23789305
Krysiak, Robert; Okopie?, Bogus?aw
... Lindor KD. Primary biliary cirrhosis. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal ... Czaia AJ. Autoimmune hepatitis. In: In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal ...
Ion channels are complex transmembrane proteins that orchestrate the electrical signals necessary for normal function of excitable tissues, including the central nervous system, peripheral nerve, and both skeletal and cardiac muscle. Progress in molecular biology has allowed cloning and expression of genes that encode channel proteins, while comparable advances in biophysics, including patch-clamp electrophysiology and related techniques, have made the functional assessment of expressed proteins at the level of single channel molecules possible. The role of ion channel defects in the pathogenesis of numerous disorders has become increasingly apparent over the last two decades. Neurological channelopathies are frequently genetically determined but may also be acquired through autoimmune mechanisms. All of these autoimmune conditions can arise as paraneoplastic syndromes or independent from malignancies. The pathogenicity of autoantibodies to ion channels has been demonstrated in most of these conditions, and patients may respond well to immunotherapies that reduce the levels of the pathogenic autoantibodies. Autoimmune channelopathies may have a good prognosis, especially if diagnosed and treated early, and if they are non-paraneoplastic. This review focuses on clinical, pathophysiologic and therapeutic aspects of autoimmune ion channel disorders of the nervous system. PMID:22379460
Kleopa, Kleopas A
Autoimmune disease-the condition in which the body attacks its own tissue-has been an object of public concern recently. Former President George Bush and his wife Barbara both are afflicted with Graves' disease in which the body's own immune system attakcs the thyroid gland. The safety of breast implants was called into question because of evidence that some recipients had developed autoimmune disorders such a rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. Women, the media pointed out, have a higher-than-average incidence of many autoimmune disorders. These events suggest the need to know more about what makes the immune system work so well and what makes it go awry. At ORNL's Biology Division, progress is being in understanding the underlying causes of immune disease by studying mice having a disease that causes them to be underdeveloped; to have scaly skin, small ears, and large spleens; to open their eyes late; and to die early. These [open quotes]scurfy[close quotes]mice are helping us better understand the role of the thymus gland in autoimmune disease.
The initiation and perpetuation of autoimmunity recognize numerous checkpoints, from the genomic susceptibility to the breakdown of tolerance. This latter phenomenon includes the loss of B cell anergy and T regulatory cell failure, as well as the production of autoantibodies and autoreactive T cells. These mechanisms ultimately lead to tissue injury via different mechanisms that span from the production of proinflammatory cytokines to the chemotaxis of immune cells to the target sites. The pathways to autoimmunity have been widely investigated over the past year and resulted in a number of articles in peer-reviewed journals that has increased by nearly 10 % compared to 2011. We herein follow on the attempt to provide a brief discussion of the majority of articles on autoimmune diseases that were published in the major immunology journals in the previous solar year. The selection is necessarily arbitrary and may thus not be seen as comprehensive but reflects current research trends. Indeed, 2012 articles were mostly dedicated to define new and old mechanisms with potential therapeutic implications in autoimmunity in general, though based on specific clinical conditions or animal models. As paradigmatic examples, the environmental influence on autoimmunity, Th17 changes modulating the autoimmune response, serum autoantibodies and B cell changes as biomarkers and therapeutic targets were major issues addressed by experimental articles in 2012. Further, a growing number of studies investigated the sex bias of autoimmunity and supported different working hypotheses to explain the female predominance, including sex chromosome changes and reproductive life factors. In conclusion, the resulting scenario illustrates that common factors may underlie different autoimmune diseases and this is well represented by the observed alterations in interferon-? and TGF? or by the shared signaling pathways. PMID:23975606
The autoimmune diseases are more common in females.The sex hormones have an important role in this gender bias, mainly estrogen and prolactin (PRL) which modulate the immune response.PRL is secreted from the pituitary gland and other organs and cells mainly the lymphocytes. PRL has an immunostimulatory effect and promotes autoimmunity:PRL impairs the negative selection of autoreactive B lymphocytes occurring during
Hedi Orbach; Yehuda Shoenfeld
Autoantibodies directed against human CD38 (an enzyme catalysing the interconversion of NAD+ and cyclic ADP-ribose) have been demonstrated recently in patients with type 2 diabetes. We tested 220 consecutive Caucasian patients with autoimmune chronic thyroiditis, 104 patients with Graves' disease, 220 subjects from the general population (control I) and 78 healthy control subjects not affected by thyroid autoimmune disorders (control II) for the presence of anti-CD38 autoimmunity. Using Western blot analysis and optical densitometry, a specific band corresponding to human recombinant CD38 was identified in the serum of several subjects. By defining anti-CD38 positivity as a standardized optical reading >3 s.d. higher than the mean value of control I, 10·4% of patients with thyroiditis and 7·7% of Graves' patients were anti-CD38 positive (P = 0·0009 versus 1·8% of control I). Similarly, 13·1% of patients with thyroiditis and 10·5% of Graves' patients had a standardized optical reading >3 s.d. higher than the mean value of the subjects not affected by thyroid autoimmune disorders (P = 0·002 versus 1·2% of control II). Anti-CD38 autoimmunity did not differ between euthyroid, hyperthyroid or hypothyroid patients or between patients with or without thyroid hypoechogenicity. Anti-CD38 autoantibodies were associated with higher levels of circulating antithyroid-peroxidase antibodies (P = 0·03) and they were more frequent in Graves' patients with ophthalmopathy (P < 0·05). Anti-CD38 autoantibodies are a new autoimmune marker in chronic autoimmune thyroiditis and Graves' disease. The specific role of CD38 and its autoantibodies in the modulation of thyroid cell function or growth remains to be investigated.
Antonelli, A; Fallahi, P; Nesti, C; Pupilli, C; Marchetti, P; Takasawa, S; Okamoto, H; Ferrannini, E
Recent evidences suggest that the apoptotic pathway plays a central role in tolerazing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon in the salivary glands. We found that retinoblastoma-associated protein RbAp48 overexpression induces p53-mediated apoptosis in the salivary glands caused by estrogen deficiency. We demonstrated that transgenic (Tg) expression of RbAp48 resulted in the development of autoimmune exocrinopathy resembling Sjögren's syndrome (SS). CD4(+)T cell-mediated autoimmune lesions in the salivary glands were aggravated with age, in association with autoantibody productions. We obtained evidences that salivary epithelial cells can produce interferon-gamma (IFN-gamma) besides interleukin (IL)-18, which activates interferon regulatory factor-1 (IRF-1), and class II transactivator (CIITA). Indeed, the autoimmune lesions into Rag2(-/-) mice were induced by the adoptive transfer of lymph node cells from RbAp48-Tg mice. These results indicate a novel immunocompetent role of epithelial cells that can produce IFN-gamma, resulting in loss of local tolerance prior to developing gender-based autoimmunity. The studies reviewed the molecular mechanisms on the development of salivary gland autoimmunity, and gender-related differences in SS. PMID:20224179
Hayashi, Yoshio; Arakaki, Rieko; Ishimaru, Naozumi
Structurally and therefore antigenically the retina is a complex tissue. Since it develops as an extension from the neural tube it shares with the brain several cell membranes and cytoplasm associated antigens including those present in neurofilaments of the various neurones and the glial filaments of the astrocytes. The advent of monoclonal antibodies has helped to dissect, in detail, the antigenic makeup of the retina. Nervous system antigens (NS-3, 4 and 7) are generously represented in the retina. At least in the chick eye there seems to be a concentration gradient of retinal antigens along a dorsoventral axis which is believed to provide means by which neurones of developing retinal signal and receive the positional information necessary for the formation of specific synapses. It now seems certain that organ-specific antigens are presented not only in the photoreceptors and the retinal pigment epithelium but also in the retinal ganglion cells and the astrocytes. Photoreceptor outer-segment contains soluble antigens which when injected in rats, rabbits, guinea-pigs or monkeys produce varying degrees of intraocular inflammation leading to uveitis, retinal detachment, photoreceptor degeneration and occasionally retinal vasculitis. Both cell-mediated and humoral immunity to photoreceptor antigen has been demonstrated in various types of uveitis (including toxoplasmosis and sarcoidosis), pars planitis, vitriitis, Behçets disease, sympathetic ophthalmitis, Vogt-Koyanagi-Harada syndrome, birdshot retinopathy, retinitis pigmentosa and retinal vasculitis. Retinal autoimmunity is also found in retinal detachment and diabetic retinopathy, particularly after Argon laser photocoagulation. Antibodies to retinal antigens are also found in patients with systemic lupus erythematosus and other systemic immune disorders without ocular involvement. The precise pathogenetic role of retinal autoimmunity in eye disease is therefore uncertain. It may simply represent an epiphenomenon which develops afer retinal damage due to physical, micro-organismal or immunological insult. Alternatively it is possible that although autoimmunity does not initiate ocular inflammation it perpetuates and maintains the inflammatory state and produces further damage to ocular tissues. PMID:6611615
Rahi, A H; Addison, D J
Venous thromboembolism (VTE) is major health problem and is sometimes complicated by lethal pulmonary embolism (PE). Disturbances of the coagulation and anticoagulation systems are important risk factors for VTE. Comparative studies suggest that coagulation and innate immunity have a shared evolutionary origin. It is therefore unsurprising that the immune and coagulation systems are linked, with many molecular components being important for both systems. Systemic inflammation modulates thrombotic responses by suppressing fibrinolysis, upregulating procoagulant, and downregulating anticoagulants, and autoimmune disorders such as systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and Behçet's syndrome have been linked to an increased risk of VTE. Recent reports have further shown that a majority of autoimmune and immune-mediated disorders are linked to an increased risk of venous thrombosis, PE, or VTE. For instance, a Swedish nationwide study found that the risk of PE was increased in the first year after hospitalization for 33 different autoimmune disorders. Especially high risks were noted for several autoimmune diseases such as immune thrombocytopenic purpura, polyarteritis nodosa, polymyositis/dermatomyositis, ulcerative colitis, and SLE. Another study from England, also based on hospitalization data, found that immune-mediated disorders were associated with an increased risk of VTE compared with other medical causes of hospitalization. Multiple mechanisms may operate and disease-specific factors, such as cardiolipin antibodies, have been identified. However, inflammation by itself appears to change the hemostatic balance in a thrombogenic direction. Recent epidemiological studies, together with previous experimental and clinical studies, indicate that autoimmune disorders should not only be viewed as inflammatory disorders, but also hypercoagulable disorders. Research to identify thrombotic risk factors, elucidate the mechanisms involved, and investigate prophylactic regiments is needed. The present review describes the epidemiological, clinical, and experimental evidence for the connection between VTE and autoimmune and immune-mediated disorders. PMID:22937487
Zöller, Bengt; Li, Xinjun; Sundquist, Jan; Sundquist, Kristina
Venous thromboembolism (VTE) is major health problem and is sometimes complicated by lethal pulmonary embolism (PE). Disturbances of the coagulation and anticoagulation systems are important risk factors for VTE. Comparative studies suggest that coagulation and innate immunity have a shared evolutionary origin. It is therefore unsurprising that the immune and coagulation systems are linked, with many molecular components being important for both systems. Systemic inflammation modulates thrombotic responses by suppressing fibrinolysis, upregulating procoagulant, and downregulating anticoagulants, and autoimmune disorders such as systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and Behçet’s syndrome have been linked to an increased risk of VTE. Recent reports have further shown that a majority of autoimmune and immune-mediated disorders are linked to an increased risk of venous thrombosis, PE, or VTE. For instance, a Swedish nationwide study found that the risk of PE was increased in the first year after hospitalization for 33 different autoimmune disorders. Especially high risks were noted for several autoimmune diseases such as immune thrombocytopenic purpura, polyarteritis nodosa, polymyositis/dermatomyositis, ulcerative colitis, and SLE. Another study from England, also based on hospitalization data, found that immune-mediated disorders were associated with an increased risk of VTE compared with other medical causes of hospitalization. Multiple mechanisms may operate and disease-specific factors, such as cardiolipin antibodies, have been identified. However, inflammation by itself appears to change the hemostatic balance in a thrombogenic direction. Recent epidemiological studies, together with previous experimental and clinical studies, indicate that autoimmune disorders should not only be viewed as inflammatory disorders, but also hypercoagulable disorders. Research to identify thrombotic risk factors, elucidate the mechanisms involved, and investigate prophylactic regiments is needed. The present review describes the epidemiological, clinical, and experimental evidence for the connection between VTE and autoimmune and immune-mediated disorders.
Zoller, Bengt; Li, Xinjun; Sundquist, Jan; Sundquist, Kristina
Idiopathic (autoimmune) thrombocytopenic purpura (ATP) is accepted to be a disorder resulting from accelerated platelet destruction attributed to an autoimmune process. The patient whose case is presented in this article was first seen by a dentist. The oral findings have been documented as the case was followed for 3 years through acute exacerbations, pregnancy, and delivery of an infant with thrombocytopenia. The patient was managed with intermittent steroid therapy and splenectomy. PMID:6576288
Fotos, P G; Graham, W L; Bowers, D C; Perfetto, S P
Autoimmunity may evolve in predisposed individuals following an exogenous trigger. Autoimmunity is affected by genetic, immune,\\u000a hormonal, and environmental factors. Immune mechanisms in heart diseases are complex and often not completely understood.\\u000a Several cardiac disorders are believed to be mediated by an immune reaction. Both humoral and cellular immunity are associated\\u000a with the development of myocarditis, dilated cardiomyopathy, heart failure,
Udi Nussinovitch; Yehuda Shoenfeld
We provide a review of recent research findings which support the involvement of autoimmunity in childhood-onset tic disorders, in particular the presence of antineuronal autoantibodies, D8\\/17 B lymphocyte overexpression, a marker of chorea associated with streptococcal infection, and possible beneficial effects of immunomodulatory intervention. One of the most controversial areas in this field is the validity of the proposed PANDAS
P J Hoekstra; C G M Kallenberg; J Korf; R B Minderaa
This review will describe adult onset mucocutaneous\\/autoimmune diseases that involve defects in cell-to-cell, cell-to-matrix, or cell-to-basement membrane adhesion. Included in this group are pemphigus, cicatricial pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and bullous systemic lupus erythematous. Detection and treatment of blistering disorders that manifest early in the oral cavity may prevent widespread involvement of skin. During the past
Mea A Weinberg; Michael S Insler; Rebecca B Campen
Background—Both celiac disease (CD) and myocarditis can be associated with systemic autoimmune disorders; however, the coexistence of the 2 entities has never been investigated, although its identification may have a clinical impact. Methods and Results—We screened the serum of 187 consecutive patients with myocarditis (118 males and 69 females, mean age 41.714.3 years) for the presence of cardiac autoantibodies, anti-tissue
Andrea Frustaci; Lucio Cuoco; Cristina Chimenti; Maurizio Pieroni; Giuseppina Fioravanti; Nicola Gentiloni; Attilio Maseri; Giovanni Gasbarrini
Mastitis is a substantial clinical problem in lactating women that may result in severe pain and abrupt termination of breastfeeding, thereby predisposing infants to long-term health risks. Many cases of mastitis involve no known infectious agent and may fundamentally be due to autoimmune-mediated inflammation of the breast. Herein, we develop a murine model of autoimmune mastitis and provide a detailed characterization of its resulting phenotype of breast failure and lactation insufficiency. To generate breast-specific autoimmunity, we immunized SWXJ mice with recombinant mouse ?-lactalbumin, a lactation-dependent, breast-specific differentiation protein critical for production of lactose. Mice immunized with ?-lactalbumin showed extensive T-cell–mediated inflammation in lactating normal breast parenchyma but none in nonlactating normal breast parenchyma. This targeted autoimmune attack resulted in breast failure characterized by lactation insufficiency and decreased ability to nurture offspring. Although immunization with ?-lactalbumin had no effect on fertility and birth numbers, pups nursed by ?-lactalbumin–immunized mice showed significantly disrupted growth often accompanied by kwashiorkor-like nutritional abnormalities, including alopecia, liver toxicity, and runting. This experimental model of autoimmune breast failure has useful applications for prophylactic breast cancer vaccination and for addressing inflammatory complications during breastfeeding. In addition, this model is suited for investigating nutritionally based “failure-to-thrive” issues, particularly regarding the long-term implications of postnatal nutritional deprivation.
Kesaraju, Pavani; Jaini, Ritika; Johnson, Justin M.; Altuntas, Cengiz Z.; Gruden, Jessica J.; Sakalar, Cagri; Tuohy, Vincent K.
... Diseases Association’s goals are set forth in our Mission Statement: AARDA is dedicated to the eradication of autoimmune ... patients suffering from an autoimmune disease. About AARDA Mission Statement Financial Information Accomplishments Meet Our Board AARDA Facts ...
Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches.
Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis
The association of RASopathies [Noonan syndrome (NS) and Noonan-related syndromes] and autoimmune disorders has been reported sporadically. However, a concomitant evaluation of autoimmune diseases and an assessment of multiple autoantibodies in a large population of patients with molecularly confirmed RASopathy have not been performed. The clinical and laboratory features were analyzed in 42 RASopathy patients, the majority of whom had NS and five individuals had Noonan-related disorders. The following autoantibodies were measured: Anti-nuclear antibodies, anti-double stranded DNA, anti-SS-A/Ro, anti-SS-B/La, anti-Sm, anti-RNP, anti-Scl-70, anti-Jo-1, anti-ribosomal P, IgG and IgM anticardiolipin (aCL), thyroid, anti-smooth muscle, anti-endomysial (AE), anti-liver cytosolic protein type 1 (LC1), anti-parietal cell (APC), anti-mitochondrial (AM) antibodies, anti-liver-kidney microsome type 1 antibodies (LKM-1), and lupus anticoagulant. Six patients (14%) fulfilled the clinical criteria for autoimmune diseases [systemic lupus erythematous, polyendocrinopathy (autoimmune thyroiditis and celiac disease), primary antiphospholipid syndrome (PAPS), autoimmune hepatitis, vitiligo, and autoimmune thyroiditis]. Autoimmune antibodies were observed in 52% of the patients. Remarkably, three (7%) of the patients had specific gastrointestinal and liver autoantibodies without clinical findings. Autoimmune diseases and autoantibodies were frequently present in patients with RASopathies. Until a final conclusion of the real incidence of autoimmunity in Rasopathy is drawn, the physicians should be alerted to the possibility of this association and the need for a fast diagnosis, proper referral to a specialist and ultimately, adequate treatment. PMID:22488759
Quaio, Caio R D C; Carvalho, Jozélio F; da Silva, Clovis A; Bueno, Cleonice; Brasil, Amanda S; Pereira, Alexandre C; Jorge, Alexander A L; Malaquias, Alexsandra C; Kim, Chong A; Bertola, Débora R
Injection of animals with purified acetylcholine receptor in complete Freund's adjuvant causes development of antibodies which crossreact with receptors in muscle. The crossreacting antibodies impair neuromuscular transmission. Animals with experimental autoimmune myasthenia gravis (EAMG) are excellent models for studying the complex mechanisms by which the autoimmune response to receptor in myasthenia gravis causes muscle weakness. This review first briefly describes the discovery of EAMG. Then, to provide the necessary perspective, receptor structure and function and properties of anti-receptor antibodies are discussed, followed by a brief review of the pathological mechanisms in EAMG.
Autoimmune diseases are a clinically heterogeneous group of disorders that represent a challenge for the general practitioner in daily routine. Except for rheumatoid arthritis, which is one of the most frequent autoimmune diseases with a prevalence of approximately 1 % of the population, systemic autoimmune disorders are rare. Thus outside specialized wards it might be a challenge to diagnose the underlying autoimmune disease considering the often kaleidoscopic clinical manifestations. Together with careful anamnesis and suspicious clinical symptoms determination of specific autoantibodies can support the suspected diagnosis. The Austrian group of the European autoimmune standardization initiative (EASI) firstly published this guide 2009 with the aim to provide a map through the jungle of the biomarkers for autoimmune diseases for the general practitioner. PMID:22890524
Endler, Georg; Demel, Ulrike; Forster, Ernst; Griesmacher, Andrea; Hübner, Christin; Klotz, Werner; Steiner, Günter; Wagner, W; Herold, Manfred
Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH. PMID:22426958
Glezer, A; Bronstein, M D
It is well-known that autoimmunity is significantly more prevalent in females. Growing evidence indicates that genes located\\u000a on the X chromosome may play a role in autoimmunity and immune dysregulation, as also indicated by the frequent association\\u000a of autoimmune phenomena in patients with X-linked primary immune deficiencies (PIDs). Hence, this group of genetic disorders\\u000a is of particular interest to study
Itai M. Pessach
This review gives an overview of the rehabilitation of autoimmune diseases. After general remarks on rehabilitation, the effects of acute and chronic exercises on inflammatory markers are summarized. Most of the available literature deals with rheumatoid arthritis (RA) and multiple sclerosis (MS), and therefore, rehabilitation of these diseases is described in more detail. Exercise is the main component in the
Background Autoimmune diseases are disorders caused by an immune response directed against the body's own organs, tissues and cells. In practice more than 80 clinically distinct diseases, among them systemic lupus erythematosus and rheumatoid arthritis, are classified as autoimmune diseases. Although their etiology is unclear these diseases share certain similarities at the molecular level i.e. susceptibility regions on the chromosomes or the involvement of common genes. To gain an overview of these related diseases it is not feasible to do a literary review but it requires methods of automated analyses of the more than 500,000 Medline documents related to autoimmune disorders. Results In this paper we present the first version of the Autoimmune Disease Database which to our knowledge is the first comprehensive literature-based database covering all known or suspected autoimmune diseases. This dynamically compiled database allows researchers to link autoimmune diseases to the candidate genes or proteins through the use of named entity recognition which identifies genes/proteins in the corresponding Medline abstracts. The Autoimmune Disease Database covers 103 autoimmune disease concepts. This list was expanded to include synonyms and spelling variants yielding a list of over 1,200 disease names. The current version of the database provides links to 541,690 abstracts and over 5,000 unique genes/proteins. Conclusion The Autoimmune Disease Database provides the researcher with a tool to navigate potential gene-disease relationships in Medline abstracts in the context of autoimmune diseases.
Karopka, Thomas; Fluck, Juliane; Mevissen, Heinz-Theodor; Glass, Anne
Autoimmune conditions are associated with an elevated risk of lymphoproliferative malignancies, but few studies have investigated the risk of myeloid malignancies. From the US Surveillance Epidemiology and End Results (SEER)-Medicare database, 13?486 myeloid malignancy patients (aged 67+ years) and 160?086 population-based controls were selected. Logistic regression models adjusted for gender, age, race, calendar year and number of physician claims were used to estimate odds ratios (ORs) for myeloid malignancies in relation to autoimmune conditions. Multiple comparisons were controlled for using the Bonferroni correction (P<0.0005). Autoimmune conditions, overall, were associated with an increased risk of acute myeloid leukaemia (AML) (OR 1.29) and myelodysplastic syndrome (MDS, OR 1.50). Specifically, AML was associated with rheumatoid arthritis (OR 1.28), systemic lupus erythematosus (OR 1.92), polymyalgia rheumatica (OR 1.73), autoimmune haemolytic anaemia (OR 3.74), systemic vasculitis (OR 6.23), ulcerative colitis (OR 1.72) and pernicious anaemia (OR 1.57). Myelodysplastic syndrome was associated with rheumatoid arthritis (OR1.52) and pernicious anaemia (OR 2.38). Overall, autoimmune conditions were not associated with chronic myeloid leukaemia (OR 1.09) or chronic myeloproliferative disorders (OR 1.15). Medications used to treat autoimmune conditions, shared genetic predisposition and/or direct infiltration of bone marrow by autoimmune conditions, could explain these excess risks of myeloid malignancies.
Anderson, L A; Pfeiffer, R M; Landgren, O; Gadalla, S; Berndt, S I; Engels, E A
Thyroid autoimmunity is the most prevalent autoimmune state that affects up to 5-20% of women during the age of fertility. Prevalence of thyroid autoimmunity is significantly higher among infertile women, especially when the cause of infertility is endometriosis or polycystic ovary syndrome. Presence of thyroid autoimmunity does not interfere with normal embryo implantation and have been observed comparable pregnancy rates after assisted reproduction techniques in patients with or without thyroid autoimmunity. Instead, the risk of early miscarriage is substantially raised with the presence of thyroid autoimmunity, even if there was a condition of euthyroidism before pregnancy. Furthermore the controlled ovarian hyperstimulation, used as preparation for assisted reproduction techniques, can severely impair thyroid function increasing circulating estrogen levels. Systematic screening for thyroid disorders in women with a female cause of infertility is controversial but might be important to detect thyroid autoimmunity before to use assisted reproduction techniques and to follow-up these parameters in these patients after controlled ovarian hyperstimulation and during pregnancy. PMID:22835333
Artini, Paolo Giovanni; Uccelli, Alessia; Papini, Francesca; Simi, Giovanna; Di Berardino, Olga Maria; Ruggiero, Maria; Cela, Vito
Extraordinary technical advances in the field of human genetics over the past few years have catalyzed an explosion of new information about the genetics of human autoimmunity. In particular, the ability to scan the entire genome for common polymorphisms that associate with disease has led to the identification of numerous new risk genes involved in autoimmune phenotypes. Several themes are emerging. Autoimmune disorders have a complex genetic basis; multiple genes contribute to disease risk, each with generally modest effects independently. In addition, it is now clear that common genes underlie multiple autoimmune disorders. There is also heterogeneity among subphenotypes within a disease and across major racial groups. The current crop of genetic associations are only the start of a complete catalog of genetic factors for autoimmunity, and it remains unclear to what extent common variation versus multiple rare variants contribute to disease susceptibility. The current review focuses on recent discoveries within functionally related groups of genes that provide clues to novel pathways of pathogenesis for human autoimmunity.
Gregersen, Peter K.; Olsson, Lina M.
The aim of this study was to determine if the prevalence of autoimmune disorders in the relatives of patients with systemic lupus erythematosus (SLE) is greater than that of relatives of patients with juvenile rheumatoid arthritis (JRA). Interviews were used to obtain histories of the following autoimmune disorders among living or deceased first-, second-, and third-degree relatives of 91 SLE
Chun-Mei Huang; Yao-Hsu Yang; Bor-Luen Chiang
Keeping a delicate balance in the immune system by eliminating invading pathogens, while still maintaining self-tolerance to avoid autoimmunity, is critical for the body’s health. The gut microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis. Moreover, it has recently become obvious that alterations of these gut microbial communities can cause immune dysregulation, leading to autoimmune disorders. Here we review the advances in our understanding of how the gut microbiota regulates innate and adaptive immune homeostasis, which in turn can affect the development of not only intestinal but also systemic autoimmune diseases. Exploring the interaction of gut microbes and the host immune system will not only allow us to understand the pathogenesis of autoimmune diseases but will also provide us new foundations for the design of novel immuno- or microbe-based therapies.
Wu, Hsin-Jung; Wu, Eric
Autoimmune hepatitis (AIH) is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level or serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation) in the absence of other causes. AIH is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type 2 (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of AIH that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish AIH from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. Treatment basis of AIH have not changed for the last 30 years. Initial treatment consists of corticosteroids associated with azathioprine. Budesonide may be at least as effective as systemic corticosteroids and reduces the frequency of side effects in non-cirrhotic patients. Long-term treatment consists of azathioprine. This treatment is rapidly effective but usually only suspensive since relapse after treatment withdrawal is the rule (80 % of cases). The probability of relapse is lower in case of complete biochemical response defined by normalization of transaminases, gamma-globulins and IgG and in case of histological response defined by the lack of interface hepatitis. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment. PMID:19762185
A collection of molecular sensors has been defined by studies in the last decade that can recognize a diverse array of pathogens and initiate protective immune and inflammatory responses. However, if the molecular signatures recognized are shared by both foreign and self-molecules, as is the case of nucleic acids, then the responses initiated by these sensors may have deleterious consequences. Notably, this adverse occurrence may be of primary importance in autoimmune disease pathogenesis. In this case, microbe-induced damage or mishandled physiologic processes could lead to the generation of microparticles containing self-nucleic acids. These particles may inappropriately gain access to the cytosol or endolysosomes and, hence, engage resident RNA and DNA sensors. Evidence, as reviewed here, strongly indicates that these sensors are primary contributors to autoimmune disease pathogenesis, spearheading efforts toward development of novel therapeutics for these disorders.
Kono, Dwight H.; Beutler, Bruce
The thyroid glands of patients with autoimmune diseases such as Graves' disease and certain forms of goiter contain infiltrating activated T lymphocytes and, unlike cells of normal glands, the epithelial follicular cells strongly express histocompatability antigens of the HLA-DR type. In a study of such autoimmune disorders, the infiltrating T cells from the thyroid glands of two patients with Graves'
Marco Londei; G. Franco Bottazzo; Marc Feldmann
Chronic lymphocytic leukemia is frequently associated with immune disturbances. The relationship between chronic lymphocytic leukemia and autoimmune cytopenias, particularly autoimmune hemolytic anemia and immune thrombocytopenia, is well established. The responsible mechanisms, particularly the role of leukemic cells in orchestrating the production of polyclonal autoantibodies, are increasingly well understood. Recent studies show that autoimmune cytopenia is not necessarily associated with poor prognosis. On the contrary, patients with anemia or thrombocytopenia due to immune mechanisms have a better outcome than those in whom these features are due to bone marrow infiltration by the disease. Moreover, fears about the risk of autoimmune hemolysis following single agent fludarabine may no longer be appropriate in the age of chemo-immunotherapy regimens. However, treatment of patients with active hemolysis may pose important problems needing an individualized and clinically sound approach. The concept that autoimmune cytopenia may precede the leukemia should be revisited in the light of recent data showing that autoimmune cytopenia may be observed in monoclonal B-cell lymphocytosis, a condition that can only be detected by using sensitive flow cytometry techniques. On the other hand, there is no evidence of an increased risk of non-hemic autoimmune disorders in chronic lymphocytic leukemia. Likewise, there is no epidemiological proof of an increased risk of chronic lymphocytic leukemia in patients with non-hemic autoimmunity. Finally, since immune disorders are an important part of chronic lymphocytic leukemia, studies aimed at revealing the mechanisms linking the neoplastic and the immune components of the disease should help our understanding of this form of leukemia.
Hodgson, Kate; Ferrer, Gerardo; Montserrat, Emili; Moreno, Carol
Neuronal nicotinic AChRs (nAChRs) are implicated in the pathogenesis of diverse neurological disorders and in the regulation of small-cell lung carcinoma growth. Twelve subunits have been identified in vertebrates, and mutations of one are recognized in a rare form of human epilepsy. Mice with genetically manipulated neuronal nAChR subunits exhibit behavioral or autonomic phenotypes. Here, we report the first model of an acquired neuronal nAChR disorder and evidence for its pertinence to paraneoplastic neurological autoimmunity. Rabbits immunized once with recombinant ?3 subunit (residues 1–205) develop profound gastrointestinal hypomotility, dilated pupils with impaired light response, and grossly distended bladders. As in patients with idiopathic and paraneoplastic autoimmune autonomic neuropathy, the severity parallels serum levels of ganglionic nAChR autoantibody. Failure of neurotransmission through abdominal sympathetic ganglia, with retention of neuronal viability, confirms that the disorder is a postsynaptic channelopathy. In addition, we found ganglionic nAChR protein in small-cell carcinoma lines, identifying this cancer as a potential initiator of ganglionic nAChR autoimmunity. The data support our hypothesis that immune responses driven by distinct neuronal nAChR subtypes expressed in small-cell carcinomas account for several lung cancer–related paraneoplastic disorders affecting cholinergic systems, including autoimmune autonomic neuropathy, seizures, dementia, and movement disorders.
Lennon, Vanda A.; Ermilov, Leonid G.; Szurszewski, Joseph H.; Vernino, Steven
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.
Teufel, Andreas; Galle, Peter R; Kanzler, Stephan
Iron, an essential element for many important cellular functions in all living organisms, can catalyze the formation of potentially toxic free radicals. Excessive iron is sequestered by ferritin in a nontoxic and readily available form in a cell. Ferritin is composed of 24 subunits of different proportions of two functionally distinct subunits: ferritin H and L. The expression of ferritin is under delicate control and is regulated at both the transcriptional and post-transcriptional levels by iron, cytokines, hormones, and oxidative stress. Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy. Hyperferritinemia is associated with inflammation, infections, and malignancies. While elevated levels of ferritin are characteristic of adult-onset Still's disease and hemophagocytic syndrome, both associated with inflammation, it has scantly been evaluated in other autoimmune diseases. In this review, we describe ferritin structure and function, hyperferritinemia in disease states and in autoimmune diseases. PMID:17643933
Zandman-Goddard, Gisele; Shoenfeld, Yehuda
Yersinia enterocolitica O:3 and the human thyrotropin receptor share a structural similarity, revealed by their serological cross-reactivity. The exact molecular basis of the similarity is open. In spite of this cross-reactivity, Yersinia seems not to be a major inducer of thyroid autoimmunity. Yersinia infections or avirulent Yersinia strains in the intestinal flora may rather contribute to the development of thyroid
Paavo Toivanen; Auli Toivanen
The relationship between prolactin and the immune system has been demonstrated in the last two decades, opening new windows\\u000a in the field of the immunoendocrinology. Prolactin has an important role in the innate and adaptive immune response. Increased\\u000a prolactin levels have been described in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren\\u000a syndrome, and systemic sclerosis among others.
Luis J. Jara; Gabriela Medina; Miguel A. Saavedra; Olga Vera-Lastra; Carmen Navarro
From a cyanogen bromide digest of the encephalitogenic basic protein of human brain a polypeptide—derived from the N-terminal end of the protein—was isolated and shown to induce experimental autoimmune encephalomyelitis. At low doses this peptide induced typical histological lesions unaccompanied by clinical symptoms and humoral antibody. Digestion of the protein with trypsin did not destroy its encephalitogenic activity. The basic protein of human myelin contains more than one encephalitogenic determinant.
Carnegie, P. R.; McPherson, T. A.; Robson, G. S. M.
We have described a case of a rare autoimmune disease, called autoimmune polyglandular syndrome type I (APS type I), in a 44-year-old woman. APS type I is an autosomal recessively inherited disorder, connected with mutations in AIRE (autoimmune regulator) gene. Subsequently, autoantibodies directed towards tissue-specific enzymes are produced, which causes destruction of multiple tissues and organs, first of all--endocrine glands. In the described woman, primary hypoparathyroidism occurred in childhood. Addison disease, chronic candidiasis of the nails and vitiligo developed in adolescence. Before she was 30, a premature ovarian failure, and axilla and pubis alopecia occurred. The last recognized disorders were cholelithiasis and candidiasis of oesophagus. The late diagnosis resulted in numerous complications of the disease and the patient's life quality impairment. PMID:15771137
Dunajska, Katarzyna; Szymczak, Jadwiga
Necrotizing autoimmune myopathies are included in the spectrum of inflammatory myopathies, together with polymyosis, dermatopolymyosis and inclusion body myositis, despite the characteristic feature of marked muscular necrosis without inflammatory infiltrates. The clinical presentation is highly variable, often similar to the other inflammatory myopathies. The most common finding is nevertheless the severe form with rhabdomyolysis. The creatine kinase level is elevated (around 10,000IU/l) and electromyography shows myopathic changes with increased spontaneous activities reflecting the importance of the muscular necrosis. Muscle biopsy is required for diagnosis, revealing active necrosis of the muscle fibers without inflammatory invasion by CDA+ or CD8+ T-cells. Deposition of a microvascular membrane attack complex (C5b9) is often noted, whereas the upregulation of MHC class 1 is rarely detected. Signs of endomysial microangiopathy are frequently reported. Necrotizing autoimmune myopathies can be associated with antisignal recognition particle (SRP) antibodies or more rarely with the usual inflammatory myopathy antibodies. Paraneoplasic forms are described but remain exceptional. Lastly, necrotizing autoimmune myopathies, sometimes associated with statin therapy, have been recently described. They are linked with an antibody directed against 3-hydroxy-3-methyglutaryl-coenzyme A. Treatment is based on corticosteroid therapy, immunosuppressive drugs or intravenous immunoglobulins. Response is variable, depending on the clinical form. PMID:23999024
Petiot, P; Choumert, A; Hamelin, L; Devic, P; Streichenberger, N
The trace element selenium (Se) occurs in the form of the amino acid selenocysteine in selenoproteins. Selenoproteins exerts multiple physiological effects in human health, many of which are related with regulation of reduction-oxidation processes. In fact, the selenoenzyme families of glutathione peroxidase (GPx) and thioredoxin reductase (TRx) display the ability to act as antioxidants, protecting cells from oxidative damage. Furthermore, another class of selenoproteins are the iodothyronine deiodinase enzymes (DIO), which catalyze the conversion of thyroxine (T4) in triiodothyronine (T3), then exerting a fine tuned control on thyroid hormones metabolism. Several studies have investigated the potential positive effects of Se supplementation in thyroid diseases, characterized by increased levels of hydrogen peroxide and free radicals, like autoimmune chronic thyroiditis. These studies have supplied evidences indicating that Se supplementation, maximizing the antioxidant enzymes activity, may reduce the thyroid inflammatory status. Then, it may be postulated that Se could play a therapeutical role in thyroid autoimmune diseases. Despite the fact that recent studies seem to be concordant about Se beneficial effects in decreasing thyroid peroxidase antibodies (TPOAb) titers and ameliorating the ultrasound echogenicity pattern, several doubts have to be still clarified, before advising Se supplementation in chronic autoimmune thyroiditis.
The autoimmune polyglandular syndrome (APS) is defined as the manifestation of at least two endocrine autoimmune diseases. In order to take the wide spectrum of components and the variations of the disease fully into account, APS is usually divided up into the rare juvenile type (APS I) and the more common adult type (APS II-IV). APS I is caused by a monogenetic mutation whereas APS II-IV has a multifactorial genesis with combination related subgroups. Early diagnosis, individual adjustment of therapy and screening of high risk patients in particular are regarded as clinically relevant. In addition to the patient's history, the diagnosis of APS encompasses serologic measurement of organ-specific autoantibodies as well as a clinical examination and functional tests. However, the analysis of immunological modificating, zytokine-coding and tissue-specific genes could also be important within a screening. Although APS is a rather rare disease with an incidence of 1:100 000 (juvenile APS) and 1:20 000 (adult APS), the possibility of an autoimmune polyglandular syndrome should be timely considered. By this means, severe complications can be avoided to some extent and the patients' physical as well as psychological quality of life can be ensured. PMID:23393002
Hansen, M P; Kahaly, G J
Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity.
Kanatsuna, Norio; Papadopoulos, George K.; Moustakas, Antonis K.; Lenmark, Ake
Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on celiac disease (CD), an autoimmune enteropathy, and type 1 diabetes (T1D), a hyperglycosaemia caused by a destructive autoimmune process targeting the insulin-producing pancreatic islet cells. Even if environmental factors and genetic susceptibility are clearly involved in the pathogenesis of autoimmunity, for most autoimmune disorders there is no or little knowledge about the causing agent or genetic makeup underlying the disease. In this respect, CD represents a unique autoimmune disorder because a close genetic association with HLA-DQ2 or HLA-DQ8 haplotypes and, more importantly, the environmental trigger (the gliadin fraction of gluten-containing grains wheat, barley, and rye) are known. Conversely, the trigger for autoimmune destruction of pancreatic ss cells in T1D is unclear. Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity. In this review, each of these components will be briefly reviewed. PMID:19538307
Visser, Jeroen; Rozing, Jan; Sapone, Anna; Lammers, Karen; Fasano, Alessio
Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency or mutation of coinhibitory molecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e.g., CTLA-4?Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4?Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans.
Watanabe, Norihiko; Nakajima, Hiroshi
Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency or mutation of coinhibitory molecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e.g., CTLA-4?Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4?Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans. PMID:22997525
Watanabe, Norihiko; Nakajima, Hiroshi
We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders in 48 patients with chronic lymphocytic leukemia (CLL). The diagnosis of autoimmune disease (AID) was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenic purpura (AITP) in nine (18.8%), Evans syndrome in eight (16.7%), and pure red cell anemia (PRCA) in five patients (10.5%). CLL was considered progressive in 40% of subjects upon AID diagnosis. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). The median duration of autoimmunity was 24 months, but the duration of response of autoimmunity (DR-AI) was higher for patients presenting with: (1) AID early during the CLL course (<3 years), or (2) both and pure red cell aplasia (PRCA) in five patients (10.5%) and AIHA. PMID:21699387
Michallet, Anne-Sophie; Rossignol, Julien; Cazin, Bruno; Ysebaert, Loic
|Background: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS) is a recently recognized syndrome in which pre-adolescent children have abrupt onsets of tics and/or obsessive-compulsive symptoms, a recurring and remitting course of illness temporally related to streptococcal infections, and associated…
Swedo, Susan E.; Grant, Paul J.
Discoveries revealing the molecular basis of innate immune responses, particularly the identification of Toll-like receptors (TLRs) as the major recognition sensors for microbial and even self-molecules, have provided new insights into the pathogenesis of both systemic and organ-specific autoimmune diseases. These insights will permit the development of novel treatment modalities for these disorders. PMID:23154274
Theofilopoulos, Argyrios N
A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a self-reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. Type I IFN cytokines are pleiotropic in their effects, mediating antiviral and antitumor activities, and possess numerous immunomodulatory functions for both the innate and adaptive
John C. Hall; Antony Rosen
Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical
F. Rieux-Laucat; F. Le Deist; C. Hivroz; I. A. G. Roberts; K. M. Debatin; A. Fischer; J. P. de Villartay
Discoveries revealing the molecular basis of innate immune responses, particularly the identification of Toll-like receptors (TLRs) as the major recognition sensors for microbial and even self-molecules, have provided new insights into the pathogenesis of both systemic and organ-specific autoimmune diseases. These insights will permit the development of novel treatment modalities for these disorders.
Theofilopoulos, Argyrios N.
ABSTRACT: Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice,
Aryl hydrocarbon receptor (Ahr) is thought to be a crucial factor that regulates immune responses. Many Ahr-mediated immune regulatory mechanisms have been discovered, which will likely enhance our understanding of the molecular pathogenesis of autoimmune inflammation including rheumatoid arthritis (RA). RA is a systemic inflammatory disease that affects approximately 1 % of the population and is characterized by chronic inflammation of the synovium and subsequent joint destruction. Recent findings showed that Ahr plays critical roles in the development of Th17 cells, which are key effector T cells in a variety of human autoimmune diseases including RA. Consistent with these findings, our previous study demonstrated that Ahr in T cells is important for the development of collagen-induced arthritis, a widely used murine model of human RA, possibly via the induction of Th17 cells. In addition, Ahr is an attractive molecule because tobacco smoke is a well-known environmental risk factor for RA development and Ahr agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methyl cholanthrene, and benzo[a]pyrene, are major toxic components in cigarettes. This review summarizes recent findings on Ahr functions in immune cells in the context of RA pathogenesis during stimulation with smoking-derived ligands. We also discuss the potential link between Ahr and novel factors, such as microRNAs, in the development of RA, thereby providing further mechanistic insight into this autoimmune disorder. PMID:23982178
Nguyen, Nam Trung; Nakahama, Taisuke; Kishimoto, Tadamitsu
The elucidation of the genes leading to selected immune defects has accelerated our understanding of the molecular basis of tolerance in autoimmunity disorders. Mutations in genes of the immune system are known to lead to a catalogue of functional deficits, including loss of activation-induced Fas-mediated apoptosis, an inability to remove self-reactive T and/or B cells and insufficient numbers or functions of regulatory T cells. In most cases, microbial antigen stimulation occurs simultaneously, leading to further inflammatory responses. In each case, probing the molecular pathways involved in these primary immune defects has led to a better understanding of autoimmune diseases in general. While subjects with X-linked agammaglobulinaemia are almost devoid of autoimmune diseases, B cells which are present, but dysfunctional in other defects, lead to a significant incidence of autoimmune disease. Autoimmunity is also particularly common in the antibody deficiency states. Although organ-based autoimmunity also occurs, for unclear reasons the main conditions are immune thrombocytopenia purpura and autoimmune haemolytic anaemia. The common variable immune deficiency subjects most afflicted by these cytopenias are those with specific peripheral blood memory B cell phenotypes. B cells of these subjects have a retained autoimmune potential, lack of somatic hypermutation, profound loss of proliferative potential, accelerated apoptosis and loss of normal Toll-like receptor signalling. Treatment with high-dose immunoglobulin and/or steroids can be helpful, while rituximab provides benefits in the treatment of refractory cytopenias with apparently little risk, even with repeated use, due to ongoing immune globulin therapy.
The elucidation of the genes leading to selected immune defects has accelerated our understanding of the molecular basis of tolerance in autoimmunity disorders. Mutations in genes of the immune system are known to lead to a catalogue of functional deficits, including loss of activation-induced Fas-mediated apoptosis, an inability to remove self-reactive T and/or B cells and insufficient numbers or functions of regulatory T cells. In most cases, microbial antigen stimulation occurs simultaneously, leading to further inflammatory responses. In each case, probing the molecular pathways involved in these primary immune defects has led to a better understanding of autoimmune diseases in general. While subjects with X-linked agammaglobulinaemia are almost devoid of autoimmune diseases, B cells which are present, but dysfunctional in other defects, lead to a significant incidence of autoimmune disease. Autoimmunity is also particularly common in the antibody deficiency states. Although organ-based autoimmunity also occurs, for unclear reasons the main conditions are immune thrombocytopenia purpura and autoimmune haemolytic anaemia. The common variable immune deficiency subjects most afflicted by these cytopenias are those with specific peripheral blood memory B cell phenotypes. B cells of these subjects have a retained autoimmune potential, lack of somatic hypermutation, profound loss of proliferative potential, accelerated apoptosis and loss of normal Toll-like receptor signalling. Treatment with high-dose immunoglobulin and/or steroids can be helpful, while rituximab provides benefits in the treatment of refractory cytopenias with apparently little risk, even with repeated use, due to ongoing immune globulin therapy. PMID:21466546
Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections. PMID:23725858
Mahlios, Josh; De la Herrán-Arita, Alberto K; Mignot, Emmanuel
In recent years, active research using genomic, cellular and animal modeling approaches has revealed the fundamental forces driving the development of autoimmune diseases. Type I interferon imprints unique molecular signatures in a list of autoimmune diseases. Interferon is induced by diverse nucleic acid-containing complexes, which trigger innate immune activation of plasmacytoid dendritic cells. Interferon primes, activates or differentiates various leukocyte populations to promote autoimmunity. Accordingly, interferon signaling is essential for the initiation and/or progression of lupus in several experimental models. However, the heterogeneous nature of systemic lupus erythematosus requires better characterization on how interferon pathways are activated and subsequently promote the advancement of autoimmune diseases. Given the central role of type I interferon, various strategies are devised to target these cytokines or related pathways to curtail the progression of autoimmune diseases. PMID:23445195
Di Domizio, Jeremy; Cao, Wei
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.
Gilbert, Kathleen M.
Autoimmune diseases are often characterized as clinical syndromes caused by the inappropriate activation of T or B cells resulting in systemic or organ-specific damage. However, studies support a role for the innate immune system, and in particular natural killer (NK) cells, in stimulating or suppressing autoimmunity. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells
Anthony R French; Wayne M Yokoyama
Autoimmune thyroiditis is among the most prevalent of all the autoimmunities. Autoimmune thyroiditis is multifactorial with contributions from genetic and environmental factors. Much information has been published about the genetic predisposition to autoimmune thyroiditis both in experimental animals and humans. There is, in contrast, very little data on environmental agents that can serve as the trigger or autoimmunity in a genetically predisposed host. The best-established environmental factor is excess dietary iodine. Increased iodine consumption is strongly implicated as a trigger for thyroiditis, but only in genetically susceptible individuals. However, excess iodine is not the only environmental agent implicated as a trigger leading to autoimmune thyroiditis. There are a wide variety of other synthetic chemicals that affect the thyroid gland or have the ability to promote immune dysfunction in the host. These chemicals are released into the environment by design, such as in pesticides, or as a by-product of industry. Candidate pollutants include polyaromatic hydrocarbons, polybrominated biphenols, and polychlorinated biphenols, among others. Infections are also reputed to trigger autoimmunity and may act alone or in concert with environmental chemicals. We have utilized a unique animal model, the NOD.H2h4 mouse to explore the influence of iodine and other environmental factors on autoimmune thyroiditis.
Burek, C. Lynne; Talor, Monica V.
Autoimmune hepatitis (AIH) is a chronic, progressive liver disease that occurs predominantly in genetically predisposed individuals. The condition is characterized by the presence of autoantibodies and is associated with elevated serum globulin levels. AIH generally responds to steroid therapy by suppressing the autoimmune response. Over the last decade, a scoring system has been developed that can assist in making the
Ganesh R. Veerappan; Brian P. Mulhall; Kent C. Holtzmuller
Sex hormones, especially estrogen and prolactin (PRL), have an important role in modulating the immune response. PRL is secreted from the pituitary gland as well as other organs and cells particularly lymphocytes. PRL has an immune stimulatory effect and promotes autoimmunity. PRL interferes specifically with B cell tolerance induction, enhances proliferative response to antigens and mitogens and increases the production of immune globulins, cytokines and autoantibodies. Hyperprolactinemia (HPRL) in women present with clinical manifestations of galactorrhea, primary or secondary amenorrhea, delayed menarche or a change in the menses either in the amount or in the regularity. Furthermore in the last 2 decades multi-organ and organ specific autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS), Hashimoto's thyroiditis (HT), multiple sclerosis (MS), psoriasis, hepatitis C patients, Behçet's disease, peripartum cardiomyopathy (PPCM) and active celiac disease were discussed to be associated with HPRL. There is data showing correlation between PRL level and diseases activity in few diseases. Genetic factors may have a role in humans as in animal models. The PRL isoforms based on the differences in the amino acid sequence and size of the cytoplasmic domain have an important effect on the bioactivity on prolactin receptors (PRL-Rs). PMID:22155203
Shelly, Shahar; Boaz, Mona; Orbach, Hedi
The majority of autoimmune diseases predominate in females. In searching for an explanation for this female excess, most attention has focused on hormonal changes - both exogenous changes (for example, oral contraceptive pill) and fluctuations in endogenous hormone levels particularly related to menstruation and pregnancy history. Other reasons include genetic differences, both direct (influence of genes on sex chromosomes) and indirect (such as microchimerism), as well as gender differences in lifestyle factors. These will all be reviewed, focusing on the major autoimmune connective tissue disorders: rheumatoid arthritis, systemic lupus erythematosus and scleroderma.
Summary A number of autoimmune diseases, including multiple sclerosis, are mediated by self-reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms including regulation through coinhibitory receptors and suppression by regulatory T cells (Tregs). However, if these mechanisms fail, self-reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA-4, PD-1, Tim-3 and TIGIT act at different checkpoints to inhibit autoreactive T cells and suppress the development of CNS autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non-redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. We therefore propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.
Joller, Nicole; Peters, Anneli; Anderson, Ana C.; Kuchroo, Vijay K.
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.
Agarwal, Shradha; Cunningham-Rundles, Charlotte
Multicomponent analysis of variations of serum marker antibodies is an efficacious tool for preventive (pre-clinical) diagnosis of immune disorders causing serious diseases. Successful development of this method may lead to revision of the approaches accepted in modern medicine and facilitate practical transition to the prognosis-prevention paradigm. The study of antibody spectra reflecting individual genetic and epigenetic features provides a basis for prognostication of health and pathological conditions. We believe that in most cases early diagnosis of reversible pathologic processes their further development can be arrested which provides a real opportunity to preserve health. PMID:20922842
Pal'tsev, M A; Poletaev, A B; Suchkov, S V
Heterotrimeric Gi signaling regulates immune homeostasis, since autoimmunity occurs upon disruption of this pathway. However, the role of the lymphocyte-expressed Gai subunits (Gai2 and 3) on T cell activation and cytokine production is poorly understood. To examine this role, we studied T lymphocytes from mice deficient in the Gai2 or Gai3 subunits. Gai2-\\/- but not Gai3-\\/- splenocytes were hyper-responsive for
Tiffany T. Huang; Yumei Zong; Harnisha Dalwadi; Chan Chung; M. Carrie Miceli; Karsten Spicher; Lutz Birnbaumer; Jonathan Braun; Richard Aranda
Rheumatoid arthritis (RA) is a debilitating autoimmune disease of global prevalence. The disease is characterized by synovial inflammation leading to cartilage and bone damage. Most of the conventional drugs used for the treatment of RA have severe adverse reactions and are quite expensive. Over the years, increasing proportion of patients with RA and other immune disorders are resorting to complementary and alternative medicine (CAM) for their health needs. Natural plant products comprise one of the most popular CAM for inflammatory and immune disorders. These herbal CAM belong to diverse traditional systems of medicine, including traditional Chinese medicine, Kampo, and Ayurvedic medicine. In this paper, we have outlined the major immunological pathways involved in the induction and regulation of autoimmune arthritis and described various herbal CAM that can effectively modulate these immune pathways. Most of the information about the mechanisms of action of herbal products in the experimental models of RA is relevant to arthritis patients as well. The study of immunological pathways coupled with the emerging application of genomics and proteomics in CAM research is likely to provide novel insights into the mechanisms of action of different CAM modalities.
Venkatesha, Shivaprasad H.; Rajaiah, Rajesh; Berman, Brian M.; Moudgil, Kamal D.
The concept that autoimmunity may damage the inner ear was introduced by McCabe in 1979. Audiovestibular symptoms may occur in isolation or may be mediated by vasculitis in patients affected by systemic autoimmune disorders. Sensorineural hearing loss (SNHL) is typical in Cogan's syndrome but occurs less frequently in Beçhet's syndrome and in systemic necrotizing vasculitides. Patients affected by immune-mediated profound SNHL represent ideal candidates for cochlear implantation as these patients become deaf after years of hearing. The disease itself and the medication taken may, however, influence the prognosis of cochlear implantation in these patients. We retrospectively evaluated the pre- and intraoperative findings as well as the postoperative course and performance of a group of five patients affected by a systemic vasculitis syndrome who received a cochlear implant. Implantation was successful in all patients, no complications occurred and excellent postoperative speech perception was achieved. We conclude that cochlear implantation in patients affected by immune-mediated inner ear disorders is effective although the long-term results remain to be evaluated. PMID:12211357
Quaranta, Nicola; Bartoli, Roberto; Giagnotti, Francesca; Di Cuonzo, Franca; Quaranta, Antonio
Autoimmune cytopenias are a recognized complication of hematopoietic stem cell transplant (HSCT), and are considered to be a feature of chronic graft-versus-host disease (cGVHD). We report on a cohort of very young infants (?3 months of age) receiving HSCT from unrelated donor umbilical cord blood for genetic disorders who developed posttransplant autoimmune cytopenias at an increased rate compared to older
Kristin M. Page; Adam M. Mendizabal; Vinod K. Prasad; Paul L. Martin; Suhag Parikh; Susan Wood; Gregory D. Sempowski; Paul Szabolcs; Joanne Kurtzberg
Autoimmune hepatitis (AIH) is occasionally triggered by drug treatments. Recently, as biological agents are becoming widely used for autoimmune disorders, there have been a growing number of reports of the development of autoimmune processes related to these agents. A 52-year-old Japanese woman with psoriasis developed liver damage two months after initiation of anti-TNF-? therapy with adalimumab. Liver histological findings were compatible with AIH, and positive conversions of ANAs were detected. The patient was treated with prednisolone and had a good response. While some cases of AIH triggered by anti-TNF-? therapies have been reported, the pathogenesis remains unspecified. When elevation of liver enzymes is observed with high IgG levels and seropositivity of ANA during the course of anti-TNF-? therapy, liver biopsy findings may be essential and important to make definitive diagnosis of AIH.
The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low-grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here, we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.
The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.
Grolleau-Julius, Annabelle; Ray, Donna; Yung, Raymond L.
Epidemiological and experimental immunological evidence suggest that estrogens enhance the humoral immune response, and at the same time, seem to play important roles in pathophysiology of autoimmune rheumatic diseases. Estrogens in human subjects are generally considered as enhancers of cell proliferation (anti-apoptotic), however, rather than through their serum levels (that may exert opposite dose-related effects), they play important roles through their peripheral metabolites especially in autoimmune rheumatic diseases. Several investigations strongly support an accelerated aromatase-mediated peripheral metabolic conversion of upstream androgen precursors to estrogen metabolites in peripheral tissues affected by immune/inflammatory reactions, both, in male and female patients. In RA synovial tissue, biological effects of these metabolites as a consequence of altered peripheral sex hormone synthesis (intracrine, e.g., at the level of macrophages and fibroblasts) mainly results in stimulation of cell proliferation and cytokine production (i.e. TNF). It was shown that RA synovial cells mainly produce the cell proproliferative 16alpha-hydroxyestrone which, in addition to 16alpha-hydroxy-17beta-estradiol, is the downstream estrogen metabolite that interferes with monocyte proliferation. Therefore, a preponderance of 16alpha-hydroxylated estrogens is an unfavorable sign, at least, in synovial inflammation and possibly related synovial tissue hyperplasia. Interestingly, urinary concentration and total urinary loss of 2-hydroxyestrogens was found 10 times higher in healthy subjects compared to RA or SLE patients irrespective of prior prednisolone treatment or sex. The intracrine synthesis of active estrogen metabolites at the level of cells involved in the immune response (e.g. macrophages and fibroblasts) represents a common pathway that characterizes a similar final immune reactivity in both male and female patients. PMID:22155198
Cutolo, Maurizio; Sulli, Alberto; Straub, Rainer H
Sensory neuronopathies (SNs) are a specific subgroup of peripheral nervous system diseases characterized by primary degeneration of dorsal root ganglia and their projections. Multifocal sensory symptoms often associated to ataxia are the classical features of SN. Several different etiologies have been described for SNs, but immune-mediated damage plays a key role in most cases. SN may herald the onset of some systemic autoimmune diseases, which further emphasizes how important the recognition of SN is in clinical practice. We have thus reviewed available clinical, neurophysiological, and therapeutic data on autoimmune disease-related SN, namely, in patients with Sjögren's syndrome, autoimmune hepatitis, and celiac disease.
Martinez, Alberto R. M.; Nunes, Marcelo B.; Nucci, Anamarli; Franca, Marcondes C.
The concept of shared autoimmunity comprises various forms of disease: rheumatic diseases in several members of the same family, the coincidence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in healthy relatives of autoimmune disease patients, and the development of two or more autoimmune rheumatic diseases in one patient, the so-called overlap syndromes. The
Tatiana Sofía Rodríguez-Reyna; Donato Alarcón-Segovia
Air pollution consists of a heterogeneous mixture of gasses and particles that include carbon monoxide, nitrates, sulfur dioxide, ozone, lead, toxic by-product of tobacco smoke and particulate matter. Oxidative stress and inflammation induced by inhaled pollutants may result in acute and chronic disorders in the respiratory system, as well as contribute to a state of systemic inflammation and autoimmunity. This paper reviews the mechanisms of air contaminants influencing the immune response and autoimmunity, and it focuses on studies of inhaled pollutants triggering and/or exacerbating rheumatic diseases in cities around the world. Remarkably, environmental factors contribute to the onset of autoimmune diseases, especially smoking and occupational exposure to silica in rheumatoid arthritis and systemic lupus erythematosus. Other diseases such as scleroderma may be triggered by the inhalation of chemical solvents, herbicides and silica. Likewise, primary vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) may be triggered by silica exposure. Only few studies showed that air pollutants could trigger or exacerbate juvenile idiopathic arthritis and systemic lupus erythematosus. In contrast, no studies of tropospheric pollution triggering inflammatory myopathies and spondyloarthropathies were carried out. In conclusion, air pollution is one of the environmental factors involved in systemic inflammation and autoimmunity. Further studies are needed in order to evaluate air pollutants and their potentially serious effects on autoimmune rheumatic diseases and the mechanisms involved in the onset and the exacerbation of these diseases. PMID:21763467
Farhat, Sylvia C L; Silva, Clovis A; Orione, Maria Angelica M; Campos, Lucia M A; Sallum, Adriana M E; Braga, Alfésio L F
Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFN?/? by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFN? activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.
Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFN?/? by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFN? activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways. PMID:20392289
Delgado-Vega, Angélica M; Alarcón-Riquelme, Marta E; Kozyrev, Sergey V
Treatment of experimental autoimmune disorders of the nervous system with high doses of glucocorticosteroids (GC) or with administration of the specific antigen is effective and associated with marked T cell apoptosis in situ. Here we investigated in adoptive transfer-experimental autoimmune neuritis (AT-EAN) of the Lewis rat whether induction of T cell apoptosis resulting from T cell activation by antigen therapy
Andreas Weishaupt; Lisa M. Schönrock; Martina Stienekemeier; Klaus V. Toyka; Ralf Gold
A 55-year-old Egyptian woman with chronic hepatitis C undergoing treatment with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin was referred to our hospital on November 2010 with prolonged easy fatigability and an attack of syncope; she had no prior history of autoimmune disorders or allergy. Laboratory investigations documented the presence of Peg-IFN induced autoimmune haemolytic anaemia and autoimmune thyroiditis. Intravenous ? globulin (IVGG) failed to correct the autoimmune process; on the other hand steroid therapy dramatically corrected both haematological and thyroid values, and step down the immune process. Our report indicated that Peg-IFN de novo-induce autoimmune haemolysis, documenting a previous report. IVGG failed to step down the immune process in our case.
Said, Ashraf; Elbahrawy, Ashraf; Alfiomy, Mohamed; Abdellah, Mohamed; Shahat, Khaled; Salah, Mohamed; Mostafa, Sadek; Elwassief, Ahmed; Aboelfotoh, Attef; Abdelhafeez, Hafez; El-Sherif, Assem
Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.
The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders. PMID:22284419
Gall, Alevtina; Treuting, Piper; Elkon, Keith B; Loo, Yueh-Ming; Gale, Michael; Barber, Glen N; Stetson, Daniel B
Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signaling and is required for the maintenance of immunological tolerance in mice1, 2. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 Caucasian subjects with relatively common autoimmune disorders and in 2/648 Caucasian controls. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in 8 autoimmune subjects but in no control subjects. The Odds Ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.
Surolia, Ira; Pirnie, Stephan P.; Chellappa, Vasant; Taylor, Kendra N.; Cariappa, Annaiah; Moya, Jesse; Liu, Haoyuan; Bell, Daphne W.; Driscoll, David; Diederichs, Sven; Haider, Khaleda; Netravali, Ilka; Le, Sheila; Elia, Roberto; Dow, Ethan; Lee, Annette; Freudenberg, Jan; De Jager, Philip L.; Chretien, Yves; Varki, Ajit; MacDonald, Marcy E.; Gillis, Tammy; Behrens, Timothy W.; Bloch, Donald; Collier, Deborah; Korzenik, Joshua; Podolsky, Daniel K.; Hafler, David; Murali, Mandakolathur; Sands, Bruce; Stone, John H.; Gregersen, Peter K.; Pillai, Shiv
Autoimmune diseases are characterized by multiple autoantibodies and\\/or autoreactive T cells that recognize a large number of antigens. Many of these antigens undergo extensive post-translational modifications during apoptosis and act as substrates for the pro-apoptotic cystein proteases. Here, Mauro Piacentini and Vittorio Colizzi discuss the effects on autoimmunity produced by post-translational modifications of proteins catalysed by the pro-apoptotic enzyme tissue
Mauro Piacentini; Vittorio Colizzi
The objective of this study is to document a series of cases of occupationally derived autoimmune disease. Individuals with\\u000a occupational exposure to acrylamides were evaluated clinically and biochemically\\/immunologically for evidence of autoimmune\\u000a disease. Symptoms and signs and immuno-reactivity were monitored during exposure-free and re-exposure as part of the individuals’\\u000a clinical evaluation. Six individuals with occupational acrylamide exposure had clinical and
\\u000a Drug-induced autoimmune syndromes have been recognized for a long time and their frequency and complexity have increased in\\u000a recent years. Many of these conditions are associated with autoantibodies that have been classically defined as limited to\\u000a idiopathic disease states. Several medications are known to induce endocrine autoimmunity in genetically predisposed individuals,\\u000a but the mechanisms to which they owe this effect
Paolo Pozzilli; Rocky Strollo; Nicola Napoli
Autoimmune diseases appear to have multiple contributing factors including genetics, epigenetics, environmental factors, and\\u000a aging. The predominance of females among patients with autoimmune diseases suggests possible involvement of the X chromosome\\u000a and X chromosome inactivation. X chromosome inactivation is an epigenetic event resulting in multiple levels of control for\\u000a modulation of the expression of X-linked genes in normal female cells
Wesley H. Brooks
\\u000a Autoimmune disease in both mice and humans is associated with increased expression of endogenous retroviruses in the thymus\\u000a and T cells, and loss of self-tolerance by T cells. The basic genetic defect underlying autoimmune disease has been identified\\u000a as a mutation of the Fas apoptosis antigen in MRL-lpr\\/lpr mice or a mutation of the Fas ligand in C3H-gld\\/gld mice. In
J. D. Mountz; J. Cheng; X. Su; J. Wu; T. Zhou
Some adjuvants may exert adverse effects upon injection or, on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of the enormous implications for vaccine development. In the search for new and safer adjuvants, several new adjuvants were developed by pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special immune receptors called toll-like receptors (TLRs) that are expressed on leukocyte membranes. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. Alongside their supportive role, adjuvants were found to inflict by themselves an illness of autoimmune nature, defined as 'the adjuvant diseases'. The debatable question of silicone as an adjuvant and connective tissue diseases, as well as the Gulf War syndrome and macrophagic myofaciitis which followed multiple injections of aluminium-based vaccines, are presented here. Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants need to be developed and incorporated into future vaccines. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. More adjuvants were approved to date besides alum for human vaccines, including MF59 in some viral vaccines, MPL, AS04, AS01B and AS02A against viral and parasitic infections, virosomes for HBV, HPV and HAV, and cholera toxin for cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely in order to circumvent common side effects of adjuvant-activated TLRs such as local inflammation and the general malaise felt because of the costly whole-body immune response to antigen. PMID:19880572
Israeli, E; Agmon-Levin, N; Blank, M; Shoenfeld, Y
Physical inactivity in combination with a sedentary lifestyle is strongly associated with an increased risk of development of inflammatory-mediated diseases, including autoimmune disorders. Recent studies suggest that anti-inflammatory effects of physical exercise may be of therapeutic value in some affected individuals. In this study, we determined the effects of forced-exercise (treadmill running) on the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats were subjected to sedentary (control) or forced-exercise (1.2 km per day, 5 days a week) for three weeks prior to induction of EAN. P2 (53-78)-immunized sedentary control rats developed a monophasic course of EAN beginning on post-injection day 12.33 ± 0.59 (n = 18) and reaching peak severity on day 15.83 ± 0.35 (n = 18). At near peak of disease, ankle- and sciatic notch-evoked compound muscle action potential (CMAP) amplitudes in sedentary control rats were reduced (~50%) while motor nerve conduction velocity (MNCV) was slowed (~30%) compared with pre-induction evoked responses. In marked contrast, rats undergoing forced-exercise exhibited a significantly less severe clinical course of EAN beginning on post-injection day 12.63 ± 0.53 (n = 16) and reaching peaking severity on day 14.69 ± 0.73 (n = 16). At near peak of disease, ankle- and sciatic-notch-evoked CMAP amplitudes in forced-exercised rats were preserved while EAN-associated slowing of MNCV was modestly attenuated by exercise. Three weeks of forced-exercise reduced by 46% total plasma corticosterone content while elevating the levels of corticosteroid binding globulin. We conclude from this study that forced-exercise administered prior to and during development of EAN affords a novel measure of protection against autoimmune-associated deficits in peripheral nerve evoked responses independent of steroid-induced immune suppression. PMID:22569066
Calik, Michael W; Shankarappa, Sahadev A; Stubbs, Evan B
Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis with unique clinical, pathological, serological, and imaging features. AIP usually presents with obstructive jaundice. Imaging studies often reveal enlargement of the pancreas with a pancreatic mass and strictures of the main pancreatic duct. Two subtypes of AIP have recently been identified. Type I AIP is more prevalent in elderly Asian males and is characterized by lymphoplasmacytic sclerosing pancreatitis, obliterative phlebitis, and infiltration of large numbers of IgG4-positive plasma cells. Type II AIP is more prevalent in Caucasians and is characterized by granulocyte epithelial lesions. Most patients with type I AIP have a significantly elevated serum IgG4 concentration, which is an important feature for diagnosis and for differentiating between AIP and other conditions such as pancreatic cancer. Extrapancreatic complications are common, such as sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis in type I AIP, and ulcerative colitis in type II AIP. A rapid response to glucocorticoids treatment is suggestive of AIP, but the relapse rate is high, warranting the use of immunosuppressant treatment. B-cell depletion with rituximab may be a promising therapy. The prognosis of AIP is generally benign if treated promptly, and spontaneous remission occurs in a proportion of patients. PMID:23526391
Wang, Qian; Zhang, Xuan; Zhang, Fengchun
Our laboratory investigates systemic autoimmune disease in the context of mouse models of systemic lupus erythematosus (SLE). SLE is associated with high titers of serum autoantibodies of the IgG class that are predominantly directed against nuclear antigens, with pathological manifestations that are considered by many to be characteristic of an immune-complex mediated disease. In this review, we focus on the known and potential roles of somatic mutagenesis in SLE. We will argue that anti-nuclear antibodies (ANA) arise predominantly from nonautoreactive B cells that are transformed into autoreactive cells by the process of somatic hypermutation (SHM), which is normally associated with affinity maturation during the germinal center reaction. We will also discuss the role of SHM in creating antigenic peptides in the V region of the B cell receptor (BCR) and its potential to open an avenue of unregulated T cell help to autoreactive B cells. Finally, we will end this review with new experimental evidence suggesting that spontaneous somatic mutagenesis of genes that regulate B cell survival and activation is a rate-limiting causative factor in the development of ANA. PMID:23249093
Detanico, Thiago; St Clair, James B; Aviszus, Katja; Kirchenbaum, Greg; Guo, Wenzhong; Wysocki, Lawrence J
Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-?) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations. PMID:22193289
Hughes, Grant C
A review of clinical observations and literature reports leads to the hypothesis that, via a process analogous to Sydenham's chorea, infections with group A ?-hemolytic streptococci, among others, may trigger autoimmune responses that cause or exacerbate some cases of childhood-onset obsessive-compulsive disorder (OCD) or tic disorders (including Tourette's syndrome). If this hypothesis is correct, then immunological treatments should lead to
Albert J. Allen; Henrietta L. Leonard; Susan E. Swedo
Depletion of selected regulatory CD4+ T cell subsets induces the spontaneous onset of various immune or autoimmune disorders. It is not clear, however, whether a given subset, notably CD4+CD25+ regulatory T cells, protects from a wide spectrum of immune disorders, or whether specialized subsets of regulatory T cells control each given disease or group of diseases. We report here, using
Marie-Alexandra Alyanakian; Sylvaine You; Diane Damotte; Christine Gouarin; Anne Esling; Corinne Garcia; Séverine Havouis; Lucienne Chatenoud; Jean-François Bach
Watermelon stomach is characterized by prominent stripes of ectatic vascular tissue in the stomach similar to stripes on a watermelon; in patients with this disorder chronic gastrointestinal bleeding occurs and approximately half of these patients have associated autoimmune disorders. In the serum of one patient, an antinucleolar antibody titer of 1:25 600 was found; the antibodies specifically recognized a ~100
Benigno C. Valdez; Dale Henning; Rose K. Busch; Karen Woods; Hernan Flores-Rozas; Jerard Hurwitz; Laszlo Perlaky; Harris Busch
Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are considered as putative autoimmune diseases of the liver. Whereas strong evidence that bacterial infection may trigger PBC exists, the etiologies for PSC and AIH remain unknown. Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases, their associations with environmental triggers and the subsequent implications have been difficult to elucidate. While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) have been suggested as genetic susceptibility factors for all three disorders, we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC, where Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium, has recently been specifically associated with the pathogenesis of this devastating liver disease. Ultimately, the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers, establish infection and damage respective target organs.
Because there are no particular molecular signatures of self, autoimmunity is the inevitable evolutionary price of being able to make effective responses against a wide variety of pathogens by the immune system. Without the various phenomena referred to as immune tolerance, the organism would surely self-destruct. Considerable evidence suggests that various endogenous neuropeptides play a major role in the education of our immune system to be self-tolerant. The fact that neuropeptides regulate various layers involved in maintenance of tolerance, including regulation of the balance between pro-inflammatory and anti-inflammatory responses and between self-reactive Th1/Th17 cells and regulatory T cells, makes them attractive candidates for the development of new therapies for the treatment of autoimmune disorders. Here we use the vasoactive intestinal peptide of a prototype of immunomodulatory neuropeptide to review the most relevant data found for other neuropeptides with similar characteristics, including melanocyte-stimulating hormone, urocortin, adrenomedullin, neuropeptide Y, cortistatin and ghrelin. We also evaluate the challenges that must be overcome before achieving their clinical application and offer our opinion on how a physiologically functional neuropeptide system contributes to general health. PMID:20687881
Gonzalez-Rey, Elena; Delgado-Maroto, Virginia; Souza Moreira, Luciana; Delgado, Mario
MRL\\/lprmice spontaneously develop an autoimmune disease with features of systemic lupus erythematosus. They also develop a lymphoproliferative disorder characterized by a massive accumulation of double-negative (DN) T cells that lack both CD4 and CD8. To clarify the role of CD4 in autoimmunity and lymphoproliferation in these mice, CD4-deficient MRL\\/lprmice were generated. CD4-deficient MRL\\/lprmice developed massive expansion of DN T cells
Mark S. Chesnutt; Barbara K. Finck; Nigel Killeen; M. Kari Connolly; Harris Goodman; David Wofsy
Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes,\\u000a tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause,\\u000a prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders\\u000a after either autologous or allogeneic hematopoietic stem
Richard K. Burt; Shimon Slavin; William H. Burns; Alberto M. Marmont
Celiac disease has been associated withautoimmune disorders, but its frequency in autoimmunehepatitis is unknown. Sera from 157 patients with type1 autoimmune hepatitis, 24 patients with type 2autoimmune hepatitis, 62 patients with primary biliarycirrhosis, 30 patients with chronic hepatitis B, and 80patients with chronic hepatitis C were tested forimmunoglobulin A anti-endomysial antibodies by indirect immunofluorescence and immunoglobulin A and Gantibodies to
U. Volta; L. De Franceschi; N. Molinaro; F. Cassani; L. Muratori; M. Lenzi; F. B. Bianchi; A. J. Czaja
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also called APS-1,) is a rare autosomal recessive\\u000a disorder that is more frequent in certain isolated populations. It is characterized by two of the three major clinical symptoms\\u000a that may be present: Addison’s disease, and\\/or hypoparathyroidism and\\/or chronic mucocutaneous candidiasis. We have recently\\u000a identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE
M. C. Rosatelli; Alessandra Meloni; Antonella Meloni; Marcella Devoto; Antonio Cao; H. S. Scott; Pärt Peterson; Maarit Heino; Kai J. E. Krohn; Kentaro Nagamine; J. Kudoh; Nobuyoshi Shimizu; Stylianos E. Antonarakis
Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention. PMID:21364654
Tischner, D; Woess, C; Ottina, E; Villunger, A
Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention.
Tischner, D; Woess, C; Ottina, E; Villunger, A
Pregnancy loss is a frequent event. Autoimmune thyroid disorders and altered natural killer (NK) cell functions are two distinct\\u000a risk factors, which independently could induce adverse pregnancy outcome. Thyroid autoimmunity has been an object of increased\\u000a attention by investigators in the context of pregnancy loss. Peripheral NK cells and uNK cells comprise distinct cell populations\\u000a in terms of phenotype and
Almost 25 years ago, the concept of the ‘mosaic of autoimmunity’ was introduced to the scientific community, and since then this concept has continuously evolved, with new pebbles being added regularly. We are now looking at an era in which the players of autoimmunity have changed names and roles. In this issue of BMC Medicine, several aspects of autoimmunity have been addressed, suggesting that we are now at the forefront of autoimmunity science. Within the environmental factors generating autoimmunity are now included unsuspected molecules such as vitamin D and aluminum. Some adjuvants such as aluminum are recognized as causal factors in the development of the autoimmune response. An entirely new syndrome, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA), has been recently described. This is the new wind blowing within the branches of autoimmunity, adding knowledge to physicians for helping patients with autoimmune disease.
Summary. This review has focused on the evidence for the involvement of nitrative oxidation in certain neurodegenerative disorders (Parkinson’s Disease, Alzheimer’s Disease, Amyotrophic Lateral Sclerosis), stroke, and inflammatory and autoimmune disorders (with particular attention devoted to multiple sclerosis). The relationship between protein peroxidation and pathological changes observed in the above disorders has been reported. Whereas many of the findings are
P. Sarchielli; F. Galli; Ar. Floridi; Al. Floridi; V. Gallai
Acquired cerebellar ataxia has been described with hypothyroidism, and is typically reversible by thyroid hormone replacement therapy. The cerebellar dysfunction has been attributed to metabolic and physiological effects of the endocrine disorder. In a few patients, however, ataxia has persisted despite thyroid replacement therapy. Other mechanisms may be involved in ataxia associated with thyroid disorders.?OBJECTIVE—To document progressive non-familial adult onset cerebellar degeneration (PNACD) occurring in six patients with raised antithyroid antibodies (Hashimoto's/autoimmune thyroiditis), and other autoimmune manifestations, in the absence of hypothyroidism; and to document the independence of the cerebellar disorder from the endocrine dysfunction.?METHODS—A case study of six patients with PNACD reviewing the clinical course and relation to endocrine and autoimmune status.?RESULTS—All six patients were euthyroid when they developed their symptoms; had raised antithyroid antibodies consistent with Hashimoto's autoimmune thyroiditis; and had strong personal or family histories of organ specific autoimmune diatheses. Brain MRI disclosed atrophy of the cerebellar vermis in four patients and olivopontocerebellar atrophy in two. Other possible causes of cerebellar degeneration were excluded. De novo treatment (two patients) or continued treatment (three patients) with L-thyroxine did not modify the progression of the ataxia.?CONCLUSIONS—Cerebellar degeneration in these patients with raised antithyroid antibodies may be immune mediated. The presence of antithyroid antibodies may signal or cause the autoimmune process producing cerebellar degeneration. "Hashimoto's associated ataxia" seems to represent a recognisable and not uncommon condition; a trial of immunomodulating therapy should be considered in these patients.??
Selim, M; Drachman, D
Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative. PMID:24101757
Rudman Spergel, Amanda; Walkovich, Kelly; Price, Susan; Niemela, Julie E; Wright, Dowain; Fleisher, Thomas A; Rao, V Koneti
We made double transgenic mice bearing immunoglobulin heavy and light chain genes encoding an autoantibody against the mouse erythrocyte by the cross of C57BL/6 mice carrying the transgene for each chain of the immunoglobulin. Although no obvious disorders were found in the single- chain transgenic mice, severely anemic symptoms were found in some of the double transgenic mice, in which most B cells express, at least on their surface, the autoantibody reactive to self-antigens on the erythrocyte. Individual double-transgenic mice showed a wide variation of phenotypes between severe anemia and no symptoms. Both deletion and anergy of autoreactive B cells were seen in each individual mouse, but their relative contribution to self-tolerance was variable and not directly related to the severity of anemia or the amount of the autoantibody produced. This transgenic system provides a good autoimmune disease model for exploring its onset mechanism, and means of its treatment and prevention.
Myasthenia gravis (MG) is one of the best understood autoantibody-mediated disorders. The pathogenic antibodies against the acetylcholine receptor (AChR) have been well characterized and are known to impair neuromuscular transmission by direct blockade, complement mediated damage and accelerate receptor-mediated endocytosis. The clinical presentation is characterized by fatiguable weakness with a predilection for the extra-ocular, facial, bulbar, respiratory and proximal limb
Herein, we report the results of kidney transplantation in 9 of 376 patients who underwent kidney transplantation at our center between 1986 and 2007 because of chronic renal failure associated with autoimmune disease. Four of the 9 patients had systemic lupus erythematosus, 3 had Wegener granulomatosis, and 2 had Goodpasture syndrome. Six patients received organs from living donors, and 3 received cadaver organs. Infections were frequent and included cytomegalovirus and urinary tract infection in most cases. There was no difference in occurrence of metabolic and cardiovascular complications in our study patients compared with other transplant recipients. Incidence of allograft loss (n = 1) was similar to that in our entire transplantation population, with an overall rate of 2.9%. We conclude that kidney transplantation is a reasonable therapeutic option in patients with autoimmune disease with end-stage renal disease because of good graft and patient survival compared with kidney recipients without autoimmune diseases. PMID:19765434
Ounissi, M; Abderrahim, E; Hedri, H; Sfaxi, M; Fayala, H; Turki, S; Ben Maïz, H; Ben Abdallah, T; Chebil, M; Kheder, A
The objective of this study is to document a series of cases of occupationally derived autoimmune disease. Individuals with occupational exposure to acrylamides were evaluated clinically and biochemically/immunologically for evidence of autoimmune disease. Symptoms and signs and immuno-reactivity were monitored during exposure-free and re-exposure as part of the individuals' clinical evaluation. Six individuals with occupational acrylamide exposure had clinical and laboratory alterations characteristic of drug-induced autoimmune disease, specifically lupus, anti-phospholipid syndrome, Sjogren's syndrome, scleroderma, and polymyositis. The similarity of the full spectrum of disease in the reported patients to that found with procainamide strongly suggests the effects of occupational exposure. This uncontrolled study suggests the need for a full epidemiologic analysis of all individuals working with such occupational exposure, including full clinical and immunological examination. PMID:20544243
Before the concept of autoimmune pancreatitis (AIP) was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP) has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney) and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of regulatory T-cells are assumed to be involved in the underlying immune reaction. IgG4 antibodies have two unique biological functions, Fab-arm exchange and a rheumatoid factor-like activity, both of which may play immune-defensive roles. However, the exact role of IgG4 in this disease still remains to be clarified. It seems important to recognize this unique entity given that the disease is treatable with steroids.
Autoimmune pancreatitis is a type of chronic pancreatitis characterized by an inflammatory process with lymphoplasmacytic infiltration associated with fibrosis of the pancreas. Various autoimmune extrapancreatic manifestations are associated with this condition which includes biliary pathologies like sclerosing cholangitis, inflammatory bowel disease, sialadenitis, renal and pulmonary lesions and retroperitoneal fibrosis. Autoimmune prostatitis is rarely associated with autoimmune pancreatitis with only a
Divya Krishnaprasad Shanbhogue; Najla Fasih; Alampady Krishna Prasad Shanbhogue
\\u000a The autoimmune diseases can be divided into two basic categories: organ specific and systemic. Organ specific autoimmune disease can affect virtually any tissue of the body and is associated most often with evidence\\u000a of both T and B cell autoimmune responses directed against the cells of the affected organ. Examples of organ specific autoimmune\\u000a disease include multiple sclerosis, Type I
Timothy M. Wright; Dana P. Ascherman
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease. Characteristic liver-infiltrating immune cells in portal and periportal areas, hypergammaglobulinemia and typical autoantibodies indicate an ongoing autoimmune reaction against liver self antigens, which lead to irreversible cellular damage and ultimately to severe hepatic failure. A significant part of adult, but not pediatric AIH patients, exhibit concurrent autoimmune diseases, further strengthening the
Lea Campos Oliveira; Gilda Porta; Maria Lucia C. Marin; Paulo Lisboa Bittencourt; Jorge Kalil; Anna Carla Goldberg
Bone marrow transplantation (BMT) is now becoming a powerful strategy for the treatment of patients with autoimmune diseases. Using various animal models for autoimmune diseases, we have previously found that allogeneic BMT (not autologous BMT) can be used to treat autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), immune thrombocytic purpura, insulin-dependent diabetes mellitus (IDDM), chronic glomerulonephritis,
Most autoimmune diseases occur significantly more frequently in women than men. This female preponderance for abnormal autoimmune function has largely gone unexplained. Many investigations have concentrated on the effects of female and male sex hormones on immune function, by suggesting that estrogens favor the antibody production-enhancing Th2 response and, by doing so, possibly, increase the risk towards abnormal autoimmune function.
Norbert Gleicher; David H. Barad
Autoimmune reactions encoupled to many human diseases are still only partially understood. Unravelling the molecular pathogenesis of inherited diseases with a strong autoimmune component in their clinical expression could help to dissect individual components in the molecular background of abnormal immune response. One such genetic disorder is autosomal recessive autoimmune polyglandular disease type I (PGD I), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, MIM 240300). The disease is especially enriched in the genetically isolated population of Finland and we have assigned the APECED locus to human chromosome 21q22.3 in 14 Finnish families by linkage analyses. The best positional lod score of 6.49 was observed with marker D21S49. Based on the history of the Finns, the gene pool of this population clearly demonstrates the consequences of a founder effect and consequent isolation. In the Finnish population, we can take advantage of linkage disequilibrium and allelic association studies to more precisely define the critical DNA region for our disease gene of interest than would be possible by linkage analyses alone. We are now able to define the chromosomal region of interest between two flanking markers locating 1 cM apart. Linkage disequilibrium is observed with three of the markers used in the analyses and this suggests a distance of less than 500 kb to the disease locus, well approachable with molecular cloning techniques. Overlapping YAC and cosmid clones spanning our region of interest will facilitate the cloning of APECED gene in the near future.
Aaltonen, J.; Bjoerses, P.; Peltonen, L. [National Public Health Institute, Helsinki (Finland)] [and others
Ainu autoimmune hepatitis (AM) is thought to present rarely in old people. The aims of the present study were to (i) review individuals diagnosed clinically as having AIH presenting over or under 65 years of age at Freeman Hospital, Newcastle, from 1979 to 1993 and (ii) compare diagnostic and histological scores, treatment and outcome, and hence provide a useful profile
JULIA L NEWTON; ALJSTAIR D. BURT; JAY B. PARK; JOSEPH MATHEW; MARGARET F. BASSENDINE; OLIVER F. W. JAMES
Cell therapy, pioneered for the treatment of malignancies in the form of bone marrow transplantation, has subsequently been tested and successfully employed in autoimmune diseases. Autologous haemopoietic stem cell transplantation (HSCT) has become a curative option for conditions with very poor prognosis such as severe forms of scleroderma, multiple sclerosis, and lupus, in which targeted therapies have little or no
Francesco Dazzi; Jacob M van Laar; Andrew Cope; Alan Tyndall
Experimental autoimmune uveitis (EAU) in Lewis rats is a well-established model for human uveitis. During the last years we used this model to demonstrate extraocular induction of uveitis by antigenic mimicry of environmental antigens with retinal autoantigen and investigated the migration and intraocular reactivation of autoreactive green fluorescent protein (GFP)+ T cells. We could also elaborate several differences between EAU
Gerhild Wildner; Maria Diedrichs-Möhring; Stephan R. Thurau
Dengue haemorrhagic fever (DHF) is a complicated disease associated with viral and immune pathogenesis. There is still no effective vaccine to prevent the progression of DHF because of its undefined pathogenic mechanisms. The generation of autoimmunity in dengue virus (DEN) infection has been implicated in dengue pathogenesis. Based on our previous studies showing antibodies (Abs) against DEN nonstructural protein 1
Chiou-Feng Lin; Huan-Yao Lei; Ching-Chuan Liu; Hsiao-Sheng Liu; Trai-Ming Yeh; Shun-Hua Chen; Yee-Shin Lin
The Ifi-200/HIN-200 gene family encodes highly homologous human (IFI16, myeloid cell nuclear differentiation antigen, absent in melanoma 2, and IFIX) and murine proteins (Ifi202a, Ifi202b, Ifi203, Ifi204, Ifi205, and Ifi206), which are induced by type I and II interferons (IFN). These proteins have been described as regulators of cell proliferation and differentiation and, more recently, several reports have suggested their involvement in both apoptotic and inflammatory processes. The relevance of HIN-200 proteins in human disease is beginning to be clarified, and emerging experimental data indicate their role in autoimmunity. Autoimmune disorders are sustained by perpetual activation of inflammatory process and a link between autoimmunity and apoptosis has been clearly established. Moreover, the interferon system is now considered as a key player in autoimmune disorders such as systemic lupus erythemathosus, systemic sclerosis, and Sjögren's syndrome, and it is therefore conceivable to hypothesize that HIN-200 may be among the pivotal mediators of IFN activity in autoimmune disease. In particular, the participation of HIN-200 proteins in apoptosis and inflammation could support their potential role in autoimmunity. PMID:20187706
Mondini, Michele; Costa, Silvia; Sponza, Simone; Gugliesi, Francesca; Gariglio, Marisa; Landolfo, Santo
Autoimmune paraneoplastic syndromes are commonly encountered in patients with myelodysplastic syndromes (MDS). A review of case reports and small series suggest as many as 10% of MDS patients may experience various autoimmune syndromes. Clinical manifestations of such phenomena may include an acute systemic vasculitic syndrome, skin vasculitis, fever, arthritis, pulmonary infiltrates, peripheral polyneuropathy, inflammatory bowel disease, glomerulonephritis, and even classical connective tissue disorders, such as relapsing polychondritis. On the other hand, asymptomatic immunologic abnormalities have also been reported in these patients. These autoimmune manifestations frequently respond to immunosuppressive agents including steroids and occasional hematologic responses to steroid therapy have also been reported. We report five patients with history of MDS who manifested different spectrums of autoimmune phenomena including: pyoderma gangrenosum (PG), vasculitis, Coombs negative hemolytic anemia, idiopathic thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy (CIDP). We also review the incidence, nature, course and response to therapy of these manifestations and discuss potential pathogenic mechanisms. PMID:12533032
Saif, Muhammad Wasif; Hopkins, Jon L; Gore, Steven D
Autoimmunity is often observed among individuals with primary immune deficiencies; however, the frequency and role of autoimmunity in Schimke immuno-osseous dysplasia (SIOD) has not been fully assessed. SIOD, which is caused by mutations of SMARCAL1, is a rare autosomal recessive disease with its prominent features being skeletal dysplasia, T cell deficiency, and renal failure. We present a child with severe SIOD who developed rituximab resistant Evans syndrome (ES). Consistent with observations in several other immunodeficiency disorders, a review of SIOD patients showed that approximately a fifth of SIOD patients have some features of autoimmune disease. To our best knowledge this case represents the first patient with SIOD and rituximab resistant ES and the first study of autoimmune disease in SIOD.
Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA structures, signaling pathways and protein catalysts. Ferritin synthesis is regulated by cytokines (tumor necrosis factor-alpha and interleukin-1alpha) at various levels (transcriptional, post-transcriptional, translational) during development, cellular differentiation, proliferation and inflammation. The cellular response by cytokines to infection stimulates the expression of ferritin genes. The immunological actions of ferritin include binding to T lymphocytes, suppression of the delayed-type hypersensitivity, suppression of antibody production by B lymphocytes, and decreased phagocytosis of granulocytes. Thyroid hormone, insulin and insulin growth factor-1 are involved in the regulation of ferritin at the mRNA level. Ferritin and iron homeostasis are implicated in the pathogenesis of many disorders, including diseases involved in iron acquisition, transport and storage (primary hemochromatosis) as well as in atherosclerosis, Parkinson's disease, Alzheimer disease, and restless leg syndrome. Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy. Hyperferritinemia is associated with inflammation, infections and malignancies, and in systemic lupus erythematosus correlates with disease activity. Some evidence points to the importance of hyperferritinemia in dermatomyositis and multiple sclerosis, but further mechanistic investigations are warranted. PMID:18300583
Zandman-Goddard, Gisele; Shoenfeld, Yehuda
Elevated titers of antibodies against different antigens of Epstein-Barr virus (EBV) are found in some immunodeficient states, malignancies or in autoimmune disorders. We examined EBV serology in the group of 22 patients with autoimmune thyroiditis as compared with the group of 35 healthy volunteers. Titers of antibodies against viral capsid antigen (IgG-VCA) were more often found in the group of patients than in the control group (p = 0.000 35 for younger than 40 years and p = 0.00115 for older than 40 years) and the positivity of antibodies against early antigen (IgG-EA-D/DR) was also significantly more often found in the group of patients (p = 0.0031 and p = 0.0019 respectively) than in the control group. PMID:8750577
Vrbikova, J; Janatkova, I; Zamrazil, V; Tomiska, F; Fucikova, T
Exercised-induced vasculitis (EIV) is an underreported and frequently misdiagnosed condition that occurs on the lower extremities shortly after exercise. Most reported cases have presented in healthy-appearing individuals, but some cases have been linked to other disease processes. A case report is presented of recurring EIV in a 65-year-old woman with a history of dermatitis herpetiformis; chronic, mildly elevated liver transaminases of unknown cause; microscopic colitis; celiac disease; multiple miscarriages; and heart block who was found to have autoimmune hepatitis upon workup of her rash. Both EIV and autoimmune hepatitis were misdiagnosed over many years by several clinicians in various specialties. Her family history was remarkable for 2 sisters with systemic lupus erythematosus and similar recurring exercise-induced rashes of the lower extremities, suggesting a familial link for this condition. Clinicians should recognize EIV and consider the possibility that this disorder may be the presenting sign of subclinical connective-tissue diseases. PMID:19681343
Knoell, Keith Allen
The von Willebrand factor (VWF)-cleaving metalloprotease, ADAMTS13 (adisintegrin and metalloprotease with thrombospondin type 1 motifs-13) is the only known target of the dysregulated immune response in acquired TTP. Autoantibodies to ADAMTS13 either neutralize its activity or accelerate its clearance, thereby causing a severe deficiency of ADAMTS13 in plasma. As a consequence, size regulation of VWF is impaired and the persistence of ultra-large VWF (ULVWF) multimers facilitates microvascular platelet aggregation causing microangiopathic haemolytic anaemia and ischaemic organ damage. Autoimmune TTP although a rare disease with an annual incidence of 1.72 cases has a mortality rate of 20% even with adequate therapy. We describe the mechanisms involved in ADAMTS13 autoimmunity with a focus on the role of B- and T-cells in the pathogenesis of this disorder. We discuss the potential translation of recent experimental findings into future therapeutic concepts for the treatment of acquired TTP. PMID:23443151
Schaller, M; Studt, J-D; Voorberg, J; Kremer Hovinga, J A
Acquired myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which patients experience fluctuating skeletal muscle weakness that often affects selected muscle groups preferentially. The target of the autoimmune attack in most cases is the skeletal muscle acetylcholine receptor (AChR), but in others, non-AChR components of the neuromuscular junction, such as the muscle-specific receptor tyrosine kinase, are targeted. The pathophysiological result is muscle endplate dysfunction and consequent fatigable muscle weakness. Clinical presentations vary substantially, both for anti-AChR positive and negative MG, and accurate diagnosis and selection of effective treatment depends on recognition of less typical as well as classic disease phenotypes. Accumulating evidence suggests that clinical MG subgroups might respond differently to treatment. In this Review, we provide current information about the epidemiology, immunopathogenesis, clinical presentations, diagnosis, and treatment of MG, including emerging therapeutic strategies.
Meriggioli, Matthew N; Sanders, Donald B
Autoimmune thyroid disease (AITD) is an inflammatory thyroiditis that in some cases is characterized by lymphocytic infiltration of the thyroid gland, also referred to as chronic lymphocytic thyroiditis or Hashimoto thyroiditis. Hashimoto thyroiditis is one of the commonest causes of hypothyroidism. Hypothyroidism has been associated with osteoarthritis (OA) and inflammatory forms of arthritis and with several well defined connective tissue diseases, which in turn can cause arthritis. The presence of arthritis in patients with AITD with normal thyroid function is now being increasingly recognized. There is also considerable evidence to suggest that AITD is highly associated with fibromyalgia syndrome. We review the current literature on the rheumatologic manifestations of AITD and describe the features in its presentation that set it apart from other forms of autoimmune arthritis. PMID:22505695
Tagoe, Clement E; Zezon, Anna; Khattri, Saakshi
Background: Pituitary and thyroid autoimmunity can be triggered by pregnancy. We report the first association of combined growth hormone (GH) and prolactin secretion deficiency due to autoimmune damage to GH- and prolactin-secreting cells in a patient with postdelivery lactation failure, presenting subsequently with primary autoimmune hypothyroidism. Patient Findings: A 34-year-old woman presented with lactation failure following the delivery of her first child. She had a family history of hypothyroidism without a history of pituitary dysfunction. Physical examination did not show any abnormal findings. Laboratory investigations showed normal gonadotropin levels after the restoration of normal menstrual cycles following pregnancy, normal basal and stimulated cortisol levels, but an impaired GH response to insulin-induced hypoglycemia, and low basal prolactin and insulin-like growth factor-1 concentrations. Thyroid function was normal when initially investigated three months after delivery, but five months later, marked primary hypothyroidism (thyrotropin levels >100?mIU/L) occurred. Immunological investigation revealed the presence of antipituitary antibodies, identified by double immunofluorescence and targeting GH- and prolactin-secreting cells. Antithyroid antibodies, in the normal range three months postpartum, became significantly elevated when the hypothyroidism appeared. Autoimmune hypophysitis is responsible for selective or multiple pituitary-hormone deficiencies, sometimes involving thyrotropin secretion and causing secondary hypothyroidism, but usually associated with hyperprolactinemia. To our knowledge, this is the first observation of autoimmune hypopituitarism involving deficient growth hormone and prolactin secretion in a patient with lactation failure after delivery, subsequently followed by severe primary autoimmune hypothyroidism, thus falling into an unusual constellation of autoimmune polyendocrine syndrome type 3. Conclusions: Considering the well-known relationship between pregnancy and autoimmunity, an early postdelivery immunological and functional investigation in women presenting with disorders of lactation may be useful to detect potential pituitary and thyroid dysfunction even at a subclinical stage. PMID:23286389
De Bellis, Annamaria; Colella, Caterina; Bellastella, Giuseppe; Lucci, Emma; Sinisi, Antonio Agostino; Bizzarro, Antonio; Holdaway, Ian
Thyroid autoimmunity is one of the most common immune disorders in females, and its polygenic background remains to be elucidated. The human leukocyte antigen (HLA) DQ region of chromosome 6 has been shown to confer susceptibility to thyroid autoimmune disease. The aim of our present investi- gation was to determine whether the transmission of high risk HLA DQ to patients
MARIA SEGNI; MICHAEL A. PANI; ANNA MARIA PASQUINO; KLAUS BADENHOOP
Acute psychological stress has primarily been investigated regarding its effects on conventional lymphocytes such as natural killer (NK) cells and CD4(+) and CD8(+) T cells. However, it might be important to focus on more "specialized" lymphocyte subsets, playing a role, for instance, in allergic conditions and autoimmunity, to identify links between stress, the immune system and somatic diseases. Using flow cytometry we determined frequencies of circulating T helper (Th)1-type (CD226(+)) and Th2-type (CRTH2(+)) T cells, ?? T cells, conventional CD56(+) natural killer T (NKT) cells and invariant NKT cells (iNKT) in healthy young males (N?=?31; median age 26 years) undergoing a laboratory computer-based stressor lasting 12?min. We found that acute psychological stress induced a prolonged increase in CD4(+) and CD8(+) T cells expressing a Th2 phenotype. We also detected an acute increase in CD4(-) and CD8(-) double negative ?? T cells. Finally, we found that the well-known increase in NK cells under stressful conditions was paralleled by a significant increase in numbers of conventional CD56(+) NKT cells. In contrast, numbers of iNKT was not altered by stress. This study adds further evidence to a psychoneuroimmunological model proposing that under stressful conditions certain lymphocyte subsets, including iNKT and less mature T cells, are retained in lymphoid tissues while antigen-experienced effector-type T cells with a Th2 phenotype, ?? T cells and conventional CD56(+) NKT cells are mobilized into the peripheral blood. We suggest that in the case of frequent stress exposure, this might result in the promotion of, for example, allergic conditions. PMID:23425210
Atanackovic, Djordje; Nowottne, Ulrike; Freier, Eva; Weber, Cora Stefanie; Meyer, Sabrina; Bartels, Katrin; Hildebrandt, York; Cao, Yanran; Kröger, Nicolaus; Brunner-Weinzierl, Monika Christine; Bokemeyer, Carsten; Deter, Hans-Christian
Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the current largest genome-wide association study of hypothyroidism, in 3,736 cases and 35,546 controls. Hypothyroidism was assessed via web-based questionnaires. We identify five genome-wide significant associations, three of which are well known to be involved in a large spectrum of autoimmune diseases: rs6679677 near PTPN22, rs3184504 in SH2B3, and rs2517532 in the HLA class I region (-values , , and , respectively). We also report associations with rs4915077 near VAV3 (-value ) and rs925489 near FOXE1 (-value ). VAV3 is involved in immune function, and FOXE1 and PTPN22 have previously been associated with hypothyroidism. Although the HLA class I region and SH2B3 have previously been linked with a number of autoimmune diseases, this is the first report of their association with thyroid disease. The VAV3 association is also novel. We also show suggestive evidence of association for hypothyroidism with a SNP in the HLA class II region (independent of the other HLA association) as well as SNPs in CAPZB, PDE8B, and CTLA4. CAPZB and PDE8B have been linked to TSH levels and CTLA4 to a variety of autoimmune diseases. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the five genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.0.
Eriksson, Nicholas; Tung, Joyce Y.; Kiefer, Amy K.; Hinds, David A.; Francke, Uta; Mountain, Joanna L.; Do, Chuong B.
Latent Autoimmune Diabetes in Adults (LADA) is the term used to describe adults who have a slowly progressive form of diabetes mellitus (DM) of autoimmune etiology, but that may be treated initially without insulin. Although it shares some immunological and genetic aspects with type 1 DM, it affects an age group that is typically affected by type 2 DM. Therefore, it could be considered an intermediate type. Diagnosis is based on clinical and laboratory criteria: age of onset, initial response to oral hypoglycemic agents and the presence of specific antibodies for diabetes. Although the definitive treatment is insulin, glitazones may be useful in early stages of the disease. Currently, its management represents a challenge for the physician, including specialists, and it is a form of DM to keep in mind. PMID:23677196
Pollak, Felipe; Vásquez, Tatiana
As the population ages, more individuals with autoimmune diseases are experiencing reproductive senescence. Understanding the impact of menopause and age-related androgen decline on disease onset and course, as well as the potential for hormonal interventions, is critically important. In men, lupus erythematosis (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) are associated with lower androgen levels. However, the impact of age-related declines in testosterone, as well as of testosterone replacement, on disease course remains underexplored. In women, the course of all three diseases with onset after the age of menopause differs from that with onset before menopause. Early age at menopause is associated with increased disease risk, and after menopause, disease course changes in SLE and RA. Less is known about MS. This article summarizes what is known about the relationship between reproductive aging and autoimmune diseases in men and women, and highlights areas for further investigation. PMID:23522436
K\\/BxN mice develop an inflammatory joint disease with many features characteristic of rheumatoid arthritis. This model is\\u000a based on a T-cell receptor transgene, KRN, that has been shown to recognize both the foreign antigen bovine RNase, and the\\u000a ubiquitously expressed self antigen, glucose-6-phosphate isomerase (GPI). We have used this model to investigate the initial\\u000a events that occur during the autoimmune
Laura Mandik-Nayak; Paul M. Allen
For more than 2,000 years, it was thought that malignant spirits caused diseases. By the end of nineteenth century, these\\u000a beliefs were displaced by more modern concepts of disease, namely, the formulation of the “germ theory,” which asserted that\\u000a bacteria or other microorganisms caused disease. With the emergence of chronic degenerative and of autoimmune diseases in\\u000a the last century, the causative
V. Pordeus; M. Szyper-Kravitz; R. A. Levy; N. M. Vaz; Y. Shoenfeld
\\u000a Immunological mechanisms which precipitate autoimmune diabetes involve the influence of a genetic footprint on the phenotype\\u000a of the T-cell response to self-antigens, and on development of pathological outcomes in immune responses resulting in T1D.\\u000a For one of the human diabetes antigens, proinsulin, recent findings allow the emergence of a model in which elements of genetically\\u000a biased T-cell development and peptide
Ivana Durinovic-Belló; Gerald T. Nepom
OBJECTIVES:Autoimmune hepatitis (AIH) is widely believed to be a disease of young women and menopause. Little is known about the frequency and clinical characteristics in patients aged ?65 yr.METHODS:We reviewed charts of 120 consecutive outpatients with known AIH to identify patients who were diagnosed at the age of 65 or older. These 20 patients (median age, 69 yr) were compared
Christoph Schramm; Stephan Kanzler; Karl-Hermann Meyer zum Büschenfelde; Peter R. Galle; Ansgar W. Lohse
The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation. PMID:23845396
Smyk, Daniel S; Orfanidou, Timoklia; Invernizzi, Pietro; Bogdanos, Dimitrios P; Lenzi, Marco
The Tyro3, Axl and Mertk (TAM) triply knockout (TKO) mice exhibit systemic autoimmune diseases, with characteristics of increased proinflammatory cytokine production, autoantibody deposition and autoreactive lymphocyte infiltration into a variety of tissues. Here we show that TKO mice produce high level of serum TNF-? and specific autoantibodies deposited onto brain blood vessels. The brain-blood barrier (BBB) in mutant brains exhibited increased permeability for Evans blue and fluorescent-dextran, suggesting a breakdown of the BBB in the mutant brains. Impaired BBB integrity facilitated autoreactive T cells infiltrating into all regions of the mutant brains. Brain autoimmune disorder caused accumulation of the ubiquitin-reactive aggregates in the mutant hippocampus, and early formation of autofluorescent lipofuscins in the neurons throughout the entire brains. Chronic neuroinflammation caused damage of the hippocampal mossy fibers and neuronal apoptotic death. This study shows that chronic systemic inflammation and autoimmune disorders in the TKO mice cause neuronal damage and death. PMID:23840307
Li, Qiutang; Lu, Qingjun; Lu, Huayi; Tian, Shifu; Lu, Qingxian
Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well.
D'Arena, Giovanni; Rossi, Giovanni; Vannata, Barbara; Deaglio, Silvia; Mansueto, Giovanna; D'Auria, Fiorella; Statuto, Teodora; Simeon, Vittorio; De Martino, Laura; Marandino, Aurelio; Del Poeta8, Giovanni; De Feo, Vincenzo; Musto, Pellegrino
Juvenile rheumatoid arthritis (JRA), also known as juvenile idiopathic arthritis (JIA), includes the most common chronic autoimmune arthropathies of childhood. These two nomenclatures for classification include components representing the major subclasses of disease. The chromosomal regions and the genes involved in these complex genetic traits are being elucidated, with findings often specific for a particular disease subtype. With the advent of new SNP technologies, progress is being made at an ever-increasing pace. This review discusses the difficulties of deciphering the genetic components in complex disorders, while demonstrating the similarities that JRA shares with other autoimmune disorders. Particular emphasis has been placed on positive findings either for candidate genes that have been replicated independently in JRA/JIA, or findings in JRA for which consistent results have been reported in other forms of autoimmunity. PMID:16435022
Phelan, J D; Thompson, S D; Glass, D N
Schizophrenia is of mysterious causation. It is not infectious, not congenital, but shows familial aggregation, the Mendelian genetics indicating involvement of multiple codominant genes with incomplete penetrance. This is the pattern for autoimmune diseases, such as Graves' disease of the thyroid, where forbidden clones of B lymphocytes develop, and cause thyrotoxicosis by secreting autoantibodies that react with the thyroid gland's receptor for thyroid-stimulating hormone from the pituitary gland. In 1982, Knight postulated that autoantibodies affecting the function of neurons in the limbic region of the brain are a possible cause of schizophrenia. Today, this is even more probable, with genes predisposing to schizophrenia having being found to be immune response genes, one in the MHC and two for antibody light chain V genes. Immune response genes govern the immune repertoire, dictating the genetic risk of autoimmune diseases. The simplest test for an autoimmune basis of schizophrenia would be trial of immunosuppression with prednisone in acute cases. The urgent research need is to find the microbial trigger, as done by Ebringer for rheumatoid arthritis and for ankylosing spondylitis. This could lead to prophylaxis of schizophrenia by vaccination against the triggering microbe.
Adams, D. D.; Knight, J. G.; Ebringer, A.
Recent years have witnessed an explosive growth in available biological data pertaining to autoimmunity research. This includes a tremendous quantity of sequence data (biological structures, genetic and physical maps, pathways, etc.) generated by genome and proteome projects plus extensive clinical and epidemiological data. Autoimmunity research stands to greatly benefit from this data so long as appropriate strategies are available to enable full access to and utilization of this data. The quantity and complexity of this biological data necessitates use of advanced bioinformatics strategies for its efficient retrieval, analysis and interpretation. Major progress has been made in development of specialized tools for storage, analysis and modeling of immunological data, and this has led to development of a whole new field know as immunoinformatics. With advances in novel high-throughput immunology technologies immunoinformatics is transforming understanding of how the immune system functions. This paper reviews advances in the field of immunoinformatics pertinent to autoimmunity research including databases, tools in genomics and proteomics, tools for study of B- and T-cell epitopes, integrative approaches, and web servers. PMID:17178560
Petrovsky, Nikolai; Brusic, Vladimir
Stiff-person syndrome (SPS) is an autoimmune neurological disorder characterized by stiffness of the skeletal muscle with superimposed spasms and production of autoantibodies to glutamic acid decarboxylase (GAD) and amphiphysin. The disorder results from B cell-mediated clonal production of autoantibodies, requiring treatment with immunosuppressors; however, treatment results have been somewhat inconsistent. We report the results of rituximab treatment in a patient
J. L. Dupond; L. Essalmi; H. Gil; N. Meaux-Ruault; C. Hafsaoui
There is considerable debate whether chronic urticaria is an autoimmune disease or whether its features suggestive of autoimmunity are epiphenomena. A plethora of circumstantial evidence suggests that chronic urticaria is an autoimmune disease, but criteria to establish autoimmunity require direct proof and indirect evidence, and these are lacking in chronic urticaria. Current approaches to assessing for autoimmunity in vivo via the autologous serum skin test, and in vitro via either basophil histamine release or the basophil activation test are widely utilized, but the results of these tests have limited impact on prediction of the clinical course and efficacy of treatments. Recent guidelines for diagnosing autoimmune urticaria have been proposed, but further investigation is needed. PMID:23821106
Stitt, Jenny M; Dreskin, Stephen C
ABSTRACT Leptin represents a link between metabolism, nutritional status, and immune responses. Leptin is important for optimal functioning of the immune system. Leptin is a cytokine-like hormone with proinflammatory properties linked to autoimmune diseases. Moreover, there has been increasing evidence that leptin is involved in the pathogenesis of various autoimmune diseases. Leptin has been shown to enhance immune reactions in autoimmune diseases that are commonly associated with inflammatory responses. Both high and low levels of leptin might contribute to autoimmune diseases. Leptin has been explored as a potential target for therapeutic development in treating autoimmune diseases. In this review, we review here the most recent advances on the role of leptin in autoimmunity and in immune-rheumatological diseases.
COJOCARU, Manole; COJOCARU, Inimioara Mihaela; SILOSI, Isabela; ROGOZ, Suzana
Chemokine (CXC motif) ligand (CXCL)9 (CXCL9) has been shown to be involved in autoimmune thyroid disorders, however no data are present about CXCL9 circulating levels in chronic autoimmune thyroiditis (AT) vs controls.Serum CXCL9 (and for comparison CXCL10) has been measured in patients with AT vs normal control and nontoxic multinodular goiter, and this parameter has been related to the clinical
Alessandro Antonelli; Silvia Martina Ferrari; Silvia Frascerra; Fabio Galetta; Ferdinando Franzoni; Alda Corrado; Mario Miccoli; Salvatore Benvenga; Aldo Paolicchi; Ele Ferrannini; Poupak Fallahi
Autoimmune inner ear disease (AIED) is a very rare disorder with distinct clinical features and can occur in patients with\\u000a malignancy or autoimmune diseases. We report a 72-year-old male patient with polyarteritis nodosa treated continuously for\\u000a 5 years with aggressive immunosuppressive drugs, including cyclophosphamide, who experienced three episodes of acute hearing\\u000a loss during treatment. Organic lesions of the external and middle
Hsien-Tzung Liao; Chih-Hung Chien; Chung-Hsiung Chen; Hon-Pin Wang; De-Feng Huang
An increased prevalence of autoimmune diseases in family members of children with autism spectrum disorders (ASD) has been\\u000a previously reported. ASD is also a common problem co-occurring in children with fragile X syndrome (FXS). Why ASD occurs in\\u000a some individuals with FXS, but not all, is largely unknown. Furthermore, in premutation carrier mothers, there is an increased\\u000a risk for autoimmune
Weerasak Chonchaiya; Flora Tassone; Paul Ashwood; David Hessl; Andrea Schneider; Luis Campos; Danh V. Nguyen; Randi J. Hagerman
This ongoing multicentre prospective phase I\\/II trial enrolled 74 consecutive patients from 22 centres worldwide with severe autoimmune disease, 35 with rheumatological disorders, 31 with neurological, five with haematological and three with vasculitides. They were treated with autologous peripheral blood or bone marrow transplants according to predetermined criteria. Two patients died after mobilisation before transplant. Seventy-two patients were given 73
A Tyndall; A Fassas; J Passweg; C Ruiz de Elvira; M Attal; P Brooks; C Black; P Durez; J Finke; S Forman; L Fouillard; D Furst; JA Holmes; D Joske; JP Jouet; I Kötter; F Locatelli; HG Prentice; AM Marmont; P McSweeney; M Musso; HH Peter; JA Snowden; K Sullivan; A Tichelli; J Vavriec; NM Wulffraat; N Schmitz; A Gratwohl
The dermatologic disorders in polyglandular autoimmune disease (PGAD) type 1 (previously called chronic mucocutaneous candidiasis) are nail dystrophy, vitiligo, and alopecia. A patient with PGAD and erythema annulare centrifugum (EAC) is presented. This association has not been reported previously. EAC may be related to occult or low-grade Candida infection in PGAD. PMID:9836055
ABSTRACT: The neuroendocrine immune (NEI) system is regarded as a fundamental network for the maintenance of health status (homeostasis), and it plays an important role in several systemic diseases, including autoimmune disorders. Among the major players of NEI pathways are steroid hormones of the adrenal (cortisol) and gonadal glands (sex hormones), neurohormones such as melatonin, and more recently the vitamin
Maurizio Cutolo; Rainer H Straub
Background: Premature ovarian failure (POF) is often associated with autoimmune disorders. The 47,XXX karyotype has also been associated with POF and other genitourinary abnormalities. Following is a case of a 17 year old with immune thrombocytopenic purpura (ITP), POF, 47,XXX and a positive antinuclear antibody (ANA).Case Report: A 17 year old Caucasian female was referred to the Adolescent Health Clinic
Vitiligo is a common acquired hypopigmentary disorder characterized by a loss of epidermal pigment cells (melanocytes). The Smyth line (SL) chicken is the only animal model for autoimmune vitiligo that recapitulates the entire spectrum of clinical and biological manifestations of the human disease....
Summary Recent advances have revealed a fundamental contradiction in antiviral immunity: innate immune sensors that detect nucleic acids mediate both protective immunity to infection and pathological autoimmune disease. Thus, study of the mechanics of nucleic acid detection will provide insight into how these systems are inappropriately triggered in autoimmunity, and, conversely, study of autoimmune disease triggered by these sensors will tell us more about how they are linked to activation of adaptive immunity.
Stetson, Daniel B.
OBJECTIVES:The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts.METHODS:The study was based on a review of all relevant articles on the mechanisms of autoimmunity in autoimmune liver disease from 1980 to 2000, extraction of pertinent concepts from the medical literature; and integration of evolving paradigms of
Albert J. Czaja
Autoimmune hepatitis is an inflammatory liver disease affecting mainly females and characterised histologically by interface\\u000a hepatitis, biochemically by elevated transaminase levels and serologically by circulating autoantibodies and increased levels\\u000a of immunoglobulin G. Autoimmune hepatitis responds to immunosuppressive treatment, which should be instituted as soon as diagnosis\\u000a is made. Seropositivity for smooth muscle and\\/or antinuclear antibody defines type 1 autoimmune hepatitis,
Diego Vergani; Giorgina Mieli-Vergani
In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCR? locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers. PMID:23497937
Singh, Abinav Kumar; Mahlios, Josh; Mignot, Emmanuel
Background: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients.Methods: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one
S Berardi; F Lodato; A Gramenzi; A D’Errico; M Lenzi; A Bontadini; M C Morelli; M R Tame?; F Piscaglia; M Biselli; C Sama; G Mazzella; A D Pinna; G Grazi; M Bernardi; P Andreone
Autoimmune gastritis is a common autoimmune disorder characterized by chronic inflammatory cell infiltrates, atrophy of the corpus and fundus, and the occurrence of autoantibodies to parietal cell antigen. In CCR7-deficient mice, autoimmune gastritis developed spontaneously and was accompanied by metaplasia of the gastric mucosa and by the formation of tertiary lymphoid organs at gastric mucosal sites. T cells of CCR7-deficient mice showed an activated phenotype in the gastric mucosa, mesenteric lymph nodes, and peripheral blood. In addition, elevated serum IgG levels specific to gastric parietal cell antigen were detected. Because the role of organized lymphocytic aggregates at this inflammatory site is not completely understood, we first analyzed the cellular requirements for the formation of these structures. Autoreactive CD4+ T cells were pivotal for tertiary lymphoid follicle formation, most likely in cooperation with dendritic cells, macrophages, and B cells. Second, we analyzed the necessity of secondary lymph nodes and tertiary lymphoid organs for the development of autoimmune gastritis using CCR7 single- and CCR7/lymphotoxin ? double-deficient mice. Strikingly, manifestation of autoimmune gastritis was observed in the absence of secondary lymph nodes and preceded the development of tertiary lymphoid organs. Taken together, these findings identify an inflammatory process where gastric autoreactive T cells independent of organized tertiary lymphoid organs and classic lymph nodes can induce and maintain autoimmune gastritis.
Winter, Susann; Rehm, Armin; Wichner, Katharina; Scheel, Tobias; Batra, Arvind; Siegmund, Britta; Berek, Claudia; Lipp, Martin; Hopken, Uta E.
Genome-wide association (GWA) studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported association of a nonsynonymous single nucleotide polymorphism (nsSNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts towards identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2,088 cases and 3,289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1,920 controls), resulting in strong support for the Ser307 association with T1D (P= 3.46 × 10?9) and continued potential evidence for AITD (P = 0.0345), we provide convincing evidence for association of Gly307Ser with MS (P = 4.20 × 10?4) and some evidence for another autoimmune disease, rheumatoid arthritis (RA) (P = 0.017). The Ser307 allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, possibly AITD and possibly RA, and based on the tag SNP analysis, could be the causal variant.
Hafler, Jason P; Maier, Lisa M; Cooper, Jason D; Plagnol, Vincent; Hinks, Anne; Simmonds, Matthew J; Stevens, Helen; Walker, Neil; Healy, Barry; Howson, Joanna M M; Maisuria, Meeta; Duley, Simon; Coleman, Gillian; Gough, Stephen C L; Worthington, Jane; Kuchroo, Vijay K.; Wicker, Linda S; Todd, John A
Stiff-person syndrome (SPS) is an autoimmune neurological disorder characterized by autoantibodies to glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of inhibitory neurotransmitter GABA. To search for biomarkers that distinguish SPS from other neurological disorders (OND), we used surface enhanced laser desorption\\/ionization-time of flight (SELDI-TOF) mass spectrometry to obtain pro- teomic profile of sera from 25 GAD-positive SPS
Raghavan Raju; Goran Rakocevic; Ziwei Chen; Gerard Hoehn; Cristina Semino-Mora; Wei Shi; Richard Olsen; Marinos C. Dalakas
Guillain–Barré syndrome (GBS) is a rare autoimmune disorder, the incidence of which is estimated to be 0.6–4\\/100,000 person\\/year\\u000a worldwide. Often, GBS occurs a few days or weeks after the patient has had symptoms of a respiratory or gastrointestinal microbial\\u000a infection. The disorder is sub-acute developing over the course of hours or days up to 3 to 4 weeks. About a third
Eitan Israeli; Nancy Agmon-Levin; Miri Blank; Joab Chapman; Yehuda Shoenfeld
Factors of nonspecific resistance, cellular and humoral immunity were investigated before operation in 84 patients with nodular euthyroid goiter and in 50 patients with autoimmune thyroiditis, 50 patients were investigated in the long-term postoperative period. Class I HLA antigens were investigated in 205 patients. Humoral changes of immune homeostasis (hyper-production of antithyroid antibodies, an increase in the level of IgM and IgG against a background of the raised number of peripheral blood B-cells, a decrease in the level of lysozyme), disorder of the cellular factor of immunity (specific sensitization of T-lymphocytes to thyroid antigens, a decrease in the number of T-lymphocytes, especially T-suppressors) were detected in autoimmune thyroiditis. Immunological changes in nodular euthyroid goiter were characterized by T-cell sensitization to thyroid extract and microsomal antigen against a decrease in the total number of T-lymphocytes. In most patients with nodular goiter immunity indices after operation returned to normal whereas in patients with autoimmune thyroiditis they showed no tendency to improvement. These data as well as an increase in the frequency of HLA-A11, HLA-A19 and HLA-B8 were indicative of genetically determined primary nature of immune disorders in autoimmune thyroiditis. It was not typical of nodular euthyroid goiter in which an autoimmune process seemed secondary, occurring in response to damage of thyroid tissue by a growing nodule. PMID:2602347
Privalov, V A; Vasil'ev, S A
Tobacco smoking favorably influences the course of Hashimoto thyroiditis, possibly through the antiinflammatory proprieties of nicotine. In this study we tested anatabine, another tobacco alkaloid, in a model of experimental autoimmune thyroiditis. Experimental autoimmune thyroiditis was induced by different doses of thyroglobulin, to produce a disease of low, moderate, or high severity, in 88 CBA/J female mice: 43 drank anatabine supplemented water and 45 regular water. Mice were bled after immunization and killed to assess thyroid histopathology, thyroglobulin antibodies, T(4), and thyroid RNA expression of 84 inflammatory genes. We also stimulated in vitro a macrophage cell line with interferon-? or lipopolysaccharide plus or minus anatabine to quantitate inducible nitric oxide synthase and cyclooxygenase 2 protein expression. Anatabine reduced the incidence and severity of thyroiditis in the moderate disease category: only 13 of 21 mice (62%) developed thyroid infiltrates when drinking anatabine as compared with 22 of 23 (96%) controls (relative risk 0.59, P = 0.0174). The median thyroiditis severity was 0.5 and 2.0 in anatabine and controls, respectively (P = 0.0007 by Wilcoxon rank sum test). Anatabine also reduced the antibody response to thyroglobulin on d 14 (P = 0.029) and d 21 (P = 0.045) after immunization and improved the recovery of thyroid function on d 21 (P = 0.049). In the thyroid transcriptome, anatabine restored expression of IL-18 and IL-1 receptor type 2 to preimmunization levels. Finally, anatabine suppressed in a dose-dependent manner macrophage production of inducible nitric oxide synthase and cyclooxygenase 2. Anatabine ameliorates disease in a model of autoimmune thyroiditis, making the delineation of its mechanisms of action and potential clinical utility worthwhile. PMID:22807490
Caturegli, Patrizio; De Remigis, Alessandra; Ferlito, Marcella; Landek-Salgado, Melissa A; Iwama, Shintaro; Tzou, Shey-Cherng; Ladenson, Paul W
The present invention discloses administering steroid hormones to mammals to treat autoimmune related diseases, more particularly, Th1-mediated (cell-mediated) autoimmune diseases including: multiple sclerosis (MS), rheumatoid arthritis (RA), autoimmune t...
R. R. Voskuhl
In this issue, Singh and co-workers describe the results of classical typing of human leukocyte antigen (HLA) alleles in 1,404 vitiligo patients and 902 unaffected controls from North India and follow-up HLA typing in 355 cases and 441 controls from Gujarat. The increased frequency of DRB1*07:01 in North Indian and Gujarat populations with generalized and localized vitiligo and in several vitiligo populations studied previously suggests that it contributes to autoimmunity and destruction of melanocytes. PMID:22158608
Bowcock, Anne M; Fernandez-Vina, Marcelo
Summary The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense, but is also associated with specific autoimmune diseases. Mutations in the human 3? repair exonuclease 1 (Trex1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to non-hematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.
Gall, Alevtina; Treuting, Piper; Elkon, Keith B.; Loo, Yueh-Ming; Gale, Michael; Barber, Glen N.; Stetson, Daniel B.
Genetic defects in the adenosine deaminase (ADA) gene are among the most common causes for severe combined immunodeficiency (SCID). ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive, and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA (PEG-ADA), or hematopoietic stem cell gene therapy (HSC-GT). Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment. A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T- and B-cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties. PMID:22969765
Sauer, Aisha Vanessa; Brigida, Immacolata; Carriglio, Nicola; Aiuti, Alessandro
The signal transducer and activator of transcription (STAT) 5b is a universal transcription factor that plays key biological roles in allergic diseases, immunodeficiencies, autoimmunities, cancers, hematological diseases, growth disorders, and lung diseases. The identification of distinct pathological manifestations of STAT5b deficiency in humans has highlighted the critical role of the STAT5b pathway. Proper gene transcription at IL-2R ?, FOXP3, Bcl-2, and growth hormone (GH) associated loci are thought to be associated with normal STAT5b transcriptional activity. These genes are thought to play important roles in allergy/autoimmunity, immunodeficiency, cancer/anemia, and growth, respectively. The STAT5A and STAT5B genes are collocated on 17q11. Although these two monomeric proteins exhibit peptide sequence similarities of >90%, it is known through observations of STAT5b deficient subjects that STAT5a and STAT5b are not fully redundant in humans. Patients with STAT5b deficiency have decreased numbers of regulatory CD4+CD25high T cell (Treg) despite their STAT5a levels being normal. Prior studies on STAT5b deficient subjects have revealed immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, ??? T cells, and natural killer (NK) cells. Most subjects with STAT5b deficiency show severe eczema, and autoimmune disease (juvenile idiopathic arthritis, autoimmune thyroiditis, idiopathic thrombocytic purpura) which are thought to be associated with Treg dysfunction. We will review the likely pathophysiological mechanisms associated with STAT5b deficiency.
Kanai, Takahiro; Jenks, Jennifer; Nadeau, Kari Christine
Genetic defects in the adenosine deaminase (ADA) gene are among the most common causes for severe combined immunodeficiency (SCID). ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive, and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA (PEG-ADA), or hematopoietic stem cell gene therapy (HSC-GT). Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment. A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T- and B-cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.
Sauer, Aisha Vanessa; Brigida, Immacolata; Carriglio, Nicola; Aiuti, Alessandro
T-regulatory disorders are a heterogenous group characterized by autoimmune and allergic manifestations of varying onset, severity, and progression. The advent of sophisticated molecular and immunologic diagnostic techniques has resulted in accurate elucidation of etiopathogenesis of many immunoregulatory disorders previously clubbed under the autoimmune umbrella. The severity of presentation and progression, early morbidity and mortality, poor quality of life, and frequent
Autoimmune Polyendocrine Syndromes (APS) were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. Neufeld & Blizzard (1980) suggested a classification of APS, based on clinical criteria only, describing four main types. APS-1 is characterized by presence of chronic candidiasis, chronic hypoparathyroidism, Addison's disease. It is a very rare syndrome in- teresting young
Corrado Betterle; Renato Zanchetta
Macrophage activation syndrome (MAS) is a phenomenon characterized by cytopenia, organ dysfunction, and coagulopathy associated with an inappropriate activation of macrophages. Current diagnostic criteria are imprecise, but the syndrome is now recognized as a form of hemophagocytic lymphohistiocytosis that is characteristically associated with autoimmune diatheses. The diagnosis of incipient MAS in patients with autoimmune disease requires a high index of
Sean Deane; Carlo Selmi; Suzanne S. Teuber; M. Eric Gershwin
A case is described of scleroderma with asymptomatic autoimmune liver disease. The patient presented with the features of CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly and telangiectasia) and a raised plasma alkaline phosphatase was found on routine investigation. It is suggested that this latter biochemical finding is likely to indicate associated autoimmune liver disease in patients with scleroderma.
M. M. Gupta; T. W. Warnes; L. Watson
Previous investigations have shown that in pathology of the main part of the limbic system of the brain, autoimmune responses to brain tissue antigens (TA) are induced . The aim of this investigation was to study the possibility of synthesis of autoantibodies to NA and 5-HT and autoimmune responses to antigens of the hippocampus and viscera. EXPERIMENTAL METHOD Experiments were
A. V. Martynenko; S. V. Magaeva; L. A. Basharova; M. V. Martynenko
Gender affects the susceptibility to many autoimmune diseases. Women have an increased risk of developing diseases such as rheumatoid arthritis and multiple sclerosis compared with men. The female preponderance is believed to depend in part on the influence of sex hormones on the immune system. The mechanism of estrogen-induced immune suppression both in human autoimmune diseases and their experimental animal
L. Jansson; R. Holmdahl
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, in which the myelin sheath has been considered to be the primary target for many years. However, an increasing number of reports have focused on neurodegenerative aspects of the disease pathogenesis. Recent studies in post-mortem MS biopsies and in the animal model Experimental Autoimmune Encephalomyelitis (EAE) have shown that key features of neurodegeneration, i.e. axonal transection, neuronal cell atrophy and neuronal death already occur in early disease phases. Furthermore, it has become clear that irreversible disability correlates stronger with the neuronal affectation than with demyelination. However the cause of neuronal damage still remains elusive, since both demyelination-dependent and direct immune cell-mediated mechanisms have been suggested so far. Here, we summarize the current concepts and recently identified molecular mechanisms of inflammatory neurodegeneration in autoimmune CNS inflammation and highlight the role of different immune cells in the complex network of interactions leading to neuronal damage. PMID:19961850
Herz, Josephine; Zipp, Frauke; Siffrin, Volker
CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal.\\u000a Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form\\u000a of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80\\/CD86 binding activity\\u000a and in vitro immunoregulatory functions. sCTLA-4 is
Daniele Saverino; Rita Simone; Marcello Bagnasco; Giampaola Pesce
Patients with autoimmune inner ear disease develop rapidly progressive sensorineural hearing loss over a period of several weeks or months, often accompanied by vestibular loss. This disease can occur as a distinct clinical entity or in association with an underlying autoimmune disorder. Treatment comprises immunosuppression by corticosteroids, cytostatic drugs or tumor necrosis factor-? antagonists. We report histopathological and immunohistochemical findings of the inner ear of a patient with a granulomatous inner ear disease suffering from Crohn's disease that was nonresponsive to treatment and who underwent surgery for bilateral cochlear implants. PMID:20523038
Dettmer, M; Hegemann, I; Hegemann, S C A
Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented. This trial was registered at www.clinicaltrial.gov as #NCT00001350.
Oliveira, Joao Bosco
Objective: To evaluate the association between celiac disease and specific anxiety and depressive disorders and to identify potential common pathogenetic links, with particular regard to thyroid function and autoimmunity. Methods: Cases included 36 adult celiac patients, 25 females and 11 males, aged 18–64 years. Controls comprised 144 healthy subjects matched by sex and age with no clinical evidence or family
Mauro Giovanni Carta; Maria Carolina Hardoy; Maria Francesca Boi; Stefano Mariotti; Bernardo Carpiniello; Paolo Usai
Antibody against liver cytosol (anti-LC1) was proposed in 1988 as a new and very specific immunoserologic marker of autoimmune hepatitis of childhood and young age. In adults, anti-LC1 might be masked by the presence in serum of anti-LKM1, usually associated with antibodies to hepatitis-C virus. We report the case of a 60-year-old woman who had active chronic hepatitis not related to infection by hepatitis C virus, with autoantibody reacting against liver cytosol as the unique marker of autoimmune hepatitis. Treated with corticosteroids (prednisone, 1 mg/kg per day), coagulation disorder, bilirubin, transaminase activity and immunoglobulins normalized in the following months. A year and a half later, autoantibodies anti-LC1 and p-ANCAs were no longer detected. We have only found one report of a young patient with anti-LC1 autoimmune hepatitis who had cirrhosis and portal hypertension, in national publications. PMID:9711010
Cosme, A; Gil, I; Alvarez, R; Ruiz, I; de Juan, M D; Ojeda, E; Barrio, J
Autoimmunity cannot yet be prevented or cured, in large part due to our poor understanding of disease etiology. Remarkable advances in genomic technology have recently enabled the discovery of a large number of disease-associated gene variations by genome-wide association studies. The next step towards understanding autoimmune disorders entails the functional study of susceptibility genes within experimental disease models. RNA interference (RNAi) is a promising tool for such investigations. Several features of RNAi, including its specificity, versatility and reversible nature, allow experimental systems to be tailored to relevant gene variations. This review discusses how the experimental use of RNAi is invaluable in bridging the gap between the identification of susceptibility genes and the elucidation of their functional contribution to autoimmune disease. PMID:21783421
IgE recognition of autoantigens might augment allergic inflammation in the absence of exogenous allergen exposure. Among allergy and autoimmunity, there is disproportionate representation of males before puberty and females after puberty, suggesting a role for sex hormones. Hormone allergy is an allergic reaction where the offending allergens are one's own hormones. It is an immune reaction to the hormones, which can interfere with the normal function of the hormones. It can occur perimenstrually in women along with the variation in menstrual cycle. The perimenstrual allergies are about the cyclic abundance of the hormone causing a cyclic expression of allergic symptoms. The inflammatory mechanisms of allergic reactions to hormone allergens, which are intrinsic to the body, are the same as the mechanisms of allergic reactions to external allergens.
The activation of immune cells is mediated by a network of signaling proteins that can undergo post-translational modifications critical for their activity. Methylation of nucleic acids or proteins can have major effects on gene expression as well as protein repertoire diversity and function. Emerging data indicate that indeed many immunologic functions, particularly those of T cells, including thymic education, differentiation and effector function are highly dependent on methylation events. The critical role of methylation in immunocyte biology is further documented by evidence that autoimmune phenomena may be curtailed by methylation inhibitors. Additionally, epigenetic alterations imprinted by methylation can also exert effects on normal and abnormal immune responses. Further work in defining methylation effects in the immune system is likely to lead to a more detailed understanding of the immune system and may point to the development of novel therapeutic approaches.
Lawson, Brian R.; Eleftheriadis, Theodoros; Tardif, Virginie; Gonzalez-Quintial, Rosana; Baccala, Roberto; Kono, Dwight H.; Theofilopoulos, Argyrios N.
The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients.
Grando, Sergei A
Interleukin-7 (IL-7) is a critical survival factor for lymphocytes and recent studies suggest targeting the IL-7/IL-7R? pathway holds promise for the treatment of autoimmune diseases. Several lines of evidence, genetic as well as functional, indicate an important role for this cytokine in autoimmune inflammation: polymorphisms in the IL-7R? have been associated with increased risk for autoimmune disease and blocking IL-7/IL-7R? with antibodies showed therapeutic efficacy in several autoimmune mouse models. Insights are starting to emerge about the mechanisms underlying IL-7's role in autoimmunity and tolerance, revealing surprising novel functions beyond its traditional activity as a T cell survival factor. In the first part of this review, the functions of IL-7 in the immune system are concisely described, providing a basis for understanding their potential role in promoting autoimmune responses. In the second part, current knowledge about the role of IL-7 in various autoimmune conditions is reviewed. PMID:23831438
Autoimmune associations in myasthenia gravis (MG)-patients and their relatives have not been re-assessed since their separation into early- or late-onset MG (EOMG, LOMG), or thymoma-associated MG. Here, we analysed 226 EOMG-, 97 LOMG-, and 150 thymoma-patients for autoimmune disorders in themselves and their relatives. From 283 of them sera were tested for different organ- and non-organ-specific autoantibodies (autoAbs) by immunofluorescence test (IFT) and ELISA; genotyping was performed in 213 patients. Relatives with autoimmune disorders were reported by more patients with EOMG (40% of 210) than LOMG (20% of 89; p < 0.01) than thymomas (8% of 150; p < 0.001). In 150 genotyped EOMG-females, the known risk allele of the immuno-regulatory PTPN2 2 (R620W) appeared commoner in those with second autoimmune diseases (p ? 0.06), or with autoimmune relatives (p ? 0.03), than in those without. Organ-specific autoAbs were found in ? 30% of all MG-patients, autoAbs to striated muscle only in patients with thymoma-MG (62%) or LOMG (61%). Titers against adrenal cortex were lower in LOMG-patients. Disease-associated autoAbs against systemic targets or 'natural autoAbs' - except of autoAbs to nuclei - were uncommon in all groups (< 13%). Thus-with rare exceptions in EOMG and LOMG-we found minimal support for the notion that autoimmune patients have wide-ranging autoreactivity that causes disease only if it targets such Achilles' heels as the muscle acetylcholine receptor; even in thymoma-patients the autoAbs are sharply focused on a restricted range of muscle, cytokine and endocrine targets. PMID:23792059
Klein, Reinhild; Marx, Alexander; Ströbel, Philipp; Schalke, Berthold; Nix, Wilfred; Willcox, Nick
Autoimmune gastritis is the outcome of a pathological CD4 T cell-mediated autoimmune response directed against the gastric H/K-ATPase. Silent initially, the gastric lesion becomes manifest in humans by the development of megaloblastic pernicious anemia arising from vitamin B12 deficiency. Cutting edge issues in this disease relate to its epidemiology, immunogenetics, a role for Helicobacter pylori as an infective trigger through molecular mimicry, its immunopathogenesis, associated organ-specific autoimmune diseases, laboratory diagnosis, and approaches to curative therapy. PMID:21174235
Toh, Ban-Hock; Chan, James; Kyaw, Tin; Alderuccio, Frank
Autoimmune hemolytic anemia is rare in children and infants and steroids are the corner stone of therapy. Management of the patients with steroid refractory/dependent disease is difficult .Rituximab is being used in the treatment of a variety of autoimmune diseases including Autoimmune hemolytic anemia (AIHA),especially in adults but there is scarce data regarding the use of this agent in pediatric AIHA patients.The authors report two cases of steroid refractory AIHA, who responded to rituximab with review the literature of its use in pediatrics. PMID:21830023
Gupta, Nitin; Sharma, Sanjeev; Seth, Tulika; Mishra, Pravas; Mahapatra, Manoranjan; Kumar, Suman; Kapoor, Rajan; Agarwal, Narendra
Trichloroethene (TCE) has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma in humans. However, experimental studies have not been conducted to establish the role of TCE in causing autoimmunity and\\/or SLE. To clarify the role of TCE in autoimmune responses, subchronic studies were carried out in female autoimmune prone mice (MRL +\\/+).
M. F. Khan; B. S. Kaphalia; B. S. Prabhakar; M. F. Kanz; G. A. S. Ansari
Both genetic and environmental factors contribute to the development of autoimmunity. Animals and humans exposed to natural infections have a reduced rate of autoimmune diseases. There is increasing evidence that immune stimulation prevents autoimmune diseases. Our hypothesis is that the process of the development of pathogenic cells involved in autoimmunity can be modulated by early stimulation of the immune system
To assess the validity of a scoring system developed by the International Autoimmune Hepatitis Group for the definite diagnosis of autoimmune hepatitis, 119 patients with autoimmune hepatitis by standard clinical criteria and 131 patients with other chronic liver diseases were evaluated. Each patient was graded on 35 items in 13 clinical categories. Ninety-seven patients diagnosed as having autoimmune hepatitis by
Albert J. Czaja; Herschel A. Carpenter
Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented.
Sakic, Boris; Kirkham, David L.; Ballok, David A.; Mwanjewe, James; Fearon, Ian M.; Macri, Joseph; Yu, Guanhua; Sidor, Michelle M.; Denburg, Judah A.; Szechtman, Henry; Lau, Jonathan; Ball, Alexander K.; Doering, Laurie C.
Sensorineural hearing loss of immune-mediated origin may be present as a symptom in systemic autoimmune diseases or may occur as a primary disorder without other organ involvement (auto-immune inner ear disease). The diagnosis of auto-immune inner ear disease is still predicated on clinical features and to date specific diagnostic tests are not available. We report a case of right-sided sudden hearing loss in a female patient in which the clinical manifestations, in addition to ANA positivity and hypocomplementaemia allowed us to hypothesize an auto-immune inner ear disease. The immunosuppressive treatment with cyclosporine-A was capable of a recovery of the hearing that, however, occurred progressively with normalization of the hearing function after 1 year of treatment. cyclosporine-A could be proposed as a therapeutic option in case of auto-immune inner ear disease allowing the suspension of corticosteroids that, at high dose, expose patients to potentially serious adverse events. PMID:22323852
Di Leo, E; Coppola, F; Nettis, E; Vacca, A; Quaranta, N
Evidence has been growing that the pathogenesis of lymphoproliferative disease involves immune processes deregulation. It is believed that antigens or immunological elements can trigger transformation of normal lymphocyte polyclonal population into monoclonal neoplastic disorder--lymphoproliferative disease. Extensive studies point to the link between malignant lymphoma development and autoimmune or inflammatory diseases--namely rheumatoid arthritis, Sjörgen's syndrome, coeliac disease, systemic lupus erythematosus or thyroiditis. Increased risk of lymphoproliferative disease development was also proved for some infections. These infections involve both viral (e.g. Epstein-Barr virus, HIV or hepatitis C virus) and bacterial agents (e.g. Helicobacter pylori, Borrelia burgdorferi). Besides various lymphomas, the links to autoimmune/inflammatory diseases have also been described in chronic lymphocytic leukaemia. Regarding clinical medicine, it is necessary to distinguish patients with autoimmune, inflammatory and infectious diseases who are at the increased risk of tumour development. New approaches must be found to lower this risk. Also, the relationship between autoimmune/inflammatory disease therapy and lymphoma development should be clarified. Although lymphomas associated with autoimmune and inflammatory diseases represent only a small proportion of all lymphomas, any new findings regarding these diseases can cast light on lymphoma pathogenesis as a whole. PMID:21560455
Tvar?zková, Zuzana; Pavlová, Sárka; Doubek, Michael; Mayer, Jirí; Pospísilová, Sárka
Background Ophthalmopathy is the most common extrathyroidal manifestation of Graves’ disease. However, in approximately 5% of cases this autoimmune eye disorder occurs in the apparent absence of Graves’ hyperthyroidism: the so-called euthyroid Graves’ disease (EGD). Methods Seven patients with EGD were followed for evidence of thyroid and orbital autoimmunity, for up to 10 years. Calsequestrin and collagen XIII antibodies were measured by enzyme linked immunosorbent assay (ELISA), and TSH-receptor (TSH-r) antibodies were measured as TSH-r-binding antibody (TRAb) and thyroid-stimulating immunoglobulin (TSI). Eye signs were characterized and quantified as clinical activity score (CAS), NOSPECS classes, Nunery types 1 and 2, and margin-reflex distance (MRD). Results Calsequestrin antibodies were detected on at least one occasion in three of the seven patients and collagen XIII antibodies were detected one or more times in five patients. In one patient with isolated congestive ophthalmopathy who was studied intensely, collagen XIII antibodies were initially positive and then became negative as the eye disease stabilized, while antibodies targeting calsequestrin were always negative. TRAb was not detected in any patient, but TSI was detected in three patients on one occasion each. Ultrasound abnormalities were found in four of the six patients for whom this was carried out, but there was no clear evidence for thyroiditis in any of these patients. For comparison, 13 patients were studied with typical Graves’ ophthalmopathy. There were no significant differences compared to EGD in respect to the prevalence of positive calsequestrin or collagen XIII antibodies, but these patients included more smokers (eight out of 13 versus none out of seven). Conclusions Earlier studies suggesting that patients with EGD eventually develop thyroid dysfunction have not been confirmed here, although follow-up continues, and the possibility that such patients have had thyroid autoimmunity in the past, or that they will develop it in the future cannot be excluded. Overall, it is likely that the ophthalmopathy associated with Graves’ hyperthyroidism is the same disease as that observed in patients – such as those reported here – in whom thyroid dysfunction and thyroid autoimmunity are not present during the period of follow- up. The role of autoimmunity against the TSH-r in euthyroid patients with ophthalmopathy has not been proven and the significance of the orbital antibodies is unclear.
McCorquodale, Tom; Lahooti, Hooshang; Gopinath, Bamini; Wall, Jack R
Summary of Recent Advances Human regulatory T cells (Tregs) play a critical role in preventing autoimmunity, and their failure contributes to autoimmune diseases. In recent years, our understanding of human Tregs has been greatly enhanced by improvements in the definition and isolation of pure human Tregs, as well as by the discovery of phenotypically and functionally distinct human Treg subsets. This progress has also yielded a better understanding of the mechanisms of human Treg suppression and the role of human Tregs in autoimmune diseases. An unexpected discovery is that human Tregs have considerable plasticity that allows them to produce the pro-inflammatory cytokine IL-17 under certain conditions. These recent advances highlight the importance of studying the roles of both mouse and human Tregs in autoimmunity.
Cvetanovich, Gregory L.
Systemic lupus erythematosus, Sjögren's syndrome, and dermatomyositis are systemic autoimmune diseases that develop after environmental triggering of genetically susceptible individuals. The precise cellular and molecular mechanisms leading to autoimmune disease, and what factors determine which organs are involved, remain poorly understood. Recent insights into genetic susceptibility now make obvious that environmental triggers often act via cellular pathways containing disease-associated polymorphisms. In the breaking of tolerance, the initiating tissue--including dendritic cells--provides a decisive microenvironment that affects immune-cell differentiation, leading to activation of adaptive immunity. Type 1 interferon produced by innate immune cells has a central role in systemic autoimmunity and activates B cells and T cells. In turn, B-cell-derived autoantibodies stimulate dendritic cells to produce type 1 interferon; thus, a positive feedforward loop is formed that includes both the innate and adaptive systems. New treatments could simultaneously and specifically target several such vital pathways in autoimmunity. PMID:23993191
Wahren-Herlenius, Marie; Dörner, Thomas
Data on clinical, genetic, and immunological aspects of sixty patients with type 2 polyglandular autoimmune disease (PGAD) are presented. The literature on this is reviewed and discussed. PMID:8887161
Betterle, C; Volpato, M; Greggio, A N; Presotto, F
The present invention provides methods for treating inflammatory conditions, rheumatoid diseases, autoimmune conditions, and conditions associated with bone loss, comprising administering to a subject with an inflammatory condition an amount effective to ...
C. Lubahn D. Lorton D. Wilson G. R. Pettit Y. Chang
The complex interplay between environmental factors and genetic susceptibility plays an essential role in disease pathogenesis. This is especially true for autoimmunity, where clinical reports, genomic and epidemiological studies, as well as animal models have identified several environmental and genetic risk factors associated with autoimmune disease. The complexity of this relationship is demonstrated by the vast array of environmental factors that have now been implicated in the induction, and possibly the maintenance of autoimmune disease. The multitude of environmental factors implicated includes both infectious and non-infectious agents. Here, we review one specific autoimmune disease, primary biliary cirrhosis (PBC), as a model for environmental risk factors acting in concert with genetic susceptibility in the disease pathogenesis. PBC is an ideal model, as both infectious and non-infectious environmental agents have been identified as risk factors, and their study provides clues for unravelling the pathogenesis of the disease. PMID:21337133
Smyk, Daniel; Rigopoulou, Eirini I; Baum, Harold; Burroughs, Andrew K; Vergani, Diego; Bogdanos, Dimitrios P
Autoimmune diseases represent robust and inappropriate immune reactions arising out of a background of immunodefectiveness and immune dysregulation. For too many years our only approach to therapy has been generalized and nonspecific immunosuppression with powerful and highly toxic drugs.
A recent advance in the treatment and understanding of autoimmune disease has been the efficacy of B cell targeted therapy. Such therapies are effective for several such diseases, with systemic autoimmunity being a prototypical example. The mechanism of action is not fully defined, but blocking B cell Ag presentation to T cells is likely to be important. T-B interactions probably engender a positive feedback loop that amplifies and sustains autoimmunity. But how is self-tolerance first broken to initiate this loop? I propose, based on recent data, a model in which autoreactive B cells are activated first, independent of T cells, but dependent upon BCR and TLR signals. These activated B cells then break T celltolerance, initiating full-blown autoimmunity.
Shlomchik, Mark J.
The human RAC2 gene encodes a small GTP-binding protein with a pivotal role in immune activation and in the induction of peripheral immune tolerance through restimulation-induced cell death (RICD). Different human pathogens target the protein product of RAC2, suggesting that the gene may be subject to natural selection, and that variants in RAC2 may affect immunological phenotypes in humans. We scanned the genomic region encompassing the entire transcription unit for the presence of putative noncoding regulatory elements conserved across mammals. This information was used to select two RAC2 gene regions and analyze their intraspecific genetic diversity. Results suggest that a region covering the 3' untranslated region has been a target of multiallelic balancing selection (or diversifying selection), and three major RAC2 haplogroups occur in human populations. Haplotypes belonging to one of these clades are associated with increased susceptibility to multiple sclerosis (P = 0.022) and earlier onset of disease symptoms (P = 0.025). This same haplogroup is significantly more common in patients with Crohn's disease compared with healthy controls (P = 0.048). These data reinforce recent evidences that susceptibility alleles/haplotypes are shared among multiple autoimmune disorders and support a causal "role for RAC2" variants in the pathogenesis of autoimmune diseases. Other genes with a role in RICD have previously been associated with autoimmunity in humans, suggesting that this pathway and RAC2 may represent novel therapeutic targets in autoimmune disorders. PMID:21680873
Sironi, Manuela; Guerini, Franca Rosa; Agliardi, Cristina; Biasin, Mara; Cagliani, Rachele; Fumagalli, Matteo; Caputo, Domenico; Cassinotti, Andrea; Ardizzone, Sandro; Zanzottera, Milena; Bolognesi, Elisabetta; Riva, Stefania; Kanari, Yasuyoshi; Miyazawa, Masaaki; Clerici, Mario
In April 2007, an international Colloquium bridging scientific and clinical disciplines was held to discuss the role of cellular and tissue damage in the initiation, development and persistence of autoimmune disease. Five potential etiologic and pathophysiologic processes fundamental to autoimmune disease (i.e. inflammation, infection, apoptosis, environmental exposure and genetics were the focus of the presentations and integrative discussions at the Colloquium. The information presented on these topics is condensed in this review. Inflammation has close clinico-pathologic associations with autoimmunity, but future analyses will require better definition and metrics of inflammation, particularly for the earliest cellular and molecular components dependent on recruitment of elements of innate immunity. Although infection may be associated with increased levels of autoantibodies, most infections and virtually all vaccinations in humans lack well-established links to autoimmune diseases. Further application of well designed, long-term epidemiologic and population-based studies are urgently needed to relate antecedent exposures with later occurring stigmata of autoimmunity with a goal of discerning potentially susceptible individuals or subpopulations. Suspect infections requiring closer interrogation include EB virus (SLE and other diseases), HCV (autoimmune hepatitis), beta hemolytic streptococci (rheumatic carditis) and H. pylori (autoimmune gastritis) among others. And even if a micro-organism were to be incriminated, mechanisms of initiation/perpetuation of autoimmunity continue to challenge investigators. Plausible mechanisms include potentiation and diversion of innate immunity; exposure or spillage of intracellular autoantigens; or provision of autoantigenic mimics. Integrity of apoptosis as a critical safeguard against autoimmunity was discussed in the contexts of overreactivity causing autoantigens to gain enhanced exposure to the immune system, or under-reactivity producing insufficient elimination of autoreactive clones of lymphocytes. Although environmental agents are widely believed to serve as necessary “triggers” of autoimmune disease in genetically predisposed individuals, only a few such agents (mainly drugs and some nutrients) have been clearly identified and their mechanism of action defined. Finally an essential genetic foundation underlies all these hazards for autoimmunity in the form of risk-associated polymorphisms in immunoregulatory genes. They may be predictive of future or impending disease.
Leskovek, Natasha V.; Mackay, Ian R.; Rose, Noel R.
Summary T cells and antibodies against self and non-self hsp are present in both patients and healthy controls. T cells responding to hsp65 can be involved in autoimmune diseases, this was demonstrated for two site-specific animal autoimmune diseases: AA in Lewis rats and diabetes (IDDM) in NOD mice. In human ReA there is evidence for a direct stimulation of joint
Pieter Res; Jelle Thole; René de Vries
The complex interplay between environmental factors and genetic susceptibility plays an essential role in disease pathogenesis.\\u000a This is especially true for autoimmunity, where clinical reports, genomic and epidemiological studies, as well as animal models\\u000a have identified several environmental and genetic risk factors associated with autoimmune disease. The complexity of this\\u000a relationship is demonstrated by the vast array of environmental factors
Daniel Smyk; Eirini I. Rigopoulou; Harold Baum; Andrew K. Burroughs; Diego Vergani; Dimitrios P. Bogdanos
Autoimmune diseases are frequently postulated to arise as post-infectious phenomena. Here we survey the evidence supporting\\u000a these theories, with particular emphasis on Crohn’s disease and ankylosing spondylitis. Direct proof that infection establishes\\u000a persistent autoimmunity remains lacking, although it may provoke a prolonged inflammatory response when occurring on a susceptible\\u000a immunological background. The argument of infective causality is by nomeans trivial,
D. J. B. Marks; N. A. Mitchison; A. Segal; J. Sieper
Conclusion HSCT in autoimmune diseases has now become one of the potential therapeutic options for physicians looking after patients\\u000a with severe intractable autoimmune diseases. It has now progressed beyond theory based on animal and human case reports, but\\u000a at this stage it has been appropriately reserved for patients with resistant disease in a clinical trial setting. Ongoing\\u000a analysis of the safety
John Moore; P. Brooks
Chemical exposure can trigger or accelerate the development of autoimmune manifestations. Although heavy metals are elementary chemical structures, they can have profound and complex effects on the immune system. In genetically susceptible mice or rats, administration of subtoxic doses of mercury induces both the production of highly specific autoantibodies and a polyclonal activation of the immune system. We review in this article some of the mechanisms by which heavy metal exposure can lead to autoimmunity. PMID:15829271
Rowley, Benjamin; Monestier, Marc
\\u000a Autoimmune thyroid disease includes Graves’ disease and Hashimoto’s thyroiditis; the former is characterized by hyperthyroidism\\u000a induced by agonistic antithyrotropin receptor (TSHR), whereas the latter by hypothyroidism mediated by cytotoxic T lymphocytes\\u000a against thyroglobulin and\\/or thyroid peroxidase and cytokine-induced thyroid cell apoptosis. Animal models of autoimmune thyroid\\u000a diseases, including spontaneous and inducible models of Hashimoto’s thyroiditis and inducible models of Graves’
Yuji Nagayama; Norio Abiru
Autoimmune thyroid diseases (AITD) cover the spectrum from hypothyroid Hashimoto’s thyroiditis (HT) to hyperthyroid Graves’\\u000a disease (GD). The main autoimmune targets are thyroglobulin (TG), thyroid peroxidase (TPO) and the thyrotropin receptor (TSHR).\\u000a Autoantibodies and specific T cells directed against all three autoantigens can be detected in the circulation of HT and GD\\u000a patients and also in a significant proportion of
B-CLL patients have a high prevalence of autoimmune phenomena due to polyclonal autoantibodies (Abs) restricted to blood cell self-antigens (Ag) and progressively develop a severe hypogammaglobulinemia. Autoimmunity and immunodeficiency have been related to B-CLL biological properties and cellular origin. Three major issues have emerged: 1) the relevance of B cell receptor abnormalities. More specifically, the importance of the defective expression
Although the cause of autoimmune diseases is unknown, it has long been speculated that an infectious agent might have a role in their initiation and progression. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been used to study factors in disease pathogenesis. A recent study shows that pertussis toxin, which is used as an adjuvant in EAE, uses Toll-like receptor 4 signaling to mediate its disease-inducing effect. PMID:15922942
Racke, Michael K; Hu, Wei; Lovett-Racke, Amy E
When immune dysfunction affects two or more endocrine glands and other non-endocrine immune disorders are present, the polyglandular autoimmune (PGA) syndromes should be considered. The PGA syndromes are classified as two main types: PGA type I and PGA type II. We are reporting this case in which a patient had primary adrenal insufficiency, autoimmune hypothyroidism and insulin dependent diabetes mellitus and was diagnosed as "Schmidt's syndrome" (PGA type II). This syndrome is a very rare autoimmune disorder and difficult to diagnose because the symptoms of this syndrome depends on the gland which gets involved first. Our patient was treated and improved with corticosteroid, thyroxine and insulin therapy.
Gupta, Amit Narayan; Nagri, Shivashankara Kaniyoor
Background Environmental exposures, ranging from perchlorate in rocket fuel to polychlorinated biphenols, have been shown to influence thyroid function. Although most of these agents are associated with reduced thyroid hormone levels or impaired thyroid hormone action, a number of environmental exposures confer an increased risk of autoimmune thyroid disease. Summary Factors that increase autoimmune thyroid disease risk include radiation exposure, both from nuclear fallout and medical radiation, increased iodine intake, as well as several contaminants in the environment that influence the thyroid. Although ?70% of the risk for developing autoimmune thyroid disease is attributable to genetic background, environmental triggers are thought to play a role in the development of autoimmune thyroid disease in susceptible individuals. Conclusions Understanding the association of environmental agents with thyroid dysfunction can be utilized to reduce the risk to populations. Knowledge of the specific factors that trigger autoimmune thyroid disease and their mode of action, however, may also inform risk reduction in the individual patient. These factors are especially relevant for those at increased risk of autoimmune thyroid disease based on family history.
OBJECTIVE: To define the diagnostic characteristics and predictors of treatment response in patients with suspected autoimmune dementia. PATIENTS AND METHODS: Between January 1, 2002, and January 1, 2009, 72 consecutive patients received immunotherapy for suspected autoimmune dementia. Their baseline clinical, radiologic, and serologic characteristics were reviewed and compared between patients who were responsive to immunotherapy and those who were not. Patients were classified as responders if the treating physician had reported improvement after immunotherapy (documented in 80% by the Kokmen Short Test of Mental Status, neuropsychological testing, or both). RESULTS: Initial immunotherapeutic regimens included methylprednisolone in 56 patients (78%), prednisone in 12 patients (17%), dexamethasone in 2 patients (3%), intravenous immune globulin in 1 patient (1%), and plasma exchange in 1 patient (1%). Forty-six patients (64%) improved, most in the first week of treatment. Thirty-five percent of these immunotherapy responders were initially diagnosed as having a neurodegenerative or prion disorder. Pretreatment and posttreatment neuropsychological score comparisons revealed improvement in almost all cognitive domains, most notably learning and memory. Radiologic or electroencephalographic improvements were reported in 22 (56%) of 39 patients. Immunotherapy responsiveness was predicted by a subacute onset (P<.001), fluctuating course (P<.001), tremor (P=.007), shorter delay to treatment (P=.005), seropositivity for a cation channel complex autoantibody (P=.01; neuronal voltage-gated potassium channel more than calcium channel or neuronal acetylcholine receptor), and elevated cerebrospinal fluid protein (>100 mg/dL) or pleocytosis (P=.02). Of 26 immunotherapy-responsive patients followed up for more than 1 year, 20 (77%) relapsed after discontinuing immunotherapy. CONCLUSION: Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.
Flanagan, Eoin P.; McKeon, Andrew; Lennon, Vanda A.; Boeve, Bradley F.; Trenerry, Max R.; Tan, K. Meng; Drubach, Daniel A.; Josephs, Keith A.; Britton, Jeffrey W.; Mandrekar, Jayawant N.; Lowe, Val; Parisi, Joseph E.; Pittock, Sean J.
Liver transplantation remains an effective treatment for those with end-stage disease and with intractable liver-related symptoms. The shortage of organs for transplantation has resulted in the need for rationing. A variety of approaches to selection and allocation have been developed and vary from country to country. The shortage of donors has meant that new approaches have to be adopted to make maximal use of the available organs; these include splitting grafts, use of extended criteria livers, livers from non-heart-beating donors and from living donors. Post transplantation, most patients will need life-long immunosuppression, although a small proportion can have immunosuppression successfully withdrawn. Newer immunosuppressive drugs and different strategies may allow a more targeted approach with a reduction in side-effects and so improve the patient and graft survival. For autoimmune diseases, transplantation is associated with significant improvement in the quality and length of life. Disease may recur after transplantation and may affect patient and graft survival.
Mottershead, Marcus; Neuberger, James
Liver transplantation remains an effective treatment for those with end-stage disease and with intractable liver-related symptoms. The shortage of organs for transplantation has resulted in the need for rationing. A variety of approaches to selection and allocation have been developed and vary from country to country. The shortage of donors has meant that new approaches have to be adopted to make maximal use of the available organs; these include splitting grafts, use of extended criteria livers, livers from non-heart-beating donors and from living donors. Post transplantation, most patients will need life-long immunosuppression, although a small proportion can have immunosuppression successfully withdrawn. Newer immunosuppressive drugs and different strategies may allow a more targeted approach with a reduction in side-effects and so improve the patient and graft survival. For autoimmune diseases, transplantation is associated with significant improvement in the quality and length of life. Disease may recur after transplantation and may affect patient and graft survival. PMID:18528936
Mottershead, Marcus; Neuberger, James
Autoimmune hepatitis is an immune-mediated disease targeting hepatocytes. It is more common in middleaged Caucasian females, although may affect other patient populations and age groups. The diagnosis is made according to criteria based on the alkaline phosphatase: ALT ratio, IgG, the presence of autoantibodies, liver histology, response to therapy, and the absence of a viral, alcohol or drug etiology. More recently a simplified scoring system has been proposed. In the absence of treatment, the prognosis is very poor with a 60% three year mortality. There are guidelines on the indications for treatment and some groups of patients may not require treatment. The main element of treatment is prednisolone which decreases the 3 year mortality to 10%. Prednisolone is tapered down to 5-10 mg per day, as monotherapy or in combination with azathioprine. Approximately 80% of patients will respond to therapy with prednisolone with or without azathioprine and this should be given for at least 2 years. Remission is defined as an asymptomatic patient with serum aminotransferases that are normal or less than two-fold elevated, a normal level of IgG and inactive liver histology. Relapse occurs in up to 90% of patients following drug withdrawal. The sensitivity and specificity of liver histology to predict relapse off treatment is not high. Other treatments that have been proposed include mycophenolate mofetil, budesonide, cyclosporine A, tacrolimus, 6-MP, methotrexate, ursodeoxycholic acid, rapamycin and rituximab although experience with all these agents is limited. PMID:22794160
Malnick, Stephen; Duek, Gabriel; Melzer, Ehud; Basevitz, Alon
Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders. PMID:21217752
Lausch, Ekkehart; Janecke, Andreas; Bros, Matthias; Trojandt, Stefanie; Alanay, Yasemin; De Laet, Corinne; Hübner, Christian A; Meinecke, Peter; Nishimura, Gen; Matsuo, Mari; Hirano, Yoshiko; Tenoutasse, Sylvie; Kiss, Andrea; Rosa, Rafael Fabiano Machado; Unger, Sharon L; Renella, Raffaele; Bonafé, Luisa; Spranger, Jürgen; Unger, Sheila; Zabel, Bernhard; Superti-Furga, Andrea
During the past 10 yrs, over 700 patients suffering from severe autoimmune disease (AD) have received an autologous haematopoietic stem cell transplant as treatment of their disorder with durable remission being obtained in around one-third. The most commonly transplanted ADs have been systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. A fewer number of patients have received an allogeneic transplant. The initially reported overall treatment-related mortality of 7% has since fallen, with no further cases being reported in systemic sclerosis or multiple sclerosis in the past 3 yrs. This is thought to be due to more careful patient selection. The phase I/II data has led to currently running prospective randomised trials in systemic sclerosis, multiple sclerosis and systemic lupus erythematosus in Europe and North America. Immune reconstitution data suggests a 'resetting' of autoimmunity in those patients achieving stable remission, rather than simply prolonged immunosuppression. Recent results from in vitro experiments, animal models and early human experience in severe acute graft vs host disease suggest that multipotent mesenchymal stromal cells obtained from the bone marrow and expanded ex vivo, may exert a clinically useful immunomodulatory effect. Such cells are immune privileged and apparently of low toxicity. Further characterization of these cells and consideration of their possible clinical application in AD is underway. PMID:16777856
van Laar, J M; Tyndall, A
Diabetes, one of the most commonly seen metabolic disorders, is affecting a major area of population in many developing as well as most of the developed countries and is becoming an alarming concern for the rising cost of the healthcare system. Latent Autoimmune Diabetes in Adults (LADA) is a form of diabetes which is less recognized and underdiagnosed type of diabetes which appears to have characteristics of both type 1 (autoimmune in nature) and type 2 diabetes (adult age at onset and initial response to oral hypoglycemic agents). An epidemiological study was carried out on 500 patients in the western region of India. Various parameters such as age at onset, duration of diabetes, gender, basal metabolic index (BMI), type of diabetes, family history, HbA1c levels, cholesterol levels, and current treatment regimen were evaluated and correlated with type 1 and type 2 diabetes. Moreover, diagnostic markers for LADA, namely, GAD autoantibodies and C-peptide levels, were determined for 80 patients selected from the epidemiological study. Some of the results obtained were found to be consistent with the literature whereas some results were found to be contradictory to the existing data. PMID:22577577
Brahmkshatriya, Priyanka P; Mehta, Anita A; Saboo, Banshi D; Goyal, Ramesh K
Diabetes, one of the most commonly seen metabolic disorders, is affecting a major area of population in many developing as well as most of the developed countries and is becoming an alarming concern for the rising cost of the healthcare system. Latent Autoimmune Diabetes in Adults (LADA) is a form of diabetes which is less recognized and underdiagnosed type of diabetes which appears to have characteristics of both type 1 (autoimmune in nature) and type 2 diabetes (adult age at onset and initial response to oral hypoglycemic agents). An epidemiological study was carried out on 500 patients in the western region of India. Various parameters such as age at onset, duration of diabetes, gender, basal metabolic index (BMI), type of diabetes, family history, HbA1c levels, cholesterol levels, and current treatment regimen were evaluated and correlated with type 1 and type 2 diabetes. Moreover, diagnostic markers for LADA, namely, GAD autoantibodies and C-peptide levels, were determined for 80 patients selected from the epidemiological study. Some of the results obtained were found to be consistent with the literature whereas some results were found to be contradictory to the existing data.
Brahmkshatriya, Priyanka P.; Mehta, Anita A.; Saboo, Banshi D.; Goyal, Ramesh K.
Autoimmune hepatitis (AIH) is a form of chronic hepatitis of unknown etiology. It was first described in the 1950s as a form of chronic hepatitis noted in younger women. It was later termed lupoid hepatitis due to its association with autoantibodies before being named AIH in 1965. Corticosteroids and azathioprine have been the standard therapy for AIH, but due to treatment failures and toxicities from these medications, new medications are being investigated as possible treatment options. Rituximab has been used in various autoimmune disorders with good success. We report the case of a 34-year-old Caucasian woman with a history of B cell lymphoma and concurrent AIH treated with rituximab. The diagnosis of AIH was made by classic serological and histological features. The patient was initially treated with steroids but had a progression of her disease as well as suffering toxicities from the steroids. She was then given eight weeks of rituximab with good improvement in both laboratory and histological findings.
Barth, E.; Clawson, J.
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.
Pestronk, A.; Drachman, D.B.; Teoh, R.; Adams, R.N.
Rationale Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined. Objective Here we addressed the role of platelets in mediating CNS inflammation in EAE. Results We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control non-diseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression upon platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ib alpha (GPIb?) promotes both platelet adhesion as well as inflammatory actions of platelets, and, targeting of GPIb? attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa) also reduced EAE severity in mice. Conclusions Thus, platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.
Langer, Harald F.; Choi, Eun Young; Zhou, Hong; Schleicher, Rebecca; Chung, Kyoung-Jin; Tang, Zhongshu; Gobel, Kerstin; Bdeir, Khalil; Chatzigeorgiou, Antonios; Wong, Connie; Bhatia, Sumeena; Kruhlak, Michael J.; Rose, John W.; Burns, James B.; Hill, Kenneth E.; Qu, Hongchang; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G.; Wang, Yunmei; Simon, Daniel I.; Nieswandt, Bernhard; Lambris, John D.; Li, Xuri; Meuth, Sven G.; Kubes, Paul; Chavakis, Triantafyllos
Bilirubin, an abundant bile pigment in mammalian serum, was once considered a toxic waste product and has more recently been recognized as a potent antioxidant of physiological importance. However, its potential biological functions in other fields are not well understood. Herein we show that bilirubin is also a powerful immunomodulatory agent. Bilirubin significantly inhibited Ag-specific and polyclonal T cell responses, while other similar antioxidants completely lacked this effect. Bilirubin suppressed CD4(+) T cell responses at multiple steps. High levels of bilirubin could induce apoptosis in reactive CD4(+) T cells. Bilirubin at nonapoptotic concentrations suppressed CD4(+) T cell reactivity through a wide range of actions, including inhibition of costimulator activities, suppression of immune transcription factor activation, and down-regulation of inducible MHC class II expression. Further studies suggest that bilirubin actions were direct, rather than via induction of immune deviation or regulatory T cells. In vivo, treatment with bilirubin effectively suppressed experimental autoimmune encephalomyelitis in SJL/J mice. In contrast, depletion of endogenous bilirubin dramatically exacerbated this disease. In summary, our results identify bilirubin as an important immunomodulator that may protect mammals against autoimmune diseases, thereby indicating its potential in the treatment of multiple sclerosis and other immune disorders. PMID:18641326
Liu, Yingru; Li, Ping; Lu, Jie; Xiong, Wei; Oger, Joel; Tetzlaff, Wolfram; Cynader, Max
Autoimmune hemolytic anemia (AIHA) is an infrequent group of diseases defined by autoantibody mediated red blood cell destruction. Correct diagnosis and classification of this condition are essential to provide appropriate treatment. AIHA is divided into warm and cold types according to the characteristics of the autoantibody involved and by the presence of an underlying or associated disorder into primary and secondary AIHA. Due to its low frequency, treatment for AIHA is largely based on small prospective trials, case series, and empirical observations. This review describes in detail the different treatment approaches for autoimmune hemolytic anemia. Warm antibody type AIHA should be treated with steroids, to which most patients respond, although relapse can occur and maintenance doses are frequently required. Splenectomy is an effective second line treatment and can provide long-term remission without medication. Rituximab is a useful alternative for steroid refractory patients, those requiring high maintenance doses and unfavorable candidates for surgery. Promising therapeutic modifications with this monoclonal antibody are emerging including drug combinations, lower doses, and long-term use. Primary cold agglutinin disease has been recognized as having a lymphoproliferative monoclonal origin. It is unresponsive to both steroids and splenectomy. Rituximab is currently the best therapeutic alternative for this condition, and several treatment regimens are available with variable responses. PMID:23689532
Jaime-Pérez, José Carlos; Rodríguez-Martínez, Marisol; Gómez-de-León, Andrés; Tarín-Arzaga, Luz; Gómez-Almaguer, David
Sera from 300 Italian patients with Addison's disease were collected over a 30 year period. Among these patients, 82% had autoimmune disease, 13% had tuberculosis and 5% had another causal condition. In 59% of the cases, autoimmune disease was associated with the autoimmune manifestations contributing to the description of polyglandular autoimmune disease (PGAD). In PGAD type 1, the disease was associated with chronic candidiasis and/or chronic hypoparathyroidism. In PGAD type 2, the patients had autoimmune thyroid disease and/or diabetes mellitus type 1, and in PGAD type 4, they presented a combination with other autoimmune diseases excluding those previously mentioned. Finally, the autoimmune disease was apparently isolated in 41% of the cases. In addition, patients with these four forms of disease exhibited a different genetic pattern, sex distribution, and age at presentation in addition to minor frequency of autoimmune diseases. Adrenal cortex autoantibodies directed against 21-hydroxylase were common serological markers for these four main clinical forms, showing a very high frequency at clinical onset of adrenal insufficiency. In some patients, steroid-producing cell autoantibodies were also present and correlated with gonadal failure and they recognize of 17alpha-hydroxylase or P450 side chain cleavage enzymes as target antigens. PMID:11353894
Betterle, C; Dalpra, C; Greggio, N; Volpato, M; Zanchetta, R
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,
Autism spectrum disorder (ASD) is a spectrum of behavioral anomalies characterized by impaired social interaction and communication, often accompanied by repetitive and stereotyped behavior. The condition manifests within the first 3 years of life and persists into adulthood. There are numerous hypotheses regarding the etiology and pathology of ASD, including a suggested role for immune dysfunction. However, to date, the
Paul Ashwood; Judy Van de Water
Hematopoietic stem cell transplantation (HSCT) is becoming an increasingly recognized indication for treatment of autoimmune diseases and severe immune-mediated disorders. However, multicenter registry data have demonstrated higher than anticipated early toxicity, approximately 10% for autoimmune diseases in general, and 20–27% for diffuse systemic sclerosis (scleroderma). If uncorrected, this high treatment-related mortality will hinder development of stem cell therapy for immune-mediated
R K Burt; K Kallunian; D Patel; J Thomas; A Yeager; A Traynor; F Heipe; R Arnold; A Marmont; D Collier; E Glatstein; J Snowden
Primary sclerosing cholangitis (PSC) is an enigmatic disorder with a suggested autoimmune basis. A variety of autoantigens have been suggested but no specific or highly directed epitope has been identified. To address this issue, we constructed a cDNA library from normal human choledochus and screened expressing clones with serum from a patient with PSC and inflammatory bowel disease (IBD). Based
Brita Ardesjö; Caisa M. Hansson; Carl E. G. Bruder; Fredrik Rorsman; Corrado Betterle; Jan P. Dumanski; Olle Kämpe; Olov Ekwall
Tumor necrosis factor (TNF) antagonists are effective treatments for immune-mediated inflammatory disorders. The most dreaded adverse events associated with these agents are severe infections. Occasionally, patients develop autoimmune-like syndromes (AILS), which include episodes of lupus-like syndrome, multiple-sclerosis-like demyelination and inflammatory neuropathies. The underlying pathologic mechanisms of these syndromes remain, however, matters of debate. Evidence indicates that the onset of systemic
Joerg C. Prinz
Amphiphysin, a synaptic vesicle protein, is an auto-immune target in rare cases of paraneoplastic neurological disorders. We report two additional cases with distinct neurological syndromes and paraneoplastic anti-amphiphysin antibodies. The first patient, a 59-year-old man, presented with cerebellar and cranial nerve dysfunction and small cell lung carcinoma. The second, a 77-year- old woman, presented with left brachial plexopathy followed by sensorimotor neuropathy and breast carcinoma. PMID:16567945
Coppens, T; Van den Bergh, P; Duprez, T J; Jeanjean, A; De Ridder, F; Sindic, C J M
Amphiphysin, a synaptic vesicle protein, is an auto-immune target in rare cases of paraneoplastic neurological disorders. We report two additional cases with distinct neurological syndromes and paraneoplastic anti-amphiphysin antibodies. The first patient, a 59-year-old man, presented with cerebellar and cranial nerve dysfunction and small cell lung carcinoma. The second, a 77-year- old woman, presented with left brachial plexopathy followed by
T. Coppens; P. Van den Bergh; T. J. Duprez; A. Jeanjean; F. De Ridder; C. J. M. Sindic
Previous investigations have suggested that Sydenham's chorea (SC) may be an autoantibody mediated disorder. We examined this autoimmune hypothesis by measuring Th1 (IFN-?, IL-12) and Th2 (IL-4, IL-10) cytokines, oligoclonal bands (OCB) and anti-basal ganglia antibodies (ABGA). CSF IL-4 was elevated in 31% of acute SC and 50% of persistent SC. CSF IL-10 was also elevated in 31% of acute
Andrew J Church; Russell C Dale; Francisco Cardoso; Paul M Candler; Miles D Chapman; Meredith L Allen; Nigel J Klein; Andrew J Lees; Gavin Giovannoni
Experimental autoimmune myocarditis (EAM) in rats is a T-cell-mediated disorder and has been shown to involve immune imbalance. The aim of this study was to examine the immunomodulatory effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, atorvastatin, on the expression of MHC class II molecules in the myocardium of rats with EAM, and to examine its therapeutic potential for EAM. EAM
Wei-Min Li; Wei Liu; Cheng Gao; Bao-Guo Zhou
We describe a case of autoimmune hemolytic anemia (AIHA) due to anti-N in a young male patient with cellulitis. There have been several reports of anti-N in N positive individuals. But in all these reports, auto anti-N was mostly associated with underlying immunological conditions. We report here a case of auto anti-N in a patient of bacterial sepsis without any underlying immune disorder. PMID:22985536
Singh, Lakhvinder; Malhotra, Sheetal; Kaur, Gagandeep; Basu, Sabita; Kaur, Ravneet
Primary immunodeficiency diseases (PIDs) are a heterogeneous group of disorders that genetically affect distinct components of the immune system; thus, predispose individuals to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (ADs), which developed during the course of PID in children, were discussed.Twenty-five patients were included in this study. Symptoms related to ADs, such as autoimmune thyroiditis, type 1 diabetes mellitus, coeliac disease, juvenile idiopathic arthritis, dermatomyositis, autoimmune haemolytic anaemia, leukocytoclastic vasculitis, Henoch-Schonlein purpura, hypoparathyroidism, alopecia areata, Addison's disease, vitiligo and systemic lupus erythematosus were detected in these patients, who have been followed with diagnosis of PID including common variable immunodeficiency, selective and partial IgA deficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, hyperimmunoglobulin E syndrome, chronic mucocutaneous candidiasis, Griscelli syndrome, and partial C4 deficiency.Immunodeficiency and autoimmune phenomenon may concomitantly present in an individual, although they seem to be incompatible ends in the spectrum of the clinical immune response. Patients with primary immune deficiency should be closely monitored for development of autoimmune diseases. PMID:22982638
Patiroglu, Turkan; Gungor, Hatice Eke; Unal, Ekrem
Unlike type 2 diabetes which is caused by the loss of insulin sensitivity, type 1 diabetes (T1D) is manifested by the absolute deficiency of insulin secretion due to the loss of ? mass by autoimmune response against ?-cell self-antigens. Although significant advancement has been made in understanding the pathoetiology for type 1 diabetes, the exact mechanisms underlying autoimmune-mediated ?-cell destruction, however, are yet to be fully addressed. Accumulated evidence demonstrates that endoplasmic reticulum (ER) stress plays an essential role in autoimmune-mediated ?-cell destruction. There is also evidence supporting that ER stress regulates the functionality of immune cells relevant to autoimmune progression during T1D development. In this paper, we intend to address the role of ER stress in autoimmune-mediated ?-cell destruction during the course of type 1 diabetes. The potential implication of ER stress in modulating autoimmune response will be also discussed. We will further dissect the possible pathways implicated in the induction of ER stress and summarize the potential mechanisms underlying ER stress for mediation of ?-cell destruction. A better understanding of the role for ER stress in T1D pathoetiology would have great potential aimed at developing effective therapeutic approaches for the prevention/intervention of this devastating disorder.
Zhong, Jixin; Rao, Xiaoquan; Xu, Jun-Fa; Yang, Ping; Wang, Cong-Yi
The thymus is a specialized organ that provides an inductive environment for the development of T cells from multipotent hematopoietic progenitors. Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Tolerance represents a state of immunologic nonresponsiveness in the presence of a particular antigen. The immune system becomes tolerant to self-antigens through the two main processes, central and peripheral tolerance. Central tolerance takes place within the thymus and represents the mechanism by which T cells binding with high avidity self-antigens, which are potentially autoreactive, are eliminated through so-called negative selection. This process is mostly mediated by medullary thymic epithelia cells (mTECs) and medullary dendritic cells (DCs). A remarkable event in the process is the expression of tissue-specific antigens (TSA) by mTECs driven by the transcription factor autoimmune regulator (AIRE). Mutations in this gene result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a rare autosomal recessive disease (OMIM 240300). Thus far, this syndrome is the paradigm of a genetically determined failure of central tolerance and autoimmunty. Patients with APECED have a variable pattern of autoimmune reactions, involving different endocrine and nonendocrine organs. However, although APECED is a monogenic disorder, it is characterized by a wide variability of the clinical expression, thus implying a further role for disease-modifying genes and environmental factors in the pathogenesis. Studies on this polyreactive autoimmune syndrome contributed enormously to unraveling several issues of the molecular basis of autoimmunity. This review focuses on the developmental, functional, and molecular events governing central tolerance and on the clinical implication of its failure. PMID:23083345
Capalbo, Donatella; Giardino, Giuliana; Martino, Lucia De; Palamaro, Loredana; Romano, Rosa; Gallo, Vera; Cirillo, Emilia; Salerno, Mariacarolina; Pignata, Claudio
Introduction The emergence of hepatic injury in patients with human immunodeficiency virus infection during highly active therapy presents a diagnostic dilemma. It may represent treatment side effects or autoimmune disorders, such as autoimmune hepatitis, emerging during immune restoration. Case presentation We present the case of a 42-year-old African-American woman with human immunodeficiency virus infection who presented to our emergency department with severe abdominal pain and was found to have autoimmune hepatitis. A review of the literature revealed 12 reported cases of autoimmune hepatitis in adults with human immunodeficiency virus infection, only three of whom were diagnosed after highly active anti-retroviral treatment was initiated. All four cases (including our patient) were women, and one had a history of other autoimmune disorders. In our patient (the one patient case we are reporting), a liver biopsy revealed interface hepatitis, necrosis with lymphocytes and plasma cell infiltrates and variable degrees of fibrosis. All four cases required treatment with corticosteroids and/or other immune modulating agents and responded well. Conclusion Our review suggests that autoimmune hepatitis is a rare disorder which usually develops in women about six to eight months after commencing highly active anti-retroviral treatment during the recovery of CD4 lymphocytes. It represents either re-emergence of a pre-existing condition that was unrecognized or a de novo manifestation during immune reconstitution.
Autoimmune disease affects a significant proportion of the population. The etiology of most autoimmune diseases is largely unknown, but it is thought to be multifactorial with both environmental and genetic influences. Rare monogenic autoimmune diseases, however, offer an invaluable window into potential disease mechanisms. In this review, we will discuss the autoimmune polyglandular syndrome (APS1), the immunedysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), and autoimmune lymphoproliferative syndrome (ALPS). Significantly, the information gained from the study of these diseases has provided new insights into more common autoimmune disease and have yielded new diagnostics and therapeutic opportunities.
Waterfield, Michael; Anderson, Mark S.
Recent evidence suggests that systemic autoimmunity and immunodeficiency are not separate entities, but rather interconnected processes. Immunodeficiency results from distinct defects of the immune response and primarily presents as infections, but also frequently with autoimmune features. Systemic autoimmunity is the combined effect of multiple genetic variations, infectious and immunoregulatory factors that result in dominant autoimmune manifestations in addition to frequent and opportunistic infections. The overlap in disease manifestations and symptoms suggests that immunodeficiency should be considered in the presence of autoimmunity, and vice versa. In this review, we present the shared or similar aspects of immunodeficiency and autoimmunity using systemic lupus erythematosus as a paradigm and discuss the implications for clinical care.
Grammatikos, Alexandros P.; Tsokos, George C.
Although the clinic picture is often indicative of muscle manifestations in patients with hypothyroidism, signs and symptoms of this condition are variable from simple elevation of serum muscle enzymes with myalgia, muscle weakness, cramps to rhabdomyolysis with acute renal failure which remains a rare event. Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Hypothyroidism is associated with significant effects on the kidney which the pathophysiology seems to be multifactorial, but the exact mechanisms remain poorly understood. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. The main objective of our observation is to report a case of acute renal failure revealing an autoimmune hypothyroidism in which thyroid hormone substitution led to a significant improvement in muscular, thyroid and renal disorders. PMID:20185381
Montasser, Dina Ibrahim; Hassani, Mohamed; Zajjari, Yassir; Bahadi, Abdelali; Alayoud, Ahmed; Hamzi, Amine; Hassani, Kawtar; Moujoud, Omar; Asseraji, Mohamed; Kadiri, Moncif; Aatif, Taoufik; El Kabbaj, Driss; Benyahia, Mohamed; Allam, Mustapha; Akhmouch, Ismail; Oualim, Zouhir
Splenic atrophy is an uncommon diagnosis associated with celiac sprue or other well-characterized connective tissue diseases, drepanocytosis, or amyloidosis. We report two patients with splenic atrophy revealed by thrombocytosis. Both patients had anti-nuclear antibodies. Patient 1 also had a grade III Chisholm lymphocytic sialadenitis with a rheumatoid factor, anti-extractable nuclear antibodies, and a polyclonal hypergammaglobulinemia consistent with the diagnosis of Sjögren's syndrome. Patient 2 displayed a previous history of idiopathic pericarditis. An anti-pneumococcal vaccination was given to both patients and neither experienced infectious complications. Splenic atrophy should be suspected in patients with thrombocytosis of unexplained origin and a blood smear consistent with asplenia. Such patients must be checked for clinical and biological symptoms of autoimmune disorders. PMID:17142180
Coppo, P; Saadoun, D; Varet, B
Direct antiglobulin test (DAT) with only complement detected on red blood cells is a rare laboratory finding, and its significance in the setting of warm autoimmune hemolytic anemia (AIHA) is controversial. During 2 years (2003-2004) 277 patients with positive DAT were recorded in the blood bank registries, 17 of them had DAT reactive with C3 alone with no cold agglutinin or other nonimmune causes for hemolysis diagnosed. Red cell eluate disclosed small amounts of IgG in two patients. In nine patients no signs of clinical hemolysis were found, however, all these patients had underlying conditions that are known to be associated with red cells autoantibodies (autoimmune disorder or malignancy). Eight patients developed AIHA, seven of them with severe hemolysis. Three patients had idiopathic AIHA, and the others have been diagnosed with infectious, lymphoproliferative and autoimmune disorders. In two patients with acute infection the hemolytic process spontaneously resolved, three responded to corticosteroid therapy, while three patients were refractory to two lines of drug therapy and underwent splenectomy. Reticulocytopenia was found in four patients. Our results emphasize that AIHA with DAT reactive with complement alone is a rare disorder and might be accompanied by severe, refractory to conventional treatment and life-threatening hemolysis. PMID:18983301
Shvidel, L; Shtalrid, M; Duek, A; Haran, M; Berrebi, A; Sigler, E
Autoimmune cytopenias are a recognized complication of hematopoietic stem cell transplant (HSCT), and are considered to be a feature of chronic graft-versus-host disease (cGVHD). We report on a cohort of very young infants (?3 months of age) receiving HSCT from unrelated donor umbilical cord blood for genetic disorders who developed posttransplant autoimmune cytopenias at an increased rate compared to older aged controls. These infants received a conditioning regimen consisting of busulfan, cyclophosphamide, and antithymocyte globulin (ATG). All infants received HLA mismatched unrelated umbilical cord blood as graft source. GVHD prophylaxis was either cyclosporine + methylprednisolone (n = 16) or cyclosporine + mycophenolate mofetil (n =3). Engraftment, acute GVHD (aGVHD) and cGVHD, survival, treatment-related mortality (TRM), and deaths were evaluated. Ten patients developed cGVHD manifesting as autoimmune cytopenias at a median 247 days posttransplant with a cumulative incidence of 44% (95% confidence interval [CI] 21%–68%) and 56% (95% CI 32%–80%) at 1 and 2 years, respectively. In 6 of 10 patients developing autoimmune cytopenias, cGVHD presented as autoimmune cytopenia de novo. The cytopenias observed included anemia (n =4), thrombocytopenia (n =1), anemia with thrombocytopenia (n =3), and pancytopenia (n =2). No graft factors were identified as being significant to development of cGVHD. All patients responded to treatment with methylprednisolone, azithioprine ± rituximab. One patient required splenectomy. We hypothesize that posttransplant immunosuppression interferes with normal immune ontogeny creating immune dysregulation and graft directed cell destruction. Alternative strategies to prevent GVHD should be considered for this unique patient population.
Page, Kristin M.; Mendizabal, Adam M.; Prasad, Vinod K.; Martin, Paul L.; Parikh, Suhag; Wood, Susan; Sempowski, Gregory D.; Szabolcs, Paul; Kurtzberg, Joanne
We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders (AIDs) in 48 chronic lymphocytic leukemia (CLL) patients. Overall, 81% of patients were relapsing for AID after previous treatment with corticosteroids, splenectomy, rituximab or alemtuzumab. Diagnosis of AID was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenia (AITP) in 9 (18.8%), Evan's syndrome in 8 (16.7%) and pure red cell aplasia (PRCA) in 5 patients (10.5%). Median time of autoimmune disorder (AID) onset from CLL diagnosis was 60 months (range: 0-240), and CLL was considered progressive in 40% of subjects upon AID diagnosis (complex AID). Median hemoglobin pre-treatment was 7.7?g/100?ml, and median platelet count 36.5 × 10(9)/l, returning to a median of 12.5?/100ml and 37.5 × 10(9)/l, respectively. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). Median duration of response for autoimmunity (DR-AI) was 24 months, but DR-AI was higher for patients presenting: (1) AID early during CLL course (<3 years), or (2) both PRCA and AIHA. Median time to CLL progression in 48 patients was 16 months, but this time was statistically shorter for Evan's syndrome and AITP patients as compared with AIHA and PRCA patients. This study emphasizes the relevance of CLL-directed immune chemotherapy in the management of CLL-associated AID. PMID:21127498
Rossignol, J; Michallet, A-S; Oberic, L; Picard, M; Garon, A; Willekens, C; Dulery, R; Leleu, X; Cazin, B; Ysebaert, L