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Therapy of Autoimmune Connective Tissue Diseases  

Microsoft Academic Search

\\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


Skin manifestations of systemic autoimmune connective tissue disease: diagnostics and therapeutics.  


Skin disease can significantly affect the quality of life of patients suffering from rheumatic diseases. In addition, important relationships exist between the cutaneous and systemic manifestations of rheumatic disease. It is thus important for practicing rheumatologists to have a solid working understanding of the subject of rheumatic skin disease. Unfortunately, it is not possible within the scope of this chapter to provide a comprehensive overview of the recognition and management of all of the cutaneous manifestations of lupus erythematosus (LE), much less those of dermatomyositis (DM)/polymyositis and scleroderma/systemic sclerosis (SSc) as well. As can be seen in in the text, the cutaneous manifestations of polygenic autoimmune disorders such as LE can be as heterogeneous clinically as are its systemic manifestations. This discussion will therefore focus on recent key developments concerning the diagnosis and management of the more common skin changes that the practicing rheumatologist is likely to encountered in the three major rheumatic diseases: LE, DM and SSc. PMID:15158749

Sontheimer, Richard D



Autoantibodies to type II collagen: occurrence in rheumatoid arthritis, other arthritides, autoimmune connective tissue diseases, and chronic inflammatory syndromes.  

PubMed Central

Serum IgG antibodies to native and denatured human type II collagen (Col II) were measured using an enzyme linked immunosorbent assay (ELISA). One hundred and thirty one patients with various forms of arthritis such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PSA). Reiter's Syndrome (RS), osteoarthritis (OA), and gout, 60 with autoimmune connective tissue disease, and 37 with the chronic inflammatory conditions--graft versus host disease and leprosy--were studied. With the exception of RS, PSA, OA, and gout, significant levels of Col II antibodies were detected in each disease group. Blocking studies with types I and II collagen on selected serum samples confirmed the specificity to native Col II, though some cross reactivity was apparent with denatured collagen. The patients with RA who were Col II antibody positive tended to fall into stage III of disease progression. There was, however, no correlation with rheumatoid factor, erythrocyte sedimentation rate, or disease duration and this, together with the finding that Col II antibodies are present in a wide array of diseases, makes their role in the pathogenesis of RA questionable. They may arise as a secondary disease perpetuating mechanism in some patients, or in turn may be an epiphenomenon secondary to generalised disturbed immunoregulation or B cell hyperreactivity, or both, that characterises these clinical conditions.

Choi, E K; Gatenby, P A; McGill, N W; Bateman, J F; Cole, W G; York, J R



Tissue transglutaminase: apoptosis versus autoimmunity  

Microsoft Academic Search

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



Undifferentiated Connective Tissue Disease  


... vessels. Examples of connective tissue diseases include lupus , scleroderma , rheumatoid arthritis , Sjögren's syndrome , myositis , and vasculitis . There ... connective tissue diseases, such as lupus, Sjögren's or scleroderma. More UCTD Information Overview Causes Symptoms Diagnosis Treatment ...


351 Prevalence of Thyroid Peroxidase Autoantibodies (ANTI-TPO) in Women with Autoimmune Connective Tissue Diseases (ACTD)  

PubMed Central

Background Chronic autoimmune thyroiditis, manifested by positive test for antithyroid antibodies, is common in the general population, occurring in 10 to 20 percent of women. The aim of the study was to determine whether Anti-TPO is more prevalent in women with ACTD, compared to the general population. Methods Anti-TPO was determined in 290 women diagnosed with ACTD based on ACR (American College of Rheumatology) criteria and in 50 healthy women (control group). Among ACTD patients, 121 were diagnosed with Rheumatoid Arthritis (RA), 44 Systemic Lupus Erythematosus (SLE), 43 Sj?gren's Syndrome (SS), 42 Systemic Scleroderma (SScl) and 40 Psoriatic Arthritis (PsA). Anti-TPO was measured by Chemiluminescent Microparticle Immunoassay (CMIA) on Architect i2000SR (ABBOT Laboratories). Results The prevalence of Anti-TPO in separate groups of patients had as follow: RA 28.93%, SLE 29.55%, SS 27.91%, SScl 23.81%, PsA 30% and control group 12%. Conclusions ACTD and thyroid autoimmune diseases often overlap with each other. Increased Anti-TPO may be most common among women patients with ACTD. On the other hand, these systemic diseases are often present in Hasimoto's thyroiditis subjects. Therefore it is clinically important to screen women patients with ACTD for the co-existence of thyroid disorders.

Papadopoulos, Georgios; Vakaloudi, Anastasia; Koutsika, Eirene; Anastasiou, Ekarerini; Koteli, Asimoula



Immunoadsorption for connective tissue disease.  


Distinct connective tissue diseases (CTD's) such as systemic lupus erythematosus (SLE), systemic sclerosis, mixed connective tissue disease as well as dermato- and polymyositis comprise a group of diseases, where autoantibodies are not merely indicators of autoimmune disease, but also play an relevant role in the underlying pathogenicity. This knowledge led to the development of antibody targeting therapies using rituximab or belimumab. Upon this, therapeutic plasma exchange, and more recently immunoadsorption (IAS) have been successfully applied to remove pathogenic autoantibodies under various conditions in some of these CTD's. While the technique of IAS is superior to plasma exchange in regard to specificity and efficacy, the clinical use of IAS in CTD's is currently restricted to a small proportion of clinical situations with either refractory disease or the necessity to avoid aggressive immunosuppressive regimens. Despite the presence of a large number of case series and few controlled trials using IAS, there is a need for further prospective randomized trials to clearly define the role of IAS in these CTD's. PMID:23357163

Hohenstein, B; Bornstein, S R; Aringer, M



Connections between antiviral defense and autoimmunity  

PubMed Central

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.



Connective tissue tumors.  


Connective tissue consists of collagen, elastic fibers and ground substances produced by fibrocytes. These cells are usually spindle-shaped with slender nuclei and bipolar cytoplasmic extensions. Apart from labeling for vimentin and variable reactivity for factor XIIIa and CD34, fibrocytes are immunonegative. Electron microscopy reveals prominent endoplasmic reticulum, but is otherwise indistinct. Lesions with fibrocytic differentiation can be divided into five categories: scars, keloids, dermatofibromas, nodular fasciitis, and superficial fibromatoses are inflammatory lesions. Thereby, dermatofibromas and their subcutaneous/deep soft tissue counterpart nodular fasciitis can present with a wide variety of clinicopathologic variants which may be misinterpreted as malignancies. Prurigo nodularis, chondrodermatitis nodularis helicis, acanthoma fissuratum, and knuckle pads are hyperplasias; fibroma molle, fibrous papules, connective tissue nevi, and elastofibroma are hamartomas; and fibroma of tendon sheath, pleomorphic fibroma, and giant cell tumor of tendon sheath are benign neoplasms. Deep fibromatoses, dermatofibrosarcoma protuberans, giant cell fibroblastoma, giant cell angiofibroma, hyalinizing spindle cell tumor with giant rosettes, solitary fibrous tumor, myxofibrosarcoma, low-grade fibromyxoid sarcoma, acral myxoinflammatory fibroblastic sarcoma, and classical fibrosarcoma, are malignant neoplasms, that is fibrosarcomas of variable malignant potential. Lesions dominated by myocytes/ myofibroblasts, e.g. cutaneous myofibroma/infantile myofibromatosis, or by macrophages, e.g. xanthogranulomas, are not part of this chapter. PMID:12079232

Zelger, Bernhard



Bone and Connective Tissue Tumors  


... Tumor (ATRT) Bone and Connective Tissue Brain Cysts Choroid Plexus Craniopharyngioma Ependymoma Germ Cell Glioblastoma Gliomas Hemangioma ... Tumor (ATRT) Bone and Connective Tissue Brain Cysts Choroid Plexus Craniopharyngioma Ependymoma Germ Cell Glioblastoma Gliomas Hemangioma ...


Tissue antibodies in idiopathic autoimmune haemolytic anaemia  

PubMed Central

Sera from patients with idiopathic autoimmune haemolytic anaemia (AIHA) were studied, by the immunofluorescent technique, for the presence of circulating organ-specific and non-organ-specific autoantibodies. In patients with warm AIHA there was an increased incidence in the non-organ-specific autoantibodies, compared to normal controls: In 15% of sera studied there were antinuclear antibodies detectable, and in 5% antimitochondrial antibodies were present. In cold AIHA, however, the frequency of these autoantibodies was not increased. The incidence of organ-specific autoantibodies was normal in both cold and warm AIHA. No correlation was found between the occurrence of these autoantibodies and pattern of serum immunoglobulin concentration, specific serological feature, or clinical manifestation. The significance of the increased incidence of tissue autoantibodies and their relation to autoimmune haemolytic anaemia remains to be elucidated, but in some way may be due to increased immunological reactivity.

Blajchman, M. A.



Liver abnormalities in connective tissue diseases.  


The liver is a lymphoid organ involved in the immune response and in the maintenance of tolerance to self molecules, but it is also a target of autoimmune reactions, as observed in primary liver autoimmune diseases (AILD) such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Further, the liver is frequently involved in connective tissue diseases (CTD), most commonly in the form of liver function test biochemical changes with predominant cholestatic or hepatocellular patterns. CTD commonly affecting the liver include systemic lupus erythematosus, antiphospholypid syndrome, primary Sjögren's syndrome, systemic sclerosis, dermatomyositis, polimyositis, and anti-synthetase syndrome, while overlap syndromes between AILD and CTD may also be diagnosed. Although liver cirrhosis and failure are extremely rare in patients with CTD, unusual liver conditions such as nodular regenerative hyperplasia or Budd-Chiari syndrome have been reported with increasing frequency in patients with CTD. Acute or progressing liver involvement is generally related to viral hepatitis reactivation or to a concomitant AILD, so it appears to be fundamental to screen patients for HBV and HCV infection, in order to provide the ideal therapeutic regimen and avoid life-threatening reactivations. Finally, it is important to remember that the main cause of biochemical liver abnormalities in patients with CTD is a drug-induced alteration or coexisting viral hepatitis. The present article will provide a general overview of the liver involvement in CTD to allow rheumatologists to discriminate the most common clinical scenarios. PMID:24090941

De Santis, Maria; Crotti, Chiara; Selmi, Carlo



Associated Pulmonary Arterial Hypertension in Connective Tissue Diseases  

PubMed Central

ABSTRACT In recent years, major advances have been achieved in the understanding of pulmonary arterial hypertension (PAH) patho-physiology. Associated pulmonary arterial hypertension (APAH) can occur in a variety of other conditions and circumstances including a number of systemic autoimmune diseases. As with PAH in general, clinical symptoms of APAH in systemic autoimmune diseases are unspecific. In addition, there is a long standing association between autoimmunity and APAH. It has been postulated that autoimmunity may play a role in the pathogenesis of APAH. This argument has been based on frequent coexisting clinical and serological rheumatic findings. There is no experimental model of immune mechanism-dependent severe APAH. The loss of self-tolerance could initiate a process which ultimately results in APAH. It is possible that T-cell deficiencies (in either function or number) may contribute to pulmonary vascular injury or disease. These conditions are often associated with autoantibodies as well as defects in the CD4 T-cell compartiment. However, it remains uncertain how autoimmune mechanisms contribute to the pathogenesis of APAH. There are data that show a significant association between APAH and connective tissue diseases (CTD). In this regard, systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, dermato/polymyositis and primary Sjögren's syndrome are associated with APAH. The study of APAH in the systemic autoimmune diseases and its relation to basic immunologic disturbances may yet bring effective therapies in the future. APAH can be a severe complication attracting a high excess mortality in autoimmune diseases. The present review will focus on what is known about autoimmune phenomena in APAH patients.

COJOCARU, Manole; COJOCARU, Inimioara Mihaela; SILOSI, Isabela; VRABIE, Camelia Doina



Contractile connective tissue in crinoids.  


Active movements in animals are usually attributed to cellular protein engines, e.g., the actin-myosin system of muscle cells. Here we report the first evidence of an extracellular contractile connective tissue, which we have found in sea lilies and feather stars (Echinodermata, Crinoida). These marine animals have arm muscles that are antagonized, not by other muscles, but by ligaments consisting of extracellular fibrils interspersed with neuron-like cell processes. Contractile cells are lacking, yet these arm ligaments actively contracted upon stimulation. The ligaments stayed in a contracted condition even after the stimulus had stopped. The stresses generated were lower than those of typical skeletal muscles. Additional data from crinoid cirri, which lack muscles entirely, corroborate the hypothesis that the connective tissue of the ligaments is contractile. PMID:8776839

Birenheide, R; Motokawa, T



[Connective tissue and prolapse genesis].  


The pathophysiology of pelvic floor disorders still remains not well understood. Increasing age as well as vaginal multiparity are the main commonly accepted factors. The hypothesis of a defect of connective tissues of the pelvic floor with aging due to collagen deficiency and/or elastic fiber degradation is often highlighted. The issue of a potential protective role of HRT is also discussed although the recent results from the WHI would suggest a negative impact of HRT on urinary incontinence, especially when HRT is initiated in elderly women, far from the menopause. Nevertheless, environmental factors cannot explain the full pathogenesis of pelvic organ prolapse (POP) and the contribution of genetic factors to the development of pelvic floor disorders is widely recognized. Support for a genetic influence on POP derives from reports suggesting that heritability is a strong contributing factor and a familial history of POP is considered as a classical risk factor. However, the characterization of the underlying molecular mechanisms remains limited, since POP may be considered the end result of a multifactorial process leading to destruction of vaginal wall connective tissue. Experimental studies in mice with null mutations in the genes encoding different putative factors involved in elastic fibers remodeling and homeostasis are crucial in the understanding of the pathogenesis of POP. Mice with null mutation in the gene encoding lysyl oxidase-like 1 (LOXL1) or fibulin-5, demonstrate signs of elastinopathy including the development of a POP in the postpartum. Likewise, homeobox genes such as HOXA11, which are essential in the embryonic development of the urogenital tract might also be involved in the pathogenesis of POP. The better understanding of the underlying determinants of pelvic floor disorders with a special focus on genetic factors may offer new therapeutic strategies, in addition to or replacement of surgical procedures. PMID:20576547

Tremollieres, F



Homocysteine toxicity in connective tissue: theories, old and new.  


Hyperhomocysteinemia causes connective tissue pathology. Several theories on the mechanism of homocysteine toxicity in connective tissue are reviewed briefly. A possible new mechanism was revealed recently in the discovery of a reaction in which homocysteine thiolactone is converted to mercaptopropionaldehyde. The reaction is the Strecker degradation of amino acids in which ninhydrin is replaced by the structurally similar dehydroascorbic acid. The reaction may occur in vivo and may be pathogenic to connective tissue in four ways: (1) the reaction may deplete ascorbic acid that is required for collagen synthesis, (2) the mercaptoaldehyde product may interfere with collagen synthesis, (3) the mercaptoaldehyde may cause abnormal cross-linking of collagen molecules, and (4) the mercaptoaldehyde may attach to collagen molecules rendering them antigenic and triggering an autoimmune response. PMID:18382890

Toohey, John I



Pulmonary hypertension associated with connective tissue disease  

Microsoft Academic Search

Pulmonary arterial hypertension is a life threatening complication of several connective tissue diseases including scleroderma (both diffuse and limited scleroderma, or the CREST syndrome—calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangectasia), systemic lupus erythomatosis (SLE), mixed connective tissue disease (MCTD), and less commonly, rheumatoid arthritis (RA) and dermatomyositis\\/polymyositis. This report reviews the occurrence of this complication, potential etiologies, clinical

Karen A. Fagan; David B. Badesch



Four Easy Pieces Interconnections between Tissue Injury, Intermediary Metabolism, Autoimmunity, and Chronic Degeneration  

Microsoft Academic Search

Four questions are posed: (1) Can tissue damage itself provoke autoimmunity? (2)Cangenetic mutationsofkeystructuresproduce tissue pathology and thus provoke autoimmunity? (3) Can acute immune damage produce tissue degeneration without further hall- marks of an immune response? (4) Can intermediary metabolism modulate immune damage to tissues? Four answers are given: (1) Tissue injuryitself mayleadtoautoimmunity. Bothinnateandadap- tive immunity may arise as a response

Lawrence Steinman


Cellular control of connective tissue matrix tension.  


The biomechanical behavior of connective tissue in response to stretching is generally attributed to the molecular composition and organization of its extracellular matrix. It also is becoming apparent that fibroblasts play an active role in regulating connective tissue tension. In response to static stretching of the tissue, fibroblasts expand within minutes by actively remodeling their cytoskeleton. This dynamic change in fibroblast shape contributes to the drop in tissue tension that occurs during viscoelastic relaxation. We propose that this response of fibroblasts plays a role in regulating extracellular fluid flow into the tissue, and protects against swelling when the matrix is stretched. This article reviews the evidence supporting possible mechanisms underlying this response including autocrine purinergic signaling. We also discuss fibroblast regulation of connective tissue tension with respect to lymphatic flow, immune function, and cancer. PMID:23444198

Langevin, Helene M; Nedergaard, Maiken; Howe, Alan K



Potassium Channel Complex Autoimmunity Induced by Inhaled Brain Tissue Aerosol  

PubMed Central

Objective Test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory-predominant polyradiculoneuropathy among swine abattoir employees in Midwestern USA Methods Mice were exposed intranasally, 5 days weekly, to liquefied brain tissue. Serum from exposed mice, patients and unaffected abattoir employees were analyzed for clinically pertinent neural autoantibodies. Results Patients, coworkers and mice exposed to liquefied brain tissue had an autoantibody profile dominated by neural cation channel IgGs. The most compelling link between patients and exposed mice was MRI evidence of grossly swollen spinal nerve roots. Autoantibody responses in patients and mice were dose-dependent and declined after antigen exposure ceased. Autoantibodies detected most frequently, and at high levels, bound to detergent-solubilized macromolecular complexes containing neuronal voltage-gated potassium channels ligated with a high affinity Kv1 channel antagonist, 125I-?-dendrotoxin. Exposed mice exhibited a behavioral phenotype consistent with potassium channel dysfunction recognized in drosophila with mutant (“shaker”) channels: reduced sensitivity to isoflurane-induced anesthesia. Pathological and electrophysiological findings in patients supported peripheral nerve hyperexcitability over destructive axonal loss. The pain-predominant symptoms were consistent with sensory nerve hyperexcitability Interpretation Our observations establish that inhaled neural antigens readily induce neurological autoimmunity and identify voltage-gated potassium channel complexes as a major immunogen.

Meeusen, Jeffrey W.; Klein, Christopher J.; Pirko, Istvan; Haselkorn, Keegan E.; Kryzer, Thomas J.; Pittock, Sean J.; Lachance, Daniel H.; Dyck, P. James; Lennon, Vanda A.



Growth hormone and connective tissue in exercise.  


Over the last few years, growth hormone (GH) has become increasingly popular as doping within different sports. However, the precise mechanisms behind the ergogenic (performance enhancing) effects of GH in athletes are still being debated. Besides a well-documented stimulatory effect of GH on carbohydrate and fatty acid metabolism, and a possible anabolic effect on myofibrillar muscle protein, we suggest a role for GH as an anabolic agent in connective tissue in human skeletal muscle and tendon. Given the importance of the connective tissue for the function of skeletal muscle and tendon, a strengthening effect of GH on connective tissue could fit with the ergogenic effect of GH experienced by athletes. This review examines the endogenous secretion of GH and its mediators in relation to exercise. Furthermore, we consider the effect of endogenous GH and administered recombinant human GH (rhGH) on both myofibrillar and connective tissue protein synthesis, thus offering an alternative explanation for the ergogenic effect of GH. Finally, we suggest a possible therapeutic role for rhGH in clinical management of the frequently suffered injuries in the connective tissue. PMID:15998337

Doessing, S; Kjaer, M



Cytomechanics in Connective Tissue Repair and Engineering  

Microsoft Academic Search

Mechanical forces are central to the control of 3D spatial organisation in connective tissue remodelling, repair and scarring.\\u000a How this operates is increasingly seen as the next major research focus in this area. In contrast to mechanics at the tissue-scale,\\u000a cell-level mechanics (or cytomechanics) is dominated by the cell-matrix-material interplay. The matrix completely modifies\\u000a incoming, external mechanical cues whilst fibroblasts

Robert A. Brown


Gastrointestinal manifestations of mixed connective tissue disease.  


We examined the gastrointestinal tract abnormalities in 61 patients with mixed connective tissue disease. The first 34 were part of a prospective longitudinal study that included manometric and radiographic evaluation of the esophagus. Heartburn (48%) and dysphagia (38%) were by far the most common gastrointestinal symptoms. Seventeen percent of patients undergoing manometry had distal esophageal aperistalsis, and 43% low-amplitude peristalsis (less than 30 mmHg). Studies in 10 patients before and after treatment suggested that esophageal dysfunction in mixed connective tissue disease may be responsive to corticosteroids. Upper esophageal sphincter hypotension was also common. One patient had marked upper esophageal sphincter hypotension and recurrent aspiration, which resolved with corticosteroid therapy. Findings on radiographic studies of the stomach and small bowel in 54 patients and barium enemas in 16 patients were reviewed. Our series included one case each of malabsorption, colonic and small bowel perforations due to vasculitis, chronic active hepatitis, and acute pancreatitis. In conclusion, any area of the gastrointestinal tract may be affected by mixed connective tissue disease, although the esophagus is the most common location. The gastrointestinal aspects of mixed connective tissue disease overlap with those of progressive systemic sclerosis, polymyositis, and systemic lupus erythematosus. PMID:2323516

Marshall, J B; Kretschmar, J M; Gerhardt, D C; Winship, D H; Winn, D; Treadwell, E L; Sharp, G C



Cutaneous Connective Tissue Diseases: Epidemiology, Diagnosis, and Treatment  

PubMed Central

Connective tissue diseases (CTDs) are a group of clinical disorders that have an underlying autoimmune pathogenesis. These include a diverse set of diseases such as relapsing polychondritis, rheumatoid arthritis, and eosinophilic fasciitis, along with more common entities like Sjogren’s syndrome, dermatomyositis, scleroderma, and lupus erythematosus. The latter three will be the focus of this review, as they constitute the most significant and common CTD with cutaneous manifestations. The cutaneous signs often represent the preliminary stages of disease and the presenting clinical symptoms. Therefore, comprehensive knowledge of CTD manifestations is essential for accurate diagnosis, better assessment of prognosis, and effective management. Although the precise etiologies of CTDs remain obscure, recent advances have allowed for further understanding of their pathogenesis and improved disease classifications. In addition, there have been developments in therapeutic options for CTDs. This review provides an overview of the epidemiology, clinical presentations, and current treatment options of cutaneous lupus erythematous, dermatomyositis and scleroderma.

Reddy, Bobby Y.; Hantash, Basil M.



Update on Management of Connective Tissue Panniculitides  

PubMed Central

In connective tissue diseases panniculitis can be the sole manifestation or occur along with the underlying disease process. The best described forms of connective tissue panniculitis are lupus erythematosus panniculitis (LEP) and lupus profundus, panniculitis associated with dermatomyositis, and morphea and scleroderma associated panniculitis. These processes cause significant morbidity, such as deep atrophic scars, cosmetic disfigurement and psychiatric sequelae. Due to the location of the inflammation in the subcutaneous adipose layer, topical therapies may not penetrate enough to be effective, and systemic agents are required. Despite the large number of reported cases and therapies, recommendations for treatment are based largely on case series and expert opinion due to a lack of controlled therapeutic trials. All treatments are off-label in the United States. The lack of validated clinical outcome measures makes systematic and controlled studies difficult. Nonetheless further investigation into the most effective therapies for these conditions are needed.

Braunstein, Inbal; Werth, Victoria P.



[Family physician and connective tissue disorders].  


The exact place of the family physician in the diagnosis and management of connective tissue disease is poorly studied moreover will essentially depend on the health system and the organization of medical network of each country. Connective tissue diseases are rare and complex diseases that require in all cases referral to specialists for their diagnosis as well as monitoring. All patients must still keep a family doctor whose importance increases more and more as our specialized treatments prolong survival of patients who become chronically ill with multi-organic sequelae. A closely interaction between the various specialists and family physicians is necessary to ensure a good long-term follow-up. PMID:23534243

Zufferey, P



Some connective tissue disorders of the lung.  

PubMed Central

Many connective tissue disorders involve the lungs. The same clinical syndrome may be associated with several distinctive types of pathology in different patients. Fibrosing alveolitis is a common feature of a number of different syndromes. An hypothesis is set out in schematic form which may help to account for some of these differences and emphasizes the potential importance of the pulmonary vasculature in pathogenesis. Images Figure 3 Figure 4 Figure 5 Figure 8 Figure 9

Turner-Warwick, M.



Identifying heritable connective tissue disorders in childhood.  


Heritable connective tissue diseases are rare. Each disorder estimated at 1-10 per 100,000. However, as a group they are prevalent enough to constitute an important diagnostic challenge. Connective tissue disorders most significantly affect three systems: musculoskeletal, ocular and cardiovascular. The cardinal feature of the majority of these disorders is ligamentous laxity, or joint hypermobility. The joints show an increased range of movement, and the child may present with arthralgias, effusions and an increased risk of joint or soft tissue injury. Marfan syndrome is the most common heritable connective tissue disorder. It is an autosomal dominant condition with high penetrance but with striking pleiomorphism. In 25% of individuals there is no family history. The diagnosis is often not made until late childhood. Individuals are tall with a low upper: lower segment ratio and an arm span greater than height. Other skeletal characteristics include pectus deformity and scoliosis. Myopia and astigmatism are common. Cardiac abnormalities include mitral valve prolapse, mitral regurgitation and arrhythmias. Early diagnosis, meticulous echocardiographic follow-up and multidisciplinary assessment are essential. The Ehlers-Danlos syndromes share a triad of features: skin hyperextensibility, articular hypermobility, and tissue fragility. The abnormalities are caused by genetic defects resulting in the faulty synthesis or structure of collagen. There is a wide variety of phenotypes and mode of inheritance. Symptom management and joint protection are important to improve quality of life and prevent secondary complications. Osteogenesis imperfecta encompasses a group of rare heritable disorders associated with low bone mass and increased susceptibility to fractures. Increased bone fractures after minimal trauma is the cardinal feature. Other features include blue sclera, hearing loss, scoliosis, deafness, and hypermobility. PMID:22916581

Armon, Kate; Bale, Peter



[B-cell-directed therapy in patients with connective tissue diseases].  


B cells are able to present antigen, secrete cytokines and differentiate into (auto)antibody secreting cells and are therefore considered as an important therapeutic target in patients with autoantibody-mediated autoimmune disease. Benefits and limitations of B-cell-directed therapies and unmet medical needs are discussed in this minireview. B cell targeting broadens our armamentarium available to treat SLE and other connective tissue diseases. But further research addressing unmet medical needs is required and refractory patients receiving B cell-directed off-label therapeutics should be enrolled in registries to collect information on the value and safety of these drugs in rare autoimmune diseases. PMID:22933200

Jacobi, A M; Dörner, T



[Eye connective tissues: cornea and vitreous body].  


The authors, ophtalmologist (Y.P.) and basic scientists (J.L.-R and L.R.), collaborated on eye-research since 1962 on normal and pathological aspects of eye tissues, considered as specialized forms of connective tissues, and on specific aspects of the physiology and pathology of the eye. This date coincides with the foundation of the French Society of Connective Tissues, which celebrates the 50th anniversary of its creation. We shall present here some of our work on the ontogenetic and phylogenetic aspects of the cornea, on its structure, function and regulation in normal and pathological states, taken from a large number of publications of our laboratories. Our work on cornea started with the study of the morphogenesis of its lamellar structure, made of collagen fibers and proteoglycans. This led us to the isolation and characterization of structural (or matrix) glycoproteins, a new class of matrix components, present also in all other connective tissues, and to the study of their biosynthesis by keratocytes. Corneal wounds and regeneration were also studied, as well as some corneal pathologies such as keratoconus. The confrontation of quantitative morphological methods with biochemical procedures were to yield important results on the mechanisms of the maintenance of corneal structure and function. Another series of studies concerned the vitreous where we detected, besides previously characterized components, such as hyaluronan and collagens, fibronectin which plays an important role in the adhesion of hyaluronan to the collagen network. Its age-dependent modifications were also studied, with a special focus on the role of reactive oxygen species (ROS)-mediated degradation of hyaluronan, especially important for the aging of the vitreous. PMID:22748052

Labat-Robert, Jacqueline; Pouliquen, Yves; Robert, Ladislas



Tissue Stretch Induces Nuclear Remodeling in Connective Tissue Fibroblasts  

PubMed Central

Studies in cultured cells have shown that nuclear shape is an important factor influencing nuclear function, and that mechanical forces applied to the cell can directly affect nuclear shape. In a previous study, we demonstrated that stretching of whole mouse subcutaneous tissue causes dynamic cytoskeletal remodeling with perinuclear redistribution of ?-actin in fibroblasts within the tissue. We have further shown that the nuclei of these fibroblasts have deep invaginations containing ?-actin. In the current study, we hypothesized that tissue stretch would cause nuclear remodeling with a reduced amount of nuclear invagination, measurable as a change in nuclear concavity. Subcutaneous areolar connective tissue samples were excised from 28 mice and randomized to either tissue stretch or no stretch for 30 minutes, then examined with histochemistry and confocal microscopy. In stretched tissue (vs. non-stretched), fibroblast nuclei had a larger cross sectional area (p<.001), smaller thickness (p<.03) in the plane of the tissue, and smaller relative concavity (p<.005) indicating an increase in nuclear convexity. The stretch-induced loss of invaginations may have important influences on gene expression, RNA trafficking and/or cell differentiation.

Langevin, Helene M.; Storch, Kirsten N.; Snapp, Robert R.; Bouffard, Nicole A.; Badger, Gary J.; Howe, Alan K.; Taatjes, Douglas J.



Effector and regulatory T cell subsets in autoimmunity and tissue inflammation  

PubMed Central

Many autoimmune diseases are driven by self-reactive T helper cells. Until recently, organ-specific autoimmune diseases were primarily associated with Th1 cells but not Th2 cells. However, the discovery of a number of new effector T cell subsets, like Th17 and Th9 cells, and regulatory T cells, like Tregs and Tr1 cells, has changed the way we view and understand autoimmunity at cellular and molecular levels. In recent years, IL-17 producing Th17 cells have emerged as major players in autoimmunity. The complicated relationship between Th1 and Th17 cells, as well as the intricate balance between Tregs and Th17 cells, provide a basis for understanding the immunological mechanisms that induce and regulate autoimmunity. Here, we give an overview of the interplay between different effector T cell subsets and regulatory T cell subsets, and how they contribute to the development of autoimmunity and tissue inflammation.

Jager, Anneli; Kuchroo, Vijay K.



Comparative Glycomics of Connective Tissue Glycosaminoglycans  

PubMed Central

Homeostasis of connective joint tissues depends on the maintenance of an extracellular matrix, consisting of an integrated assembly of collagens, glycoproteins, proteoglycans and glycosaminoglycans (GAGs). Isomeric chondroitin sulfate (CS) glycoforms differing in position and degree of sulfation and uronic acid epimerization play specific and distinct functional roles during development and disease onset. This work profiles the CS epitopes expressed by different joint tissues as a function of age and osteoarthritis. Glycosaminoglycans were extracted from joint tissues (cartilage, tendon, ligment, muscle and synovium) and partially depolymerized using chondroitinase enzymes. The oligosaccharide products were differentially stable isotope labeled by reductive amination using 2-anthranilic acid- d0 or -d4 and subjected to amide-HILIC on-line liquid chromatography-tandem mass spectrometry. The analysis presented herein enables simultaneous profiling of the expression of non-reducing end, linker region, and ?-unsaturated interior oligosaccharide domains of the CS chains among the different joint tissues. The results provide important new information on the changes to the expression of CS GAG chains during disease and development.

Hitchcock, Alicia M.; Yates, Karen E.; Costello, Catherine E.; Zaia, Joseph



Generalized Connective Tissue Disease in Crtap-/- Mouse  

PubMed Central

Mutations in CRTAP (coding for cartilage-associated protein), LEPRE1 (coding for prolyl 3-hydroxylase 1 [P3H1]) or PPIB (coding for Cyclophilin B [CYPB]) cause recessive forms of osteogenesis imperfecta and loss or decrease of type I collagen prolyl 3-hydroxylation. A comprehensive analysis of the phenotype of the Crtap-/- mice revealed multiple abnormalities of connective tissue, including in the lungs, kidneys, and skin, consistent with systemic dysregulation of collagen homeostasis within the extracellular matrix. Both Crtap-/- lung and kidney glomeruli showed increased cellular proliferation. Histologically, the lungs showed increased alveolar spacing, while the kidneys showed evidence of segmental glomerulosclerosis, with abnormal collagen deposition. The Crtap-/- skin had decreased mechanical integrity. In addition to the expected loss of proline 986 3-hydroxylation in ?1(I) and ?1(II) chains, there was also loss of 3Hyp at proline 986 in ?2(V) chains. In contrast, at two of the known 3Hyp sites in ?1(IV) chains from Crtap-/- kidneys there were normal levels of 3-hydroxylation. On a cellular level, loss of CRTAP in human OI fibroblasts led to a secondary loss of P3H1, and vice versa. These data suggest that both CRTAP and P3H1 are required to maintain a stable complex that 3-hydroxylates canonical proline sites within clade A (types I, II, and V) collagen chains. Loss of this activity leads to a multi-systemic connective tissue disease that affects bone, cartilage, lung, kidney, and skin.

Baldridge, Dustin; Lennington, Jennifer; Weis, MaryAnn; Homan, Erica P.; Jiang, Ming-Ming; Munivez, Elda; Keene, Douglas R.; Hogue, William R.; Pyott, Shawna; Byers, Peter H.; Krakow, Deborah; Cohn, Daniel H.; Eyre, David R.; Lee, Brendan; Morello, Roy



Pulmonary arterial hypertension in connective tissue diseases.  


Pulmonary arterial hypertension (PAH) is an entity that is known to complicate connective tissue diseases (CTD). PAH in CTD is a very important diagnosis which greatly affects treatment and prognosis. The most commonly affected CTD is scleroderma, although lupus, inflammatory myopathies such as poly and dermatomyositis, and mixed CTD are also associated with PAH. The manifestations of PAH have both similarities and differences when occurring in the setting of CTD as compared with idiopathic PAH. These differences are most notable in scleroderma. In this section we will discuss the features of PAH as they appear in CTDs, and in particular, scleroderma. The focus of this article is an approach to the diagnosis and treatment of PAH in CTD, and how this setting might differ from idiopathic and other forms of PAH. PMID:20160534

Goldberg, Avram


Fibroblast involvement in soft connective tissue calcification  

PubMed Central

Soft connective tissue calcification is not a passive process, but the consequence of metabolic changes of local mesenchymal cells that, depending on both genetic and environmental factors, alter the balance between pro- and anti-calcifying pathways. While the role of smooth muscle cells and pericytes in ectopic calcifications has been widely investigated, the involvement of fibroblasts is still elusive. Fibroblasts isolated from the dermis of pseudoxanthoma elasticum (PXE) patients and of patients exhibiting PXE-like clinical and histopathological findings offer an attractive model to investigate the mechanisms leading to the precipitation of mineral deposits within elastic fibers and to explore the influence of the genetic background and of the extracellular environment on fibroblast-associated calcifications, thus improving the knowledge on the role of mesenchymal cells on pathologic mineralization.

Ronchetti, Ivonne; Boraldi, Federica; Annovi, Giulia; Cianciulli, Paolo; Quaglino, Daniela



Connective tissue growth factor in tumor pathogenesis  

PubMed Central

Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood. High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors.



Connective Tissue Disorders and Smooth Muscle Disorders in Cardiology  

Microsoft Academic Search

\\u000a The hereditary disorders of connective tissue encompass a spectrum of clinically and genetically heterogeneous conditions caused by genetic defects in structural connective\\u000a tissue proteins, such as collagen, fibrillin, and elastin. Clinical manifestations of these disorders are variable, and include\\u000a musculoskeletal, skin, ocular, cardiovascular, and other visceral pathologies. Substantial overlap in clinical features between\\u000a different disorders of connective tissue is present.

K. van Engelen; B. J. M. Mulder


Expression of connective tissue growth factor in human renal fibrosis  

Microsoft Academic Search

Expression of connective tissue growth factor in human renal fibrosis. Chronic renal failure may occur in etiologically diverse renal diseases and can be caused by hemodynamic, immunologic and metabolic factors. Initial damage may evoke irreversible scarring, which involves production of a number of proinflammatory and fibrogenic cytokines, including platelet-derived growth factor (PDGF) and transforming growth factor ? (TGF-?). Connective tissue

Yasuhiko Ito; Jan Aten; Richard J. Bende; Barry S. Oemar; Ton J. Rabelink; Jan J. Weening; Roel Goldschmeding



Virus-Induced Autoimmunity: Monoclonal Antibodies that React with Endocrine Tissues  

Microsoft Academic Search

Mice infected with reovirus type 1 develop an autoimmune polyendocrine disease. Spleen cells from these mice were fused with myeloma cells and the culture fluids were screened by indirect immunofluorescence for autoantibodies reactive with normal mouse tissues. A large panel of cloned, stable antibody-producing hybridomas has been obtained. Fourteen of the hybridomas make autoantibodies that react with cells in the

Martin V. Haspel; Takashi Onodera; Bellur S. Prabhakar; Masakazu Horita; Hoshibumi Suzuki; Abner Louis Notkins



[Connective tissue diseases during pregnancy - therapeutic aspect. Part 1: SLE, antiphosholipid syndrome].  


Connective tissue diseases, defined as chronic, multi-system autoimmune dysfunctions, occur predominantly in women of childbearing age. Pregnancy, as a specific state of hormonal and immunological diversity, may involve adverse influence on maternal disease activity, causing remission or exacerbation necessitating appropriate therapy. In the first part of the article the influence of female hormones on the immunological cells is presented, as well as their role in the autoimmunological process. The special emphasis is put on most frequent connective tissue diseases among young women- systemic lupus erythematosus and antiphospholipid syndrome. The article also highlights the risk of potential obstetric complications, the gravity of careful planning, restrictive monitoring and necessary treatment to minimalize the risk of intricacy. PMID:23646451

Puta?a-Po?piech, Ma?gorzata; Robak, Ewa



Epidemiology of organic solvents and connective tissue disease  

Microsoft Academic Search

Case reports suggest that solvents are associated with various\\u0009\\u0009\\u0009 connective tissue diseases (systemic sclerosis, scleroderma, undifferentiated\\u0009\\u0009\\u0009 connective tissue disease, systemic lupus erythematosis, and rheumatoid\\u0009\\u0009\\u0009 arthritis), particularly systemic sclerosis. A small number of epidemiological\\u0009\\u0009\\u0009 studies have shown statistically significant but weak associations between\\u0009\\u0009\\u0009 solvent exposure, systemic sclerosis, and undifferentiated connective tissue\\u0009\\u0009\\u0009 disease. However, the interpretation of these positive findings is tempered

David H Garabrant; Constantine Dumas



Bioreactors for Connective Tissue Engineering: Design and Monitoring Innovations  

Microsoft Academic Search

The challenges for the tissue engineering of connective tissue lie in creating off-the-shelf tissue constructs which are capable\\u000a of providing organs for transplantation. These strategies aim to grow a complex tissue with the appropri ate mechanical integrity\\u000a necessary for functional load bearing. Monolayer culture systems lack correlation with the in vivo environment and the naturally\\u000a occur ring cell phenotypes. Part

A. J. El Haj; K. Hampson; G. Gogniat



Epidemiology of organic solvents and connective tissue disease  

PubMed Central

Case reports suggest that solvents are associated with various connective tissue diseases (systemic sclerosis, scleroderma, undifferentiated connective tissue disease, systemic lupus erythematosis, and rheumatoid arthritis), particularly systemic sclerosis. A small number of epidemiological studies have shown statistically significant but weak associations between solvent exposure, systemic sclerosis, and undifferentiated connective tissue disease. However, the interpretation of these positive findings is tempered by a lack of replication, an inability to specify which solvents convey risk, and an absence of increasing risk with increasing exposure. Existing studies, on aggregate, do not show conclusively that solvents (either as a group of chemicals or individual chemicals) are causally associated with any connective tissue disease. Further investigations should be carried out to replicate the positive existing findings and to specify the solvents and circumstances of exposure that carry risk.

Garabrant, David H; Dumas, Constantine



Unusual manifestation of histoplasmosis in connective tissue diseases.  


This report describes the coexistence of three patients with rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis) and infections because of Histoplasma capsulatum. Connective tissue diseases and histoplasmosis share several clinical findings. Therefore, histoplasmosis could be misdiagnosed as connective tissue disease or a flare of these diseases. Such cases highlight the importance of awareness of histoplasmosis in immunocompromised patients, particularly in those originating from endemic areas. PMID:17541496

Ceccato, F; Gongora, V; Zunino, A; Roverano, S; Paira, S



Fibroblast cytoskeletal remodeling contributes to connective tissue tension.  


The visco-elastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the visco-elastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast's processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the visco-elastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular, and immune cell populations residing within connective tissue. PMID:20945345

Langevin, Helene M; Bouffard, Nicole A; Fox, James R; Palmer, Bradley M; Wu, Junru; Iatridis, James C; Barnes, William D; Badger, Gary J; Howe, Alan K



Evaluation of connective tissue cell responses to orthopaedic implant materials.  


We have developed an in vitro cell culture model to examine the interaction between connective tissue cells and orthopaedic implant biomaterials. Human connective tissue cells grown on different materials exhibit distinct responses in terms of attachment, morphology, proliferative capacity and matrix biosynthesis. Our results closely complement in vivo observations concerning biocompatibility and demonstrate the usefulness of this in vitro system for evaluating biomaterials. More importantly, this model can be used to define the specific cellular and biochemical processes that are responsible for the local tissue responses to orthopaedic implant materials. PMID:2338027

Goldring, S R; Flannery, M S; Petrison, K K; Evins, A E; Jasty, M J



[Stereological analysis of human gingival connective tissues. Clinically healthy gingiva].  


The purpose of this study was to analyse stereologically the composition of the human gingival connective tissue after a period to two weeks of intense oral hygiene. Thiry young adults participated in this study. A clinical examination (plaque index and gingival index) was made at day 0 and day 14: on this last day an interdental papilla in the premolar region was sampled. The stereological analysis on point integration field has been made on serial sections of the interdental papillae sectioned in a buccal lingual plane. The gingivodental status of the subjects after the period of intense hygiene was characterized by a total absence of dental plaque and signs of gingival inflammation. The connective tissue was mainly made of by a dense network of collagen fibers. However an infiltrated zone of inflammatory cells (about 25% of the connective tissue) was always present. As a whole the gingival connective tissue was made of 88.4% of collagen, 7.3% of blood and lymph vessels, 4.9% of edema, 8.4% of fibroblasts, 8.2% of inflammatory cells and 2.7% of residual tissue (unidentified cells, nerves...). The infiltrated zone showed a certain number of differences with the non-infiltrated zone (collagen decrease, increase in oedema, vessels and mainly in inflammatory cells, principally monocytes, polymorphonuclear leukocytes and lymphocytes). PMID:6930378

Daniel, A; Dupont, M



Sustained deep-tissue pain alters functional brain connectivity.  


Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, frontoparietal control, and default mode networks: SMN, SLN, DAN, FCN, and DMN) was evaluated with functional-connectivity magnetic resonance imaging, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable, with no significant changes of subjects' pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula, and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to interindividual differences in pain sensitivity. PMID:23718988

Kim, Jieun; Loggia, Marco L; Edwards, Robert R; Wasan, Ajay D; Gollub, Randy L; Napadow, Vitaly



Anticentromere antibodies in subjects with no apparent connective tissue disease.  

PubMed Central

OBJECTIVES--To study the association of anticentromere antibodies (ACA) in various diseases. METHODS--A total of 4800 consecutive serum samples were tested for ACA by indirect immunofluorescence using HEp-2 cells as substrates and by immunoblotting of Molt-4 cell mitotic chromosomal antigens and recombinant CENP-B protein. RESULTS--Anticentromere antibodies were identified in the serum samples of 24 subjects, including eight without apparent connective tissue diseases, six with primary biliary cirrhosis, two with diffuse scleroderma, one with pulmonary hypertension, one with primary Raynaud's phenomenon, one with CREST syndrome (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia), and five with other connective tissue diseases. By immunoblotting using Molt-4 cells mitotic chromosomal antigens three centromere antigens were recognised by these serum samples. These were: CENP-A (17 kilodalton recognised by 22 of 24 ACA positive serum samples); CENP-B (80 kilodalton recognised by 22 of 24 ACA positive serum samples); and CENP-C (140 kilodalton recognised by 19 of 24 ACA positive serum samples). There was no specific pattern for serum samples from patients with different groups of diseases on immunoblotting. Recombinant CENP-B proteins were all recognised by these samples. Patients without apparent connective tissue disease often had a lower ACA titre than patients with primary biliary cirrhosis. CONCLUSIONS--These data suggest that a positive result for ACA does not always indicate the presence of a connective tissue disease. Images

Lee, S L; Tsay, G J; Tsai, R T



[The Marfan syndrome and related connective tissue disorders].  


The Marfan syndrome is an inherited disorder of the connective tissue which is mainly caused by a mutation in the fibrillin-1 gene. The defect in the connective tissue protein can lead to several organ dysfunctions. For the life expectancy, the cardiovascular aspect is of paramount importance. Patients with Marfan syndrome may develop aortic aneurysms and valvular heart defects. The risk of aortic aneurysms consists in the development of aortic dissection or rupture with their fatal consequences. Besides the cardiovascular manifestation, the skeletal and ocular system can also be affected. The skeletal manifestation is often characterised by long limbs, arachnodactyly, and abnormal joint flexibility along with other signs. Patients may also have dislocated lenses, ectasia of the dural sac, stretch marks, spontaneous pneumothorax, recurrent hernia, or a family history suspicious for Marfan. During the past years, other related connective tissue disorders with analogous organ manifestation have been described (e.g., Loeys-Dietz syndrome). In this article we present the basic knowledge about these connective tissue disorders, and we mention new insights in the recently explored pathophysiology of the disorder which is a possible target for future medical treatment options. Furthermore, recent new concepts for the prophylactic treatment of the aortic manifestation are explained. PMID:19554831

Siepe, Matthias; Löffelbein, Florian



Lipodermatosclerosis in patients with diffuse connective tissue diseases  

Microsoft Academic Search

Lipodermatosclerosis (LDS) is a clinical condition characterized by the appearance of hardened, painful, and hyperchromic plaques on the legs. We describe three patients with diffuse connective tissue diseases (DCTD) who developed this clinical condition. The first one was a systemic lupus erythematosus patient with secondary antiphospholipid syndrome; the second patient had a superposition of DCTD (rheumatoid arthritis, Sjögren's syndrome, morphea);

Fernanda Dias Gonzalez; Fernanda Pedreira Magalhăes; Alice Pontes Vilas Boas Freitas; Humberto Castro Lima Filho; Mittermayer B. Santiago



Occult connective tissue diseases mimicking idiopathic interstitial pneumonias  

Microsoft Academic Search

In patients with interstitial lung disease (ILD), the diagnosis of idiopathic interstitial pneumonia is usually made after excluding, among other conditions, connective tissue diseases (CTDs). Although in most patients with a CTD and respiratory symptoms, the systemic nature of the disease is obvious, the ILD-related manifestations in CTDs may often dominate the clinical picture or precede systemic findings and thus

G. E. Tzelepis; S. P. Toya; H. M. Moutsopoulos



Synaptic activity and connective tissue remodeling in denervated frog muscle  

Microsoft Academic Search

Denervation of skeletal muscle results in dramatic remodeling of the cellular and molecular composition of the muscle connective tissue. This remodeling is concentrated in muscle near neuromus- cular junctions and involves the accumulation of inter- stitial cells and several extracellular matrix molecules. Given the role of extracellular matrix in neurite out- growth and synaptogenesis, we predict that this remodeling of

Elizabeth A. Connor; Ke Qin; Haya Yankelev; Diana DeStefano



Force Transmission between Synergistic Skeletal Muscles through Connective Tissue Linkages  

PubMed Central

The classic view of skeletal muscle is that force is generated within its muscle fibers and then directly transmitted in-series, usually via tendon, onto the skeleton. In contrast, recent results suggest that muscles are mechanically connected to surrounding structures and cannot be considered as independent actuators. This article will review experiments on mechanical interactions between muscles mediated by such epimuscular myofascial force transmission in physiological and pathological muscle conditions. In a reduced preparation, involving supraphysiological muscle conditions, it is shown that connective tissues surrounding muscles are capable of transmitting substantial force. In more physiologically relevant conditions of intact muscles, however, it appears that the role of this myofascial pathway is small. In addition, it is hypothesized that connective tissues can serve as a safety net for traumatic events in muscle or tendon. Future studies are needed to investigate the importance of intermuscular force transmission during movement in health and disease.

Maas, Huub; Sandercock, Thomas G.



Bioreactors for Connective Tissue Engineering: Design and Monitoring Innovations  

NASA Astrophysics Data System (ADS)

The challenges for the tissue engineering of connective tissue lie in creating off-the-shelf tissue constructs which are capable of providing organs for transplantation. These strategies aim to grow a complex tissue with the appropri ate mechanical integrity necessary for functional load bearing. Monolayer culture systems lack correlation with the in vivo environment and the naturally occur ring cell phenotypes. Part of the development of more recent models is to create growth environments or bioreactors which enable three-dimensional culture. Evidence suggests that in order to grow functional load-bearing tissues in a bioreactor, the cells must experience mechanical loading stimuli similar to that experienced in vivo which sets out the requirements for mechanical loading bioreactors. An essential part of developing new bioreactors for tissue growth is identifying ways of routinely and continuously measuring neo-tissue formation and in order to fully identify the successful generation of a tissue implant, the appropriate on-line monitoring must be developed. New technologies are being developed to advance our efforts to grow tissue ex vivo. The bioreactor is a critical part of these develop ments in supporting growth of biological implants and combining this with new advances in the detection of tissue formation allows us to refine our protocols and move nearer to off-the-shelf implants for clinical applications.

Haj, A. J. El; Hampson, K.; Gogniat, G.


Smooth Muscle-Mediated Connective Tissue Remodeling in Pulmonary Hypertension  

NASA Astrophysics Data System (ADS)

Abnormal accumulation of connective tissue in blood vessels contributes to alterations in vascular physiology associated with disease states such as hypertension and atherosclerosis. Elastin synthesis was studied in blood vessels from newborn calves with severe pulmonary hypertension induced by alveolar hypoxia in order to investigate the cellular stimuli that elicit changes in pulmonary arterial connective tissue production. A two- to fourfold increase in elastin production was observed in pulmonary artery tissue and medial smooth muscle cells from hypertensive calves. This stimulation of elastin production was accompanied by a corresponding increase in elastin messenger RNA consistent with regulation at the transcriptional level. Conditioned serum harvested from cultures of pulmonary artery smooth muscle cells isolated from hypertensive animals contained one or more low molecular weight elastogenic factors that stimulated the production of elastin in both fibroblasts and smooth muscle cells and altered the chemotactic responsiveness of fibroblasts to elastin peptides. These results suggest that connective tissue changes in the pulmonary vasculature in response to pulmonary hypertension are orchestrated by the medial smooth muscle cell through the generation of specific differentiation factors that alter both the secretory phenotype and responsive properties of surrounding cells.

Mecham, Robert P.; Whitehouse, Loren A.; Wrenn, David S.; Parks, William C.; Griffin, Gail L.; Senior, Robert M.; Crouch, Edmond C.; Stenmark, Kurt R.; Voelkel, Norbert F.



T-Cell Avidity and Tuning: The Flexible Connection Between Tolerance and Autoimmunity  

PubMed Central

Thymic T-cell selection mechanisms generate a cross-reactive, self-MHC restricted peripheral T-cell pool. Affinity and avidity are of profound influence on this selection and the generation of immunity. Autoreactive T cells can escape thymic deletion by lowering their avidity and retain this “tuned” state in the periphery. Upon activation, tuned T cells can cause autoimmunity, while immunotherapeutic strategies may be hampered by existing T-cell tolerance. The regulation of T-cell avidity and tuning therefore determines the balance between tolerance and autoimmunity and should be taken into account in the design of therapeutic strategies aimed at T-cell reactivity.

van den Boorn, Jasper G.; Le Poole, I. Caroline; Luiten, Rosalie M.



Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease  

PubMed Central

Background Human T-lymphotropic virus type 1 (HTLV-1) proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. Results HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. Conclusions These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load.

Yakova, Maria; Lezin, Agnes; Dantin, Fabienne; Lagathu, Gisele; Olindo, Stephane; Jean-Baptiste, Georges; Arfi, Serge; Cesaire, Raymond



Thrombotic Thrombocytopenic Purpura Associated with Mixed Connective Tissue Disease: A Case Report  

PubMed Central

Thrombotic thrombocytopenic purpura (TTP) is a multisystemic disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia, which may be accompanied by fever, renal, or neurologic abnormalities. Cases are divided into acute idiopathic TTP and secondary TTP. Autoimmune diseases, especially systemic lupus erythematosus, in association with TTP have been described so far in many patients. In contrast, TTP occurring in a patient with mixed connected tissue disease (MCTD) is extremely rare and has only been described in nine patients. We describe the case of a 42-year-old female with MCTD who developed thrombocytopenia, microangiopathic hemolytic anemia, fever, and neurological symptoms. The patient had a good clinical evolution with infusion of high volume of fresh frozen plasma, steroid therapy, and support in an intensive care unit. Although the occurrence of TTP is rare in MCTD patients, it is important to recognize TTP as a cause of thrombocytopenia and hemolytic anemia in any patient with autoimmune diseases. Prompt institution of treatment remains the cornerstone of treatment of TTP even if plasma exchange is not available like what frequently happens in developing countries.

Souto Filho, Joao Tadeu Damian; de Barros, Philipe Vianna; da Silva, Aline Maria Yamaguti Rios Paes; Barbosa, Fernanda Alves; Ribas, Gustavo Fernandes



Anticentromere antibodies in subjects with no apparent connective tissue disease  

Microsoft Academic Search

OBJECTIVES--To study the association of anticentromere antibodies (ACA) in various diseases. METHODS--A total of 4800 consecutive serum samples were tested for ACA by indirect immunofluorescence using HEp-2 cells as substrates and by immunoblotting of Molt-4 cell mitotic chromosomal antigens and recombinant CENP-B protein. RESULTS--Anticentromere antibodies were identified in the serum samples of 24 subjects, including eight without apparent connective tissue

S L Lee; G J Tsay; R T Tsai



Silicone breast implants and connective tissue disease: no association  

Microsoft Academic Search

The association of silicone breast implants with connective tissue diseases (CTDs), including systemic sclerosis, systemic\\u000a lupus erythematosus, rheumatoid arthritis, and fibromyalgia, as well as a hypothesized new “atypical” disease, which does\\u000a not meet established diagnostic criteria for any known CTD, has been extensively studied. We have reviewed the epidemiologic\\u000a literature regarding an association between cosmetic breast implants and CTDs, with

Loren Lipworth; Lisbet R. Holmich; Joseph K. McLaughlin



Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: Case report and review of literature  

PubMed Central

Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported. We describe a case of a female patient who developed significant respiratory dysfunction as the principal clinical sign. Video-assisted thoracoscopy was performed and a histological pattern of nonspecific interstitial pneumonia (NSIP) was found. A pathological diagnosis suggested careful follow-up with extensive immunological screening which then detected Raynaud's phenomenon and positivity of antinuclear antibodies. After a multidisciplinary discussion (pneumologist, radiologist, pathologist and rheumatologist) a final diagnosis of NSIP associated with UCTD was made. The diagnosis of UCTD should be considered when NSIP is diagnosed even in cases with evident first clinical manifestations of severe respiratory dysfunction. A multidisciplinary approach in the field of interstitial lung disease with NSIP, also including rheumatologic expertise, is fundamental to achieve a prompt and correct diagnosis.



Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease  

PubMed Central

The CD40 gene, an important immune regulatory gene, is also expressed and functional on non-myeloid derived cells, many of which are targets for tissue specific autoimmune diseases, including beta cells in type 1 diabetes, intestinal epithelial cells in Crohn’s disease, and thyroid follicular cells in Graves’ disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. Here we show, that target-tissue over-expression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 over-expression augmented the production of thyroid specific antibodies, resulting in more severe experimental autoimmune Graves’ disease (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 over-expression, and showed decreased levels of TSHR stimulating antibodies and frequency of disease. We conclude that target tissue over-expression of CD40 plays a key role in the etiology of organ specific autoimmune disease.

Huber, Amanda K.; Finkelman, Fred D.; Li, Cheuk Wun; Concepcion, Erlinda; Smith, Eric; Jacobson, Eric; Latif, Rauf; Keddache, Mehdi; Zhang, Weijia; Tomer, Yaron



Expression profiling of autoimmune regulator AIRE mRNA in a comprehensive set of human normal and neoplastic tissues.  


Defects in the autoimmune regulator (AIRE) gene cause the monogenic autoimmune disease autoimmune polyendocrinopathy syndrome type 1 (APS-1), which is characterized by a loss of self-tolerance to multiple organs. In concordance with its role in immune tolerance, AIRE is strongly expressed in medullary thymic epithelial cells (mTECs). Data on mechanisms controlling AIRE activation and the expression of this gene in other tissues are fragmentary and controversial. We report here AIRE mRNA expression profiling of a large set of normal human tissues and cells, tumor specimen and methylation deficient cell lines. On this broad data basis we found that AIRE mRNA expression is confined to mTECs in thymus and to lymph node tissue and that DNA hypomethylation contributes to transcriptional control of this gene. PMID:16876259

Klamp, Thorsten; Sahin, Ugur; Kyewski, Bruno; Schwendemann, Jochen; Dhaene, Karl; Türeci, Ozlem



Absence of autoantibodies connected to autoimmune polyendocrine syndrome type I and II and Addison's disease in girls and women with Turner syndrome  

Microsoft Academic Search

BACKGROUND: A disturbance in the immune system has been described in Turner syndrome (45,X), with an association to low levels of IgG and IgM and decreased levels of T- and B-lymphocytes. Also different autoimmune diseases have been connected to Turner syndrome (45,X), thyroiditis being the most common. Other autoimmune diseases seen are inflammatory bowel disease, insulin dependent diabetes mellitus, Addison's

Annika E Stenberg; Lisskulla Sylvén; Hĺkan Hedstrand; Olle Kämpe; Malou Hultcrantz



Relation between myofibers and connective tissue during muscle injury repair.  


The connective tissue framework in skeletal muscle combines the contractile myofibers into a functional unit, in which the contraction of myofibers is transformed into movement via myotendinous junctions (MTJs) at their ends, where myofibers attach to tendons/fascia. The cytoskeletal contractile myofilament apparatus adheres through subsarcolemmal and transmembrane molecules to the surrounding extracellular matrix, with integrin and dystrophin associated chains of molecules being the two main adhesion complexes. In shearing type of muscle injury both myofibers and the connective tissue framework are ruptured and thereby the functional tendon-muscle-tendon units are disrupted. The stumps of the ruptured myofibers are separated and at the same time joined by a connective tissue scar, through which the ends of regenerating myofibers try to pierce, but as the scar becomes more compact the ends attach to the scar by new mini-MTJs. During the early phase ruptured myofibers try to compensate for the lost MTJ attachment by reinforcing their integrin mediated lateral adhesion, which returns to normal low level after formation of the mini-MTJs and at which time complementary increase of dystrophin and associated molecules on lateral sarcolemma takes place. The stumps appear to remain separated by and attached to the interposed scar for many months, possibly for ever, i.e. the original tendon-muscle-tendon units may have become permanently divided into two consecutive units. Remarkably, axon sprouts are able to penetrate through the interposed scar to form new neuromuscular junctions on those abjunctional stumps which were denervated by the rupture. PMID:11085560

Kääriäinen, M; Järvinen, T; Järvinen, M; Rantanen, J; Kalimo, H



Connective Tissue Disease-associated Interstitial Lung Disease: A review  

PubMed Central

Interstitial lung disease (ILD) is commonly encountered in patients with connective tissue diseases (CTD). Besides the lung parenchyma, the airways, pulmonary vasculature and structures of the chest wall may all be involved, depending on the type of CTD. As a result of this so-called multi-compartment involvement, airflow limitation, pulmonary hypertension, vasculitis and extrapulmonary restriction can occur alongside fibro-inflammatory parenchymal abnormalities in CTD. Rheumatoid arthritis (RA), systemic sclerosis (SSc), poly-/dermatomyositis (PM/DM), Sjögren’s syndrome (SjS), systemic lupus erythematosus (SLE), and undifferentiated (UCTD) as well as mixed connective tissue disease (MCTD) can all be associated with the development of ILD. Non-specific interstitial pneumonia (NSIP) is the most commonly observed histopathological pattern in CTD-ILD, but other patterns including usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP) may occur. Although the majority of patients with CTD-ILD experience stable or slowly advancing ILD, a small yet significant group exhibits a more severe and progressive course. Randomized placebo-controlled trials evaluating the efficacy of immunomodulatory treatments have been conducted only in SSc-associated ILD. However, clinical experience suggests that a handful of immunosuppressive medications are potentially effective in a sizeable portion of patients with ILD caused by other CTDs. In this manuscript, we review the clinical characteristics and management of the most common CTD-ILDs.

Gutsche, Markus; Rosen, Glenn D.; Swigris, Jeffrey J.



Genetic Analysis of Familial Connective Tissue Alterations Associated With Cervical Artery Dissections Suggests Locus Heterogeneity  

Microsoft Academic Search

Background and Purpose—Cervical artery dissections (CAD) can be associated with connective tissue aberrations in skin biopsies. The analysis of healthy relatives of patients suggested that the connective tissue phenotype is familial with an autosomal dominant inheritance. Methods—We performed genetic linkage studies in 3 families of patients with CAD. Connective tissue phenotypes for the patients and all family members were assessed

Tina Wiest; Sonja Hyrenbach; Pinar Bambul; Birgit Erker; Alessandro Pezzini; Ingrid Hausser; Marie-Luise Arnold; Juan JoseMartin; Stefan Engelter; Philippe Lyrer; Otto Busse; Tobias Brandt; Caspar Grond-Ginsbach



Cell-based and biomaterial approaches to connective tissue repair  

NASA Astrophysics Data System (ADS)

Connective tissue injuries of skin, tendon and ligament, heal by a reparative process in adults, filling the wound site with fibrotic, disorganized scar tissue that poorly reflects normal tissue architecture or function. Conversely, fetal skin and tendon have been shown to heal scarlessly. Complete regeneration is not intrinsically ubiquitous to all fetal tissues; fetal diaphragmatic and gastrointestinal injuries form scars. In vivo studies suggest that the presence of fetal fibroblasts is essential for scarless healing. In the orthopaedic setting, adult anterior cruciate ligament (ACL) heals poorly; however, little is known about the regenerative capacity of fetal ACL or fetal ACL fibroblasts. We characterized in vitro wound healing properties of fetal and adult ACL fibroblasts demonstrating that fetal ACL fibroblasts migrate faster and elaborate greater quantities of type I collagen, suggesting the healing potential of the fetal ACL may not be intrinsically poor. Similar to fetal ACL fibroblasts, fetal dermal fibroblasts also exhibit robust cellular properties. We investigated the age-dependent effects of dermal fibroblasts on tendon-to-bone healing in rat supraspinatus tendon injuries, a reparative injury model. We hypothesized delivery of fetal dermal fibroblasts would increase tissue organization and mechanical properties in comparison to adult dermal fibroblasts. However, at 1 and 8 weeks, the presence of dermal fibroblasts, either adult or fetal, had no significant effect on tissue histology or mechanical properties. There was a decreasing trend in cross-sectional area of repaired tendons treated with fetal dermal fibroblasts in comparison to adult, but this finding was not significant in comparison to controls. Finally, we synthesized a novel polysaccharide, methacrylated methylcellulose (MA-MC), and fabricated hydrogels using a well-established photopolymerization technique. We characterized the physical and mechanical properties of MA-MC hydrogels in vitro as well as in a subcutaneous mouse model. Stable MA-MC hydrogels, of varying weight percentages, demonstrated tunable swelling and mechanical properties in the absence of cytotoxic degradation products. In vivo, 6wt% MA-MC hydrogels maintained their shape and mechanical integrity while eliciting a minimal inflammatory response; highly desirable properties for soft tissue reconstruction. These cellulose-based photopolymerizable hydrogels can be further optimized for drug delivery and tissue engineering applications to enhance wound repair.

Stalling, Simone Suzette


Myocardial performance in children with autoimmune hepatitis: Doppler tissue imaging study.  


Autoimmune hepatitis (AIH) is a member of autoimmune diseases family which can increase risk of cardiovascular morbidity and mortality. This study aimed to assess subclinical impact of AIH on global myocardial performance in affected children using Doppler tissue imaging (DTI) and to correlate it with total serum immunoglobulin-G (IgG). Thirty children with AIH (mean age?=?12.67?±?2.9 years) was included as the study group and 20 age- and sex-matched healthy children (mean age?=?11.93?±?2.66 years) as the control group. Conventional two-dimensional echocardiography was performed to both groups and DTI were used to determine right ventricular (RV) and left ventricular (LV) Tei indexes. Total serum IgG levels at initial diagnosis of AIH were correlated to the cardiac functions of AIH patients. RV and LV Tei indexes were significantly higher in AIH group (mean?±?SD: 0.46?±?0.088 vs. 0.26?±?0.01, P?

Abo-Haded, Hany M; Barakat, Tarik S; Hafez, Mona M




PubMed Central

Interferon alpha (IFN?) is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN? is consistent with primarily immuno-modulatory effects, the high frequency of non-autoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN? treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin (Tg), thyroid stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and sodium iodide transporter (NIS). RNAseq analysis demonstrated that pathways of antigen presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased non-apoptotic thyroid cell death suggesting direct toxicity. To corroborate these in vitro findings we created transgenic mice with thyroid specific overexpression of IFN? under control of the Tg promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thryocytes. In particular, expression of granzyme B, CXCL10, a subset of the TRIM (tripartite motif containing) family and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN? involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.

Akeno, Nagako; Smith, Eric P.; Stefan, Mihaela; Huber, Amanda K.; Zhang, Weijia; Keddache, Mehdi; Tomer, Yaron



Derailed B cell homeostasis in patients with mixed connective tissue disease.  


Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19+CD27-IgD+CD38(high)); (2) naive B cells (CD19+CD27-IgD+CD38(low)); (3) non-switched memory B cells (CD19+CD27+IgD+); (4) switched memory B cells (CD19+CD27+IgD-); (5) double negative (DN) memory B cells (CD19+CD27-IgD-) and (6) plasma cells (CD19+CD27(high)IgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27(high) B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis. PMID:23608739

Hajas, A; Barath, S; Szodoray, P; Nakken, B; Gogolak, P; Szekanecz, Z; Zold, E; Zeher, M; Szegedi, G; Bodolay, E



Lipodermatosclerosis in patients with diffuse connective tissue diseases.  


Lipodermatosclerosis (LDS) is a clinical condition characterized by the appearance of hardened, painful, and hyperchromic plaques on the legs. We describe three patients with diffuse connective tissue diseases (DCTD) who developed this clinical condition. The first one was a systemic lupus erythematosus patient with secondary antiphospholipid syndrome; the second patient had a superposition of DCTD (rheumatoid arthritis, Sjögren's syndrome, morphea); and the last one had been diagnosed with CREST 10 years earlier but had more recently developed primary biliary cirrhosis. Although its etiopathogenesis is unknown, LDS has been frequently seen in association with venous insufficiency. Its recognition by professionals who deal with DCTD is very relevant since it is characterized by thickening of the skin, similar to scleroderma. Its identification can avoid the inadvertent use of medications such as penicillamine and immunosuppressants, which have potentially serious side effects. PMID:16762781

Dias Gonzalez, Fernanda; Pedreira Magalhăes, Fernanda; Pontes Vilas Boas Freitas, Alice; Castro Lima Filho, Humberto; Santiago, Mittermayer B



Paraneoplastic syndromes with connective tissue involvement. "It's not always lupus!".  


Paraneoplastic syndromes (PNS) are remote effects of cancer that are, by definition, caused neither by invasion of the tumor or its metastases nor by infection, ischemia, metabolic and nutritional deficits, surgery or other forms of tumor treatment. The purpose of the current review was to present the challenging elements of differential diagnosis in oncology, as they may represent the main clinical problem in a patient diagnosed with cancer, even though the complete knowledge of both their clinical aspects and pathogenesis remain quite poor. This review focuses on the paraneoplastic syndromes related to dermatology and rheumatology, as the most frequent manifestations come from connective tissues that might determine a patient to ask for consultation by a general practitioner. PMID:23033275

Timis, T; Berce, C; Duarte-Garcia, A; Petrushev, B; Cristea, V; Tomuleasa, C


Association of Thy1 cell surface differentiation antigen with certain connective tissues in vivo  

Microsoft Academic Search

The cell surface differentiation antigen, Thy-1, has been demonstrated by immunofluorescence to be associated with some collagen-based connective tissue. In the rat, the basement membrane of kidney collecting tubules and of certain blood vessels, reticulin of the lamina propria, loose connective tissue in the dermis, and collagen fibres within certain nerve cell tumours, bear the antigen. Other, apparently similar, connective

Roger J. Morris; Mary A. Ritter



A Neoplastic Connective Tissue Mast Cell Capable of Continuous Growth In Tissue Culture  

PubMed Central

A neoplastic connective tissue mast cell from a dog mast cell sarcoma has been grown in tissue culture for 50 passages over a period of 2 years. The cells were grown as monolayer cultures in glass bottles, using Eagle's basal medium fortified with calf serum. The cultures were contaminated with an Alkaligenes sp. for 10 months but finally were sterilized bacteriologically by treatment with specific antiserum combined with antibiotics. The cells grow in a fibroblastic pattern, and contain mitochondria, mast cell granules, and lipid granules or droplets. The mast cell granules stain basophilic with Giemsa's stain and metachromatically with azure A or toluidine blue. They also stain with Sudan black B and with periodic acid-Schiff stain. The interphase nuclei are vesicular, contain from 1 to 20 nucleoli, and frequently show bizarre outlines. Multinucleate cells are often seen, as are mitotic figures. Extracellular fibrous material occurs in all cultures and apparently originates from the cell surface. This material does not have the structure of connective tissue fibers and has not been identified. The cells develop an increased number of metachromatic granules when grown in medium containing heparin and an increased number of sudanophilic granules when grown in medium containing stearic acid. Only small amounts of histamine were present in the tumor from which this cell line was derived and in the cells grown in tissue culture.

Williams, William J.; Larson, Edna; Phillips, Theodore L.



[Targeted treatment of rare connective tissue tumors and sarcomas].  


The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease. Six subgroups of sarcomas are identified with specific molecular alterations, the targeted treatments of which are the object of this article: 1) sarcomas with specific translocations with fusion oncogenes (DFSP, PVNS); 2) sarcomas with tyrosine kinase mutations (KIT in GIST); 3) tumors with deletion of tumor suppressor genes (TSC in the PEComes, NF1 involved in type 1 neurofibromatosis; 4) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon, i.e. well differentiated or dedifferentiated liposarcomas; 5) sarcomas with complex genetics present more unrefined genetic changes (leiomyosarcomas, osteosarcomas). On top these 5 groups, desmoids tumors characterized by alterations of the Wnt, beta catenin, APC, and giant cell tumors of the bone, in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells. The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness, in particular DFSP, PVNS, GCST, PEComes, endometrial stromal sarcomas, Ewing sarcomas, etc. Imatinib is used in the treatment of DFSP, characterized by a translocation of the gene PDGF, or in pigmented villonodular synovitis (PVNS), a tumor of soft part also locally aggressive, caused by an abnormality of the gene coding for the M-CSF. Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing, whose fusion gene downregulates IGFBP3. Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas. Inhibitors of mTOR (sirolimus, temsirolimus) demonstrated an antitumoral activity in the PEComas. The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities. Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors. PMID:20497911

Cassier, P; Pissaloux, D; Alberti, L; Ray-Coquard, I; Blay, J-Y



Mechanical mutability in connective tissue of starfish body wall.  


Stiffness changes in response to mechanical and chemical stimulation were studied in muscle-free dermal samples from the body wall of the starfish Linckia laevigata. The ultrastructural study showed that the dermis was packed with collagen fibrils between which only a small number of cells were observed. Muscles were found only in the walls of coelomic extensions leading to papulae. Stress-strain tests were performed on isolated dermis containing no muscles. The tangent modulus was 27.5 MPa at 0.04% strain rate in the stress-strain tests. It was increased to 40.7 MPa by mechanical stimulation, which also increased the tensile strength and breaking-strain energy density. Dynamic mechanical tests showed that the increase in stiffness in response to mechanical stimulation was transient. Acetylcholine (10(-6)-10(-3) mol l(-1)) and artificial seawater with an elevated potassium concentration (KASW) stiffened the dermis. Mechanical stimulation caused a 12% mass loss. KASW also caused mass loss, which was inhibited by anesthesia. These results clearly showed that the stiffness changes in the starfish dermis were based on a non-muscular mechanism that was similar to that of other echinoderm connective tissues with mechanical mutability. PMID:22186916

Motokawa, Tatsuo



Silicone breast implants and connective tissue disease: no association.  


The association of silicone breast implants with connective tissue diseases (CTDs), including systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and fibromyalgia, as well as a hypothesized new "atypical" disease, which does not meet established diagnostic criteria for any known CTD, has been extensively studied. We have reviewed the epidemiologic literature regarding an association between cosmetic breast implants and CTDs, with particular emphasis on results drawn from the most recent investigations, many of which are large cohort studies with long-term follow-up, as well as on those studies that address some of the misinformation and historically widespread claims regarding an association between breast implants and CTDs. These claims have been unequivocally refuted by the remarkably consistent evidence from published studies, as well as numerous independent meta-analyses and critical reviews, which have demonstrated that cosmetic breast implants are not associated with a subsequent increased occurrence of individual CTDs or all CTDs combined, including fibromyalgia. Moreover, there is no credible evidence for the conjectured excess of "atypical" CTD among women with cosmetic breast implants, or of a rheumatic symptom profile unique to these women. No increased risk of CTDs is evident in women with extracapsular ruptures in two studies, which evaluated risk by implant rupture status, and no consistent association has been observed between silicone breast implants and a variety of serologic markers or autoantibodies. Thus, any claims that remain regarding an association between cosmetic breast implants and CTDs are not supported by the scientific literature but rather are a residual byproduct of the unprecedented large-scale product liability litigation in the USA. PMID:21369953

Lipworth, Loren; Holmich, Lisbet R; McLaughlin, Joseph K



Topical estrogens: their effects on connective tissue synthesis in hairless mouse skin  

Microsoft Academic Search

Skin is an important target organ for estrogens. The major reported effects of estrogens are as regulators of connective tissue molecules, namely collagen and hyaluronic acid. We investigated the regulation of connective tissue synthesis by topical estrogens in a hairless mouse model of photodamaged skin, which has been previously shown to respond to topical retinoids. The naturally occurring estrogen, 17#-estradiol

Gerard J. Gendimenico; Vincent J. Mack; Paul A. Siock; James A. Mezick



Stretching of the Back Improves Gait, Mechanical Sensitivity and Connective Tissue Inflammation in a Rodent Model  

Microsoft Academic Search

The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and\\/or fibrosis in the low back pain subjects. Mechanical input in the form

Sarah M. Corey; Margaret A. Vizzard; Nicole A. Bouffard; Gary J. Badger; Helene M. Langevin



Clinical characteristics and mycology of onychomycosis in autoimmune patients.  


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



Lack of ‘tissue’ transglutaminase protein cross-linking leads to leakage of macromolecules from dying cells: relationship to development of autoimmunity in MRLlpr\\/lpr mice  

Microsoft Academic Search

Genetic defects of the CD95 (Fas\\/Apo-1) receptor\\/ligand system, has recently been involved in the development of human and murine autoimmunity. We investigated whether a deregulation of the ‘tissue’ transglutaminase (tTG), a multifunctional enzyme which is part of the molecular program of apoptosis, may act as a cofactor in the development of autoimmunity. We found that MRLlpr\\/lpr, which are characterized by

Lucia Piredda; Alessandra Amendola; Vittorio Colizzi; Peter JA Davies; Maria Grazia Farrace; Maurizio Fraziano; Vittorio Gentile; Ivan Uray; Mauro Piacentini; Laszlo Fesus



The microvacuolar system: how connective tissue sliding works.  


The term 'fascia' has been applied to a large number of very different tissues within the hand. These range from aligned ligamentous formations such as the longitudinal bands of the palmar fascia or Grayson's and Cleland's ligaments, to the loose packing tissues that surround all of the moving structures within the hand. In other parts of the body the terms 'superficial' and 'deep fascia' are often used but these have little application in the hand and fingers. Fascia can be divided into tissues that restrain motion, act as anchors for the skin, or provide lubrication and gliding. Whereas the deep fascia is preserved and easily characterized in anatomical dissection, the remaining fascial tissue is poorly described. Understanding its structure and dynamic anatomy may help improve outcomes after hand injury and disease. This review describes the sliding tissue of the hand or the 'microvacuolar system' and demonstrates how movement of tissues can occur with minimal distortion of the overlying skin while maintaining tissue continuity. PMID:20571142

Guimberteau, J C; Delage, J P; McGrouther, D A; Wong, J K F



Skin manifestations of systemic autoimmune connective tissue disease: diagnostics and therapeutics  

Microsoft Academic Search

Skin disease can significantly affect the quality of life of patients suffering from rheumatic diseases. In addition, important relationships exist between the cutaneous and systemic manifestations of rheumatic disease. It is thus important for practicing rheumatologists to have a solid working understanding of the subject of rheumatic skin disease. Unfortunately, it is not possible within the scope of this chapter

Richard D Sontheimer



Proteolytic Processing of Connective Tissue Growth Factor in Normal Ocular Tissues and during Corneal Wound Healing  

PubMed Central

Purpose. Connective tissue growth factor (CTGF) is a fibrogenic cytokine that is up-regulated by TGF-? and mediates most key fibrotic actions of TGF-?, including stimulation of synthesis of extracellular matrix and differentiation of fibroblasts into myofibroblasts. This study addresses the role of proteolytic processing of CTGF in human corneal fibroblasts (HCF) stimulated with TGF-?, normal ocular tissues and wounded corneas. Methods. Proteolytic processing of CTGF in HCF cultures, normal animal eyes, and excimer laser wounded rat corneas were examined by Western blot. The identity of a 21-kDa band was determined by tandem mass spectrometry, and possible alternative splice variants of CTGF were assessed by 5? Rapid Amplification of cDNA Ends (RACE). Results. HCF stimulated by TGF-? contained full length 38-kDa CTGF and fragments of 25, 21, 18, and 13 kDa, while conditioned medium contained full length 38- and a 21-kDa fragment of CTGF that contained the middle “hinge” region of CTGF. Fragmentation of recombinant CTGF incubated in HCF extracts was blocked by the aspartate protease inhibitor, pepstatin. Normal mouse, rat, and rabbit whole eyes and rabbit ocular tissues contained abundant amounts of C-terminal 25- and 21-kDa fragments and trace amounts of 38-kDa CTGF, although no alternative transcripts were detected. All forms of CTGF (38, 25, and 21 kDa) were detected during healing of excimer ablated rat corneas, peaking on day 11. Conclusions. Proteolytic processing of 38-kDa CTGF occurs during corneal wound healing, which may have important implications in regulation of corneal scar formation.

Robinson, Paulette M.; Smith, Tyler S.; Patel, Dilan; Dave, Meera; Lewin, Alfred S.; Pi, Liya; Scott, Edward W.; Tuli, Sonal S.; Schultz, Gregory S.



Gene Therapy Approaches for Autoimmune Diseases of the Central Nervous System and Other Tissues  

Microsoft Academic Search

The gene therapy of autoimmunity has held many promises for the last ten years, owing to its potential as an alternative therapeutic\\u000a approach for diseases lacking a definitive cure and with a devastating social impact. However, there are still several issues\\u000a to solve before these approaches would be transferable to humans.\\u000a \\u000a Some studies are conceptually non applicable to human diseases.

Roberto Furlan; Erica Butti; Stefano Pluchino; Gianvito Martino


Autoimmune Inner Ear Disease (AIED)  


Autoimmune Inner Ear Disease What is autoimmunity? How is it connected to vestibular disorders? Parts of the immune system, working constantly ... reaction. The immune system can attack just the ear, attack the ear and some other body part ...


Stretching of the Back Improves Gait, Mechanical Sensitivity and Connective Tissue Inflammation in a Rodent Model  

PubMed Central

The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.

Corey, Sarah M.; Vizzard, Margaret A.; Bouffard, Nicole A.; Badger, Gary J.; Langevin, Helene M.



Transplantation of human endocrine tissues to nude mice: a suitable in vivo model for the study of pathomechanisms involved in autoimmune thyroid diseases.  


After transplantation of human tissue to nu/nu mice the human lymphocytes disappear. In this context, interestingly, the DR-expression is not detectable anymore after transplantation of the tissues from patients with autoimmune thyrotoxicosis and cancer. Neopterin release was only demonstrable when T-lymphocytes from patients with autoimmune thyrotoxicosis or PHA-stimulated lymphocytes were added, independently of the presence of DR-expression in the used culture tissues. These results seem to exclude a functional role of DR-expression as a trigger mechanism of autoimmunity. It is supposed that DR-priming on epithelial cells is mediated by kinine production of activated T-lymphocytes or macrophages. PMID:3497513

Usadel, K H; Teuber, J; Paschke, R; Junker, M; Schwedes, U



Connective Tissue Breakdown and Bone Morphology Change Following Increased Intensity Exercise.  

National Technical Information Service (NTIS)

Two plasma indicators of connective tissue (CT) degradation have been identified in previous work. One of the these, hydroxyproline (OHP), is a widely accepted measure of CT turnover; the other, hydroxylysylpyridinoline (HP), has only recently been isolat...

J. A. Hodgdon M. Riedy H. W. Gorth



Force Transmission in Wrinkled Membranes: A Numerical Tool to Study Connective Tissue Structures.  

National Technical Information Service (NTIS)

Experiments demonstrate that a quantitative prediction of force transmission in wrinkled and non-wrinkled membranes is possible with the developed numerical tool. Theoretical results for force transmission in collagenous connective tissue structures show ...

D. G. Roddeman



The connective tissue index of Helix aspersa as a metal biomarker.  


The digestive gland of adult land snails, Helix aspersa, sampled from four different sites in Săo Miguel island (Azores) was submitted to chemical analyses, autometallography and haemalum/eosin staining, in order to quantify the relative abundance of heavy metals, calcium cells and connective tissue cells. Metals were visualized, through light microscopy, as black silver deposits mostly in the connective tissue cells. Metal levels, essentially of Cu and Fe, were related to the relative volumetric density of connective tissue cells but not to the relative volumetric density of calcium cells from the digestive gland epithelium. Thus, the connective tissue index presented herein is suggested as a biomarker of Cu exposure in terrestrial mollusks. PMID:15689105

Amaral, André Filipe Santos; Anselmo, Henrique; da Cunha, Regina Maria Pires Toste Tristăo; Rodrigues, Armindo Santos



Interleukin-21 Is Critically Required in Autoimmune and Allogeneic Responses to Islet Tissue in Murine Models  

PubMed Central

OBJECTIVE Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21–targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. RESEARCH DESIGN AND METHODS NOD mice were treated with IL-21R/Fc, an IL-21–neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R–deficient mice was also assessed. RESULTS Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21–responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. CONCLUSIONS Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes.

McGuire, Helen M.; Walters, Stacey; Vogelzang, Alexis; Lee, Carol M.Y.; Webster, Kylie E.; Sprent, Jonathan; Christ, Daniel; Grey, Shane; King, Cecile



The significance of IgM antinuclear antibody in rheumatoid arthritis and other connective tissue diseases  

Microsoft Academic Search

An investigation of the incidence of IgG and IgM antinuclear antibodies (ANA) in patients with connective tissue diseases showed that IgM ANA predominated in rheumatoid arthritis, whilst in systemic lupus erythematosus IgG antibodies were more common. Patients with other connective tissue diseases less frequently had antinuclear antibodies and there was little difference in the incidence of IgG and IgM antibodies.

M. C. Chellingworth; M. Salmon; D. L. Scott; P. A. Bacon



Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management  

Microsoft Academic Search

Interstitial lung disease (ILD) is a challenging clinical entity associated with multiple connective tissue diseases, and is a significant cause of morbidity and mortality. Effective therapies for connective tissue disease-associated interstitial lung disease (CTD-ILD) are still lacking. Multidisciplinary clinics dedicated to the early diagnosis and improved management of patients with CTD-ILD are now being established. There is rapid progress in

Flavia V Castelino; John Varga



Three-Dimensional Architecture of the Subepithelial Connective Tissue in the Omasal Laminae of Sheep and Cattle  

Microsoft Academic Search

The three-dimensional architecture of the subepithelial connective tissue in the omasal laminae of sheep and cattle was studied by scanning electron microscopy after treatment with 2 N NaOH solution. The omasal laminae were equipped with highly undulated subepithelial connective tissue showing various projections or ridges. In the sheep, the subepithelial connective tissue in the omasal papillae formed flat papillary projections

Y. Yamamoto; N. Kitamura; J. Yamada; T. Yamashita



Tissue response to a new methacrylate-based root canal sealer: preliminary observations in the subcutaneous connective tissue of rats.  


Silicone tubes filled with EndoRez, a methacrylate-based root canal sealer, were implanted in the subcutaneous connective tissue of the rat. Solid, silicone rods of the same size as the tubes also were implanted and used as negative controls. The tissue reaction to test and control materials was histologically studied and analyzed by elemental electron-microprobe analysis. After 10, 30, 90, and 120 days of implantation, different grades of tissue reaction to the tested materials were recorded. A granulomatous tissue containing numerous polymorphonuclear leukocytes, lymphocytes, and plasmocytes, as well as macrophages and foreign-body giant cells with engulfed material in their cytoplasm, was initially observed in contact with EndoRez. Fibroblasts and newly formed vessels also were observed. This cellular profile persisted after 30 days. The severity of the reaction decreased with time, and connective tissue healing was observed at the 120-day observation period, even though some specimens exhibited a slight, persistent, inflammatory cell infiltration. The electron-microprobe analysis of the tissues revealed the presence of heavy components of EndoRez in all observation periods. In contact with the controls, there was an initially slight concentration of inflammatory cells. This reaction rapidly subsided after 30 days, and a fibrous connective tissue encapsulation, free of inflammatory cells, could be observed at the 90- and 120-day observation periods. PMID:15107648

Zmener, Osvaldo



Malignant lymphoma-associated autoimmune diseases--a descriptive epidemiological study.  


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



Expression and activation of matrix metalloproteinase-9 and NADPH oxidase in tissues and plasma of experimental autoimmune encephalomyelitis in mice.  


Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple sclerosis (MS) that can be induced by immunization with myelin antigens such as myelin oligodendrocyte glycoprotein (MOG). The objective of this study was (i) to investigate how matrix metalloproteinase-9 (MMP-9) and NADPH oxidase enzymes are affected in the EAE mouse model and (ii) to know whether peripheral organs also express these enzymes in the EAE model. MOG(33-55) was administered subcutaneously on two sites over the back. Pertussis toxin was administered intraperitoneally immediately after MOG and again two days later. A significant difference was observed in body weights and clinical signs of EAE-induced mice. MMP-9 and NADPH oxidase enzymes were measured in central nervous system (CNS) tissues, peripheral tissues and plasma of EAE-induced mice. The primary findings include the distribution pattern of MMP-9 in CNS and peripheral tissues, and alterations in the enzymatic expression of MMP-9 and NADPH oxidase in the CNS tissues, spleen and plasma of EAE-induced mice. From these results, it can be considered that the spleen as well as the CNS can act as target organs in EAE disease, and plasma MMP-9 and NADPH oxidase may contribute to the pathogenesis of the disease. PMID:20810258

Kandagaddala, Lakshmi Devi; Kang, Min-Jung; Chung, Bong Chul; Patterson, Tucker A; Kwon, Oh-Seung



[Cellularity and extracellularity: the multi-fibrillar system: from cytoskeleton to connective tissue].  


This brief text aims at illustrating the interactions between connective tissue fibers and cell cytoskeleton fibers. These two networks are connected by molecular bridges at the level of the cell membrane of the cells of the connective and vascular tissues, allowing functional adjustments across the two domains, but also the transduction of forces and tensions into a biochemical alphabet. The signaling between the cell kern and its environment, but equally the other way round, from the environment to the core of the cell, depends on it. PMID:22939699

d'Alessio, P A



Effect of sample geometry on the apparent biaxial mechanical behaviour of planar connective tissues  

Microsoft Academic Search

Mechanical testing methodologies developed for engineering materials may result in artifactual material properties if applied to soft planar connective tissues. The use of uniaxial tissue samples with high aspect ratios or biaxial samples with slender cruciform arms could lead to preferential loading of only the discrete subset of extracellular fibres that fully extend between the grips. To test this hypothesis,

Stephen D. Waldman; J. Michael Lee



Intrinsic connective tissue abnormalities in the heart muscle of cardiomyopathic Syrian hamsters.  

PubMed Central

Significant connective tissue abnormalities occurring in hearts of cardiomyopathic Syrian hamsters are reported. These abnormalities include a pronounced loss of the intrinsic connective tissue skeletal framework around foci of myocytolytic necrosis within the non-necrotic myocardium. These changes were demonstrated by a silver impregnation technique, and they were confirmed by scanning electron microscopy. Quantitation demonstrated more than a twofold increase in the area of ventricular wall affected by pathologic changes, when the connective tissue alterations were included with the myocardial necrosis. In addition, the authors also observed focal, thick "tethering" connective tissue fibers at the termini of necrotic lesions, seemingly connecting them to normal muscle. These connective tissue abnormalities may contribute to the progressive loss of ventricular function that occurs in this model of cardiomyopathy. They may permit greater wall thinning than would occur with focal necrosis alone, and they may increase focal mural stiffness in the tethered regions. Further investigation of the pathogenesis of these changes and their mechanical significance is indicated. Images Figure 5 Figure 6 Figure 1 Figure 2 Figure 3 Figure 4

Cohen-Gould, L.; Robinson, T. F.; Factor, S. M.



Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry.  


Autoimmune uveitis is a blinding disease presenting with autoantibodies against eye-specific proteins as well as autoagressive T cells invading and attacking the immune-privileged target tissue retina. The molecular events enabling T cells to invade and attack the tissue have remained elusive. Changes in membrane protein expression patterns between diseased and healthy stages are especially interesting because initiating events of disease will most likely occur at membranes. Since disease progression is accompanied with a break-down of the blood-retinal barrier, serum-derived proteins mask the potential target tissue-related changes. To overcome this limitation, we used membrane-enriched fractions derived from retinas of the only available spontaneous animal model for the disease equine recurrent uveitis, and compared expression levels by a label-free LC-MSMS-based strategy to healthy control samples. We could readily identify a total of 893 equine proteins with 57% attributed to the Gene Ontology project term "membrane." Of these, 179 proteins were found differentially expressed in equine recurrent uveitis tissue. Pathway enrichment analyses indicated an increase in proteins related to antigen processing and presentation, TNF receptor signaling, integrin cell surface interactions and focal adhesions. Additionally, loss of retina-specific proteins reflecting decrease of vision was observed as well as an increase in Müller glial cell-specific proteins indicating glial reactivity. Selected protein candidates (caveolin 1, integrin alpha 1 and focal adhesion kinase) were validated by immunohistochemistry and tissue staining pattern pointed to a significant increase of these proteins at the level of the outer limiting membrane which is part of the outer blood-retinal barrier. Taken together, the membrane enrichment in combination with LC-MSMS-based label-free quantification greatly increased the sensitivity of the comparative tissue profiling and resulted in detection of novel molecular pathways related to equine recurrent uveitis. PMID:20601722

Hauck, Stefanie M; Dietter, Johannes; Kramer, Roxane L; Hofmaier, Florian; Zipplies, Johanna K; Amann, Barbara; Feuchtinger, Annette; Deeg, Cornelia A; Ueffing, Marius



Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue.  


Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison's disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn's disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations. PMID:23076337

Zheng, J; Ibrahim, S; Petersen, F; Yu, X



Shear Strain and Motion of the Subsynovial Connective Tissue and Median Nerve During Single Digit Motion  

PubMed Central

Purpose The objective of this study was to measure the relative motion of the middle finger flexor digitorum superficialis tendon, its adjacent subsynovial connective tissue, and the median nerve during single digit motion within the carpal tunnel in human cadaver specimens, and estimate the relative motions of these structures in different wrist positions. Methods Using fluoroscopy during simulated single digit flexion, we measured the relative motion of the middle finger flexor digitorum superficialis (FDS) tendon, subsynovial connective tissue and median nerve within the carpal tunnel in twelve human cadavers. Measurements were obtained for three wrist positions: neutral; 60 degrees flexion; and 60 degrees extension. After testing with an intact carpal tunnel was completed, the flexor retinaculum was cut with a scalpel and the same testing procedure was repeated for each wrist position. The relative motions of the tendon, subsynovial connective tissue and median nerve were compared using a shear index, defined as the ratio of the difference in motion along the direction of tendon excursion between two tissues divided by tendon excursion, expressed as a percentage. Results Both tendon-subsynovial connective tissue and tendon-nerve shear index were significantly higher in the 60 degrees of wrist flexion and extension positions, compared to the neutral position. After division of the flexor retinaculum, the shear index in the 60 degrees of wrist extension position remained significantly different, compared to the neutral position. Conclusions In summary, we have found that the relative motion between a tendon and subsynovial connective tissue in the carpal tunnel is maximal at extremes of wrist motion. These positions may predispose the subsynovial connective tissue to shear injury.

Yoshii, Yuichi; Zhao, Chunfeng; Henderson, Jacqueline; Zhao, Kristin D.; An, Kai-Nan; Amadio, Peter C.



Cell-matrix and cell-cell contacts of myofibroblasts: role in connective tissue remodeling.  


It is presently accepted that fibroblast/myofibroblast modulation represents a crucial step in granulation tissue contraction and in the production of the connective tissue deformations typical of fibrocontractive diseases. In addition to synthesizing extracellular matrix (ECM) components, myofibroblasts can develop tensile force through the neoformation of alpha-smooth muscle actin (alpha-SMA) containing cytoplasmic stress fibers. Tension has been shown to be a crucial regulator of connective tissue remodeling. In order to coordinate tension distribution within connective tissue, cell-matrix and cell-cell contacts appear essential. This review addresses the formation, molecular structure and function of such structures that are characterized by their association with intracytoplasmic actin filaments. Actin associated cell-matrix adhesions appear to provide the interface between ECM components and intracellular stress fibers, thus contributing to the transmission of force to the substrate and to the detection of stress level in the matrix. Cell-cell adherens junctions appear to synchronize myofibroblast contractile activity. Further studies investigating the functions of these structures will be important for the understanding of the mechanisms of granulation tissue evolution and for the planification of strategies in view of influencing connective tissue deformations. PMID:14652629

Hinz, Boris; Gabbiani, Giulio



Associated Autoimmune Diseases  


... follow up with the doctor? With the dietitian? Celiac Disease and Associated Autoimmune Diseases: The Connection People who ... is available at www.GLUTEN. net. Advances in celiac disease are fast-paced. If this document is more ...


TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis.  


Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1(-/-) B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1(+) neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy. PMID:23689362

Paltser, Geoffrey; Liu, Xue Jun; Yantha, Jason; Winer, Shawn; Tsui, Hubert; Wu, Ping; Maezawa, Yuko; Cahill, Lindsay S; Laliberté, Christine L; Ramagopalan, Sreeram V; Deluca, Gabriele C; Sadovnick, A Dessa; Astsaturov, Igor; Ebers, George C; Henkelman, R Mark; Salter, Michael W; Dosch, H-Michael



Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis  

PubMed Central

Antibodies against citrullinated proteins are specific and predictive markers for rheumatoid arthritis although the pathologic relevance of these antibodies remains unclear. To investigate the significance of these autoantibodies, collagen-induced arthritis (CIA) in mice was used to establish an animal model of antibody reactivity to citrullinated proteins. DBA/1J mice were immunized with bovine type II collagen (CII) at days 0 and 21, and serum was collected every 7 days for analysis. Antibodies against both CII and cyclic citrullinated peptide, one such citrullinated antigen, appeared early after immunization, before joint swelling was observed. Further, these antibodies demonstrated specific binding to citrullinated filaggrin in rat esophagus by indirect immunofluorescence and citrullinated fibrinogen by Western blot. To evaluate the role of immune responses to citrullinated proteins in CIA, mice were tolerized with a citrulline-containing peptide, followed by antigen challenge with CII. Tolerized mice demonstrated significantly reduced disease severity and incidence compared with controls. We also identified novel murine monoclonal antibodies specific to citrullinated fibrinogen that enhanced arthritis when coadministered with a submaximal dose of anti-CII antibodies and bound targets within the inflamed synovium of mice with CIA. These results demonstrate that antibodies against citrullinated proteins are centrally involved in the pathogenesis of autoimmune arthritis.

Kuhn, Kristine A.; Kulik, Liudmila; Tomooka, Beren; Braschler, Kristin J.; Arend, William P.; Robinson, William H.; Holers, V. Michael



TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis  

PubMed Central

Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1?/? B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.

Paltser, Geoffrey; Liu, Xue Jun; Yantha, Jason; Winer, Shawn; Tsui, Hubert; Wu, Ping; Maezawa, Yuko; Cahill, Lindsay S; Laliberte, Christine L; Ramagopalan, Sreeram V; DeLuca, Gabriele C; Sadovnick, A Dessa; Astsaturov, Igor; Ebers, George C; Henkelman, R Mark; Salter, Michael W; Dosch, H-Michael



Significance of connective tissue proliferation in the breakdown of cartilage: a novel in vivo model.  

PubMed Central

The implantation of homologous femoral head cartilage in subcutaneous tissues of random bred Wistar rats results in both subchondral and articular surfaces becoming overlaid by an adherent granulation tissue comprising predominantly fibroblast-like cells. The response of the tissue to cartilage encapsulated with cotton fibres was also similar but erosions, mainly subchondral, were more evident and proteoglycan loss markedly greater. The connective tissue response to cotton was the progressive formation of a foreign body granuloma comprising mononuclear cells, multinucleated giant cells, and fibroblasts with very few polymorphonuclear leucocytes. Images

De Brito, F B; Moore, A R; Adhya, S; Al-Duaij, A Y; Willoughby, D A



[Binding affinity of ibuprofen to collagen and other connective tissue components].  


In vitro binding of ibuprofen to various tissue components was studied to explain differences in tissue concentration after local application of ibuprofen cream (Dolgit Creme). Radioactive ibuprofen was incubated with human Collagen Type I to V, Elastine, bovine, Mouse-Laminin, and Matrigel of the mouse, respectively. In low concentrations--similar to plasmaconcentrations after percutaneous application of ibuprofen--a specific binding especially to Laminin and Collagen Type IV could be found. This finding possibly explains previous autoradiographic results, which showed higher concentrations of ibuprofen in connective tissue compared with fat and other surrounding tissues. PMID:2357251

Menzel, E J; Kolarz, G



Diagnostic and management problems in a complex case of connective tissue disease.  


A 28-year-old Nigerian woman presented with persistent pyrexia, marked pruritus, eosinophilia, myalgias, flitting arthralgias, serositis and massive splenomegaly. Intensive investigation for an infective or neoplastic aetiology proved negative. Empirical treatment for helminthic infections and tuberculosis was unhelpful. Although there were no specific clues to suggest an underlying connective tissue disease, a trial of steriods and azathioprine was introduced, with no obvious response. Her condition deteriorated to a point where it was decided that intravenous immunosuppressive therapy was needed and subsequently, her condition improved remarkably. This patient illustrates the problems in the diagnosis and management of complex disorders, particularly when classical tests for connective tissue diseases are absent. Also, we would like to report that marked pruritus can be associated with connective tissue disease. PMID:8552544

Yeap, S S; Deighton, C M; Powell, R J; Read, R C; Finch, R G



Diagnostic and management problems in a complex case of connective tissue disease.  

PubMed Central

A 28-year-old Nigerian woman presented with persistent pyrexia, marked pruritis, eosinophilia, myalgias, flitting arthralgias, serositis and massive splenomegaly. Intensive investigation for an infective or neoplastic aetiology proved negative. Empirical treatment for helminthic infections and tuberculosis was unhelpful. Although there were no specific clues to suggest an underlying connective tissue disease, a trial of steriods and azathioprine was introduced, with no obvious response. Her condition deteriorated to a point where it was decided that intravenous immunosuppressive therapy was needed and subsequently, her condition improved remarkably. This patient illustrates the problems in the diagnosis and management of complex disorders, particularly when classical tests for connective tissue diseases are absent. Also, we would like to report that marked pruritis can be associated with connective tissue disease.

Yeap, S. S.; Deighton, C. M.; Powell, R. J.; Read, R. C.; Finch, R. G.



Epithelial and Connective Tissue Cell CTGF/CCN2 expression in Gingival Fibrosis  

PubMed Central

Gingival overgrowth and fibrosis is a side effect of certain medications and occurs in non-drug induced forms either as inherited (human gingival fibromatosis) or idiopathic gingival overgrowth. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Connective tissue growth factor (CTGF/CCN2) expression is positively related to the degree of fibrosis in these tissues. In the present study, the hypothesis was investigated that CTGF/CCN2 is expressed in human gingival fibromatosis tissues and contributes to this form of non-drug-induced gingival overgrowth. Histopathology/immunohistochemistry studies show that human gingival fibromatosis lesions are highly fibrotic, similar to phenytoin-induced lesions. Connective tissue CTGF/CCN2 levels were equivalent to the expression in phenytoin-induced gingival overgrowth. The additional novel observation was made that CTGF/CCN2 is highly expressed in the epithelium of fibrotic gingival tissues. This finding was confirmed by in situ hybridization. Real time PCR analyses of RNA extracted from control and drug-induced gingival overgrowth tissues for CTGF/CCN2 were fully consistent with these findings. Finally, normal primary gingival epithelial cell cultures were analyzed for the basal and TGF-?1 or lysophosphatidic acid stimulated CTGF/CCN2 expression at the protein and RNA levels. Data indicate that fibrotic human gingival tissues express CTGF/CCN2 in both the epithelium and connective tissues and cultured gingival epithelial cells express CTGF/CCN2, and lysophosphatidic acid further stimulates CTGF/CCN2 expression. These findings suggest that interactions between epithelial and connective tissues could contribute to gingival fibrosis.

Kantarci, Alpdogan; Black, Samuel A.; Xydas, Cristina E.; Murawel, Peggy; Uchida, Yuushi; Yucekal-Tuncer, Berrak; Atilla, Gul; Emingil, Gulnur; Uzel, Mehmet Ilhan; Lee, Alan; Firatli, Erhan; Sheff, Michael; Hasturk, Hatice; Van Dyke, Thomas E.; Trackman, Philip C.



Fibroblast spreading induced by connective tissue stretch involves intracellular redistribution of alpha- and beta-actin.  


Mechanical stretching of connective tissue occurs with normal movement and postural changes, as well as treatments including physical therapy, massage and acupuncture. Connective tissue fibroblasts were recently shown to respond actively to short-term mechanical stretch (minutes to hours) with reversible cytoskeletal remodeling, characterized by extensive cell spreading and lamellipodia formation. In this study, we have examined the effect of tissue stretch on the distribution of alpha- and beta-actin in subcutaneous tissue fibroblasts ex vivo. Normal fibroblasts uniformly exhibited alpha-smooth muscle actin (alpha-SMA) immunoreactivity. Unlike cultured fibroblasts and smooth muscle cells, alpha-SMA in these fibroblasts was not in F-actin form (indicated by lack of phalloidin co-localization) nor was it organized into distinct stress fibers. The lack of stress fibers and fibronexus was confirmed by electron microscopy, indicating that these cells were not myofibroblasts. In unstretched tissue, the pattern of alpha-actin was diffuse and granular. With tissue stretch (30 min), alpha-actin formed a star-shaped pattern centered on the nucleus, while beta-actin extended throughout the cytoplasm including lamellipodia and cell cortex. This dual response pattern of alpha- and beta-actin may be an important component of cellular mechanotransduction mechanisms relevant to physiologic and therapeutic mechanical forces applied to connective tissue. PMID:16416024

Langevin, Helene M; Storch, Kirsten N; Cipolla, Marilyn J; White, Sheryl L; Buttolph, Thomas R; Taatjes, Douglas J



Rheumatic manifestations of autoimmune thyroid disease: the other autoimmune disease.  


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



[Paravasal connective tissue of the in-wall blood vessels of the heart during aging].  


The structural organization of the paravasal connective tissue of the in-wall myocardial blood vessels in the stages of postnatal ontogenesis was studied. The study was carried out on preparations of the heart 80 corpses of men in three age groups (the first period of adulthood (n = 20) and elderly (n = 30) and old (n = 30) ages.) The peculiarities of the structure as well as qualitative and quantitative transformation of fibrous component of the paravasal connective tissue in each age period were revealed. PMID:23734505

Nikel', V V; Kasimtsev, A A; Efremova, V P



Hereditary Connective Tissue Diseases in Young Adult Stroke: A Comprehensive Synthesis  

PubMed Central

Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis.

Vanakker, Olivier M.; Hemelsoet, Dimitri; De Paepe, Anne



Energy expenditure associated with softening and stiffening of echinoderm connective tissue.  


Catch connective tissue of echinoderms at rest (in the standard state) either stiffens or softens in response to different kinds of stimulation. The energy consumption associated with the changes was estimated by measurement of the oxygen consumption rate (VO(2)) in three types of connective tissues-echinoid catch apparatus (CA), holothuroid body-wall dermis (HD), and asteroid body-wall dermis (AD). Mechanical stimulation by repetitive compression (10%-15% strain), which increased viscosity measured by creep tests, was employed for inducing the stiff state. Noradrenaline (10(-3) mol l(-1)), which decreased viscosity of CA, and static 80% compressive strain, which decreased viscosity of HD, were used to induce the soft state in the respective tissues. The VO(2) (in ?l/g/h) values of the standard state were 2.91 (CA), 1.41 (HD), and 0.56 (AD), which were less than 1/4 of the VO(2) of the resting body-wall muscle of the starfish. The VO(2) of the stiff state was about 1.5 times greater than that of the standard state in all types of connective tissues. The VO(2) of the soft state was 3.4 (CA)-9.1 (HD) times greater than that of the standard state. The economical nature of catch connective tissue in posture maintenance is discussed. PMID:22589405

Motokawa, Tatsuo; Sato, Eriko; Umeyama, Kenichi



A small angle light scattering device for planar connective tissue microstructural analysis  

Microsoft Academic Search

The planar fibrous connective tissues of the body are composed of a dense extracellular network of collagen and elastin fibers\\u000a embedded in a ground matrix, and thus can be thought of as biocomposites. Thus, the quantification of fiber architecture is\\u000a an important step in developing an understanding of the mechanics of planar tissues in health and disease. We have used

Michael S. Sacks; David B. Smith; Erik D. Hiester



TGF ?1 and PDGF AA override Collagen type I inhibition of proliferation in human liver connective tissue cells  

Microsoft Academic Search

BACKGROUND: A marked expansion of the connective tissue population and an abnormal deposition of extracellular matrix proteins are hallmarks of chronic and acute injuries to liver tissue. Liver connective tissue cells, also called stellate cells, derived from fibrotic liver have been thoroughly characterized and correspond phenotypically to myofibroblasts. They are thought to derive from fat-storing Ito cells in the perisinusoidal

Alvaro T Geremias; Marcelo A Carvalho; Radovan Borojevic; Alvaro NA Monteiro



Connective Tissue Growth Factor is Involved in Pancreatic Repair and Tissue Remodeling in Human and Rat Acute Necrotizing Pancreatitis  

PubMed Central

Objective To analyze the involvement of connective tissue growth factor (CTGF) in the transforming growth factor-? (TGF-?) pathway during acute necrotizing pancreatitis (ANP) in humans and rats. Summary Background Data Connective tissue growth factor is involved in several fibrotic diseases and has a critical role in fibrogenesis and tissue remodeling after injury. Methods Normal human pancreas tissue samples were obtained through an organ donor program from five individuals without a history of pancreatic disease. Human ANP tissues were obtained from eight persons undergoing surgery for this disease. In rats, ANP was induced by intraductal infusion of taurocholate. The expression of CTGF was studied by Northern blot analysis, in situ hybridization, and immunohistochemistry in both human and rat pancreatic tissue samples. Results Northern blot analysis revealed enhanced CTGF mRNA expression in human ANP tissue samples compared with normal controls. In addition, a concomitant increase in TGF-?1 was present. By in situ hybridization, CTGF mRNA was localized in the remaining acinar and ductal cells and in fibroblasts. In regions of intense damage adjacent to areas of necrosis, CTGF mRNA signals were most intense. Inflammatory cells were devoid of any CTGF mRNA signals. By immunohistochemistry, CTGF protein was localized at high levels in the same cell types as CTGF mRNA. In ANP in rats, concomitantly enhanced mRNA levels of CTGF, TGF-?1, and collagen type 1 were present, with a biphasic peak pattern on days 2 to 3 and day 7 after induction of ANP. Conclusions These data indicate that CTGF participates in tissue remodeling in ANP. The expression of CTGF predominantly in the remaining acinar and ductal cells indicates that extracellular matrix synthesis after necrosis is at least partly regulated by the remaining pancreatic parenchyma and only to a minor extent by inflammatory cells. Blockage of CTGF, a downstream mediator of TGF-? in fibrogenesis, might be useful as a target to influence and reduce fibrogenesis in this disorder.

di Mola, Fabio F.; Friess, Helmut; Riesle, Erick; Koliopanos, Alexander; Buchler, Peter; Zhu, Zhaowen; Brigstock, David R.; Korc, Murray; Buchler, Markus W.



Zebrafish collagen XII is present in embryonic connective tissue sheaths (fascia) and basement membranes.  


Connective tissues ensure the cohesion of the tissues of the body, but also form specialized structures such as tendon and bone. Collagen XII may enhance the stability of connective tissues by bridging collagen fibrils, but its function is still unclear. Here, we used the zebrafish model to visualize its expression pattern in the whole organism. The zebrafish col12a1 gene is homologous to the small isoform of the tetrapod col12a1 gene. In agreement with the biochemical data reported for the small isoform, the zebrafish collagen XII alpha1 chain was characterized as a collagenase sensitive band migrating at approximately 200 kDa. Using newly generated polyclonal antibodies and anti-sense probes, we performed a comprehensive analysis of its expression in developing zebrafish. Collagen XII exhibited a much broader expression pattern than previously thought: it was ubiquitously expressed in the connective tissue sheaths (fascia) that encase the tissues and organs of the body. For example, it was found in sclera, meninges, epimysia and horizontal and vertical myosepta. Collagen XII was also detected in head mesenchyme, pharyngeal arches and within the spinal cord, where it was first expressed within and then at the lateral borders of the floor plate and at the dorsal midline. Furthermore, double immunofluorescence staining with laminin and immunogold electron microscopy revealed that collagen XII is associated with basement membranes. These data suggest that collagen XII is implicated in tissue cohesion by stabilizing fascia and by linking fascia to basement membranes. PMID:18983916

Bader, Hannah L; Keene, Douglas R; Charvet, Benjamin; Veit, Guido; Driever, Wolfgang; Koch, Manuel; Ruggiero, Florence



Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway  

PubMed Central

Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52?/?), which appear phenotypically normal if left unmanipulated. However, Ro52?/? mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52?/? mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23–Th17 pathway.

Espinosa, Alexander; Dardalhon, Valerie; Brauner, Susanna; Ambrosi, Aurelie; Higgs, Rowan; Quintana, Fransisco J.; Sjostrand, Maria; Eloranta, Maija-Leena; Ni Gabhann, Joan; Winqvist, Ola; Sundelin, Birgitta; Jefferies, Caroline A.; Rozell, Bjorn; Kuchroo, Vijay K.



Lung Function Tests in Connective Tissue Diseases Associated with Raynaud’s Phenomenon  

Microsoft Academic Search

13 patients with various connective tissue diseases associated with Raynaud’s phenomenon were studied with pulmonary physiologic techniques to see the alterations of lung functions and also whether spasm of pulmonary circulation occurs in these patients. We found that an increase in the dead space ventilation was common and associated with normal tidal volume. We interpreted this finding as evidence of

Yongyudh Ploysongsang; Baher S. I. Foad



Connective tissue growth factor in indomethacin-induced rat gastric ulcer.  


The healing of gastric ulcers requires not only the complete epithelial covering but also the restitution of connective tissue. Transforming growth factor-beta (TGF-beta) and its downstream mediator, connective tissue growth factor (CTGF), are potent stimulators for connective tissue formation during wound healing. The expression of TGF-beta, CTGF and type III collagen mRNA in indomethacin-induced gastric ulcers in rat, was investigated by Northern blot analysis. We also examined the localization of CTGF producing cells by in situ hybridization. Northern blot analysis showed expression of TGF-beta mRNA on days 1 and 3 after indomethacin administration, expression of CTGF mRNA on days 1, 3 and 7 and type III collagen mRNA expression on days 1, 3, 7 and 12, respectively. Control animals showed no expression of TGF-beta, CTGF or type III collagen mRNA. In situ hybridization showed CTGF mRNA positive cells on days 1, 3 and 7 after ulcer induction in fibroblast-like cells and in some of the blood vessels. Thus our findings indicate that growth factor CTGF, together with TGF-beta, participates in gastric ulcer healing by regulating connective tissue formation and angiogenesis. These results are compatible with the role of CTGF as a downstream mediator of TGF-beta effects. PMID:12077510

Lempinen, Marko; Inkinen, K; Wolff, H; Ahonen, J


Pulmonary vascular reactivity in severe pulmonary hypertension associated with mixed connective tissue disease  

Microsoft Academic Search

Pulmonary vascular reactivity tests were performed in a young woman with mixed connective tissue disease and severe pulmonary hypertension. Vasoreactivity was documented in response to intravenous prostacyclin (PGI2), oral nifedipine, and inhaled nitric oxide, with quantitative differences. Nitric oxide produced a moderate lowering of pulmonary arterial pressure and resistance without any deleterious systemic effect. The use of nitric oxide in

P Jolliet; J B Thorens; J C Chevrolet



Evaluation of muscular lesions in connective tissue diseases: thallium 201 muscular scans  

Microsoft Academic Search

We performed thallium 201 muscle scans to assess muscular involvement in 40 patients with different connective tissue diseases (7 with dermatomyositis, 7 with systemic lupus erythematosus, 12 with progressive systemic scleroderma, 2 with calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome, 3 with monomelic scleroderma, 6 with morphea, and 3 with Raynaud's disease). Only 12 of these patients

G. Guillet; J. Guillet; C SANCIAURAE; J. Maleville; M. Geniaux; P. Morin



Mediastinal lymphadenopathy and pulmonary arterial hypertension in mixed connective tissue disease  

SciTech Connect

A case of mixed connective tissue disease (MCTD) is presented in which mediastinal lymphadenopathy was the most prominent radiological finding detected by plain chest radiographs and computed tomography. Pulmonary arterial hypertension, which is a rare and often fatal complication of MCTD, also developed in this patient.

Guit, G.L.; Shaw, P.C.; Ehrlich, J.; Kroon, H.M.; Oudkerk, M.



Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis  

Microsoft Academic Search

INTRODUCTION: A protein analysis using a mass spectrometry indicated that there are serum proteins showing significant quantitative changes after the administration of infliximab. Among them, connective tissue growth factor (CTGF) seems to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, this study was conducted to investigate how CTGF is associated with the disease progression of RA. METHODS: Serum

Kazuhisa Nozawa; Maki Fujishiro; Mikiko Kawasaki; Hiroshi Kaneko; Kazuhisa Iwabuchi; Mitsuaki Yanagida; Fujihiko Suzuki; Keiji Miyazawa; Yoshinari Takasaki; Hideoki Ogawa; Kenji Takamori; Iwao Sekigawa



The human optic nerve: fascicular organisation and connective tissue types along the extra-fascicular matrix  

Microsoft Academic Search

Fibres in the mammalian optic nerve are arranged into fascicles between which there is an extra-fascicular matrix containing connective tissue, a feature similar to that found in association with fibres in peripheral nerves, but not otherwise found in the CNS. The relationship between these major features of the nerve architecture are not known. We have addressed this question by examining

G. Jeffery; A. Evans; J. Albon; V. Duance; J. Neal; G. Dawidek



Ultraviolet Radiation-Induced Connective Tissue Changes in the Skin of Hairless Mice  

Microsoft Academic Search

Hairless mice (Skh\\/hrl) were exposed to ultraviolet A (UVA; peak irradiance at 365 nm), or to ultraviolet B (UVB; peak irradiance at 313 nm) radiation. The animals received 12 treatments on alternate days. Connective tissue changes in the skin were monitored by assaying hydroxyproline and desmosine as an indication of collagen and elastin concentrations, respectively. The activities of prolyl hydroxylase

Kathryn J. Johnston; Aarne I. Oikarinen; Nicholas J. Lowe; Joan G. Clark; Jouni Uitto



Periostin Regulates Collagen Fibrillogenesis and the Biomechanical Properties of Connective Tissues  

PubMed Central

Periostin is predominantly expressed in collagen-rich fibrous connective tissues that are subjected to constant mechanical stresses including: heart valves, tendons, perichondrium, cornea, and the periodontal ligament (PDL). Based on these data we hypothesize that periostin can regulate collagen I fibrillogenesis and thereby affect the biomechanical properties of connective tissues. Immunoprecipitation and immunogold transmission electron microscopy experiments demonstrate that periostin is capable of directly interacting with collagen I. To analyze the potential role of periostin in collagen I fibrillogenesis, gene targeted mice were generated. Transmission electron microscopy and morphometric analyses demonstrated reduced collagen fibril diameters in skin dermis of periostin knockout mice, an indication of aberrant collagen I fibrillogenesis. In addition, differential scanning calorimetry (DSC) demonstrated a lower collagen denaturing temperature in periostin knockout mice, reflecting a reduced level of collagen cross-linking. Functional biomechanical properties of periostin null skin specimens and atrioventricular (AV) valve explant experiments provided direct evidence of the role that periostin plays in regulating the viscoelastic properties of connective tissues. Collectively, these data demonstrate for the first time that periostin can regulate collagen I fibrillogenesis and thereby serves as an important mediator of the biomechanical properties of fibrous connective tissues.

Norris, Russell A.; Damon, Brook; Mironov, Vladimir; Kasyanov, Vladimir; Ramamurthi, Anand; Moreno-Rodriguez, Ricardo; Trusk, Thomas; Potts, Jay D.; Goodwin, Richard L.; Davis, Jeff; Hoffman, Stanley; Wen, Xuejun; Sugi, Yukiko; Kern, Christine B.; Mjaatvedt, Corey H.; Turner, Debi K.; Oka, Toru; Conway, Simon J.; Molkentin, Jeffery D.; Forgacs, Gabor; Markwald, Roger R.



Treatment of Raynaud's phenomenon with ketanserin in patients with connective tissue disorders  

Microsoft Academic Search

The serotonin receptor blocker ketanserin was given orally in a double blind crossover study to 10 patients with connective tissue disorders and Raynaud's phenomenon. Eight of the 10 patients improved clinically on ketanserin and none on placebo. Digital blood flow was assessed with laser Doppler flowmetry (LDF), photoplethysmography, and skin temperature measurements. Laser Doppler flowmetry was the most useful method,

O K Roald; E Seem



Safety and efficacy of iloprost for the treatment of ischaemic digits in paediatric connective tissue diseases  

Microsoft Academic Search

Objective. We analysed our experience with the use of iloprost for the treatment of critical ischaemic digits (ID) in children with connective tissue diseases (CTD) in order to assess its safety and efficacy. Methods. This was a retrospective analysis of paediatric patients with CTD who were treated with iloprost for critical ID resistant to conventional therapy. Information on demographics, clinical

F. Zulian; F. Corona; V. Gerloni; F. Falcini; A. Buoncompagni; M. Scarazatti; G. Martini; F. Zacchello



Durability of thoracoabdominal aortic aneurysm repair in patients with connective tissue disorders  

Microsoft Academic Search

Objective: Thoracoabdominal aortic aneurysm (TAAA) repair is a durable procedure performed with reasonable perioperative mortality and morbidity in patients with atherosclerotic aortic disease. However, the long-term outcome and durability of TAAA repair performed in patients with a connective tissue disorder (CTD) is not well known. Methods: The records of 257 patients who underwent TAAA repair at the Johns Hopkins Hospital

Alan Dardik; Teresa Krosnick; Bruce A. Perler; Glen S. Roseborough; G. Melville Williams



Foreign Body in the Oral Cavity Mimicking a Benign Connective Tissue Tumor  

PubMed Central

Foreign bodies may be embedded in the oral cavity either by traumatic injury or iatrogenically. The commonly encountered iatrogenic foreign bodies are restorative materials like amalgam, obturation materials, broken instruments, needles, and impression materials. This paper describes an asymptomatic presentation of a foreign body in the oral mucosa which clinically appeared like a benign connective tissue tumor.

Ram, Saravanan; Sedghizadeh, Parish P.



The arrangement and function of octopus arm musculature and connective tissue  

Microsoft Academic Search

The morphology of the musculature and connective tissues of the arms of Octopus bimaculoides was analyzed with light microscopy. We also studied O. briareus and O. digueti, which possess relatively more elongate and less elongate arms, respectively. The mor- phology of the arms was found to be remarkably uniform among species. The arms consist of a densely packed three-dimensional arrangement

William M. Kier; Michael P. Stella



Initial characterization of the microenvironment that regulates connective tissue degradation in amniochorion during normal human labor  

Microsoft Academic Search

Extracellular matrix degradation in fetal membranes leading to its rupture is coupled to myometrial activity and cervical ripening during human normal labor. Mechanisms which modulate collagen degradation in amniochorion during labor have not been elucidated. Initial characterization of the effect of different blood compartments on connective tissue degradation in amniochorion during human labor was explored. Amniochorion explants were stimulated with

Guadalupe Estrada-Gutierrez; Veronica Zaga; Marco Antonio Gonzalez-Jimenez; Jorge Beltran-Montoya; Rolando Maida-Claros; Silvia Giono-Cerezo; Felipe Vadillo-Ortega



Optimizing Gingival Biotype Using Subepithelial Connective Tissue Graft: A Case Report and One-Year Followup  

PubMed Central

Gingival recession is the exposure of root surfaces due to apical migration of the gingival tissue margins. The principal objectives of treating a gingival recession are to achieve better esthetics and reduce hypersensitivity. The gingival biotype is an important modifying factor in the treatment of gingival recession. The purpose of this paper is to highlight the significance of changing the soft tissue biotype to a more favorable one while attempting root coverage, to achieve more stable and long-lasting results using subepithelial connective tissue graft.

Grover, Harpreet Singh; Yadav, Anil; Yadav, Priya; Nanda, Prashant



Effect of enamel matrix proteins on the periodontal connective tissue-material interface after wound healing.  


The periodontal ligament has the potential to regenerate a complete periodontal connective tissue attachment, starting with the deposition of cementum, on pathologically exposed root surfaces as well as several materials including titanium oxide. However, most commonly used dental materials result in a fibrous encapsulation or a chronic inflammatory response after periodontal wound healing rather than the formation of a periodontal connective tissue attachment. Recently, an extract of porcine enamel matrix (Emdogain(R), EMD) has been reported inductive of cementum formation in both in vivo and in vitro studies. The aim of this study was to determine the effect of EMD, when applied to materials previously reported not supportive of periodontal connective tissue formation, on the periodontal connective tissue-material interface obtained with these materials in vivo. Bilateral osteotomies were performed on the mandible of a Yucatan minipig exposing the buccal root surface of four premolars. A series of four preparations were placed in each root surface that were subsequently filled with calcium hydroxide, gutta percha, mineral trioxide aggregate (MTA), or left unfilled. One side, in addition, received an application of EMD prior to surgical closure. A bioabsorbable surgical barrier membrane was placed over the osteotomy sites to exclude gingival connective tissue from the wound-healing environment. The mucoperiosteal flaps were then readapted and sutured in position. The animal was euthanized 10 weeks after the procedure, block sections obtained and prepared for light microscopy. Results demonstrated complete regeneration of alveolar bone and periodontal ligament in all four teeth from the EMD-treated side. Fibers from the periodontal ligament were observed to insert into a mineralized matrix consistent with cementum on all four root preparations. In contrast, massive root resorption without regeneration of alveolar bone was found on all teeth from the side not treated with EMD. The results of this pilot study suggest that the application of EMD to material surfaces that normally do not support periodontal connective tissue attachment formation can alter the type of periodontal connective tissue interface obtained with these materials. PMID:14999766

Craig, R G; Kallur, S P; Inoue, M; Rosenberg, P A; LeGeros, R Z



A novel composition for in vitro and in vivo regeneration of skin and connective tissues.  


The particular combination of polydeoxyribonucleotides, l-carnitine, calcium ions, proteolytic enzyme and other ingredients acts in a synergetic way in the regeneration of skin and connective tissues. This new formulation of active principles was tested in vitro as a cell and tissue culture medium and in vivo for various preparations in support of tissue regeneration. In vitro, the new blend allowed the maintenance of skin biopsies for more than 1 year in eutrophic conditions. Immunocytochemical analyses of fibroblasts isolated from these biopsies confirmed a significant increase of the epidermal and connective wound-healing markers such as collagen type I, collagen type IV, cytokeratin 1 (CK1), CK5, CK10 and CK14 versus controls. To examine the effects of the new compound in vivo, we studied impaired wound healing in genetically diabetic db/db mice. At day 18, diabetic mice treated with the new composition showed 100% closure of wounds and faster healing than mice treated with the other solutions. This complex of vital continuity factors or life-keeping factors could be used as a tissue-preserving solution or a cosmetic/drug/medical device to accelerate wound healing in the treatment of patients with deficient wound repair to promote the regeneration of cutaneous and connective tissues (injuries-wound, dermatitis) and prevent the recurrent relapses. PMID:21491468

Gennero, Luisa; De Siena, Rocco; Denysenko, Tetyana; Roos, Maria Augusta; Calisti, Gian Franco; Martano, Manuela; Fiobellot, Simona; Panzone, Michele; Reguzzi, Stefano; Gabetti, Luisa; Vercelli, Andrea; Cavallo, Giovanni; Ricci, Elia; Pescarmona, Gian Piero



Ultrasound evidence of altered lumbar connective tissue structure in human subjects with chronic low back pain  

PubMed Central

Background Although the connective tissues forming the fascial planes of the back have been hypothesized to play a role in the pathogenesis of chronic low back pain (LBP), there have been no previous studies quantitatively evaluating connective tissue structure in this condition. The goal of this study was to perform an ultrasound-based comparison of perimuscular connective tissue structure in the lumbar region in a group of human subjects with chronic or recurrent LBP for more than 12 months, compared with a group of subjects without LBP. Methods In each of 107 human subjects (60 with LBP and 47 without LBP), parasagittal ultrasound images were acquired bilaterally centered on a point 2 cm lateral to the midpoint of the L2-3 interspinous ligament. The outcome measures based on these images were subcutaneous and perimuscular connective tissue thickness and echogenicity measured by ultrasound. Results There were no significant differences in age, sex, body mass index (BMI) or activity levels between LBP and No-LBP groups. Perimuscular thickness and echogenicity were not correlated with age but were positively correlated with BMI. The LBP group had ~25% greater perimuscular thickness and echogenicity compared with the No-LBP group (ANCOVA adjusted for BMI, p < 0.01 and p < 0.001 respectively). Conclusion This is the first report of abnormal connective tissue structure in the lumbar region in a group of subjects with chronic or recurrent LBP. This finding was not attributable to differences in age, sex, BMI or activity level between groups. Possible causes include genetic factors, abnormal movement patterns and chronic inflammation.




ERIC Educational Resources Information Center

Connectivity has dramatically changed the landscape of higher education IT. From "on-demand" services for net-gen students and advanced eLearning systems for faculty, to high-performance computing grid resources for researchers, IT now provides more networked services than ever to connect campus constituents to each other and to the world.…

Grush, Mary, Ed.



Morphological and histochemical changes in the connective tissue of the skin of newborn albino rats from mothers with pancreatic dysfunction  

Microsoft Academic Search

There were changes of the quantitative content of mucopolysaccharides in the skin connective tissue of embryos and newborn rats from mother rats with pancreatic dysfunction. In experimentally induced hypoglycemia there is a reduction of the mucopolysaccharide content in the ground substance of the skin connective tissue; it rises in experimental alloxan diabetes. There were no other changes of the ground

V. P. Zhuk; M. Ya; N. A. Kraevskii



Specialized connective tissue: bone, the structural framework of the upper extremity  

PubMed Central

Bone is a connective tissue containing cells, fibers and ground substance. There are many functions in the body in which the bone participates, such as storing minerals, providing internal support, protecting vital organs, enabling movement, and providing attachment sites for muscles and tendons. Bone is unique because its collagen framework absorbs energy, while the mineral encased within the matrix allows bone to resist deformation. This article provides an overview of the structure and function of bone tissue from a macroscopic to microscopic level and discusses the physiological processes contributing to upper extremity bone health. It concludes by discussing common conditions influencing upper extremity bone health.

Weatherholt, Alyssa M.; Fuchs, Robyn K.; Warden, Stuart J.



Stem cell therapy for autoimmune disease: overview of concepts from the Snowbird 2002 tolerance and tissue regeneration meeting.  


Hematopoietic stem cell transplantation as a treatment for autoimmune disease began in 1996 and has subsequently spread worldwide. In Europe phase III trials have opened, while in America phase III trials are being designed and funded by the National Institutes of Health. On 6 June 2002, clinicians and scientists from around the world met at Snowbird, Utah to discuss the results and future directions of stem cell therapy for autoimmune diseases. What follows are general concepts from chairpersons of this meeting. PMID:12931231

Burt, R K; Arnold, R; Emmons, R; Oyama, Y; Marmont, A



The connective tissue response to Ti, NiCr and AgPd alloys.  


The aim of the study was to compare the connective tissue response of Lewis rats to Ti, NiCr and AgPd alloys. It was found that implants were covered by collagen-rich, well vascularized capsules. Titanium was covered by the thinnest capsule (57 ± 20 ?m) and AgPd alloy was covered by the thickest capsule (239 ± 50 ?m). The PCNA+ cell prevalence in the capsules was lower for titanium than for AgPd and NiCr. Mast cells formed a gradient to a depth of 1200 ?m only for titanium implants. Cells with brown to black silver granules in the cytoplasm were observed close to AgPd implants. The results suggest that titanium implants induce a weaker connective tissue response than implants made from NiCr and AgPd alloys. PMID:21071336

?ukomska-Syma?ska, Monika; Brzezi?ski, Piotr M; Zieli?ski, Andrzej; Soko?owski, Jerzy



Genetic dissection of marfan syndrome and related connective tissue disorders: an update 2012.  


Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue characterized by early development of thoracic aortic aneurysms/dissections together with symptoms of the ocular and skeletal systems. While most patients/families with a classic phenotypic expression of MFS harbour mutations in the gene encoding fibrillin-1 (FBN1), genetic studies of the recent years revealed that the clinical features, as well as the mutated genes, show a high degree of overlap between MFS and other connective tissue diseases (e.g. Loeys-Dietz syndrome, Ehlers-Danlos syndrome, familial thoracic aneurysms and dissections and others). We summarize herein the current knowledge about the wide spectrum of differential diagnoses and their genetic background as well as novel therapeutic approaches in order to provide appropriate counselling and clinical follow-up for the patients. PMID:23326250

Hoffjan, S



Invertebrate connective tissue. Isolation of d-arabinose from sponge acidic polysaccharide  

PubMed Central

1. d-Arabinose, an extremely rare sugar in the animal kingdom, was isolated from a complex acidic polysaccharide obtained from the connective tissue of the sponge Hippospongia gossypina. A crystalline derivative of arabinose, the 1-benzyl-1-phenylhydrazone, was prepared and characterized by its melting point, optical rotation, and mixed melting point with authentic d- and l-enantiomers. 2. The distribution of arabinose within the animal kingdom is discussed, and a biological role is proposed for the spongonucleotides.

Katzman, Richard L.; Lisowska, Elwira; Jeanloz, Roger W.



Pulmonary vascular reactivity in severe pulmonary hypertension associated with mixed connective tissue disease.  


Pulmonary vascular reactivity tests were performed in a young woman with mixed connective tissue disease and severe pulmonary hypertension. Vasoreactivity was documented in response to intravenous prostacyclin (PGI2), oral nifedipine, and inhaled nitric oxide, with quantitative differences. Nitric oxide produced a moderate lowering of pulmonary arterial pressure and resistance without any deleterious systemic effect. The use of nitric oxide in testing for pulmonary vasoreactivity merits further evaluation. PMID:7886662

Jolliet, P; Thorens, J B; Chevrolet, J C



Value of Finger Arterial Blood Pressure in Diagnosis of Vascular Changes in Some Connective Tissue Diseases  

Microsoft Academic Search

This study was performed in 60 patients with the following connective tissue diseases: rheumatoid arthritis (RA—20 patients), systemic lupus erythematosus (SLE—20), and progressive systemic sclerosis (scleroderma=PSS-20). Twenty normal persons served as controls.All patients and controls were subjected to complete history taking, complete physical examination, and laboratory investigations including: rheumatoid fac tor, anti-DNA, LE cell test, antinuclear factor (ANF), and ECG.Finger

Mohamed El-Sayed Salem; Amira Hassan El-Girby; Nadia Ahmed Abd El-Moneim; Selim Ahmed Khalil



Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a growth and chemotactic factor for fibroblasts encoded by an immediate early gene that is transcriptionally activated by transforming growth factor-b. Previous studies have shown that both CTGF messenger ribonuclear acid (mRNA) and protein are expressed in renal fibrosis and bleomycin-induced pulmonary fibrosis in mice. The aim of the present study was to investigate

L. H. Pan; K. Yamauchi; M. Uzuki; T. Nakanishi; M. Takigawa; H. Inoue; T. Sawai



Connective tissue growth factor: Potential role in glomerulosclerosis and tubulointerstitial fibrosis  

Microsoft Academic Search

Connective tissue growth factor: Potential role in glomerulosclerosis and tubulointerstitial fibrosis. Transforming growth factor beta (TGF-?) is a pivotal driver of glomerulosclerosis and tubulointerstitial fibrosis in renal diseases. Because TGF-? also plays important anti-inflammatory and antiproliferative roles in mammalian systems, there has been a recent drive to elucidate downstream mediators of TGF-?'s pro-fibrotic effects with the ultimate goal of developing

Sunil Gupta; Michael R. Clarkson; Joseph Duggan; Hugh R. Brady



Indices of skeletal muscle damage and connective tissue breakdown following eccentric muscle contractions  

Microsoft Academic Search

Indirect indices of exercise-induced human skeletal muscle damage and connective tissue breakdown were studied following\\u000a a single bout of voluntary eccentric muscle contractions. Subjects (six female, two male), mean (SD) age 22 (2) years performed\\u000a a bout of 50 maximum voluntary eccentric contractions of the knee extensors of a single leg. The eccentric exercise protocol\\u000a induced muscle soreness (P?

S. J. Brown; R. B. Child; S. H. Day; A. E. Donnelly



Cell-mediated immunity against connective tissue in experimental pulmonary fibrosis  

Microsoft Academic Search

Cell-mediated immunity against an extract of homologous normal lung connective tissue was determined in vitro in spleen cells\\u000a from CD1 mice with bleomycin-induced pulmonary fibrosis. Blastoid transformation and macrophage migration inhibitory factor\\u000a (MIF) were measured at intervals in spleen lymphocytes for a total of seven weeks after the initiation of the fibrogenic process.\\u000a MIF production was evident from the third

R. E. Carvajal; R. González; M. Selman




Microsoft Academic Search

The collagens are the major structural glycoproteins of connective tissues. A unique primary structure and a multiplicity of post-translational modification reactions are required for normal fibrillogenesis. The post-translational modifications include hydroxylation of prolyl and lysyl residues, glycosylation, folding of the molecule into triple-helical conformation, proteolytic conversion of precursor procollagen to collagen, and oxidative deamination of certain lysyl and hydroxylysyl residues.

Jouni Uitto; Jack R. Lichtenstein



Undifferentiated Connective Tissue Disease-Associated Interstitial Lung Disease: Changes in Lung Function  

Microsoft Academic Search

Undifferentiated connective tissue disease (UCTD) is a distinct clinical entity that may be accompanied by interstitial lung\\u000a disease (ILD). The natural history of UCTD-ILD is unknown. We hypothesized that patients with UCTD-ILD would be more likely\\u000a to have improvement in lung function than those with idiopathic pulmonary fibrosis (IPF) during longitudinal follow-up. We\\u000a identified subjects enrolled in the UCSF ILD

Brent W. Kinder; Cyrus Shariat; Harold R. Collard; Laura L. Koth; Paul J. Wolters; Jeffrey A. Golden; Ralph J. Panos; Talmadge E. King



Extensive proliferation of mature connective-tissue type mast cells in vitro  

Microsoft Academic Search

There are two phenotypically distinct subpopulations of mast cells in rodents: connective tissue-type mast cells (CTMC) and mucosal mast cells (MMC). These populations differ in their location, cell size, staining characteristics, ultrastructure, mediator content and T-cell dependency1-3. Several investigators4-9 recently reported a further subclass of mast cells which arise when normal mouse haematopoietic cells are cultured with interleukin-3 (IL-3); IL-3

Tatsutoshi Nakahata; Toshimi Kobayashi; Akira Ishiguro; Kohichiro Tsuji; Kuniaki Naganuma; Osaaki Ando; Yoshio Yagi; Kenji Tadokoro; Taro Akabane



Summers' technique modification for sinus floor elevation using a connective tissue graft. A case report.  


The sinus floor elevation technique with Summers' osteotome is simpler and less invasive than access through the lateral wall of the sinus; however, it is susceptible to a higher level of sinusal membrane rupture. The objective of the present study was to display a modification of the osteotomy technique by connective tissue interposition in order to weaken the impact of sinus cortical fracture, and therefore prevent perforations in the sinusal membrane. A case is reported in which a patient presented with an absent tooth #4 for osseointegrated implant rehabilitation. Maxillary sinus elevation was required to perform the procedure. Initially, the flap was raised and the receptor site was prepared with a sequence of burs, without disrupting cortical bone. In order to weaken the fracture impact with the osteotome, a connective tissue graft was interposed to allow access to the sinus. Clinically, a satisfactory primary locking was obtained with torque greater than 50 Ncm. Through radiographic evaluation, good bone filling was observed immediately after surgery, with maxillary sinus wall elevation without membrane rupture. Two years after the initial procedure, a 5.3 mm increase in bone extension formed in contact with implant distal surface was observed. Thus, the osteotomy technique modification with connective tissue interposition was successful, both clinically and radiographically, showing an image suggesting long-term osseous formation. PMID:20593636

Pontes, Fernando Salimon Ribeiro Ana Emília Farias; Zuza, Elizangela Partata; de Toledo, Benedicto Egbert Corręa



Undifferentiated connective tissue disease - an unsolved problem:revision of literature and case studies.  


In clinical practice, patients with a range of signs and symptoms suggestive of connective tissue disease, but who do not fulfil the classification criteria for a defined disease are often found. This condition is defined as, Undifferentiated Connective Tissue Disease (UCTD). Most of the authors consider UCTD as a distinct clinical entity, generally stable during follow-up. Despite this, no mutual agreement regarding criteria for its diagnosis has been reached. The clinical, serological, therapeutical and evolutional patterns of 41 patients initially diagnosed as having early UCTD during a 3-year followup are described in this study. At the end of the observational period, 21 percent of the enrolled patients, followed throughout the follow-up, demonstrated clinical evolution to a defined connective tissue disease (CTD), whereas 52 percent of the observed subjects maintained an undifferentiated profile with variable clinical findings and presenting a generally stable disease over time. The remaining patients showed clinical improvement or complete regression of the symptoms associated with normalization of the inflammatory indexes. The role of therapy in these different clinical courses is discussed. PMID:20378013

Conti, V; Esposito, A; Cagliuso, M; Fantauzzi, A; Pastori, D; Mezzaroma, I; Aiuti, F


Evaluation of the Material Properties of the Subsynovial Connective Tissue in Carpal Tunnel Syndrome  

PubMed Central

Background: The purpose of this study was to determine the material properties of the normal carpal tunnel subsynovial connective tissue in response to shear stress. Methods: The shear modulus and maximum shear strength were measured with a custom-made micro-tester in 10 specimens of subsynovial connective tissue from 10 wrists in 8 patients with idiopathic carpal tunnel syndrome and in 10 specimens from 5 fresh frozen cadavers without a history of carpal tunnel syndrome. Findings: The mean shear modulus was 22.8 (SD 15.4) kPa for the patient group and 2.7 (SD 1.8) kPa for the control group. The mean maximum shear strength was 54.6 (SD 20.3) kPa for the patient group and 23.3 (SD 10.7) kPa for the control group. The values for the patient group were significantly higher than the control group (p < 0.05). Interpretation: The material properties of subsynovial connective tissue are altered in patients with idiopathic carpal tunnel syndrome. The impact, if any, of these altered properties on carpal tunnel syndrome remains to be elucidated.

Osamura, Naoki; Zhao, Chunfeng; Zobitz, Mark E.; An, Kai-Nan; Amadio, Peter C.



Progressive Overgrowth of the Cerebriform Connective Tissue Nevus in Patients with Proteus Syndrome  

PubMed Central

Background Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. Objective Our purpose was to evaluate progression of skin lesions in patients with Proteus syndrome. Methods Skin findings were documented in 36 patients with Proteus syndrome. Progression of skin lesions in 16 of these patients was assessed by comparing photographs obtained on repeat visits for an average total duration of 53 months. Results The skin lesion most characteristic of Proteus syndrome, the cerebriform connective tissue nevus showed progression in 13 children but not in 3 adults. The cerebriform connective tissue nevus progressed by expansion into previously uninvolved skin, increased thickness, and development of new lesions. Lipomas increased in size and/or number in 8/10 children with lipomas. In contrast, epidermal nevi and vascular malformations generally did not spread or increase in number. Limitations Only 3 adults with Proteus syndrome were evaluated longitudinally. Conclusion The cerebriform connective tissue nevus in Proteus syndrome grows throughout childhood but tends to remain stable in adulthood.

Beachkofsky, Thomas M.; Sapp, Julie C.; Biesecker, Leslie G.; Darling, Thomas N.



A physiological role for connective tissue growth factor in early wound healing  

PubMed Central

Mesenchymal stem cells (MSCs) that overexpress secreted frizzled-related protein 2 (sFRP2) exhibit an enhanced reparative phenotype. The secretomes of sFRP2-overexpressing MSCs and vector control-MSCs were compared through liquid chromatography tandem mass spectrometry. Proteomic profiling revealed that connective tissue growth factor (CTGF; CCN2) was overrepresented in the conditioned media of sFRP2-overexpressing MSCs and MSC-derived CTGF could thus be an important paracrine effector. Subcutaneously implanted, MSC-loaded polyvinyl alcohol (PVA) sponges and stented excisional wounds were used as wound models to study the dynamics of CTGF expression. Granulation tissue generated within the sponges and full-thickness skin wounds showed transient upregulation of CTGF expression by MSCs and fibroblasts, implying a role for this molecule in early tissue repair. Although collagen and COL1A2 mRNA were not increased when recombinant CTGF was administered to sponges during the early phase (day 1–6) of tissue repair, prolonged administration (>15 days) of exogenous CTGF into PVA sponges resulted in fibroblast proliferation and increased deposition of collagen within the experimental granulation tissue. In support of its physiological role, CTGF immunoinhibition during early repair (days 0–7) reduced the quantity, organizational quality and vascularity of experimental granulation tissue in the sponge model. However, CTGF haploinsufficiency was not enough to reduce collagen deposition in excisional wounds. Similar to acute murine wound models, CTGF was transiently present in the early phase of human acute burn wound healing. Together, these results further support a physiological role for CTGF in wound repair and demonstrate that when CTGF expression is confined to early tissue repair, it serves a pro-reparative role. These data also further illustrate the potential of MSC-derived paracrine modulators to enhance tissue repair.

Alfaro, Maria P; Deskins, Desirae L; Wallus, Meredith; DasGupta, Jayasri; Davidson, Jeffrey M; Nanney, Lillian B; Guney, Michelle A; Gannon, Maureen; Young, Pampee P



Autoimmune Diseases  


... protects you from disease and infection. But if you have an autoimmune disease, your immune system attacks healthy cells in your body by mistake. Autoimmune diseases can affect many parts of the body. No one is sure ...


Autoimmune Keratitis  

Microsoft Academic Search

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


Molecular regulation of CCN2 in the intervertebral disc: lessons learned from other connective tissues.  


Connective tissue growth factor (CCN2/CTGF) plays an important role in extracellular matrix synthesis, especially in skeletal tissues such as cartilage, bone, and the intervertebral disc. As a result there is a growing interest in examining the function and regulation of this important molecule in the disc. This review discusses the regulation of CCN2 by TGF-? and hypoxia, two critical determinants that characterize the disc microenvironment, and discusses known functions of CCN2 in the disc. The almost ubiquitous regulation of CCN2 by TGF-?, including that seen in the disc, emphasizes the importance of the TGF-?-CCN2 relationship, especially in terms of extracellular matrix synthesis. Likewise, the unique cross-talk between CCN2 and HIF-1 in the disc highlights the tissue and niche specific mode of regulation. Taken together the current literature supports an anabolic role for CCN2 in the disc and its involvement in the maintenance of tissue homeostasis during both health and disease. Further studies of CCN2 in this tissue may reveal valuable targets for the biological therapy of disc degeneration. PMID:23567513

Tran, Cassie M; Shapiro, Irving M; Risbud, Makarand V



Connective tissue fibroblast properties are position-dependent during mouse digit tip regeneration.  


A key factor that contributes to the regenerative ability of regeneration-competent animals such as the salamander is their use of innate positional cues that guide the regeneration process. The limbs of mammals has severe regenerative limitations, however the distal most portion of the terminal phalange is regeneration competent. This regenerative ability of the adult mouse digit is level dependent: amputation through the distal half of the terminal phalanx (P3) leads to successful regeneration, whereas amputation through a more proximal location, e.g. the subterminal phalangeal element (P2), fails to regenerate. Do the connective tissue cells of the mammalian digit play a role similar to that of the salamander limb in controlling the regenerative response? To begin to address this question, we isolated and cultured cells of the connective tissue surrounding the phalangeal bones of regeneration competent (P3) and incompetent (P2) levels. Despite their close proximity and localization, these cells show very distinctive profiles when characterized in vitro and in vivo. In vitro studies comparing their proliferation and position-specific interactions reveal that cells isolated from the P3 and P2 are both capable of organizing and differentiating epithelial progenitors, but with different outcomes. The difference in interactions are further characterized with three-dimension cultures, in which P3 regenerative cells are shown to lack a contractile response that is seen in other fibroblast cultures, including the P2 cultures. In in vivo engraftment studies, the difference between these two cell lines is made more apparent. While both P2 and P3 cells participated in the regeneration of the terminal phalanx, their survival and proliferative indices were distinct, thus suggesting a key difference in their ability to interact within a regeneration permissive environment. These studies are the first to demonstrate distinct positional characteristics of connective tissue cells that are associated with their regenerative capabilities. PMID:23349966

Wu, Yuanyuan; Wang, Karen; Karapetyan, Adrine; Fernando, Warnakulusuriya Akash; Simkin, Jennifer; Han, Manjong; Rugg, Elizabeth L; Muneoka, Ken



Occurrence of large groups of mast cells in subcutaneous connective tissue in the mouse.  


Skin from the mouse trunk together with panniculus adiposus and panniculus carnosus and, separately, trunk muscles, were fixed, stained with Astra blue at pH 1.0, made translucent in methyl salicylate and whole-mounted. In the connective tissue on the surface of panniculus carnosus directed towards the trunk muscles or on the surface of trunk muscles rounded and oval mast cells occurred singly or in groups from two to several dozen cells. These groups had no association with blood vessels or hair follicles. Mast cell groups were scarse in 1-month-old, clearly recognizable in 2-months-old and conspicuous in 4-months-old mice of both sexes. The number of mast cells and their number per group was larger in CFW/Ll and C3H than in Balb/c mice. Accumulation of mast cells in subcutaneous connective tissue was noted in animals from two separate breeding centers. The animals were free of ectoparasites and dermatophytes but contained some pinworms and protozoa. Elimination of these parasites, change of diet and drinking water as well as cage lining did not prevent the appearance of mast cell accumulations. These accumulations occurred in all studied mice (over 100) at the age of 2 months or older, and were also found in 1 out of 6 four-month-old hamsters and in 2 out of 6 four-month-old rats. It is suggested that mast cells accumulate in subcutaneous connective tissue in response to some undefined noxious agent. Whatever the reason of their presence, large groups of mast cells could considerably influence the results of tests performed in the skin-hypodermis area. PMID:3240054

Moskalewski, S; Terelak, B; Majewski, S



Antifibrillarin autoantibodies present in systemic sclerosis and other connective tissue diseases interact with similar epitopes  

PubMed Central

Autoantibodies specific against fibrillarin, a 34-kD nucleolar protein associated with U3-snRNP, are present in patients with systemic sclerosis (SSc). To understand the mechanisms involved in the induction of these autoantibodies, we prepared a series of human fibrillarin recombinant proteins covering the entire molecule and analyzed their interaction with the autoantibodies present in various connective tissue diseases. Our results showed that antifibrillarin autoantibodies are present not only in SSc, as previously reported, but also in a variety of other connective tissue diseases. Patients with SSc (58%), mixed connective tissue diseases (60%), CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dismotility, sclerodactyly, and telangiectasia syndrome) (58%), systemic lupus erythematosus (39%), rheumatoid arthritis (60%), and Sjogern's syndrome (84%) showed presence of antifibrillarin autoantibodies. Results obtained from competitive inhibition radioimmunoassay and Western blot analyses with purified recombinant fusion proteins revealed that these autoantibodies react primarily with epitope(s) present in the NH2- (AA 1-80) and COOH- terminal (AA 276-321) domains of fibrillarin. Autoantibodies reacting with internal regions of fibrillarin are less frequent. Analysis of the hydrophilicity profiles of reactive peptides showed presence of three potential antigenic sites in the NH2- and two in the COOH-terminal regions. While a hexapeptide sequence NH2 terminus of fibrillarin is shared with an Epstein-Barr virus-encoded nuclear antigen, the COOH- terminal region shares sequence homology with P40, the capsid protein encoded by herpes virus type 1. Interestingly, these two regions of fibrillarin also contain the most immunodominant sequences, as predicted by surface probability and the Jameson and Wolf antigenic index. These observations suggest that molecular mimicry might play an important role in the induction of antifibrillarin autoantibodies.



Stem cell therapy for autoimmune disease: overview of concepts from the Snowbird 2002 tolerance and tissue regeneration meeting  

Microsoft Academic Search

Hematopoietic stem cell transplantation as a treatment for autoimmune disease began in 1996 and has subsequently spread worldwide. In Europe phase III trials have opened, while in America phase III trials are being designed and funded by the National Institutes of Health. On 6 June 2002, clinicians and scientists from around the world met at Snowbird, Utah to discuss the

R K Burt; R Arnold; R Emmons; Y Oyama; A Marmont



[The optimization of techniques complex of serologic diagnostics of connective tissue systemic diseases].  


The connective tissue systemic diseases originate from pathologic process following with antinuclear antibodies emergence. To detect these antibodies a significant number of diagnostic tests and techniques has been applied. Besides that, there is no conventional algorithm of antinuclear antibodies diagnostic. To detect antinuclear antibodies a two-fold diagnostic algorithm was applied In the capacity of screening techniques the indirect immunofluorescence technique was applied to the cells of line Hep-2 (antinuclear factor) and detection of antibodies to extractable nuclear antigen. The second stage of diagnostic included the detection of content of more specific antinuclear antibodies using the Lineblott method and the double-helical DNA antibodies. The blood serum from 981 patients with suspected connective tissue systemic diseases, 115 patients with systemic lupus erythematous and 57 healthy individuals was analyzed. The levels of antinuclear factor, nuclear antigen antibodies and double-helical DNA antibodies were detected. The antinuclear factor was detected in 84% and 86% of cases, double-helical DNA antibodies in 55% and 39% of cases depending of reagents using in detecting these characteristics. Among healthy individuals, antinuclear factor was detected in 5% (1/20) of blood serum samples in titers less than 1:160. In the group of patients with suspected connective tissue systemic diseases, antinuclear factor was detected in 48% (474/981) of cases and extractable nuclear antigen in 20% (326/981) of cases. The Lineblott test was positive in 33% (326/981) of patients with suspected connective tissue systemic diseases. Among antinuclear factor positive patients nuclear antigen antibodies were detected in 36% (171/474) and the Lineblott test was positive in 63% (298/474) of cases. Among antinuclear factor negative patients but positive under anti-nuclear antigen identification, the Lineblott test was positive in 6% (28/507) of cases. The two-fold algorithm of nuclear antigen testing is an effective technique to be applied in the clinical diagnostic laboratory. The results of effectiveness of this algorithm demonstrated that this method can ensure 33% of cost savings of testing individuals with higher incidence of diseases. PMID:22416425

Lazareva, N M; Lapin, S V; Mazing, A V; Bulgakova, T V; Ilivanova, E P; Maslianski?, A L; Totolian, A A



Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues  

PubMed Central

Non-invasive treatment of injuries and disorders affecting bones and connective tissue is a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair.

Nichols, Scott P.; Storm, Wesley L.; Koh, Ahyeon; Schoenfisch, Mark H.



Mixed connective tissue disease associated with skin defects of livedoid vasculitis.  


A 21-year-old woman who had a 2-year history of mixed connective tissue disease (MCTD) developed rapidly evolving ulcers consistent with livedoid vasculitis (LV) in all distal extremities. She presented clinically with Raynaud's phenomenon, polyarthritis and swollen hands; serologically with high titres of ANA and anti-nRNP; and immunogenetically with HLA-DR4 and HLA-DR53. Although there was initial success in treatment except for the skin defects over the ankles, the patient died from disseminated intravascular coagulation. We suggest that LV may be a poor prognostic manifestation in MCTD. PMID:11055828

Oh, Y B; Jun, J B; Kim, C K; Lee, C W; Park, C K; Kim, T Y; Yoo, D H; Kim, S Y



[Autoimmune multiglandular syndrome type I--a case study].  


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



Myelodysplastic Syndrome and Autoimmunity: A Case Report of an Unusual Presentation of Myelodysplastic Syndrome  

PubMed Central

Myelodysplastic syndrome (MDS) commonly presents asymptomatically or with symptomatic cytopenias. However, autoimmune phenomena in association with MDS have been well described in several case reports and case series. Typically, these autoimmune phenomena take the form of vasculitides, arthritis, connective tissue diseases, pulmonary infiltrates, or polymyalgia rheumatica. We present the case of a woman with MDS (karyotype 46,XX,+1,der(1;7)(q10;p10)[20], that evolved with an additional trisomy 8 clone) and a novel spectrum of autoimmune diseases including acute fibrinous and organizing pneumonia (AFOP) and lacrimal gland pseudotumor.

Merrill, Andrea L.; Smith, Hedy



Why are women predisposed to autoimmune rheumatic diseases?  

PubMed Central

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.



Meat Science and Muscle Biology Symposium: manipulating meat tenderness by increasing the turnover of intramuscular connective tissue.  


Controlled reduction of the connective tissue contribution to cooked meat toughness is an objective that would have considerable financial impact in terms of added product value. The amount of intramuscular connective tissue in a muscle appears connected to its in vivo function, so reduction of the overall connective tissue content is not thought to be a viable target. However, manipulation of the state of maturity of the collagenous component is a biologically viable target; by increasing connective tissue turnover, less mature structures can be produced that are functional in vivo but more easily broken down on cooking at temperatures above 60°C, thus improving cooked meat tenderness. Recent work using cell culture models of fibroblasts derived from muscle and myoblasts has identified a range of factors that alter the activity of the principal enzymes responsible for connective tissue turnover, the matrix metalloproteinases (MMP). Fibroblasts cultured from 3 different skeletal muscles from the same animal show different cell proliferation and MMP activity, which may relate to the different connective tissue content and architecture in functionally different muscles. Expression of MMP by fibroblasts is increased by vitamins that can counter the negative effects of oxidative stress on new collagen synthesis. Preliminary work using in situ zymography of myotubes in culture also indicates increased MMP activity in the presence of epinephrine and reactive oxidative species. Comparison of the relative changes in MMP expression from muscle cells vs. fibroblasts shows that myoblasts are more responsive to a range of stimuli. Muscle cells are likely to produce more of the total MMP in muscle tissue as a whole, and the expression of latent forms of the enzymes (i.e., pro-MMP) may vary between oxidative and glycolytic muscle fibers within the same muscle. The implication is that the different muscle fiber composition of different muscles eaten as meat may influence the potential for manipulation of their connective tissue turnover. PMID:21890505

Purslow, P P; Archile-Contreras, A C; Cha, M C



Evaluation of muscular lesions in connective tissue diseases: thallium 201 muscular scans  

SciTech Connect

We performed thallium 201 muscle scans to assess muscular involvement in 40 patients with different connective tissue diseases (7 with dermatomyositis, 7 with systemic lupus erythematosus, 12 with progressive systemic scleroderma, 2 with calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome, 3 with monomelic scleroderma, 6 with morphea, and 3 with Raynaud's disease). Only 12 of these patients complained of fatigability and/or myalgia. Electromyography was performed and serum levels of muscle enzymes were measured in all patients. Comparison of thallium 201 exercise recording with the other tests revealed that scan sensitivity is greater than electromyographic and serum muscle enzymes levels. Thallium 201 scans showed abnormal findings in 32 patients and revealed subclinical lesions in 18 patients, while electromyography findings were abnormal in 25 of these 32 patients. Serum enzyme levels were raised in only 8 patients. Thallium 201 scanning proved to be a useful guide for modifying therapy when laboratory data were conflicting. It was useful to evaluate treatment efficacy. Because our data indicate a 100% positive predictive value, we believe that thallium 201 scanning should be advised for severe systemic connective tissue diseases with discordant test results.

Guillet, G.; Guillet, J.; Sanciaume, C.; Maleville, J.; Geniaux, M.; Morin, P.



[Connective tissue disease-related pulmonary arterial hypertension - a pathology beyond the precapillary vessels].  


Pulmonary arterial hypertension (PAH) is a fatal and not uncommon complication in the setting of connective tissue diseases (CTD). Clinical and radiological signs of PVOD are commonly present in systemic slerosis (SSc) and involvement of the post-capillary vasculature is increasingly discussed in other forms of CTD such as Mixed Connective Tissue Disease and Lupus Erythematodes. The histological pattern of pulmonary veno-occlusive disease is frequently observed in CTD-related PAH. PVOD is histologically characterized by an obstruction of small pulmonary veins, which contribute to increasing pulmonary vascular resistance, ultimately leading to right heart failure and death. In clinical practice, it is difficult to distinguish pulmonary hypertension from PVOD. However, significant progress in the diagnosis of this rare condition has been made in recent years. Today, it is possible to approximate the diagnosis of "idiopathic" PVOD with non-invasive tools. This approach has recently been described in patients suffering from CTD-related PAH and suspicion of underlying PVOD. The present review provides an update on clinical, radiological and pathological characteristics of pulmonary veno-occlusive disease in the context of CTD. PMID:23925866

Günther, S; Montani, D; Dorfmüller, P



Functional Connectivity in Islets of Langerhans from Mouse Pancreas Tissue Slices  

PubMed Central

We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks are analyzed in the light of known structural and physiological properties of islets. Focusing on the temporal evolution of the network under stimulation with glucose, we show that the dynamics are more correlated under stimulation than under non-stimulated conditions and that the highest overall correlation, largely independent of Euclidean distances between cells, is observed in the activation and deactivation phases when cells are driven by the external stimulus. Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets. Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way. Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.

Stozer, Andraz; Gosak, Marko; Dolensek, Jurij; Perc, Matjaz; Marhl, Marko; Rupnik, Marjan Slak; Korosak, Dean



Computer-assisted analysis of the extracellular matrix of connective tissue  

NASA Astrophysics Data System (ADS)

The new computerized imaging, circular polarized light microscopy technique was developed to measure the orientation of collagen fibers in images of serial sections of connective tissue. The system consists of a modified Olympus BX50 polarized microscope, a Sony AVC-D7 video camera, and a Silicon Graphics Indy computer. Both methods required the initial segmentation of fibers and used binary images. Segments of fiber midlines were traced with vertical and horizontal scanlines, or alternately the whole midlines were identified recursively from the Euclidean Distance Map of the image suing the novel definition of the Medial Axis Transform. The last technique produced connected midlines of the fibers and handled sinuous fibers well. The fiber midlines produced by this technique were traversed by a midline traversal algorithm , and the orientation distribution was obtained by least squares line fitting. The accuracy of the developed techniques was evaluated against synthetic images, composed of straight lines and sinuous curves. Kupier's statistic was used to evaluate the consistency of the fiber orientation calculations. Statistical analysis of the results showed, that the proposed Medial Axis Transform with Hilditch's connectivity preserving skeletonization produced the most accurate results. The developed method was used to measure collagen fiber orientation in microscopy images of canine meniscus, porcine aortic valve leaflet, bovine pericardium and bio- textiles.

Krucinski, Slawomir; Krucinska, Izabella; Veeravanallur, Srinivasan; Slot, Krzysztof



Pituitary Autoimmunity  

Microsoft Academic Search

\\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


Irradiation by pulsed Nd:YAG laser induces the production of extracellular matrix molecules by cells of the connective tissues: a tool for tissue repair  

NASA Astrophysics Data System (ADS)

Many studies demonstrated that mechanical stress is a key factor for tissue homeostasis, while unloading induce loss of mass and impairment of function. Because of their physiological function, muscle, connective tissue, bone and cartilage dynamically interact with mechanical and gravitational stress, modifying their properties through the continuous modification of their composition. Indeed, it is known that mechanical stress increases the production of extracellular matrix (ECM) components by cells, but the mechanotransduction mechanisms and the optimal loading conditions required for an optimal tissue homeostasis are still unknown. Considering the importance of cell activation and ECM production in tissue regeneration, a proper use of mechanical stimulation could be a powerful tool in tissue repair and tissue engineering. Studies exploring advanced modalities for supplying mechanical stimuli are needed to increase our knowledge on mechanobiology and to develop effective clinical applications. Here we describe the effect of photomechanical stress, supplied by a pulsed Nd:YAG laser on ECM production by cells of connective tissues. Cell morphology, production of ECM molecules (collagens, fibronectin, mucopolysaccharides), cell adhesion and cell energy metabolism have been studied by using immunofluorescence and autofluorescence microscopy. The results show that photomechanical stress induces cytoskeleton remodelling, redistribution of membrane integrins, increase in production of ECM molecules. These results could be of consequence for developing clinical protocols for the treatment of connective tissue dideases by pulsed Nd:YAG laser.

Monici, Monica; Basile, Venere; Cialdai, Francesca; Romano, Giovanni; Fusi, Franco; Conti, Antonio



Expression of connective tissue growth factor (CCN2) in desmoplastic small round cell tumour  

PubMed Central

Background: Desmoplastic small round cell tumour (DSRCT) is a rare and often fatal abdominal tumour that is distinguished by well defined islands of cells, surrounded by prominent desmoplastic stroma. As in certain other tumours, the function of the Wilms’s tumour protein (WT1) in repressing gene transcription is lost in DSRCT. Aims: To assess the expression and localisation of connective tissue growth factor (CCN2) in DSRCT because this protein is transcriptionally repressed by WT1 and is associated with the production of abundant extracellular matrix. Methods: CCN2 was assessed by in situ hybridisation and immunohistochemistry. Results: CCN2 mRNA and protein were colocalised to the tumour cells themselves, in addition to stromal fibroblasts and vascular endothelial cells. Conclusions: These data show that CCN2 is produced in high amounts by several cell types in DSRCT, and highlight a potential role for this factor in the autocrine and paracrine regulation of tumour cell growth, matrigenesis, and angiogenesis.

Rachfal, A W; Luquette, M H; Brigstock, D R



Connective Tissue and Related Disorders and Preterm Birth: Clues to Genes Contributing to Prematurity  

PubMed Central

To identify candidate genes contributing to preterm birth, we examined the existing literature on the association between known disorders of connective tissue synthesis and metabolism and related diseases and prematurity. Our hypothesis was that abnormal matrix metabolism contributes to prematurity by increasing risk of preterm premature rupture of membranes (PPROM) and cervical incompetence. Based on this review, we identified gene mutations inherited by the fetus that could predispose to preterm birth as a result PPROM. The responsible genes include COL5A1, COL5A2, COL3A1, COL1A1, COL1A2, TNXB, PLOD1, ADAMTS2, CRTAP, LEPRE1 and ZMPSTE24. Marfan syndrome, caused by FBN1 mutations, and polymorphisms in the COL1A1 and TGFB1 genes have been associated with cervical incompetence. We speculate that an analysis of sequence variation at the loci noted above will reveal polymorphisms that may contribute to susceptibility to PPROM in the general population.

Anum, Emmanuel A.; Hill, Lori D.; Pandya, Arti; Strauss, Jerome F.



Spontaneous Esophageal Perforation in a Patient with Mixed Connective Tissue Disease  

PubMed Central

Spontaneous esophageal perforation is a rare and life-threatening disorder. Failure to diagnosis within the first 24-48 hours of presentation portends a poor prognosis. A patient with mixed connective tissue disease (MCTD) on low-dose prednisone and methotrexate presented moribund with chest and shoulder pain, a left hydropneumothorax, progressive respiratory failure and shock. Initial management focussed on presumed community acquired pneumonia (CAP) in a patient on immunosuppressants. Bilateral yeast empyemas were treated and attributed to immunosuppression. On day 26, the patient developed mediastinitis, and the diagnosis of esophageal perforation was first considered. A review of the literature suggests that the diagnosis and management of spontaneous esophageal perforation could have been more timely and the outcome less catastrophic.

Lyman, David



[Treatment of Raynaud's syndrome in systemic connective tissue diseases with calcium antagonists].  


The results of a short and a prolonged treatment of Raynaud's syndrome with calcium antagonists are presented. The efficacy of Nifedipin, Verapamil and Fendiline was evaluated in a 14 day treatment of 61 patients with Raynaud's syndrome. Nifedipin and Fendiline was evaluated in a 14 day treatment of 61 patients with Raynaud's syndrome. Nifedipine and Fendiline were most efficient but Fendiline led to more untoward reactions. Verapamil was least efficient and exerted a weak vasoactive action. The influence of the hemocirculation indices on all drugs studied was insignificant. 20 patients with systemic sclerodermia were given 30-60 mg Nifedipin daily in the course of one year and the frequency, duration and expression of the attacks of Raynaud's syndrome decreased practically twice. The study allows the recommendation of Nifedipin as the drug of choice for the treatment of Raynaud's syndrome in the systemic connective tissue diseases. PMID:3247706

Shcherbakov, A B



Application of WGA lectin staining for visualization of the connective tissue in skeletal muscle, bone and ligament/tendon studies  

PubMed Central

During immunostaining of specific proteins in tissue sections using monoclonal and polyclonal antibodies visualization of general tissue staining/background or major structural features is helpful to pinpoint precise localization of the protein of interest. Often in skeletal muscle research immunostaining with antibodies against connective tissue or plasma membrane proteins (collagen 1, laminin, caveolin 3) are used for this purpose. Although immunostaining for these proteins works well, it is time consuming, costly, limits the number of antibodies against protein of interest that can be used on a single section, and is not applicable to some staining techniques. Lectins were frequently used in earlier publications for skeletal muscle fiber boundaries and connective tissue visualization, but are not common in the current research studies. The present paper investigates co-staining of muscle, bone, ligament and tendon tissue sections with fluorescently tagged wheat germ agglutinin (WGA) lectin as a tool for visualization of connective tissue. The results of the current study show that fluorescent WGA lectin co-staining is a cost-effective, fast and convenient method for connective tissue visualization, especially in the studies where extensive washes reduce staining of the structures that are the primary interest of the investigation.

Kostrominova, Tatiana Y.



An improved freeze-dried PRP-coated biodegradable material suitable for connective tissue regenerative therapy.  


We previously published an investigation indicating freeze-dried platelet-rich plasma (PRP)-coated polyglactin mesh was a promising wound-dressing material. However, one of its disadvantages was the inflammatory nature due to degradation of the polyglactin. Therefore, in this study, we investigated the use of a collagen sponge as the carrier for PRP. When implanted subcutaneously in nude mice, the PRP-coated sponge alone rapidly induced angiogenesis and infiltration of surrounding connective tissue without inducing appreciable inflammation. Moreover, addition of periosteal fibroblastic cells substantially augmented the angiogenic response. With in vitro studies, the PRP-coated sponge provided various major growth factors at high levels to stimulate the proliferation of cells cultured on plastic dishes, but did not stimulate the proliferation of cells inoculated into the PRP-coated sponge. Cells were embedded in the fibrin mesh and maintained their spherical shape without stretching. The atomic force microscopic analysis demonstrated that the fibrin gel formed on the PRP-coated sponge was much softer (approx. 22 kPa) than the cross-linked collagen that formed the sponge base (appox. 1.9 MPa). Because insoluble matrices have recently and increasingly been considered important regulatory factors of cellular behavior, as are soluble growth factors, it is suggested that this soft fibrin mesh possibly suppresses cell survival. Overall, our investigation has successfully demonstrated improved wound-healing and regenerative potential of the PRP-coated mesh by combining it with the collagen sponge. In the clinical setting, this PRP-coated collagen sponge is a promising material for connective tissue regenerative therapy, such as periodontal therapy, burn victim treatment and in cosmetic or plastic surgery. PMID:23422785

Horimizu, Makoto; Kawase, Tomoyuki; Nakajima, Yu; Okuda, Kazuhiro; Nagata, Masaki; Wolff, Larry F; Yoshie, Hiromasa



Aberrant Type I Interferon Regulation in Autoimmunity: Opposite Directions in MS and SLE, Shaped by Evolution and Body Ecology  

PubMed Central

Studying the action of mechanisms of type I interferon (IFN) provides the insight to elucidate the cause and therapy for autoimmune diseases. There are high IFN responses in some diseases such as connective tissue diseases, but low responses in multiple sclerosis. Distinct IFN features lead us to understand pathology of a spectrum of autoimmune diseases and help us to search genetic changes, gene expression, and biomarkers for diagnosis, disease progression, and treatment response.

Reder, Anthony T.; Feng, Xuan



Salivary gland and autoimmunity.  


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



Connective Tissue Growth Factor Overexpression in Cardiomyocytes Promotes Cardiac Hypertrophy and Protection against Pressure Overload  

PubMed Central

Connective tissue growth factor (CTGF) is a secreted protein that is strongly induced in human and experimental heart failure. CTGF is said to be profibrotic; however, the precise function of CTGF is unclear. We generated transgenic mice and rats with cardiomyocyte-specific CTGF overexpression (CTGF-TG). To investigate CTGF as a fibrosis inducer, we performed morphological and gene expression analyses of CTGF-TG mice and rat hearts under basal conditions and after stimulation with angiotensin II (Ang II) or isoproterenol, respectively. Surprisingly, cardiac tissues of both models did not show increased fibrosis or enhanced gene expression of fibrotic markers. In contrast to controls, Ang II treated CTGF-TG mice displayed preserved cardiac function. However, CTGF-TG mice developed age-dependent cardiac dysfunction at the age of 7 months. CTGF related heart failure was associated with Akt and JNK activation, but not with the induction of natriuretic peptides. Furthermore, cardiomyocytes from CTGF-TG mice showed unaffected cellular contractility and an increased Ca2+ reuptake from sarcoplasmatic reticulum. In an ischemia/reperfusion model CTGF-TG hearts did not differ from controls. Our data suggest that CTGF itself does not induce cardiac fibrosis. Moreover, it is involved in hypertrophy induction and cellular remodeling depending on the cardiac stress stimulus. Our new transgenic animals are valuable models for reconsideration of CTGF's profibrotic function in the heart.

Panek, Anna N.; Posch, Maximilian G.; Alenina, Natalia; Ghadge, Santhosh K.; Erdmann, Bettina; Popova, Elena; Perrot, Andreas; Geier, Christian; Morano, Rainer Dietz Ingo; Bader, Michael; Ozcelik, Cemil



Intracranial phosphaturic mesenchymal tumor, mixed connective tissue variant presenting without oncogenic osteomalacia  

PubMed Central

Background: Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) is a rare tumor typically occurring in soft tissues and bone, causing oncogenic (tumor-induced) osteomalacia (TIO) through secretion of the phosphaturic hormone, fibroblast growth factor-23 (FGF-23). Rare tumors identical to PMTMCT occur without known TIO. Intracranial localization of PMTMCT is extremely rare, with only two cases reported in the literature. We present a very unusual case of a patient with an intracranial PMTMCT that presented with neurologic changes without osteomalacia. Case Description: A 67-year-old woman presented with progressive incontinence, apathy, and abulia after having undergone a total knee replacement 1 month earlier. Imaging disclosed a large left frontal anterior fossa mass. She underwent uncomplicated surgical resection of this tumor. Surprisingly, histopathology suggested PMTMCT. Reverse transcription polymerase chain reaction (RT-PCR) assay demonstrating FGF-23 expression in the tumor confirmed the diagnosis. Serum FGF-23 levels postoperatively were normal and she had no clinical or laboratory evidence of osteomalacia or phosphaturia. Conclusion: This report should serve to alert clinicians to the possibility that PMTMCT can be included in the differential diagnosis of intracranial masses even in the absence of tumor-induced osteomalacia.

Bower, Regina S.; Daugherty, Wilson P.; Giannini, Caterina; Parney, Ian F.



Autoimmunity in 2012.  


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

Selmi, Carlo



Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue.  


The therapeutic effects of ABR-215062, which is a new immunoregulator derived from Linomide, have been evaluated in experimental autoimmune neuritis (EAN), a CD4(+) T cell-mediated animal model of Guillain-Barré syndrome in man. In previous studies, we reported that Linomide suppressed the clinical EAN and myelin antigen-reactive T and B cell responses. Here EAN induced in Lewis rats by inoculation with peripheral nerve myelin P0 protein peptide 180-199 and Freund's complete adjuvant was strongly suppressed by ABR-215062 administered daily subcutaneously from the day of inoculation. ABR-215062 dose-dependently reduced the incidence of EAN, ameliorated clinical signs and inhibited P0 peptide 180-199-specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves. The suppression of clinical EAN was associated with inhibition of the inflammatory cytokines IFN-gamma and TNF-alpha, as well as the enhancement of anti-inflammatory cytokine IL-4 in lymph node cells and periphery nerve tissues, respectively, in a dose-dependent manner. These effects indicate that ABR-215062 may mediate its effects by regulation of Th1/Th2 cytokine balance and suggest that ABR-215062 is potentially a new chemical entity for effective treatment of autoimmune diseases. PMID:11985832

Zou, L-P; Abbas, N; Volkmann, I; Nennesmo, I; Levi, M; Wahren, B; Winblad, B; Hedlund, G; Zhu, J



Subcutaneous Connective Tissue Reactions to Various Endodontic Biomaterials: An Animal Study  

PubMed Central

Background and aims Biocompatibility of root-end filling materials is a matter of debate. The aim of this study was to compare the biocompatibility of a variety of commercial ProRoot WMTA cements and a resin-based cement (Geristore®) with different pH values of setting reaction and different aluminum contents, implanted into the subcutaneous connective tissue of rats at various time intervals. Materials and methods Fifty Sprague-Dawley rats were used in this study. Polyethylene tubes were filled with Angelus WMTA, ProRoot WMTA, Bioaggregate, and Geristore. Empty control tubes were implanted into subcutaneous tissues and harvested at 7-, 14-, 28- and 60-day intervals. Tissue sections of 5 ?m were stained with hematoxylin and eosin and observed under a light microscope. Inflammatory reactions were categorized as 0, none (without inflammatory cells); 1, mild (inflammatory cells ?25); 2, moderate (25–125 inflammatory cells); and 3, severe (>125 inflammatory cells). Statistical analysis was performed with Kruskal-Wallis and Mann Whitney U tests. Results ProRoot WMTA and Angelus elicited significantly less inflammation than other materials (P<0.05). After 7 days, however, all the materials induced significantly more inflammation than the controls (P<0.05). Angelus-MTA group exhi-bited no significant differences from the Bioaggregate group (P=0.15); however, ProRoot WMTA elicited significantly less inflammation than Bioaggregate (P=0.02). Geristore induced significantly more inflammation than other groups (P<0.05). Conclusion Geristore induced an inflammatory response higher than ProRoot WMTA; therefore, it is not recommended for clinical use.

Saghiri, Mohammad Ali; Tanideh, Nader; Garcia-Godoy, Franklin; Lotfi, Mehrdad; Karamifar, Kasra; Amanat, Dariush



Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes  

PubMed Central

Connective tissue growth factor (CCN2) is a matricellular protein that is up-regulated in many fibrotic disorders and co-expressed with transforming growth factor beta. CCN2 promotes fibrogenesis and survival in activated hepatic stellate cells, and injured or fibrotic liver contains up-regulated levels of CCN2 which are produced by a variety of different cell types, including hepatocytes. To investigate CCN2 action in vivo, transgenic FVB mice were created in which the human CCN2 gene was placed under the control of the albumin enhancer promoter to elevate hepatocyte CCN2 levels. Production of hCCN2 mRNA and elevated CCN2 protein levels was demonstrated in transgenic livers, while levels of endogenous mouse CCN2 were comparable between transgenic and wild-type mice. Liver histology and liver function tests were unaffected in transgenic animals. However, after chronic administration of carbon tetrachloride (CCl4), alpha-smooth muscle actin (?-SMA)-expressing cells and collagen deposition were increased as a function of the dosage of the hCCN2 transgene (i.e. hccn2+/+ > hccn2+/- > hccn2-/-). Moreover, CCl4-induced serum hyaluronic acid, hepatic tissue levels of ?-SMA or acid-soluble collagen, and mRNA expression of ?-SMA, collagen ?1 (I), matrix metalloprotease-2, or tissue inhibitor of metalloprotease-1 were greater in transgenic mice than in wild-type mice. Transgenic mice also exhibited enhanced hepatic deposition of collagen two weeks after bile duct ligation Conclusion: Production of elevated CCN2 levels in hepatocytes of transgenic mice in vivo does not cause hepatic injury or fibrosis per se but renders the livers more susceptible to the injurious actions of other fibrotic stimuli. These studies support for a central role of CCN2 in hepatic fibrosis and demonstrate a role of the micro-environment in regulating the pro-fibrotic action of CCN2.

Tong, ZhenYue; Chen, Ruju; Alt, Daniel S; Kemper, Sherri; Perbal, Bernard; Brigstock, David R



Glycoprotein 115, a glycoprotein isolated from chick blood vessels, is widely distributed in connective tissue  

PubMed Central

An extracellular glycoprotein (gp 115) with an apparent Mr = 115,000 isolated from chick aortas (Bressan, G. M., I. Castellani, A. Colombatti, and D. Volpin, 1983, J. Biol. Chem., 258:13262-13267), was used to immunize mice. The antisera were shown to specifically recognize gp 115 by numerous criteria: a major band around Mr = 115,000 plus minor bands of lower Mr were visible by immunoblotting on aorta extracts, and a similar pattern was observed with a monoclonal antibody; no cross-reactivity was detected by radioimmunobinding with other extracellular proteins, namely, fibronectin, laminin, and collagen types I, III, IV, V, and VI. Antigen distribution on frozen tissue sections from newborn chicks was investigated by using affinity- purified antibody. Strong immunoreactivity was always found in blood vessels. In the digestive tract, the fluorescent staining was localized both at the level of muscular layers and in the stromal matrix of the villi. Within skeletal muscle and myocardium, staining was associated with large connective tissue bundles and the matrix around each muscle fiber. Intense fluorescence was observed in the kidney, in smooth muscle cells rich areas of parabronchi, and within the portal space and along liver sinusoids. The antigen was not detected at the epidermal- dermal junction; immunoreactivity in the dermis was present as a diffuse fibrillar pattern. That the antigen detected by immunofluorescence in the various organs was indeed gp 115 was demonstrated by immunoblotting analysis: as in aorta extracts, a major band around Mr = 115,000 was detected in several tissues. Antibody- reacting material was also incorporated into the extracellular matrix produced by embryo smooth muscle cells grown in vitro and was organized as a meshwork of fine fibrils.



Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development  

PubMed Central

SUMMARY Coordinated production and remodeling of the extracellular matrix is essential during development. It is of particular importance for skeletogenesis, as the ability of cartilage and bone to provide structural support is determined by the composition and organization of the extracellular matrix. Connective tissue growth factor (CTGF, CCN2) is a secreted protein containing several domains that mediate interactions with growth factors, integrins and extracellular matrix components. A role for CTGF in extracellular matrix production is suggested by its ability to mediate collagen deposition during wound healing. CTGF also induces neovascularization in vitro, suggesting a role in angiogenesis in vivo. To test whether CTGF is required for extracellular matrix remodeling and/or angiogenesis during development, we examined the pattern of Ctgf expression and generated Ctgf-deficient mice. Ctgf is expressed in a variety of tissues in midgestation embryos, with highest levels in vascular tissues and maturing chondrocytes. We confirmed that CTGF is a crucial regulator of cartilage extracellular matrix remodeling by generating Ctgf?/?mice. Ctgf deficiency leads to skeletal dysmorphisms as a result of impaired chondrocyte proliferation and extracellular matrix composition within the hypertrophic zone. Decreased expression of specific extracellular matrix components and matrix metalloproteinases suggests that matrix remodeling within the hypertrophic zones in Ctgf mutants is defective. The mutant phenotype also revealed a role for Ctgf in growth plate angiogenesis. Hypertrophic zones of Ctgf mutant growth plates are expanded, and endochondral ossification is impaired. These defects are linked to decreased expression of vascular endothelial growth factor (VEGF) in the hypertrophic zones of Ctgf mutants. These results demonstrate that CTGF is important for cell proliferation and matrix remodeling during chondrogenesis, and is a key regulator coupling extracellular matrix remodeling to angiogenesis at the growth plate.

Ivkovic, Sanja; Yoon, Byeong S.; Popoff, Steven N.; Safadi, Fayez F.; Libuda, Diana E.; Stephenson, Robert C.; Daluiski, Aaron; Lyons, Karen M.



Transient inhibition of connective tissue infiltration and collagen deposition into porous poly(lactic-co-glycolic acid) discs.  


Connective tissue rapidly proliferates on and around biomaterials implanted in vivo, which impairs the function of the engineered tissues, biosensors, and devices. Glucocorticoids can be utilized to suppress tissue ingrowth, but can only be used for a limited time because they nonselectively arrest cell proliferation in the local environment. The present study examined use of a prolyl-4-hydroxylase inhibitor, 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), to suppress connective tissue ingrowth in porous PLGA discs implanted in the peritoneal cavity for 28 days. The prolyl-4-hydroxylase inhibitor was found to be effective at inhibiting collagen deposition within and on the outer surface of the disc, and also limited connective tissue ingrowth, but not to the extent of glucocorticoid inhibition. Finally, it was discovered that 1,4-DPCA suppressed Scavenger Receptor A expression on a macrophage-like cell culture, which may account for the drug's ability to limit connective tissue ingrowth in vivo. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 3599-3606, 2013. PMID:23766241

Love, Ryan J; Jones, Kim S



Introduction to the SES technique: a composite of surgical modifications which simplify the subepithelial connective tissue graft technique.  


The subepithelial connective tissue graft has been a successful procedure when the primary goal of surgery is to obtain root coverage. A multitude of authors have described variations of the original technique that have the potential to decrease morbidity and increase the overall success of the procedure. This article describes the SES modifications, which consist of scooping horizontal incisions, elevating an envelope flap, and closing with a sling suture. Several cases demonstrate the potential of the SES technique to facilitate the connective tissue graft procedure. PMID:18468303

Kang, Taeheon; Fien, Matthew J



Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL  

PubMed Central

Background: REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH). Methods: All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA). Results: Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH). Conclusions: Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH subgroups. Trial registry:; No.: NCT00370214; URL:

Liu, Juliana; Parsons, Lori; Hassoun, Paul M.; McGoon, Michael; Badesch, David B.; Miller, Dave P.; Nicolls, Mark R.; Zamanian, Roham T.



The cytotoxic evaluation of mineral trioxide aggregate and bioaggregate in the subcutaneous connective tissue of rats.  


Objectives: The purpose of this study was to evaluate and compare the cytotoxic effects of ProRoot MTA and DiaRoot BA, a bioceramic nanoparticulate cement, on subcutaneous rat tissue. Study Design: Fifty Sprouge Dawley rats were used in this study. Polyethylene tubes filled with ProRoot MTA and DiaRoot BioAggregate, along with a control group of empty, were implanted into dorsal connective tissue of rats for 7, 15, 30, 60, and 90 days. After estimated time intervals the rats were sacrificed. The specimens were fixed, stained with hematoxylin and eosin, and then evaluated under a light microscope for inflammatory reactions and mineralization. Results: All groups evoked a severe to moderate chronic inflammatory reaction at 7 and 15 days, which decreased with time. Both the MTA and BioAggregate groups showed similar inflammatory reactions, except at 90 days when MTA showed statistically significant greater inflammation (p>0.05). The MTA group showed foreign body reaction at all times. Compared to BioAggregate, MTA showed significantly more foreign body reaction at 60 and 90 days (p<0.0001). After 30 days foreign body reaction of BioAggregate decreased significantly. Both MTA and BioAggregate groups showed similar necrosis at 7 and 15 days (p=0.094 and p=0.186 respectively). No necrosis was observed after 15 days. Similarly there was no fibrosis after 30 days for both MTA and BioAggregate groups (p>0.05). Conclusions: Since DiaRoot BioAggregate showed significantly better results than MTA, we can conclude that it is more biocompatible. However, further studies are required to confirm this result. PMID:23722144

Batur, Y-B; Acar, G; Yalcin, Y; Dindar, S; Sancakli, H; Erdemir, U



The cytotoxic evaluation of mineral trioxide aggregate and bioaggregate in the subcutaneous connective tissue of rats  

PubMed Central

Objectives: The purpose of this study was to evaluate and compare the cytotoxic effects of ProRoot MTA and DiaRoot BA, a bioceramic nanoparticulate cement, on subcutaneous rat tissue. Study Design: Fifty Sprouge Dawley rats were used in this study. Polyethylene tubes filled with ProRoot MTA and DiaRoot BioAggregate, along with a control group of empty, were implanted into dorsal connective tissue of rats for 7, 15, 30, 60, and 90 days. After estimated time intervals the rats were sacrificed. The specimens were fixed, stained with hematoxylin and eosin, and then evaluated under a light microscope for inflammatory reactions and mineralization. Results: All groups evoked a severe to moderate chronic inflammatory reaction at 7 and 15 days, which decreased with time. Both the MTA and BioAggregate groups showed similar inflammatory reactions, except at 90 days when MTA showed statistically significant greater inflammation (p>0.05). The MTA group showed foreign body reaction at all times. Compared to BioAggregate, MTA showed significantly more foreign body reaction at 60 and 90 days (p<0.0001). After 30 days foreign body reaction of BioAggregate decreased significantly. Both MTA and BioAggregate groups showed similar necrosis at 7 and 15 days (p=0.094 and p=0.186 respectively). No necrosis was observed after 15 days. Similarly there was no fibrosis after 30 days for both MTA and BioAggregate groups (p>0.05). Conclusions: Since DiaRoot BioAggregate showed significantly better results than MTA, we can conclude that it is more biocompatible. However, further studies are required to confirm this result. Key words:Biocompatibility, mineral trioxide aggregate, bioAggregate.

Acar, Gozde; Yalcin, Yagmur; Dindar, Seckin; Sancakli, Hande; Erdemir, Ugur



Connective Tissue Growth Factor(CTGF, CCN2) – A Marker, Mediator and Therapeutic Target for Renal Fibrosis  

Microsoft Academic Search

Connective tissue growth factor (CTGF, CCN2) is a key mediator of tissue fibrosis. CCN2 plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. In this review, we discuss the biology of CCN2 with a focus on the regulation of CCN2 gene, cellular mechanisms of profibrotic CCN2 effects and the current in vivo and

Mysore K. Phanish; S. K. Winn; M. E. C. Dockrell



Expression of Connective Tissue Growth Factor in the Human Liver with Idiopathic Portal Hypertension  

PubMed Central

Idiopathic portal hypertension (IPH) is a disorder of unknown etiology, clinically associated with portal hypertension in the absence of cirrhosis. This study was designed to delineate the characteristics of IPH RNA expression in liver specimens from patients with IPH. Liver specimens from patients with IPH and patients without liver diseases underwent cDNA expression analysis and in situ hybridization studies. Connective tissue growth factor (CTGF) levels in serum were examined in 76 patients with IPH, 84 patients with hepatitis C virus infection (including those with cirrhosis), and 38 healthy volunteers. Among 588 genes sorted on macroarray, seven up-regulated genes, including CTGF, were detected. In situ hybridization studies showed that positive reactions for CTGF mRNA were most intense in the epithelial cells of proliferating bile ducts within portal tracts in patients with IPH. In the liver parenchyma, there was no appreciable staining of hepatocytes, sinusoidal endothelial cells, or hepatic stellate cells (HSCs), and there were few positive signals for CTGF mRNA in normal liver. The serum CTGF level in patients with IPH was significantly higher than the value in healthy volunteers. Six (8%) of the 76 patients with IPH had serum CTGF levels greater than 80 ng/mL, far exceeding the level of any patient with cirrhosis. In conclusion, overexpression of CTGF is one of the most important features of IPH.

Morikawa, Hiroyasu; Tamori, Akihiro; Nishiguchi, Shuhei; Enomoto, Masaru; Habu, Daiki; Kawada, Norifumi; Shiomi, Susumu



Silymarin decreases connective tissue growth factor to improve liver fibrosis in rats treated with carbon tetrachloride.  


Silymarin is an herbal product showing potential as protection against hepatic disorders. In an attempt to develop the agent for the treatment of hepatic fibrosis, we screened the effects of silymarin on a rat model of hepatic fibrosis induced by carbon tetrachloride (CCl?). Intraperitoneal administration of CCl? to rats for 8?weeks not only increased the plasma levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) but also induced a marked increase in the formation of hepatic fibrosis. Moreover, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were also reduced in the liver of rats treated with CCl?. Oral administration of silymarin (200?mg/kg, three times daily), in parallel, decreased the plasma levels of GOT and GPT. Furthermore, in addition to the improvement of hepatic fibrosis, the hepatic levels of hydroxyproline and connective tissue growth factor (CTGF) were both markedly decreased by silymarin. Silymarin also elevated the activities of SOD and GPx in liver isolated from CCl?-treated rats. The results suggest that oral administration of silymarin protects against CCl?-induced hepatic fibrosis in rats, likely due to the decrease in fibrotic parameters such as CTGF. PMID:22933420

Tzeng, Jann-Inn; Chen, Mei-Fen; Chung, Hsien-Hui; Cheng, Juei-Tang



TGF-? Mediates Suppression of Adipogenesis by Estradiol through Connective Tissue Growth Factor Induction  

PubMed Central

In the bone marrow cavity, adipocyte numbers increase, whereas osteoblast progenitor numbers decrease with aging. Because adipocytes and osteoblasts share a common progenitor, it is possible that this shift is due to an increase in adipocyte-lineage cells at the expense of osteoblast-lineage commitment. Estrogens inhibit adipocyte differentiation, and in both men and women, circulating estrogens correlate with bone loss with aging. In bone cells, estrogens stimulate expression of TGF-? and suppress mesenchymal cell adipogenesis. Using a tripotential mesenchymal cell line, we have examined whether estradiol suppression of adipocyte differentiation is due to stimulation of TGF-? and the mechanism by which TGF-? suppresses adipogenesis. We observed that estradiol-mediated suppression of adipogenic gene expression required at least 48 h treatment. TGF-? expression increased within 24 h of estradiol treatment, and TGF-? inhibition reversed estradiol influences on adipogenesis and adipocyte gene expression. Connective tissue growth factor (CTGF) mediates TGF-? suppression of adipogenesis in mouse 3T3-L1 cells. CTGF expression was induced within 24 h of TGF-? treatment, whereas estradiol-mediated induction required 48 h treatment. Moreover, estradiol-mediated induction of CTGF was abrogated by TGF-? inhibition. These data support that estradiol effects on adipogenesis involves TGF-? induction, which then induces CTGF to suppress adipogenesis.

Kumar, Ashok; Ruan, Ming; Clifton, Kari; Syed, Farhan; Khosla, Sundeep



Molecular mechanisms for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.  


Chronic kidney disease (CKD), marked by a progressive loss in renal function, is a leading cause of hemodialysis initiation and cardiovascular disease (CVD). There are currently 13.3 million patients with CKD and 300 thousand patients are currently undergoing hemodialysis in Japan. Therefore, preventing the initiation of dialysis and reducing the risk of cardiovascular death are high-priority issues from the viewpoint of public health and economic implications. Understanding the molecular mechanism responsible for the progression of CKD and cardiovascular damage regarding crosstalk between the kidney and cardiovascular system is an important issue in controlling the pathogenesis of CKD-CVD. However, the mechanisms involved in CKD-CVD are not well understood. This hinders the development of new treatment strategies. We have been investigating the role of protein bound uremic toxins, that are difficult to remove by hemodialysis, on the onset and progression of CKD and CVD. The relationship between their redox properties and the pathogenesis of CKD-CVD was examined. In this review, we focus on two sulfate conjugated uremic toxins, namely, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and summarize recent studies that provide new insights on the molecular mechanisms responsible for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection. PMID:23903229

Watanabe, Hiroshi



Stretch-induced upregulation of connective tissue growth factor in rabbit cardiomyocytes.  


Connective Tissue Growth Factor (CTGF, CCN2) is considered to play an important role in cardiac remodelling. We studied whether stretch is a primary stimulus to induce CTGF expression in vivo in rabbit heart, and in vitro in isolated cardiomyocytes and fibroblasts. Twenty weeks of combined volume and pressure overload resulted in eccentric left ventricular (LV) hypertrophy, with increased LV internal diameter (+36 %) and LV weight (+53 %). Myocardial CTGF mRNA and protein levels were substantially increased in the overloaded animals. In isolated adult rabbit cardiomyocytes, cyclic stretch strongly induced CTGF mRNA expression (2.9-fold at 48 h), whereas in cardiac fibroblasts CTGF-induction was transient and modest (1.4-fold after 4 h). Conditioned medium from stretched fibroblasts induced CTGF mRNA expression in non-stretched cardiomyocytes (2.3-fold at 48 h). Our findings indicate that stretch is an important primary trigger for CTGF-induction in the overloaded heart. PMID:23835778

Blaauw, Erik; Lorenzen-Schmidt, Ilka; Babiker, Fawzi A; Munts, Chantal; Prinzen, Frits W; Snoeckx, Luc H; van Bilsen, Marc; van der Vusse, Ger J; van Nieuwenhoven, Frans A



Connective Tissue Growth Factor Is Required for Normal Follicle Development and Ovulation  

PubMed Central

Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-? superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-? family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-? and progesterone signaling cascades and is necessary for normal follicle development and ovulation.

Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei; Lydon, John P.; DeMayo, Francesco J.; Lyons, Karen M.



The Mechanical Properties of the Rabbit Carpal Tunnel Subsynovial Connective Tissue  

PubMed Central

The rabbit model is commonly used to study carpal tunnel syndrome (CTS). It has been proposed that the subsynovial connective tissue (SSCT) in the carpal tunnel may play a role in the etiology of CTS, but the material properties of the rabbit SSCT are unknown. The purpose of this study was to develop a method to measure the shear properties of the rabbit SSCT. In six rabbit cadaver forepaws, the excursion of the third digit flexor digitorum superficialis (FDS) and load to failure of the SSCT were measured in a custom device. The mean excursion to full flexion in this model was 7.08 mm (SD 0.77). The mean shearing force at full flexion was 317 mN (SD 166). At full flexion percentage of maximum shear force in the SSCT was 54.5% (SD 19.4). The mean energy absorbed at full flexion was 0.29 mJ (SD 0.31). The mean excursion needed to reach 5% of the maximum shear force was 3.04 mm (SD 0.99). The testing model presented in this study demonstrates structural parameters to evaluate the shear properties of the SSCT in a rabbit model. The data presented could be used for estimating sample sizes in a more comprehensive study of the effect of CTS on the SSCT properties.

Yamaguchi, Taihei; Osamura, Naoki; Zhao, Chunfeng; Zobitz, Mark E.; An, Kai-Nan; Amadio, Peter C.



Connective tissue growth factor is a new ligand of epidermal growth factor receptor.  


Chronic kidney disease is reaching epidemic proportions worldwide and there is no effective treatment. Connective tissue growth factor (CCN2) has been suggested as a risk biomarker and a potential therapeutic target for renal diseases, but its specific receptor has not been identified. Epidermal growth factor receptor (EGFR) participates in kidney damage, but whether CCN2 activates the EGFR pathway is unknown. Here, we show that CCN2 is a novel EGFR ligand. CCN2 binding to EGFR extracellular domain was demonstrated by surface plasmon resonance. CCN2 contains four distinct structural modules. The carboxyl-terminal module (CCN2(IV)) showed a clear interaction with soluble EGFR, suggesting that EGFR-binding site is located in this module. Injection of CCN2(IV) in mice increased EGFR phosphorylation in the kidney, mainly in tubular epithelial cells. EGFR kinase inhibition decreased CCN2(IV)-induced renal changes (ERK activation and inflammation). Studies in cultured tubular epithelial cells showed that CCN2(IV) binds to EGFR leading to ERK activation and proinflammatory factors overexpression. CCN2 interacts with the neurotrophin receptor TrkA, and EGFR/TrkA receptor crosstalk was found in response to CCN2(IV) stimulation. Moreover, endogenous CCN2 blockade inhibited TGF-?-induced EGFR activation. These findings indicate that CCN2 is a novel EGFR ligand that contributes to renal damage through EGFR signalling. PMID:23929714

Rayego-Mateos, Sandra; Rodrigues-Díez, Raquel; Morgado-Pascual, Jose Luis; Rodrigues Díez, Raul R; Mas, Sebastian; Lavoz, Carolina; Alique, Matilde; Pato, Janos; Keri, Gyorgy; Ortiz, Alberto; Egido, Jesus; Ruiz-Ortega, Marta



Suppression of Estrogen Receptor Transcriptional Activity by Connective Tissue Growth Factor  

PubMed Central

Secreted growth factors have been shown to stimulate the transcriptional activity of estrogen receptors (ER) that are responsible for many biological processes. However, whether these growth factors physically interact with ER remains unclear. Here, we show for the first time that connective tissue growth factor (CTGF) physically and functionally associates with ER. CTGF interacted with ER both in vitro and in vivo. CTGF interacted with ER DNA-binding domain. ER interaction region in CTGF was mapped to the thrombospondin type I repeat, a cell attachment motif. Overexpression of CTGF inhibited ER transcriptional activity as well as the expression of estrogen-responsive genes, including pS2 and cathepsin D. Reduction of endogenous CTGF with CTGF small interfering RNA enhanced ER transcriptional activity. The interaction between CTGF and ER is required for the repression of estrogen-responsive transcription by CTGF. Moreover, CTGF reduced ER protein expression, whereas the CTGF mutant that did not repress ER transcriptional activity also did not alter ER protein levels. The results suggested the transcriptional regulation of estrogen signaling through interaction between CTGF and ER, and thus may provide a novel mechanism by which cross-talk between secreted growth factor and ER signaling pathways occurs.

Jiao, Yuanyuan; Xie, Xiangyang; Lin, Jing; Zhang, Hao; Han, Juqiang; Jiang, Kai; Ye, Qinong



The presence and regulation of connective tissue growth factor in the human endometrium  

PubMed Central

BACKGROUND The human endometrium efficiently repairs each month after menstruation. The mechanisms involved in this repair process remain undefined. Aberrations in endometrial repair may lead to the common disorder of heavy menstrual bleeding. We hypothesized that connective tissue growth factor (CTGF) is increased at the time of endometrial repair post-menses and that this increase is regulated by prostaglandins (PGs) and hypoxic conditions present during menstruation. METHODS AND RESULTS Examination of 41 endometrial biopsies from 5 stages of the menstrual cycle revealed maximal CTGF mRNA expression (using quantitative RT–PCR) at menstruation and peak protein levels during the proliferative phase. CTGF was immunolocalized to epithelial and stromal cells, with intense staining of occasional stromal cells during the proliferative phase. Dual immunohistochemistry identified these cells as macrophages. Treatment of endometrial epithelial cells with 100 nM PGE2, PGF2? or hypoxia (0.5% O2) revealed a significant increase in CTGF mRNA expression (P < 0.01 for all, versus vehicle control). Cells treated simultaneously with PGE2 and hypoxia revealed a synergistic increase in CTGF expression (P < 0.05 versus PGE2 or hypoxia alone) and maximal secreted CTGF protein levels (P < 0.05 versus control). CONCLUSIONS CTGF is increased in the human endometrium at the time of endometrial repair post-menses. The increase in CTGF may be mediated by PG production and the transient hypoxic episode observed in the endometrium at menstruation.

Maybin, J.A.; Barcroft, J.; Thiruchelvam, U.; Hirani, N.; Jabbour, H.N.; Critchley, H.O.D.



The Skeletal Site-Specific Role of Connective Tissue Growth Factor in Prenatal Osteogenesis  

PubMed Central

Background Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. Results We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-?-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. Conclusions We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation.

Lambi, Alex G.; Pankratz, Talia L.; Mundy, Christina; Gannon, Maureen; Barbe, Mary F.; Richtsmeier, Joan T.; Popoff, Steven N.



Autoimmune pancreatitis.  


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].  


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



Autoantibodies Produced at the Site of Tissue Damage Provide Evidence of Humoral Autoimmunity in Inclusion Body Myositis  

PubMed Central

Inclusion body myositis (IBM) belongs to a group of muscle diseases known as the inflammatory myopathies. The presence of antibody-secreting plasma cells in IBM muscle implicates the humoral immune response in this disease. However, whether the humoral immune response actively contributes to IBM pathology has not been established. We sought to investigate whether the humoral immune response in IBM both in the periphery and at the site of tissue damage was directed towards self-antigens. Peripheral autoantibodies present in IBM serum but not control serum recognized self-antigens in both muscle tissue and human-derived cell lines. To study the humoral immune response at the site of tissue damage in IBM patients, we isolated single plasma cells directly from IBM-derived muscle tissue sections and from these cells, reconstructed a series of recombinant immunoglobulins (rIgG). These rIgG, each representing a single muscle-associated plasma cell, were examined for reactivity to self-antigens. Both, flow cytometry and immunoblotting revealed that these rIgG recognized antigens expressed by cell lines and in muscle tissue homogenates. Using a mass spectrometry-based approach, Desmin, a major intermediate filament protein, expressed abundantly in muscle tissue, was identified as the target of one IBM muscle-derived rIgG. Collectively, these data support the view that IBM includes a humoral immune response in both the periphery and at the site of tissue damage that is directed towards self-antigens.

Ray, Arundhati; Amato, Anthony A.; Bradshaw, Elizabeth M.; Felice, Kevin J.; DiCapua, Daniel B.; Goldstein, Jonathan M.; Lundberg, Ingrid E.; Nowak, Richard J.; Ploegh, Hidde L.; Spooner, Eric; Wu, Qian



Complement and autoimmunity.  


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



Adhesion molecules mediating neutrophil migration to arthritis in vivo and across endothelium and connective tissue barriers in vitro  

Microsoft Academic Search

Neutrophils, or polymorphonuclear leukocytes (PMNLs), migrate through vascular endothelium and in connective tissue during inflammation. In rats with adjuvant arthritis, migration to joints of radiolabeled (111In) blood PMNLs was examined to define the role of specific selectin and integrin adhesion molecules in this process. Based on monoclonal antibody studies, P-selectin was required for normal PMNL migration to the joints. Although

A. C. Issekutz



[Adrenoreactivity in patients with arrhythmic syndrome associated with connective tissue dysplasia at the background of intake of the magnezium orotate].  


Elevated level of -adrenoreception of membranes is observed in patients with disturbances of heart rhythm at the background of connective tissue dysplasia. It is not related to characteristics of the arrhythmic syndrome. At the background of 4-months intake of preparation magnezium orotate significant decrease of degree of desensitization of of erythrocytes has been noted. PMID:21627614

Moskvina, Iu V; Nechaeva, G I



[Features of fluor intoxication development in patients with nondifferentiated connective tissue dysplasia and physical therapy methods for these patients].  


The article covers results of studies concerning time of fluorosis development in patients with signs of connective tissue dysplasia syndrome (CTDS). if compared with patients without CTDS, and of studies concerning hyperostosis coefficient in accordance with presence or absence of CTDS. Efficiency of physical therapy and balneotherapy for these patients are also reported by the authors. PMID:23785805

Tereshina, L G; Budkar', L N; Obukhova, T Iu; Bugaeva, I V; Karpova, E A



Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue  

Microsoft Academic Search

The degradation of soft connective tissue collagen is considered to depend on the activity of various proteolytic enzymes, particularly those belonging to the group of matrix metalloproteinases and cysteine proteinases. In the present study, we investigated the contribution of these enzymes to this process. Using a general inhibitor of MMPs (SC44463), collagen degradation was strongly inhibited, by about 40% after

Laura B. Creemers; Ineke D. C. Jansen; Andrew J. P. Docherty; John J. Reynolds; Wouter Beertsen; Vincent Everts



Contribution of Src-FAK signaling to the induction of connective tissue growth factor in renal fibroblasts  

Microsoft Academic Search

Expression of connective tissue growth factor (CTGF) is sensitive to reorganization of the actin cytoskeleton, but also to alterations in cell morphology due to extracellular forces, for example, cyclic stretching or mechanical loading. Dynamic alterations of focal adhesion proteins were thus proposed to modulate CTGF induction. Immortalized human renal fibroblasts were cultured in or on top of preformed collagen-1 gels.

A Graness; I Cicha; M Goppelt-Struebe



Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia.  


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



Adjuvants and autoimmunity.  


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



Beware of connective tissue proteins: Assignment and implications of collagen absorptions in infrared spectra of human tissues  

Microsoft Academic Search

Infrared spectra of human central nervous system tissue and human breast carcinoma are presented. The spectra are discussed in terms of the composition of the tissues. It is shown that differences between spectra of white and grey matter can be rationalised on the basis of differences in lipid content. Spectra of the choroid plexus and arachnoid villus of the meninges

Michael Jackson; Lin-P'ing Choo; Peter H. Watson; William C. Halliday; Henry H. Mantsch



Exercise training in pulmonary arterial hypertension associated with connective tissue diseases  

PubMed Central

Introduction The objective of this prospective study was to assess short- and long-term efficacy of exercise training (ET) as add-on to medical therapy in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-APAH). Methods Patients with invasively confirmed CTD-APAH received ET in-hospital for 3 weeks and continued at home for 12 weeks. Efficacy parameters have been evaluated at baseline and after 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of 2.9 ± 1.9 years. Results Twenty-one consecutive patients were included and assessed at baseline, and after 3 weeks, 14 after 15 weeks. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 67 ± 52 meters after 3 weeks (p < 0.001) and by 71 ± 35 meters after 15 weeks (p = 0.003), scores of quality of life (p < 0.05), heart rate at rest, peak oxygen consumption, oxygen saturation and maximal workload. Systolic pulmonary artery pressure and diastolic systemic blood pressure improved significantly after 3 weeks of ET. The 1- and 2-year overall-survival rates were 100%, the 3-year survival 73%. In one patient lung transplantation was performed 6 months after ET. Conclusion ET as add-on to medical therapy is highly effective in patients with CTD-APAH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further randomized controlled studies are needed to confirm these results. Trial registration NCT00491309.



Prospective cohort study of breast implants and the risk of connective-tissue diseases  

PubMed Central

Background A 2000 meta-analysis indicated no overall association between breast implants and risk of connective-tissue diseases (CTDs). However, a large retrospective cohort study we previously conducted suggested, instead, a small increased risk of CTDs. Because of limitations inherent to the retrospective cohort study design, we sought clarification by conducting a prospective cohort study of the association of breast implants with CTD risk. Methods Participants were 23?847 US women (mean age 56.6 years), 3950 of whom had breast implants and 19?897 did not. Women reported their breast implant status at baseline in 2001 and were followed for a median of 3.63 years. During follow-up, women reported incident CTD, confirmed using a CTD screening questionnaire (CSQ) and medical records. Results In multivariate analyses, the rate ratios for self-reported CTD (113 vs 377 cases in the implanted and non-implanted group, respectively) were 1.60 [95% confidence interval (CI) 1.28–2.00], for CSQ-confirmed CTD (77 vs 226 cases), 1.80 (1.37–2.38) and for medical record confirmed CTD (21 vs 74 cases), 1.39 (0.82–2.35). Conclusions Although this prospective cohort study represented a stronger design than the retrospective cohort study, the present data should still be viewed cautiously because of remaining methodological limitations, including the potential for differential self-reporting of CTD and CTD symptoms among women with and without breast implants, the difficulty of obtaining medical records for women reporting CTD and the low and possibly differential confirmation of self-reported disease against medical records. A reasonable conclusion is the lack of a large increase in CTD risk (e.g. ?2-fold) associated with breast implants.

Lee, I-Min; Cook, Nancy R; Shadick, Nancy A; Pereira, Eduardo; Buring, Julie E



Rapamycin regulates connective tissue growth factor expression of lung epithelial cells via phosphoinositide 3-kinase.  


The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains largely unknown. It is believed that IPF is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances (such as connective tissue growth factor, CTGF) that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and CTGF expression. Transformed epithelial cell line A549 and normal human pulmonary alveolar or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine CTGF mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting CTGF protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor (TGF)-? type I receptor (T?RI) inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-?1 induced CTGF expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on CTGF expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis. PMID:23986222

Xu, Xuefeng; Wan, Xuan; Geng, Jing; Li, Fei; Yang, Ting; Dai, Huaping



Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts  

PubMed Central

Connective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts from patients with SSc and healthy controls were cultured in the presence of hypoxia or cobalt chloride (CoCl2), a chemical inducer of hypoxia-inducible factor (HIF)-1?. Expression of CTGF was evaluated by Northern and Western blot analyses. Dermal fibroblasts exposed to hypoxia (1% O2) or CoCl2 (1–100 µM) enhanced expression of CTGF mRNA. Skin fibroblasts transfected with HIF-1? showed the increased levels of CTGF protein and mRNA, as well as nuclear staining of HIF-1?, which was enhanced further by treatment of CoCl2. Simultaneous treatment of CoCl2 and transforming growth factor (TGF)-? additively increased CTGF mRNA in dermal fibroblasts. Interferon-? inhibited the TGF-?-induced CTGF mRNA expression dose-dependently in dermal fibroblasts, but they failed to hamper the CoCl2-induced CTGF mRNA expression. In addition, CoCl2 treatment increased nuclear factor (NF)-?B binding activity for CTGF mRNA, while decreasing I?B? expression in dermal fibroblasts. Our data suggest that hypoxia, caused possibly by microvascular alterations, up-regulates CTGF expression through the activation of HIF-1? in dermal fibroblasts of SSc patients, and thereby contributes to the progression of skin fibrosis.

Hong, K-H; Yoo, S-A; Kang, S-S; Choi, J-J; Kim, W-U; Cho, C-S



Asthma and airways collapse in two heritable disorders of connective tissue  

PubMed Central

Objectives This study investigated the clinical impression that there was an increased prevalence of respiratory disorders in both the Hypermobility Syndrome (HMS)/Benign Joint Hypermobility Syndrome (BJHS) and Ehlers–Danlos Syndrome (EDS), compared with the normal population. Methods A questionnaire was distributed to 509 subjects (221 healthy controls, 126 HMS, 162 EDS) who documented respiratory symptoms and previously diagnosed respiratory and atopic disorders. A subgroup of 157 responders underwent full clinical and serological assessments, and 57 subjects were assessed physiologically. Results A significant increase in the frequency of a wide range of respiratory symptoms and reduced exercise tolerance was observed in subjects with both HMS and EDS compared with controls. In particular, there was an increased prevalence of asthmatic symptoms (HMS: OR 2.4, 95% CI 1.4–4.1, p?=?0.002; EDS: OR 3.1, 95% CI 1.8–5.2, p<0.001) and atopy (HMS: OR 2.7, 95% CI 1.6–4.5, p<0.001; EDS: OR 2.6, 95% CI 1.6–4.4, p<0.001), which was subsequently confirmed by clinical assessment. Pulmonary physiological studies revealed increased lung volumes, impaired gas exchange and an increased tendency of both the lower and upper airways to collapse. Conclusions We have demonstrated, for the first time, that individuals with HMS/BJHS and EDS have respiratory symptoms in association with various pulmonary physiological abnormalities. The increased prevalence of asthma may be due to linkage disequilibrium between the genes causing these conditions or a function of the connective tissue defect itself. In the non?asthmatic population, changes in the mechanical properties of the bronchial airways and lung parenchyma may underlie the observed increased tendency of the airways to collapse.

Morgan, A W; Pearson, S B; Davies, S; Gooi, H C; Bird, H A



Connective Tissue-Activating Peptide III: A Novel Blood Biomarker for Early Lung Cancer Detection  

PubMed Central

Purpose There are no reliable blood biomarkers to detect early lung cancer. We used a novel strategy that allows discovery of differentially present proteins against a complex and variable background. Methods Mass spectrometry analyses of paired pulmonary venous-radial arterial blood from 16 lung cancer patients were applied to identify plasma proteins potentially derived from the tumor microenvironment. Two differentially expressed proteins were confirmed in 64 paired venous-arterial blood samples using an immunoassay. Twenty-eight pre- and postsurgical resection peripheral blood samples and two independent, blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls) and 266 participants from the National Heart Lung and Blood Institute Lung Health Study (45 lung cancer and 221 matched controls) determined the accuracy of the two protein markers to detect subclinical lung cancer. Results Connective tissue-activating peptide III (CTAP III)/ neutrophil activating protein-2 (NAP-2) and haptoglobin were identified to be significantly higher in venous than in arterial blood. CTAP III/NAP-2 levels decreased after tumor resection (P = .01). In two independent population cohorts, CTAP III/NAP-2 was significantly associated with lung cancer and improved the accuracy of a lung cancer risk prediction model that included age, smoking, lung function (FEV1), and an interaction term between FEV1 and CTAP III/NAP-2 (area under the curve, 0.84; 95% CI, 0.77 to 0.91) compared to CAPIII/NAP-2 alone. Conclusion We identified CTAP III/NAP-2 as a novel biomarker to detect preclinical lung cancer. The study underscores the importance of applying blood biomarkers as part of a multimodal lung cancer risk prediction model instead of as stand-alone tests.

Yee, John; Sadar, Marianne D.; Sin, Don D.; Kuzyk, Michael; Xing, Li; Kondra, Jennifer; McWilliams, Annette; Man, S.F. Paul; Lam, Stephen



Downregulation of Connective Tissue Growth Factor by Three-Dimensional Matrix Enhances Ovarian Carcinoma Cell Invasion  

PubMed Central

Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancy, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intra-peritoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hours of 3-dimensional collagen culture) coupled with confirmatory real-time RT-PCR, multiple three-dimensional cell culture matrices, Western blot, immunostaining, adhesion, migration, and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion-mimicking conditions (3-dimensional type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n=41), but was present in 100% of normal ovarian epithelium samples (n=7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced, collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using ?6?1 and ?3?1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion.

Barbolina, Maria V.; Adley, Brian P.; Kelly, David L.; Shepard, Jaclyn; Fought, Angela J.; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D.; Sharon Stack, M



[Connective tissue growth factors, CTGF and Cyr61 in drug-induced gingival overgrowth--an animal model].  


Human gingival overgrowth may occur as a side effect of chronic administration of some therapeutic agents. The mechanisms responsible for the gingival tissues lesions, fibrosis and inflamation, involve an impaired balance between the production and the degradation of type I collagen. It has been demonstrated that CCN2/CTGF, a connective tissue growth factor, is highly expressed in the gingival tissues and positively correlated with the degree of fibrosis in the drug-induced gingival overgrowth. The aim of this study was to identify the presence and localization of CCN2/CTGF and CCN1/Cyr61, members of the same molecular family, in gingival tissues of cyclosporin A- and nifedipine-treated rats, by immunohistochemistry. Staining was evaluated with light microscope and the results show cellular and extracellular CTGF in nifedipin gingival overgrowth tissues with intensity of labeling higher compared to the CsA gingival overgrowth tissues or the controls. The staining for Cyr61 shows its intracellular localization with no diference of labeling intensity between drug-induced gingival overgrowth and normal tissues. Also, we were interested in the gingival TGF-â expression in those animals. We didn't find any commercial anti-rat TGF antibody and our anti-human antibody shows no cross-reactivity with rat tissues. The data from our study sustain the involvement of CTGF and Cyr61 as growth factors in the gingival tissues and the CTGF association with drug-induced gingival overgrowth. PMID:20209781

Ciobanic?, Mihaela; Cianga, Corina; C?runtu, Irina-Draga; Grigore, Georgiana; Cianga, P


The autoimmune diseases  

SciTech Connect

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.



Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue.  


The degradation of soft connective tissue collagen is considered to depend on the activity of various proteolytic enzymes, particularly those belonging to the group of matrix metalloproteinases and cysteine proteinases. In the present study, we investigated the contribution of these enzymes to this process. Using a general inhibitor of MMPs (SC44463), collagen degradation was strongly inhibited, by about 40% after 24 h and up to 80% after 72 h of culturing. Blockage of cysteine proteinase activity (with leupeptin or E-64) reduced breakdown at these time intervals by 50% and 20%, respectively. Given the abundant presence of gelatinases--in particular gelatinase A (MMP-2)--in the tissue, the effect of an inhibitor selective for gelatinases (CT1166) was studied. Gelatinase inhibition resulted in a dose-dependent decrease of collagen breakdown up to 90% after 48 h. The ability of gelatinase A to degrade collagens was demonstrated by the induction of breakdown in devitalized explants by addition of activated gelatinase A, or by activation of endogenous enzyme with 4-aminophenylmercuric acetate. This latter effect was not found with plasmin, an activator of MMPs other than gelatinase A. Finally, the relevance of gelatinase A to the in vivo degradation of soft connective tissue collagen was implicated by the significant correlation found between its activity and the collagen turnover rates of four soft connective tissues (tooth pulp, periodontal ligament, molar gingiva and skin). We conclude that collagen degradation in soft connective tissue is mediated by MMPs and to a lesser extent by cysteine proteinases. Our data are the first to attach a key role to gelatinase A in this process. PMID:9628251

Creemers, L B; Jansen, I D; Docherty, A J; Reynolds, J J; Beertsen, W; Everts, V



Expression stability of commonly used reference genes in canine articular connective tissues  

Microsoft Academic Search

BACKGROUND: The quantification of gene expression in tissue samples requires the use of reference genes to normalise transcript numbers between different samples. Reference gene stability may vary between different tissues, and between the same tissue in different disease states. We evaluated the stability of 9 reference genes commonly used in human gene expression studies. Real-time reverse transcription PCR and a

Duncan Ayers; Dylan N Clements; Fiona Salway; Philip JR Day



Detection of Parvovirus B19 Capsid Proteins in Lymphocytic Cells in Synovial Tissue of Autoimmune Chronic Arthritis  

Microsoft Academic Search

The pathogenic influence of viral agents in chronic inflammatory joint diseases like rheumatoid arthritis has been discussed for many years. More recently, DNA of several viruses, among them parvovirus B19 (B19), was traceable by PCR analysis in synovial fluid and synovial tissue. To investigate the potential role of parvovirus B19 in rheumatoid arthritis, we analyzed the expression of B19 VP1\\/VP2

Yasmin Mehraein; Carsten Lennerz; Sandra Ehlhardt; Thorsten Venzke; Andreas Ojak; Klaus Remberger; Klaus D Zang




Microsoft Academic Search

infection and xenobiotics play a critical role in the development of autism. In this study, we postulated that infectious agent antigens such as streptokinase, dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69,




[The connective tissues, from the origin of the concept to its "Maturation" to extracellular matrix. Application to ocular tissues. Contribution to the history of medical sciences].  


The "Tissue" concept emerged apparently in the medical literature at about the French revolution, during the second half of the 18(th) century. It was found in the texts written by the physicians of Béarn and Montpellier, the Bordeu-s and also by the famous physician, Felix Vicq d'Azyr, the last attending physician of the queen Marie-Antoinette, "Bordeu et al. (1775) et Pouliquen (2009)". It was elaborated into a coherent doctrine somewhat later by Xavier Bichat, considered as the founder of modern pathological anatomy, Bichat. With the advent of histochemistry, from the beginning of the 20(th) century, several of the principal macromolecular components of connective tissues, collagens, elastin, "acid mucopolysaccharides" (later glycosaminoglycans and proteoglycans) and finally structural glycoproteins were characterized. These constituents of connective tissues were then designated as components of the extracellular matrix (ECM), closely associated to the cellular components of these tissues by adhesive (structural) glycoproteins as fibronectin, several others and cell receptors, "recognising" ECM-components as integrins, the elastin-receptor and others. This molecular arrangement fastens cells to the ECM-components they synthesize and mediates the exchange of informations between the cells to the ECM (inside-out) and also from the ECM-components to the cells (outside-in). This macromolecular arrangement is specific for each tissue as a result of the differentiation of their cellular components. It is also the basis and condition of the fulfillment of the specific functions of differentiated tissues. This is a short description of the passage of the "tissue" concept from its vague origin towards its precise identification at the cellular and molecular level up to the recognition of its functional importance and its establishment as an autonomous science. This can be considered as a new example of the importance of metaphors for the progress of science, Keller (1995). PMID:21620590

Labat-Robert, J; Robert, L; Pouliquen, Y



Antibodies to carbonic anhydrase in patients with connective tissue diseases: relationship with lung involvement.  


The aim of this study is to evaluate the presence of antibodies to carbonic anhydrase I and/or II (ACAI and ACAII) in patients affected by connective tissue diseases (CTD) and to investigate their association with lung involvement evaluated by High resolution CT scan (HRCT). Ninety-six patients affected by CTD were studied, i.e. 33 rheumatoid arthritis (RA), 8 psoriatic arthritis (PA), 8 ankylosing spondilitis (AS), 23 Systemic Lupus Erythematosus (SLE), 10 Sjogren Syndrome (SS), and 14 Systemic Sclerosis (SSc). ACA were detected by ELISA. The lung involvement was evaluated by means of a previously described HRCT score. According to a receiver operator characteristic curve, patients were divided into those with HRCT score > or = 10 and those with HRCT score < 10, where HRCT score > or = 10 was predictive of interstitial lung disease. ACAI and/or ACAII were detected in 30/96 patients (31.2%) (P < 0.0001 in comparison with controls). In particular, the prevalence of ACAI and/or ACAII was significantly higher in patients with RA (P = 0.002), PA (P < 0.0001), SLE (P = 0.0003) and SSc (P < 0.0001). A positive correlation was found between HRCT scores and CRP or ACAI levels (P = < 0.0001 and P = 0.004, respectively). Thirty-nine of 96 patients (40.6%) showed a HRCT score > or = 10 and both their CRP and ACAI levels were significantly higher when compared with patients showing a HRCT score less than 10 (P < 0.0006 and P = 0.0009, respectively). Moreover, C3 and C4 complement fractions inversely correlated with HRCT scores (P = 0.0004 and P < 0.0001, respectively) and lower values of C3 and C4 complement fractions were found in patients with HRCT score > or = 10 than in those with HRCT score less than 10 (P = 0.014 and P = 0.007, respectively). Due to the lower levels of complement fractions detected in patients with HRCT score > or = 10, a possible immune-complex-mediated pathogenic mechanism of lung involvement could be suggested. PMID:18831934

Caccavo, D; Afeltra, A; Rigon, A; Vadacca, M; Zobel, B B; Zennaro, D; Arcarese, L; Buzzulini, F; Pellegrino, N M; Amoroso, A


Optimum scratch assay condition to evaluate connective tissue growth factor expression for anti-scar therapy.  


To evaluate a potential anti-scar therapy, we first need to have a reliable in vitro wound model to understand dermal fibroblast response upon cell injury and how cytokine levels are changed upon different wound heal phases. An in vitro wound model with different scratch assay conditions on primary human foreskin fibroblast monolayer cultures was prepared and cytokine levels and growth properties were evaluated with the aim of determining optimum injury conditions and observation time. Morphological characteristics of differently scratched fibroblasts from 0 to 36 h post injury (1 line, 2 lines and 3 lines) were investigated. The expression of connective tissue growth factor, CTGF, which is a key mediator in hyper-tropic scarring, and relative intensity of CTGF as a function of time were determined by western blot and gelatin Zymography. After injury (1 line), CTGF level was increased more than 2-fold within 1 h and continuously increased up to 3-fold at 6 h and was leveled down to reach normal value at 36 h, at which cell migration was complete. In more serious injury (2 lines), higher expression of CTGF was observed. The down regulation of CTGF expression after CTGF siRNA/lipofectamine transfection in control, 1 line and 2 lines scratch conditions were 40%, 75% and 55%, respectively. As a model anti-CTGF based therapy, CTGF siRNA with different ratios of linear polyethyleneimine (PEI) complexes (1:1, 1:5, 1:10, 1:20 and 1:30) were prepared and down-regulation efficacy of CTGF was evaluated with our optimized scratch assay, which is 1 line injury at 6 h post injury observation time. As the cationic linear PEI ratio increased, the down regulation efficacy was increased from 20% (1:20) to 55% (1:30). As CTGF level was increased to the highest at 6 h and leveled down afterwards, CTGF level at 6 h could provide the most sensitive response upon CTGF siRNA transfection. The scratch assay in the present study can be employed as a useful experimental tool to differentiate between anti-scar therapies for their down regulation efficacy of CTGF. PMID:22370794

Moon, Heekyung; Yong, Hyeyoung; Lee, Ae-Ri Cho



Structural changes in connective tissues caused by a moderate laser heating  

SciTech Connect

The structural changes in adipose and fibrous tissues caused by 2- and 3-W IR laser irradiation are studied by the methods of IR and Raman spectroscopy and differential scanning calorimetry. It is shown that heating of fibrous tissue samples to 50 {sup 0}C and adipose tissue samples to 75 {sup 0}C by IR laser radiation changes the supramolecular structure of their proteins and triacylglycerides, respectively, without the intramolecular bond breaking. Heating of fibrous tissue to 70 {sup 0}C and adipose tissue to 90 - 110 {sup 0}C leads to a partial reversible denaturation of proteins and to oxidation of fats.

Bagratashvili, Viktor N; Bagratashvili, N V; Sviridov, A P; Shakh, G Sh [Institute of Laser and Information Technologies, Russian Academy of Sciences, Troitsk, Moscow Region (Russian Federation); Ignat'eva, Natalia Yu; Lunin, Valery V; Grokhovskaya, T E; Averkiev, S V [Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow (Russian Federation)



Detection of Pneumocystis carinii by DNA amplification in patients with connective tissue diseases: re-evaluation of clinical features of P. carinii pneumonia in rheumatic diseases  

Microsoft Academic Search

Objectives. We evaluated the polymerase chain reaction (PCR) detection of Pneumocystis carinii DNA in induced sputum of patients with connective tissue diseases and assessed the clinical features of patients positive for P. carinii. Methods. Sputum was induced by nebulization in 29 in-patients with various connective tissue diseases who presented with symptoms suggestive of P. carinii pneumonia (PCP), and was examined

K. Saito; S. Nakayamada; K. Nakano; M. Tokunaga; S. Tsujimura; K. Nakatsuka; T. Adachi; Y. Tanaka



Autoimmune hepatitis  

Microsoft Academic Search

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



Efficacy of connective tissue massage and Mc Mennell joint manipulation in the rehabilitative treatment of the hands in systemic sclerosis  

Microsoft Academic Search

Rehabilitation may contribute to the management of systemic sclerosis (SSc) dealing with disabilities due to hand involvement.\\u000a The aim of this study is to evaluate the efficacy of a rehabilitation programme based on the combination of connective tissue\\u000a massage and Mc Mennell joint manipulation specifically conceived for SSc patients’ hands. Forty SSc patients were enrolled:\\u000a 20 (interventional group) were treated

Susanna Maddali Bongi; Angela Del Rosso; Felice Galluccio; Fabrizio Sigismondi; Irene Miniati; M. Letizia Conforti; Francesca Nacci; Marco Matucci Cerinic



Rapid Isolation of Human Stem Cells (Connective Tissue Progenitor Cells) From the Proximal Humerus During Arthroscopic Rotator Cuff Surgery  

Microsoft Academic Search

Background: Bone-to-tendon healing in the shoulder can be unpredictable. Biologic augmentation, through the implementation of adult mesenchymal stem cells, may improve this healing process.Purpose: The purpose of this study was to (1) arthroscopically obtain bone marrow aspirates from the proximal humerus during rotator cuff repair, (2) purify and concentrate the connective tissue progenitor cells (CTPs) in the operating room efficiently,

Augustus D. Mazzocca; Mary Beth R. McCarthy; David M. Chowaniec; Mark P. Cote; Robert A. Arciero; Hicham Drissi



Connective Tissue Growth Factor Is Up-Regulated in the Diabetic Retina: Amelioration by Angiotensin-Converting Enzyme Inhibition  

Microsoft Academic Search

Connective tissue growth factor (CTGF) has been postulated to have prosclerotic and angiogenic properties. The aim of this present study was to characterize retinal CTGF expres- sion in the absence and presence of diabetes and in the context of treatment with the angiotensin-converting enzyme (ACE) inhibitor, perindopril. Retinas were obtained from control, diabetic, and diabetic plus perindopril-treated (3 mg\\/d) rats.




CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes  

Microsoft Academic Search

The matricellular protein CCN2 (Connective Tissue Growth Factor; CTGF) is an essential mediator of ECM composition, as revealed through analysis of Ccn2 deficient mice. These die at birth due to complications arising from impaired endochondral ossification. However, the mechanism(s)\\u000a by which CCN2 mediates its effects in cartilage are unclear. We investigated these mechanisms using Ccn2\\u000a \\u000a ?\\/?\\u000a chondrocytes. Expression of type

Takashi Nishida; Harumi Kawaki; Ruth M. Baxter; R. Andrea DeYoung; Masaharu Takigawa; Karen M. Lyons



Serum proteins and paraproteins in women with silicone implants and connective tissue disease: a case–control study  

Microsoft Academic Search

Prior studies have suggested abnormalities of serum proteins, including paraproteins, in women with silicone implants but did not control for the presence of connective-tissue disease (CTD). This retrospective case–control study, performed in tertiary-care academic centers, assessed possible alterations of serum proteins, including paraproteins, in such a population. Seventy-four women with silicone implants who subsequently developed CTD, and 74 age-matched and

Gyorgy Csako; Rene Costello; Ejaz A Shamim; Terrance P O'Hanlon; Anthony Tran; Daniel J Clauw; H James Williams; Frederick W Miller



Regulation of connective tissue growth factor gene expression in retinal vascular endothelial cells by angiogenic growth factors  

Microsoft Academic Search

Background: Connective tissue growth factor (CTGF) is a novel, cysteine-rich secreted protein, which is implicated in fibrotic disorders\\u000a and atherosclerosis. To elucidate the role of CTGF in fibrovascular proliferative retinopathy, we investigated the regulation\\u000a of CTGF gene expression in a cell line of retinal vascular endothelial cells (RVEC) stimulated with fetal calf serum (FCS)\\u000a and angiogenic growth factors, including vascular

Kerstin Wunderlich; Brigitte C. Senn; Liliane Todesco; Josef Flammer; Peter Meyer



Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis  

Microsoft Academic Search

Ito Y, Goldschmeding R, Kasuga H, Claessen N, Nakayama M, Yuzawa Y, Sawai A, Matsuo S, Weening JJ, Aten J. Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis. Am J Physiol Renal Physiol 299: F545-F558, 2010. First published June 24, 2010; doi:10.1152\\/ajprenal.00120.2009.-Transforming growth factor (TGF)-beta(1),-beta(2), and -beta(3) are involved in control of

Y. Ito; R. Goldschmeding; H. Kasuga; N. Claessen; M. Nakayama; Y. Yuzawa; A. Sawai; S. Matsuo; J. J. Weening; J. Aten



CCN1 contributes to skin connective tissue aging by inducing age-associated secretory phenotype in human skin dermal fibroblasts  

Microsoft Academic Search

Dermal connective tissue collagen is the major structural protein in skin. Fibroblasts within the dermis are largely responsible\\u000a for collagen production and turnover. We have previously reported that dermal fibroblasts, in aged human skin in vivo, express\\u000a elevated levels of CCN1, and that CCN1 negatively regulates collagen homeostasis by suppressing collagen synthesis and increasing\\u000a collagen degradation (Quan et al. Am

Taihao Quan; Zhaoping Qin; Patrick Robichaud; John J. Voorhees; Gary J. Fisher



UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review  

PubMed Central

Background Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. Methods Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. Results Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. Conclusions Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications.

Breuckmann, Frank; Gambichler, Thilo; Altmeyer, Peter; Kreuter, Alexander



Effect of defective connective tissue on the formation of aneurysmal-like structures in the rat testicular artery.  


Microscopic aneurysmal-like structures (ALS) develop spontaneously in the convoluted rat testicular artery and have been previously proposed as a model relevant to cerebral aneurysms. The effect of defects in connective tissue fibres on ALS formation was investigated by microscopy using two approaches: (i) the study of the effect of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking of elastic and collagen fibres, on the incidence, size and morphology of ALS in spontaneously hypertensive rats (SHR) and their normotensive controls (WKY). The straight spermatic artery was studied for comparison. (ii) The determination of the incidence of spontaneous ALS in Brown Norway (BN) and Long Evans (LE) rats which are highly susceptible (BN) or resistant (LE) to the spontaneous rupture of the arterial internal elastic lamina. (i) BAPN increased the number and size of ALS in SHR and WKY rats and had no effect on the straight spermatic artery and (ii) ALS were more numerous and of greater size in BN than in LE rats. Taken together, these results show that defective connective tissue fibres may favour the formation and induce the enlargement of aneurysmal-like structures. By analogy, these data suggest that a lack of connective tissue fibre integrity may be of importance in cerebral aneurysm formation and development. PMID:8762863

Coutard, M; Osborne-Pellegrin, M



Effect of defective connective tissue on the formation of aneurysmal-like structures in the rat testicular artery  

PubMed Central

Microscopic aneurysmal-like structures (ALS) develop spontaneously in the convoluted rat testicular artery and have been previously proposed as a model relevant to cerebral aneurysms. The effect of defects in connective tissue fibres on ALS formation was investigated by microscopy using two approaches: (i) the study of the effect of ?-aminopropionitrile (BAPN), an inhibitor of the cross-linking of elastic and collagen fibres, on the incidence, size and morphology of ALS in spontaneously hypertensive rats (SHR) and their normotensive controls (WKY). The straight spermatic artery was studied for comparison. (ii) The determination of the incidence of spontaneous ALS in Brown Norway (BN) and Long Evans (LE) rats which are highly susceptible (BN) or resistant (LE) to the spontaneous rupture of the arterial internal elastic lamina. (i) BAPN increased the number and size of ALS in SHR and WKY rats and had no effect on the straight spermatic artery and (ii) ALS were more numerous and of greater size in BN than in LE rats. Taken together, these results show that defective connective tissue fibres may favour the formation and induce the enlargement of aneurysmal-like structures. By analogy, these data suggest that a lack of connective tissue fibre integrity may be of importance in cerebral aneurysm formation and development.




Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap with Ehlers-Danlos syndromes.  


Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for the alpha chains of collagen VI and characterized by generalized muscle weakness, striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints, and normal intellectual development. The diagnosis is supported by abnormal immunoreactivity for collagen VI on muscle biopsies. As patients with UCMD show clinical characteristics typical of classical disorders of connective tissue such as Ehlers-Danlos syndromes (EDS), we investigated the ultrastructure of skin biopsy samples from patients with UCMD (n=5). Electron microscopy of skin biopsies revealed ultrastructural abnormalities in all cases, including alterations of collagen fibril morphology (variation in size and composite fibers) and increase in ground substance, which resemble those seen in patients with EDS. Our findings suggest that there is a true connective tissue component as part of the phenotypic spectrum of UCMD and that there is considerable clinical as well as morphological overlap between UCMD and classic connective tissue disorders. PMID:15690374

Kirschner, Janbernd; Hausser, Ingrid; Zou, Yaqun; Schreiber, Gudrun; Christen, Hans-Jürgen; Brown, Susan C; Anton-Lamprecht, Ingrun; Muntoni, Francesco; Hanefeld, Folker; Bönnemann, Carsten G



Thyroid tissue connected to normally located thyroid gland: ectopic or exophytic?  


Ectopic thyroid tissue is seen rarely. It is often seen in cervical midline, and rarely in other areas such as submandibular area. Diagnosis is made histopathologically by fine needle biopsy after the elimination of malignancy. In the treatment of ectopic thyroid tissue, surgical excision is mostly applied. According to our knowledge, there is no exophytic thyroid tissue reported in the literature. In this paper, a 32-year-old woman who presented with a swelling under the right jaw and found a thyroid tissue attached to the normally located thyroid gland with a fibrous band in the neck was discussed. PMID:23094169

Keles, Erol; Ozkara, Sule; Karlidag, Turgut; Ozercan, Ibrahim Hanifi



Thyroid Tissue Connected to Normally Located Thyroid Gland: Ectopic or Exophytic?  

PubMed Central

Ectopic thyroid tissue is seen rarely. It is often seen in cervical midline, and rarely in other areas such as submandibular area. Diagnosis is made histopathologically by fine needle biopsy after the elimination of malignancy. In the treatment of ectopic thyroid tissue, surgical excision is mostly applied. According to our knowledge, there is no exophytic thyroid tissue reported in the literature. In this paper, a 32-year-old woman who presented with a swelling under the right jaw and found a thyroid tissue attached to the normally located thyroid gland with a fibrous band in the neck was discussed.

Keles, Erol; Ozkara, Sule; Karlidag, Turgut; Ozercan, Ibrahim Hanifi



The zinc transporter SLC39A13\\/ZIP13 is required for connective tissue development; its involvement in BMP\\/TGF-beta signaling pathways  

Microsoft Academic Search

BackgroundZinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown.Methodology\\/Principal FindingsHere we report that mice deficient in Zn transporter Slc39a13\\/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout

Toshiyuki Fukada; Natacha Civic; Tatsuya Furuichi; Shinji Shimoda; Kenji Mishima; Hiroyuki Higashiyama; Yayoi Idaira; Yoshinobu Asada; Hiroshi Kitamura; Satoru Yamasaki; Shintaro Hojyo; Manabu Nakayama; Osamu Ohara; Haruhiko Koseki; Heloisa G. dos Santos; Luisa Bonafe; Andreas Zankl; Sheila Unger; Marius E. Kraenzlin; Jacques S. Beckmann; Ichiro Saito; Carlo Rivolta; Shiro Ikegawa; Andrea Superti-Furga; Toshio Hirano



Tissue Stretch Decreases Soluble TGF-?1 and Type-1 Procollagen in Mouse Subcutaneous Connective Tissue: Evidence From Ex Vivo and In Vivo Models  

PubMed Central

Transforming growth factor beta 1 (TGF-?1) plays a key role in connective tissue remodeling, scarring, and fibrosis. The effects of mechanical forces on TGF-?1 and collagen deposition are not well understood. We tested the hypothesis that brief (10 min) static tissue stretch attenuates TGF-?1-mediated new collagen deposition in response to injury. We used two different models: (1) an ex vivo model in which excised mouse subcutaneous tissue (N = 44 animals) was kept in organ culture for 4 days and either stretched (20% strain for 10 min 1 day after excision) or not stretched; culture media was assayed by ELISA for TGF-?1; (2) an in vivo model in which mice (N = 22 animals) underwent unilateral subcutaneous microsurgical injury on the back, then were randomized to stretch (20–30% strain for 10 min twice a day for 7 days) or no stretch; subcutaneous tissues of the back were immunohistochemically stained for Type-1 procollagen. In the ex vivo model, TGF-?1 protein was lower in stretched versus non-stretched tissue (repeated measures ANOVA, P < 0.01). In the in vivo model, microinjury resulted in a significant increase in Type-1 procollagen in the absence of stretch (P < 0.001), but not in the presence of stretch (P = 0.21). Thus, brief tissue stretch attenuated the increase in both soluble TGF-?1 (ex vivo) and Type-1 procollagen (in vivo) following tissue injury. These results have potential relevance to the mechanisms of treatments applying brief mechanical stretch to tissues (e.g., physical therapy, respiratory therapy, mechanical ventilation, massage, yoga, acupuncture).

Bouffard, Nicole A.; Cutroneo, Kenneth R.; Badger, Gary J.; White, Sheryl L.; Buttolph, Thomas R.; Ehrlich, H. Paul; Stevens-Tuttle, Debbie; Langevin, Helene M.



Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice  

PubMed Central

A deficit in IL-4 production has been previously reported in both diabetic human patients and non-obese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

Creusot, Remi J; Yaghoubi, Shahriar S; Kodama, Keiichi; Dang, Demi N; Dang, Vu H; Breckpot, Karine; Thielemans, Kris; Gambhir, Sam S; Fathman., C Garrison



Repair of full-thickness tendon injury using connective tissue progenitors efficiently derived from human embryonic stem cells and fetal tissues.  


The use of stem cells for tissue engineering (TE) encourages scientists to design new platforms in the field of regenerative and reconstructive medicine. Human embryonic stem cells (hESC) have been proposed to be an important cell source for cell-based TE applications as well as an exciting tool for investigating the fundamentals of human development. Here, we describe the efficient derivation of connective tissue progenitors (CTPs) from hESC lines and fetal tissues. The CTPs were significantly expanded and induced to generate tendon tissues in vitro, with ultrastructural characteristics and biomechanical properties typical of mature tendons. We describe a simple method for engineering tendon grafts that can successfully repair injured Achilles tendons and restore the ankle joint extension movement in mice. We also show the CTP's ability to differentiate into bone, cartilage, and fat both in vitro and in vivo. This study offers evidence for the possibility of using stem cell-derived engineered grafts to replace missing tissues, and sets a basic platform for future cell-based TE applications in the fields of orthopedics and reconstructive surgery. PMID:20486794

Cohen, Shahar; Leshansky, Lucy; Zussman, Eyal; Burman, Michael; Srouji, Samer; Livne, Erella; Abramov, Natalie; Itskovitz-Eldor, Joseph



Autoimmune Pancreatitis  

PubMed Central

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



Interaction of Borrelia burgdorferi with peripheral blood fibrocytes, antigen-presenting cells with the potential for connective tissue targeting.  

PubMed Central

BACKGROUND: Borrelia Burgdorferi has a predilection for collagenous tissue and can interact with fibronectin and cellular collagens. While the molecular mechanisms of how B. burgdorferi targets connective tissues and causes arthritis are not understood, the spirochetes can bind to a number of different cell types, including fibroblasts. A novel circulating fibroblast-like cell called the peripheral blood fibrocyte has recently been described. Fibrocytes express collagen types I and III as well as fibronectin. Besides playing a role in wound healing, fibrocytes have the potential to target to connective tissue and the functional capacity to recruit, activate, and present antigen to CD4(+) T cells. MATERIALS AND METHODS: Rhesus monkey fibrocytes were isolated and characterized by flow cytometry. B. burgdorferi were incubated with human or monkey fibrocyte cultures in vitro and the cellular interactions analyzed by light and electron microscopy. The two strains of B. burgdorferi studied included JD1, which is highly pathogenic for monkeys, and M297, which lacks the cell surface OspA and OspB proteins. RESULTS: In this study, we demonstrate that B. burgdorferi binds to both human and monkey (rhesus) fibrocytes in vitro. This process does not require OspA or OspB. In addition, the spirochetes are not phagocytosed but are taken into deep recesses of the cell membrane, a process that may protect them from the immune system. CONCLUSIONS: This interaction between B. burgdorferi and peripheral blood fibrocytes provides a potential explanation for the targeting of spirochetes to joint connective tissue and may contribute to the inflammatory process in Lyme arthritis. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5

Grab, D. J.; Lanners, H.; Martin, L. N.; Chesney, J.; Cai, C.; Adkisson, H. D.; Bucala, R.



Autoimmune Diseases  

Microsoft Academic Search

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


Autoimmune hepatitis  

Microsoft Academic Search

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  

Microsoft Academic Search

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



Effects of Carpal Tunnel Release on the Relative Motion of Tendon, Nerve, and Subsynovial Connective Tissue in a Human Cadaver Model  

PubMed Central

Background The purpose of this study was to evaluate the effect of flexor retinaculum division (simulated carpal tunnel release) on the relative motion of flexor tendon, subsynovial connective tissue, and median nerve in human cadaver specimens. Methods Using fluoroscopy, we measured the relative motion of middle finger flexor digitorum superficialis tendon, subsynovial connective tissue, and median nerve in twelve human cadavers with simulated fist motion. Measurements were obtained for three wrist positions: neutral; 60 degrees flexion; and 60 degrees extension. The shear index was defined as the difference in motion between two tissues (tendon, subsynovial connective tissue, or nerve) relative to tendon excursion, expressed as a percentage. After testing with an intact carpal tunnel, the flexor retinaculum was cut and the testing procedure was repeated. Findings With an intact flexor retinaculum, the wrist flexion position showed significantly less displacement for the subsynovial connective tissue and median nerve relative to tendon displacement, and thus the highest potential shear strain between subsynovial connective tissue-tendon, and tendon-nerve. The wrist extension position also had a significantly higher potential shear strain for tendon-nerve compared to the neutral position. After division of the flexor retinaculum, the differences in shear index among wrist positions were reduced. For the wrist flexion position, the subsynovial connective tissue and median nerve displacements significantly increased, indicating lower shear index values. Interpretation These findings suggest that division of flexor retinaculum reduces the potential shear strain and thus possibly the risk of shear injury to tissues with the carpal tunnel.

Yoshii, Yuichi; Zhao, Chunfeng; Henderson, Jacqueline; Zhao, Kristin D.; Zobitz, Mark E.; An, Kai-Nan; Amadio, Peter C.



Skeletal muscle cells express the profibrotic cytokine connective tissue growth factor (CTGF/CCN2), which induces their dedifferentiation.  


Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes of different tissues. Connective tissue growth factor (CTGF) seems to be involved in the fibrotic response. Several muscular dystrophies are characterized by a progressive weakness and wasting of the musculature, and by extensive fibrosis. However, the exact role of CTGF in skeletal muscle is unknown. Here we show that myoblasts and myotubes are able to synthesize CTGF in response to transforming growth factor type-beta (TGF-beta) and lysophosphatidic acid (LPA). CTGF induced several ECM constituents such as fibronectin, collagen type I and alpha4, 5, 6, and beta1 integrin subunits in myoblasts and myotubes. CTGF had an important inhibitory effect on muscle differentiation evaluated by the decrease in the nuclear translocation of the early muscle regulatory factor myogenin and myosin. Remarkable, CTGF treatment of myoblasts induced their dedifferentiation, characterized by down regulating MyoD and desmin, two markers of committed myoblasts, together with a strong reorganization of cytoskeletal filaments. These results provide novel evidence for the underlying mechanisms and participation of skeletal muscle cells in the synthesis and role of CTGF inducing fibrosis, inhibiting myogenesis and dedifferentiating myoblasts. PMID:18064627

Vial, Cecilia; Zúńiga, Lidia Miriam; Cabello-Verrugio, Claudio; Cańón, Pablo; Fadic, Ricardo; Brandan, Enrique



Expression profile of peripheral tissue antigen genes in medullary thymic epithelial cells (mTECs) is dependent on mRNA levels of autoimmune regulator (Aire).  


In the thymus of non-obese diabetic (NOD) mice, the expression of the autoimmune regulator (Aire) gene varies with age, and its down-regulation in young mice precedes the later emergence of type 1 diabetes mellitus (T1D). In addition, the insulin (Ins2) peripheral tissue antigen (PTA) gene, which is Aire-dependent, is also deregulated in these mice. Based in these findings, we hypothesized that the imbalance in PTA gene expression in the thymus can be associated with slight variations in Aire transcript levels. To test this, we used siRNA to knockdown Aire by in vivo electro-transfection of the thymus of BALB/c mice. The efficiency of the electro-transfection was monitored by assessing the presence of irrelevant Cy3-labeled siRNA in the thymic stroma. Importantly, Aire-siRNA reached medullary thymic epithelial cells (mTECs) down-regulating Aire. As expected, the in vivo Aire knockdown was partial and transient; the maximum 59% inhibition occurred in 48 h. The Aire knockdown was sufficient to down-regulate PTA genes; however, surprisingly, several others, including Ins2, were up-regulated. The modulation of these genes after in vivo Aire knockdown was comparable to that observed in NOD mice before the emergence of T1D. The in vitro transfections of 3.10 mTEC cells with Aire siRNA resulted in samples featuring partial (69%) and complete (100%) Aire knockdown. In these Aire siRNA-transfected 3.10 mTECs, the expression of PTA genes, including Ins2, was down-regulated. This suggests that the expression profile of PTA genes in mTECs is affected by fine changes in the transcription level of Aire. PMID:22564670

Oliveira, Ernna H; Macedo, Claudia; Donate, Paula B; Almeida, Renata S; Pezzi, Nicole; Nguyen, Catherine; Rossi, Marcos A; Sakamoto-Hojo, Elza T; Donadi, Eduardo A; Passos, Geraldo A



Autoimmune response in experimental hippocampal pathology  

Microsoft Academic Search

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 [2]. 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



Exercise-induced vasculitis associated with autoimmune disease.  


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



Dermal and subdermal tissue filling with fetal connective tissue and cartilage, collagen, and silicone: Experimental study in the pig compared with clinical results. A new technique of dermis mini-autograft injections  

Microsoft Academic Search

The early reaction to the injection of silicone, collagen, and lyophilized heterologous fetal connective and cartilage tissues into the limiting zone deep dermis-superficial subcutaneous tissue was histologically examined in the pig and compared with clinical results. The inflammatory reaction to lyophilized heterologous fetal tissue is considerably more intense than that to collagen and silicone and lasts for several weeks. Therefore,

Ulrich T. Hinderer; Julio Escalona




Microsoft Academic Search

IGHTFOOT and Coolidge (1949) showed with guinea pigs that there was a significant increase in the percent collagen with age. They also concluded that fasted animals at the growing age continued to synthesize collagen at the same rate as well fed animals. Spencer et al. (1937) found a rapid development of fibrous tissue in rabbits clue to nutritional muscle dystrophy.




Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is a strong angiogenic mitogen and plays important roles in angiogenesis under various pathophysiological conditions. The in vivo angiogenic activity of secreted VEGF may be regulated by extracellular inhibitors, because it is also produced in avascular tissues such as the cartilage. To seek the binding inhibitors against VEGF, we screened the chondrocyte cDNA library by

Isao Inoki; Takayuki Shiomi; Gakuji Hashimoto; Hiroyuki Enomoto; Hiroyuki Nakamura; Ken-ichi Makino; Eiji Ikeda; Shigeo Takata; Ken-ichi Kobayashi; Yasunori Okada



Autoimmune Epilepsy  

PubMed Central

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.



Treatment of Gingival Recessions Associated to Cervical Abrasion Lesions with Subepithelial Connective Tissue Graft: A Case Report  

PubMed Central

Extensive gingival recessions associated with cervical abrasions are common among the population. Several different surgical and/or restorative therapies have been proposed to correct these lesions. This manuscript reports the treatment of multiple gingival recessions associated to cervical abrasions. The procedure involved the utilization of subepithelial connective tissue graft (SCTG) combined with coronally advanced flap onto a previously restored root surface. At the postoperative follow-up visits, the success of the restorative/surgical approach was confirmed by the absence of bleeding to probing and periodontal pockets as well as presence of gingival tissue with normal color, texture and contouring. After 18 months of follow-up, the clinical conditions are stable with satisfactory root coverage and periodontal health. An excellent esthetical outcome was achieved and the patient is satisfied with case resolution.

Deliberador, Tatiana M.; Bosco, Alvaro F.; Martins, Thiago M.; Nagata, Maria J. H.



Effects of carpal tunnel release on the relative motion of tendon, nerve, and subsynovial connective tissue in a human cadaver model  

Microsoft Academic Search

BackgroundThe purpose of this study was to evaluate the effect of flexor retinaculum division (simulated carpal tunnel release) on the relative motion of flexor tendon, subsynovial connective tissue, and median nerve in human cadaver specimens.

Yuichi Yoshii; Chunfeng Zhao; Jacqueline Henderson; Kristin D. Zhao; Mark E. Zobitz; Kai-Nan An; Peter C. Amadio



Copper-dependent antioxidase defenses in inflammatory and autoimmune rheumatic diseases  

Microsoft Academic Search

Gel-filtered sera of patients with various inflammatory and autoimmune rheumatic diseases (N=354) were screened for the presence of the inflammation marker Cu-thionein. The concentrations of Cu-thionein were significantly diminished in patients with connective tissue diseases (P 0.001). Sera of patients suffering from inflammatory rheumatic diseases were almost totally depleted of this low-molecular-weight copper protein that exerts pronounced Superoxide dismutase activity

Ralf Miesel; Margit Zuber



Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination  

PubMed Central

Background Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. However, the role of CTGF in gastric cancer remains largely unknown. Results In this study, we showed that CTGF was highly expressed in gastric cancer tissues compared with matched normal gastric tissues. The CTGF expression in tumor tissue was associated with histologic grade, lymph node metastasis and peritoneal dissemination (P < 0.05). Patients with positive CTGF expression had significantly lower cumulative postoperative 5 year survival rate than those with negative CTGF expression (22.9% versus 48.1%, P < 0.001). We demonstrated that knockdown of CTGF expression significantly inhibited cell growth of gastric cancer cells and decreased cyclin D1 expression. Moreover, knockdown of CTGF expression also markedly reduced the migration and invasion of gastric cancer cells and decreased the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Animal studies revealed that nude mice injected with the CTGF knockdown stable cell lines featured a smaller number of peritoneal seeding nodules than the control cell lines. Conclusions These data suggest that CTGF plays an important role in cell growth and invasion in human gastric cancer and it appears to be a potential prognostic marker for patients with gastric cancer.



[Autoimmune polyglandular syndromes].  


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



Connective Tissue Disease-associated Pulmonary Arterial Hypertension in the Modern Treatment Era  

Microsoft Academic Search

Rationale: Pulmonary arterial hypertension in association with con- nective tissue disease (CTD-PAH) has historically had a poor prog- nosis, with a 1-year survival rate among patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) of 45%. However, more therapies have become available. Objectives: To investigate the survival and characteristics of all patients diagnosed with CTD-PAH in the U.K. pulmonary hyperten- sion

Robin Condliffe; David G. Kiely; Andrew J. Peacock; Paul A. Corris; J. Simon; R. Gibbs; Charlie A. Elliot; Martin Johnson; Julia DeSoyza; Chantal Torpy; Kim Goldsmith; Denise Hodgkins; Rodney J. Hughes; Joanna Pepke-Zaba; J. Gerry Coghlan


Tumor necrosis factor-alpha in synovial fluid and plasma from patients with chronic connective tissue disease and its relation to temporomandibular joint pain  

Microsoft Academic Search

Purpose: The purpose of this study was to determine the level of tumor necrosis factor-alpha (TNF-?) in the temporomandibular joint (TMJ) synovial fluid (SF-TNF-?) and blood plasma (P-TNF-?) of patients with chronic inflammatory connective tissue disease and investigate its relation to TMJ pain, hyperalgesia, and allodynia.Patients and Methods: Twenty-four patients with a diagnosis of chronic inflammatory connective tissue disease and

Silvi Nordahl; Per Alstergren; Sigvard Kopp



Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee  

PubMed Central

Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.



Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee.  


Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies. PMID:23374322

Boyan, Barbara D; Hart, David A; Enoka, Roger M; Nicolella, Daniel P; Resnick, Eileen; Berkley, Karen J; Sluka, Kathleen A; Kwoh, C Kent; Tosi, Laura L; O'Connor, Mary I; Coutts, Richard D; Kohrt, Wendy M



Connective tissue differences in the strength of cooked meat across the muscle fibre direction due to test specimen size.  


Systematic variations in the tensile strenght of cooked beef M. semitendinosus across the muscle fibre direction due to the cross-sectional size of specimens are demonstrated in specimens from (a) longitudinal and (b) transverse slices. The strength perpendicular to the fibre direction of longitudinal slices of thickness 0·25-5·75 mm varied by a factor of 2, thicker slices being stronger. This factor of 2 is in approximate agreement with the difference in strength of transverse versus longitudinal slices across the fibre direction. These variations of strength due to specimen geometry are explained on the basis of the increasing likelihood of including a ribbon of the perimysial connective tissue network which is continuous along the whole length of the test piece in larger samples. The breaking strength of small cross-sectional area specimens is likely to be dominated by the strength of the endomysial-perimysial junction. Larger cross-sectioned specimens, by including continuous strands of the perimysial network, have higher strengths resulting from the necessity to break these strands. These findings highlight the need to specify specimen dimensions in tensile test results. They also show that by manipulating specimen geometry, the relative magnitude of the two mechanisms of connective tissue fracture (endomysial-perimysial separation and perimysial strand fracture) may be assessed. PMID:22055572

Lewis, G J; Purslow, P P



Extranodal connective tissue invasion and the expression of desmosomal glycoprotein 1 in squamous cell carcinoma of the oesophagus.  

PubMed Central

We investigated extranodal connective tissue involvement (ECTI) in 39 patients with oesophageal carcinoma. Both the primary tumour and ECTI were immunohistochemically examined using the monoclonal antibody 32-2B for desmosomal glycoprotein 1 (DG1). Connective tissue carcinoma deposits were identified as cells within small lymph nodes, as lymphatic or venous vessel invasion or as widespread invasion beyond the capsule of metastatic lymph nodes. These histological findings were present in at least one area in 20 of 39 patients (51.3%). DG1 immunostaining intensity by tumour was graded as DG1 (++), DG1 (+) or DG1 (-). DG1 (+) or DG1 (-) primary tumours demonstrated lymph node metastases and ECTI more frequently than DG1(++) tumours (P<0.05). Among 17 patients in whom DG1 immunohistochemistry was performed on ECTI, there were three DG1(++), five DG1(+) and nine DG1(-) patients. The DG1 expression of ECTI was equal to or less intense than the primary tumour. These results indicate that reduction or loss of DG1 expression may promote ECTI and lymph node metastases. One should be aware of the potential for ECTI in oesophageal carcinomas. In the future, adjuvant therapy may be advisable for some oesophageal carcinomas based on the phenotype of individual cancer cells, including expression of DG1. Images Figure 1 Figure 2 Figure 3 Figure 4

Natsugoe, S.; Mueller, J.; Kijima, F.; Aridome, K.; Shimada, M.; Shirao, K.; Kusano, C.; Baba, M.; Yoshinaka, H.; Fukumoto, T.; Aikou, T.



Migration of connective tissue-derived cells is mediated by ultra-low concentration gradient fields of EGF  

PubMed Central

The directed migration of cells towards chemical stimuli incorporates simultaneous changes in both the concentration of a chemotactic agent and its concentration gradient, each of which may influence cell migratory response. In this study, we utilized a microfluidic system to examine the interactions between Epidermal Growth Factor (EGF) concentration and EGF gradient in stimulating the chemotaxis of connective-tissue derived fibroblast cells. Cells seeded within microfluidic devices were exposed to concentration gradients established by EGF concentrations that matched or exceeded those required for maximum chemotactic responses seen in transfilter migration assays. The migration of individual cells within the device was measured optically after steady-state gradients had been experimentally established. Results illustrate that motility was maximal at EGF concentration gradients between .01- and 0.1-ng/( for all concentrations used. In contrast, the numbers of motile cells continually increased with increasing gradient steepness for all concentrations examined. Microfluidics-based experiments exposed cells to minute changes in EGF concentration and gradient that were in line with the acute EGFR phosphorylation measured. Correlation of experimental data with established mathematical models illustrated that the fibroblasts studied exhibit an unreported chemosensitivity to minute changes in EGF concentration, similar to that reported for highly motile cells, such as macrophages. Our results demonstrate that shallow chemotactic gradients, while previously unexplored, are necessary to induce the rate of directed cellular migration and the number of motile cells in the connective tissue-derived cells examined.

Kong, Qingjun; Majeska, Robert J.; Vazquez, Maribel



Molecular Mechanism for Connective Tissue Destruction by Dipeptidyl Aminopeptidase IV Produced by the Periodontal Pathogen Porphyromonas gingivalis  

PubMed Central

Porphyromonas gingivalis is a pathogen associated with adult periodontitis. It produces dipeptidyl aminopeptidase IV (DPPIV), which may act as a virulence factor by contributing to the degradation of connective tissue. We investigated the molecular mechanism by which DPPIV contributes to the destruction of connective tissue. DPPIV itself did not show gelatinase or collagenase activity toward human type I collagen, but it promoted the activity of the host-derived matrix metalloproteinase 2 (MMP-2) (gelatinase) and MMP-1 (collagenase). DPPIV bound to fibronectin and mediated the adhesion of P. gingivalis to fibronectin. Mutant DPPIV with catalytic Ser mutagenized to Ala (DPPSA) did not accelerate the degradation of collagen and gelatin by MMPs but retained fibronectin-binding activity. The adhesion of human gingival fibroblasts and NIH 3T3 cells to fibronectin was inhibited by DPPIV. Strain 4351ADPPSA exhibited an intermediate level of virulence in mice, between that of the strain expressing wild-type DPPIV (4351ADPP) and that of the strain harboring only the plasmid vector (4351AVEC). It is suggested that both activity promoting the degradation of collagen and gelatin and binding to fibronectin are required for full virulence. These results reveal novel biological functions of DPPIV and suggest a pathological role in the progression of periodontitis.

Kumagai, Yumi; Yagishita, Hisao; Yajima, Ayako; Okamoto, Tatsuya; Konishi, Kiyoshi



Autoimmunity—Aging Mouse Model for Autoimmune Diseases  

Microsoft Academic Search

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


Controlling the Fibroblastic Differentiation of Mesenchymal Stem Cells Via the Combination of Fibrous Scaffolds and Connective Tissue Growth Factor  

PubMed Central

Controlled differentiation of multi-potent mesenchymal stem cells (MSCs) into vocal fold-specific, fibroblast-like cells in vitro is an attractive strategy for vocal fold repair and regeneration. The goal of the current study was to define experimental parameters that can be used to control the initial fibroblastic differentiation of MSCs in vitro. To this end, connective tissue growth factor (CTGF) and micro-structured, fibrous scaffolds based on poly(glycerol sebacate) (PGS) and poly(?-caprolactone) (PCL) were used to create a three-dimensional, connective tissue-like microenvironment. MSCs readily attached to and elongated along the microfibers, adopting a spindle-shaped morphology during the initial 3 days of preculture in an MSC maintenance medium. The cell-laden scaffolds were subsequently cultivated in a conditioned medium containing CTGF and ascorbic acids for up to 21 days. Cell morphology, proliferation, and differentiation were analyzed collectively by quantitative PCR analyses, and biochemical and immunocytochemical assays. F-actin staining showed that MSCs maintained their fibroblastic morphology during the 3 weeks of culture. The addition of CTGF to the constructs resulted in an enhanced cell proliferation, elevated expression of fibroblast-specific protein-1, and decreased expression of mesenchymal surface epitopes without markedly triggering chondrogenesis, osteogenesis, adipogenesis, or apoptosis. At the mRNA level, CTGF supplement resulted in a decreased expression of collagen I and tissue inhibitor of metalloproteinase 1, but an increased expression of decorin and hyaluronic acid synthesase 3. At the protein level, collagen I, collagen III, sulfated glycosaminoglycan, and elastin productivity was higher in the conditioned PGS-PCL culture than in the normal culture. These findings collectively demonstrate that the fibrous mesh, when combined with defined biochemical cues, is capable of fostering MSC fibroblastic differentiation in vitro.

Tong, Zhixiang; Sant, Shilpa



Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and 'selective' pathway connection.  


A constant supply of cholesterol is needed as a substrate for steroid hormone synthesis in steroidogenic tissues. Although there are three potential sources, which could contribute to the 'cholesterol pool', needed for steroidogenesis (i.e., de novo synthesis, hydrolysis of stored cholesteryl esters and exogenous lipoproteins), current evidence suggests that plasma lipoproteins are the major source of cholesterol for steroid production in adrenal gland, ovary and, under certain conditions, testicular Leydig cells. In many species, steroid producing cells and tissues obtain this lipoprotein-cholesterol by a unique pathway in which circulating lipoproteins bind to the surface of the steroidogenic cells and contribute their cholesteryl esters to the cells by a 'selective' process. This is a process in which cholesterol is selectively absorbed while the lipoprotein remains at the cell surface. The discovery of a specific receptor for this process (scavenger receptor class B, type I, known as SR-BI) has revolutionized our knowledge about the selective uptake pathway. The present review summarizes the functional importance of the selective pathway as a bulk cholesterol delivery system for steroidogenesis, and attempts to detail the expression, regulation and characteristics of SR-BI as it is deployed in steroidogenic systems as a means of achieving cholesterol balance. PMID:12957864

Azhar, Salman; Leers-Sucheta, Susan; Reaven, Eve



Matrix Metalloproteinase-dependent turnover of cartilage, synovial membrane, and connective tissue is elevated in rats with collagen induced arthritis  

PubMed Central

Background Rheumatoid arthritis is a disease affecting the extracellular matrix of especially synovial joints. The thickness of the synovial membrane increases and surrounding tissue degrades, leading to altered collagen balance in the tissues. In this study, we investigated the altered tissue balance of cartilage, synovial membrane, and connective tissue in collagen induced arthritis (CIA) in rats. Methods Six newly developed ELISAs quantifying MMP-derived collagen degradation (C1M, C2M, and C3M) and formation (P1NP, P2NP, and P3NP) was used to detect cartilage turnover in rats with CIA. Moreover, CTX-II was used to detect alternative type II collagen degradation and as control of the model. 10 Lewis rats were injected with porcrine type II collagen twice with a 7 day interval and 10 rats was injected with 0.05 M acetic acid as control. The experiment ran for 26 days. Results A significant increase in the degradation of type I, II, and III collagen (C1M, C2M, and C3M, respectively) was detected on day 22 (P?=?0.0068, P?=?0.0068, P?tissues of the synovial joints, leading to increased pain and degeneration of the synovial joints.



Connective tissue growth factor—a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats  

Microsoft Academic Search

The pathophysiologic mechanisms of myocardial remodeling in heart failure (HF) remain poorly understood. Using differential mRNA display of myocardial tissue from rats with ischemic HF vs. controls we identified robust myocardial induction of the mRNA encoding connective tissue growth factor (CTGF). The aim of this study was to investigate the sites of synthesis and the mechanisms of induction of CTGF

Mohammed Shakil Ahmed; Erik Řie; Leif Erik Vinge; Arne Yndestad; Geir Řystein Andersen; Yvonne Andersson; Toril Attramadal; Hĺvard Attramadal



Analysis of human osteoarthritic connective tissue by laser capture microdissection and QRT-PCR.  


Gene expression levels for type II collagen and aggrecan have been determined as potential measures and disease markers of human osteoarthritis in patients undergoing total knee arthroplasty. In this regard, specimens of affected articular cartilage obtained intraoperatively at the time of surgery were placed in RNAlater(TM) to maintain RNA integrity and subsequently frozen-sectioned. Individual or small numbers of chondrocytes were isolated by laser capture microdissection and their total RNA was extracted and analyzed by quantitative reverse transcription-polymerase chain reaction. Results indicate that type II collagen and aggrecan mRNA expression from specific cells in osteoarthritic tissues are detectable and reproducible using these approaches. Our work is the first to demonstrate successful isolation of RNA limited to chondrocytes comprising small quantities of human osteoarthritic material. The study presents a new avenue by which the disease and its progression may be critically assayed. PMID:18075818

Scharschmidt, Thomas; Jacquet, Robin; Laskovski, Jovan; Lowder, Elizabeth; Weiner, Scott; Landis, William J



[Therapeutic options for autoimmune encephalomyelitis].  


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



Immunogenicity of influenza H1N1 vaccination in mixed connective tissue disease: effect of disease and therapy  

PubMed Central

OBJECTIVE: To assess the potential acute effects regarding the immunogenicity and safety of non-adjuvanted influenza A H1N1/2009 vaccine in patients with mixed connective tissue disease and healthy controls. METHODS: Sixty-nine mixed connective tissue disease patients that were confirmed by Kasukawa's classification criteria and 69 age- and gender-matched controls participated in the study; the participants were vaccinated with the non-adjuvanted influenza A/California/7/2009 (H1N1) virus-like strain. The percentages of seroprotection, seroconversion, geometric mean titer and factor increase in the geometric mean titer were calculated. The patients were clinically evaluated, and blood samples were collected pre- and 21 days post-vaccination to evaluate C-reactive protein, muscle enzymes and autoantibodies. Anti-H1N1 titers were determined using an influenza hemagglutination inhibition assay. NCT01151644. RESULTS: Before vaccination, no difference was observed regarding the seroprotection rates (p?=?1.0) and geometric mean titer (p?=?0.83) between the patients and controls. After vaccination, seroprotection (75.4% vs. 71%, p?=?0.7), seroconversion (68.1% vs. 65.2%, p?=?1.00) and factor increase in the geometric mean titer (10.0 vs. 8.0, p?=?0.40) were similar in the two groups. Further evaluation of seroconversion in patients with and without current or previous history of muscle disease (p?=?0.20), skin ulcers (p?=?0.48), lupus-like cutaneous disease (p?=?0.74), secondary Sjögren syndrome (p?=?0.78), scleroderma-pattern in the nailfold capillaroscopy (p?=?1.0), lymphopenia ?1000/mm3 on two or more occasions (p?=?1.0), hypergammaglobulinemia ?1.6 g/d (p?=?0.60), pulmonary hypertension (p?=?1.0) and pulmonary fibrosis (p?=?0.80) revealed comparable rates. Seroconversion rates were also similar in patients with and without immunosuppressants. Disease parameters, such as C-reactive protein (p?=?0.94), aldolase (p?=?0.73), creatine phosphokinase (p?=?0.40) and ribonucleoprotein antibody levels (p?=?0.98), remained largely unchanged pre and post-vaccination. No severe side effects were reported. CONCLUSIONS: The non-adjuvanted influenza A/H1N1 vaccination immune response in mixed connective tissue disease patients is adequate and does not depend on the disease manifestations and therapy.

Miossi, Renata; Fuller, Ricardo; Moraes, Julio C. B.; Ribeiro, Ana Cristina M.; Saad, Carla G. S.; Aikawa, Nadia E.; Miraglia, Joao L; Ishida, Maria A; Bonfa, Eloisa; Caleiro, M Teresa C.



Sex hormones and autoimmunity  

Microsoft Academic Search

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



Relation between regional echo intensity and myocardial connective tissue in chronic left ventricular disease.  

PubMed Central

Cross sectional echocardiograms were recorded within one week of death in seven patients with valvular heart disease, four with coronary artery disease, and nine with congenital heart disease. Regional echo amplitude was measured from the cross sectional display by constructing histograms of pixel intensity. Parietal pericardium was used as an internal standard for setting the gain of the instrument. At necropsy myocardium was taken from the free wall of the left ventricle, the papillary muscles, and the septum. Fibrosis was assessed histologically and biochemically as hydroxyproline content. In individual samples histological and biochemical estimates were correlated. In all regions other than the septum in patients with left ventricular hypertrophy, log [collagen] correlated with median pixel intensity. The amplitude of reflected echoes from the hypertrophied septum was significantly higher than that from other samples but was similarly correlated with collagen content. Agreement between echo amplitude and histological grade was significantly less good. Thus in chronic left ventricular disease myocardial collagen content appears to be the major determinant of regional echo intensity. Reproducibility of measurements and more rigorous definition of tissue abnormalities will, however, require further study. Images

Shaw, T R; Logan-Sinclair, R B; Surin, C; McAnulty, R J; Heard, B; Laurent, G J; Gibson, D G



Analysis of obstetric complications and uterine connective tissue in tenascin-X-deficient humans and mice  

PubMed Central

Tenascin-X (TNX) is a large, multi-domain, extracellular matrix glycoprotein. Complete deficiency of TNX in humans leads to a recessive form of Ehlers-Danlos syndrome (EDS), and TNX haploinsufficiency is a cause of hypermobility type EDS. EDS patients appear to have a higher risk of several complications during pregnancy, such as pelvic instability, premature rupture of membranes, and postpartum hemorrhage. Here, we present a study of genitourinary and obstetric complications in TNX-deficient women of reproductive age. We have found complications, such as uterus prolapses, that are in agreement with previous findings in other EDS types. In TNX knockout (KO) mice, we have observed mild pregnancy-related abnormalities. Morphological and immunohistological analysis of uterine tissues has not revealed obvious quantitative or spatial differences between TNX KO and wildtype mice with respect to collagen types I, III, V, and XII or elastic fibers. We conclude that TNX-deficient women are at risk of obstetric complications, but that TNX KO mice show only a mild phenotype. Furthermore, we show that TNX is involved in the stability of elastic fibers rather than in their initial deposition.

Egging, David F.; van Vlijmen-Willems, Ivonne; Choi, Jiwon; Peeters, Anita C. T. M.; van Rens, Desiree; Veit, Guido; Koch, Manuel; Davis, Elaine C.



Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells  

SciTech Connect

Although commonly used to control a variety of inflammatory diseases, the mechanism of action of a low dose of methotrexate remains a mystery. Methotrexate accumulates intracellularly where it may interfere with purine metabolism. Therefore, the authors determined whether a 48-hr pretreatment with methotrexate affected adenosine release from ({sup 14}C)adenine-labeled human fibroblasts and umbilical vein endothelial cells. Methotrexate significantly increased adenosine release by fibroblasts. The effect of methotrexate on adenosine release was not due to cytotoxicity since cells treated with maximal concentrations of methotrexate took up ({sup 14}C)adenine and released {sup 14}C-labeled purine (a measure of cell injury) in a manner identical to control cells. Methotrexate treatment of fibroblasts dramatically inhibited adherence to fibroblasts by both unstimulated neutrophils and stimulated neutrophils. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, methotrexate induces the accumulation of AICAR, the nucleoside precursor of which has previously been shown to cause adenosine release from ischemic cardiac tissue. The observation that the antiinflammatory actions of methotrexate are due to the capacity of methotrexate to induce adenosine release may form the basis for the development of an additional class of antiinflammatory drugs.

Cronstein, B.N.; Eberle, M.A.; Levin, R.I. (New York Univ. Medical Center, New York (United States)); Gruber, H.E. (Gensia Pharmaceuticals, Inc., San Diego, CA (United States))



Development of diagnostic and treatment strategies for glaucoma through understanding and modification of scleral and lamina cribrosa connective tissue.  


Considerable evidence indicates that the state of ocular connective tissues and their response in glaucomatous disease affect the degree of glaucoma damage. Both experimental and clinical data suggest that improved diagnostic and prognostic information can be derived from the assessment of the mechanical responsiveness of the sclera and lamina cribrosa to intraocular pressure (IOP). Controlled mutagenesis of the sclera has produced a mouse strain that is relatively resistant to increased IOP. Alteration of the baseline scleral state can be accomplished through either increased cross-linking of fibrillar components or their reduction. The sclera is a dynamic structure, altering its structure and behavior in response to IOP change. The biochemical pathways that control these responses are fertile areas for new glaucoma treatments. PMID:23535950

Quigley, Harry A; Cone, Frances E



[Immunological characteristics in subjects with heart connective tissue dysplasia depending on thyroid hormone levels and vegetative dysfunction].  


Patients with heart connective tissue dysplasia (HCTD) are known to be subject to infectious and inflammatory diseases due to peculiarities of their immune system. We studied 181 patients with HCTD depending on thyroid hormone levels and vegetative dysfunction. HCTD was shown to be associated with a significant decrease of IgM levels and increase of circulating immune complexes. The IgG level in patients with mitral valve prolapse (MVP), anomalous chord localization, and combination of MPV and tricuspid valve prolapse was significantly higher than in the absence of HCTD. Patients with and without HCTD showed the dependence of IgA levels on TSH concentration. In those with combined MPV the intensity of chemiluminescence was related to the T4 level. The dependence of IgM levels on he presence ofvegetative dysfunction was documented in patients with MVP. PMID:23285764

Gurmach, M A; Chizhov, P A; Smirnova, M P; Medvedeva, T M



Successful etanercept therapy for refractory sacroiliitis in a patient with ankylosing spondylitis and mixed connective tissue disease.  


The concurrence of ankylosing spondylitis (AS) in a patient with mixed connective tissue disease (MCTD) is rarely described in the literature. Significant and sustained efficacy with tumor necrosis factor (TNF)-alpha blockers has been demonstrated in AS patients. However, evidence to date has revealed associated side effects, including antinuclear antibody induction and development of a lupus-like syndrome. Several authors have reported lupus-like manifestations in MCTD patients treated with TNF-alpha blockers used to control peripheral polyarthritis. In our case report, we demonstrate a good response to etanercept therapy for refractory sacroiliitis in a patient with coexisting AS and MCTD, without development of a lupus-like syndrome. This demonstrates that etanercept therapy may be an appropriate therapeutic agent for sacroiliitis in MCTD patients, as it is in AS alone. PMID:18306484

Lee, Jee Young; Chang, Hyun Kyu; Kim, Seong-Kyu



[SEM studies on the connective tissue cores of the lingual papillae of the northern goshawk (Accipiter gentilis)].  


The lingual papillae and their connective tissue cores (CTCs) of the northern goshawk were examined by scanning electron microscopy (SEM). The length of the tongue was approximately 2.5 cm. The median groove divided the body of the tongue into symmetrical parts. At a point approximately 2/3 of the length, there were large conical papillae between the body and the root of the tongue, the apices of which were pointed towards the posterior part of the tongue. Under the light microscopy, the filiform papillae of the dorsal surface in the lingual body showed the desquamate cells of non-keratinized epithelium. There were openings of the lingual glands on the anterior part and root of the tongue. The lingual papillae and their CTCs of the northern goshawk had a structure similar to those of the white tailed eagle and black kite. PMID:18807946

Emura, Shoichi; Okumura, Toshihiko; Chen, Huayue



An unusual connective tissue disease in mother and son: a "new" type of Ehlers-Danlos syndrome?  


A 23-year-old woman and her 2 1/2-year-old son both had large hernias, positional foot deformities, abnormal thoracic shape, asthma, and severe eczematoid dermatitis. Their facial appearance was quite similar and included asymmetry with prominent nasal bridge and small jaw. In addition, the mother had severe thoracolumbar kyphoscolosis and "cigarette paper" scars over her legs. She died after rupture of a a thoracic aortic aneurysm and was found on postmortem examination to have cystic medionecrosis of the aorta and myxomatous degeneration and elongation of the mitral and tricuspid valves. The family history was otherwise negative; there was no consanguinity. The connective tissue disease in this mother and her son appears to be a previously unrecognized dominantly-inherited disorder with some similarity to classical Ehlers-Danlos syndrome. PMID:7094393

Friedman, J M; Harrod, M J



Expression of connective tissue growth factor and interleukin-11 in intratumoral tissue is associated with poor survival after curative resection of hepatocellular carcinoma.  


In the present study, we evaluated the prognostic value of intratumoral and peritumoral expression of connective tissue growth factor (CTGF), transforming growth factor-beta 1 (TGF-?1), and interleukin-11 (IL-11) in patients with hepatocellular carcinoma (HCC) after curative resection. Expression of CTGF, TGF-?1, and IL-11 was assessed by immunohistochemical staining of tissue microarrays containing paired tumor and peritumoral liver tissue from 290 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of these and other clinicopathologic factors were evaluated. The median follow-up time was 54.3 months (range, 4.3-118.3 months). High intratumoral CTGF expression was associated with vascular invasion (P = 0.015), intratumoral IL-11 expression correlated with higher tumor node metastasis (TNM) stage (P = 0.009), and peritumoral CTGF overexpression correlated with lack of tumor encapsulation (P = 0.031). Correlation analysis of these proteins revealed that intratumoral CTGF and IL-11 correlated with high intratumoral TGF-?1 expression (r = 0.325, P < 0.001; and r = 0.273, P < 0.001, respectively). TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.010), and intratumoral IL-11 expression (P = 0.015) were independent prognostic factors for progression-free survival (PFS). Vascular invasion (P = 0.032), TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.036), and intratumoral IL-11 expression (P = 0.013) were independent prognostic factors for overall survival (OS). High intratumoral CTGF and intratumoral IL-11 expression were associated with PFS and OS after hepatectomy, and the combination of intratumoral CTGF with IL-11 may be predictive of survival. PMID:22205539

Xiang, Zuo-Lin; Zeng, Zhao-Chong; Fan, Jia; Tang, Zhao-You; Zeng, Hai-Ying



Histological assessment of the palatal mucosa and greater palatine artery with reference to subepithelial connective tissue grafting  

PubMed Central

This study aimed to measure the thickness of the epithelium and lamina propria of the palatal mucosa and to elucidate the location of the greater palatine artery to provide the anatomical basis for subepithelial connective tissue grafting. Thirty-two maxillary specimens, taken from the canine distal area to the first molar distal area, were embedded in paraffin and stained with hematoxylin-eosin. The thickness of the epithelium and lamina propria of the palatal mucosa was measured at three positions on these specimens, starting from 3 mm below the alveolar crest and in 3-mm intervals. The location of the greater palatine artery was evaluated by using image-processing software. The mean epithelial thickness decreased significantly in the posterior teeth; it was 0.41, 0.36, 0.32, and 0.30 mm in the canine, first premolar, second premolar, and first molar distal areas, respectively. The lamina propria was significantly thicker in the canine distal; it was 1.36, 1.08, 1.09, and 1.05 mm, respectively. The mean length from the alveolar crest to the greater palatine artery increased toward the posterior molar; it was 7.76, 9.21, 10.93, and 11.28 mm, respectively. The mean depth from the surface of the palatal mucosa to the greater palatine artery decreased from the canine distal to the first premolar distal but increased again toward the posterior molar; it was 3.97, 3.09, 3.58, and 5.50 mm, respectively. Detailed histological assessments of the lamina propria of the palatal mucosa and the greater palatine artery are expected to provide useful anatomical guidelines for subepithelial connective tissue grafting.

Cho, Kwang-Hee; Yu, Sun-Kyoung; Lee, Myoung-Hwa; Lee, Dong-Seol



Autoimmune Cytopenias In Common Variable Immunodeficiency  

PubMed Central

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.



Autoimmune hepatitis  


... immune cells mistake the liver's normal cells for harmful invaders and attack them. ... tell the difference between healthy body tissue and harmful, outside substances. The result is an immune response ...



PubMed Central

CCN2, (connective tissue growth factor, CTGF) is a matricellular factor associated with fibrosis that plays an important role in the production and maintenance of fibrotic lesions. Increased collagen deposition and accumulation is a common feature of fibrotic tissues. The mechanisms by which CCN2 /CTGF contributes to fibrosis are not well understood. Previous studies suggest that CTGF exerts some of its biological effects at least in part by integrin binding, though this mechanism has not been previously shown to contribute to fibrosis. Utilizing full length CCN2/CTGF, CCN2/CTGF fragments, and integrin neutralizing antibodies, we provide evidence that the effects of CCN2/CTGF to stimulate extracellular matrix deposition by gingival fibroblasts are mediated by the C-terminal half of CCN2/CTGF, and by ?6 and ?1 integrins. In addition, a synthetic peptide corresponding to a region of CCN2/CTGF domain 3 that binds ?6?1 inhibits the collagen deposition assay. These studies employed a new and relatively rapid assay for CCN2/CTGF-stimulated collagen deposition based on Sirius Red staining of cell layers. Data obtained support a pathway in which CCN2/CTGF could bind to ?6?1 integrin and stimulate collagen deposition. These findings provide new experimental methodologies applicable to uncovering the mechanism and signal transduction pathways of CCN2/CTGF mediated collagen deposition, and may provide insights into potential therapeutic strategies to treat gingival fibrosis and other fibrotic conditions.

Heng, Edwin C. K.; Huang, Yuanyi; Black, Samuel A.; Trackman, Philip C.



Inhibition of connective tissue growth factor/CCN2 expression in human dermal fibroblasts by interleukin-1alpha and beta.  


Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)-beta and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We previously showed that keratinocytes in vitro downregulate TGF-beta-induced expression of CTGF in fibroblasts by an interleukin (IL)-1 alpha-dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL-1alpha and beta. Human dermal fibroblasts and NIH 3T3 cells were treated with IL-1alpha or beta in presence or absence of TGF-beta1. IL-1 suppressed basal and TGF-beta-induced CTGF mRNA and protein expression. IL-1alpha and beta inhibited TGF-beta-stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3-binding CAGA elements. Furthermore, IL-1alpha and beta inhibited TGF-beta-stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition, RNA interference suggested that TGF-beta activated kinase1 (TAK1) is necessary for IL-1 inhibition of TGF-beta-stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin. PMID:20544797

Nowinski, D; Koskela, A; Kiwanuka, E; Boström, M; Gerdin, B; Ivarsson, M



Increased connective tissue growth factor associated with cardiac fibrosis in the mdx mouse model of dystrophic cardiomyopathy.  


Cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disorder. A major feature of the hearts of DMD patients and the mdx mouse model of the disease is cardiac fibrosis. Connective tissue growth factor (CTGF) is involved in the fibrotic process in many organs. This study utilized the mdx mouse model to assess the role of CTGF and other extracellular matrix components during the development of fibrosis in the dystrophic heart. Left ventricular function of mdx and control mice at 6, 29 and 43 weeks was measured by echocardiography. Young (6 weeks old) mdx hearts had normal function and histology. At 29 weeks of age, mdx mice developed cardiac fibrosis and increased collagen expression. The onset of fibrosis was associated with increased CTGF transcript and protein expression. Increased intensity of CTGF immunostaining was localized to fibrotic areas in mdx hearts. The upregulation of CTGF was also concurrent with increased expression of tissue inhibitor of matrix metalloproteinases (TIMP-1). These changes persisted in 43 week old mdx hearts and were combined with impaired cardiac function and increased gene expression of transforming growth factor (TGF)-?1 and matrix metalloproteinases (MMP-2, MMP-9). In summary, an association was observed between cardiac fibrosis and increased CTGF expression in the mdx mouse heart. CTGF may be a key mediator of early and persistent fibrosis in dystrophic cardiomyopathy. PMID:21121985

Au, Carol G; Butler, Tanya L; Sherwood, Megan C; Egan, Jonathan R; North, Kathryn N; Winlaw, David S



Restricting dietary magnesium accelerates ectopic connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6?/?)  

PubMed Central

Ectopic mineralization, linked to a number of diseases, is a major cause of morbidity and mortality in humans. Pseudoxanthoma elasticum (PXE) is a heritable multisystem disorder characterized by calcium phosphate deposition in various tissues. The mineral content of diet has been suggested to modify the disease severity in PXE. The aim of this study is to explore the role of diet with reduced magnesium in modifying tissue mineralization in a mouse model of PXE. Abcc6?/? mice were placed on either standard rodent diet (control) or an experimental diet low in magnesium at weaning (4 wks) and examined for mineralization in the skin and internal organs at the ages of 1.5, 2 or 6 months by computerized morphometric analysis of histopathologic sections and by chemical assay of calcium and phosphate. Experimental Abcc6?/? mice demonstrated an accelerated, early-onset mineralization of connective tissues, as compared to control mice. Wild-type or heterozygous mice on experimental diet did not show evidence of mineralization up to 6 months of age. All mice on experimental diet showed decreased urinary calcium, increased urinary phosphate and elevated parathyroid serum levels. However, no difference in bone density at 6 months of age was noted. Our findings indicate that the mineral content, particularly magnesium, can modify the extent and the onset of mineralization in Abcc6?/? mice, and suggest that dietary magnesium levels may contribute to the phenotypic variability of PXE. The control of mineralization by dietary magnesium may have broader implications in general population in the context of vascular mineralization.

Jiang, Qiujie; Uitto, Jouni



The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-? Signaling Pathways  

PubMed Central

Background Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Methodology/Principal Findings Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-? signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. Conclusions/Significance Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-? signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-? signaling and connective tissue dysfunction.

Shimoda, Shinji; Mishima, Kenji; Higashiyama, Hiroyuki; Idaira, Yayoi; Asada, Yoshinobu; Kitamura, Hiroshi; Yamasaki, Satoru; Hojyo, Shintaro; Nakayama, Manabu; Ohara, Osamu; Koseki, Haruhiko; dos Santos, Heloisa G.; Bonafe, Luisa; Ha-Vinh, Russia; Zankl, Andreas; Unger, Sheila; Kraenzlin, Marius E.; Beckmann, Jacques S.; Saito, Ichiro; Rivolta, Carlo; Ikegawa, Shiro; Superti-Furga, Andrea; Hirano, Toshio



Estrogen metabolism and autoimmunity.  


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



Progress in Autoimmune Diseases Research.  

National Technical Information Service (NTIS)

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...



Vitamin D Status and Bone and Connective Tissue Turnover in Brown Bears (Ursus arctos) during Hibernation and the Active State  

PubMed Central

Background Extended physical inactivity causes disuse osteoporosis in humans. In contrast, brown bears (Ursus arctos) are highly immobilised for half of the year during hibernation without signs of bone loss and therefore may serve as a model for prevention of osteoporosis. Aim To study 25-hydroxy-vitamin D (25OHD) levels and bone turnover markers in brown bears during the hibernating state in winter and during the active state in summer. We measured vitamin D subtypes (D2 and D3), calcitropic hormones (parathyroid hormone [PTH], 1,25-dihydroxy-vitamin D [1,25(OH)2D]) and bone turnover parameters (osteocalcin, ICTP, CTX-I), PTH, serum calcium and PIIINP. Material and Methods We drew blood from seven immobilised wild brown bears during hibernation in February and in the same bears while active in June. Results Serum 25-hydroxy-cholecalciferol (25OHD3) was significantly higher in the summer than in the winter (22.8±4.6 vs. 8.8±2.1 nmol/l, two tailed p - 2p?=?0.02), whereas 25-hydroxy-ergocalciferol (25OHD2) was higher in winter (54.2±8.3 vs. 18.7±1.7 nmol/l, 2p<0.01). Total serum calcium and PTH levels did not differ between winter and summer. Activated 1,25(OH)2D demonstrated a statistically insignificant trend towards higher summer levels. Osteocalcin levels were higher in summer than winter, whereas other markers of bone turnover (ICTP and CTX-I) were unchanged. Serum PIIINP, which is a marker of connective tissue and to some degree muscle turnover, was significantly higher during summer than during winter. Conclusions Dramatic changes were documented in the vitamin D3/D2 ratio and in markers of bone and connective tissue turnover in brown bears between hibernation and the active state. Because hibernating brown bears do not develop disuse osteoporosis, despite extensive physical inactivity we suggest that they may serve as a model for the prevention of this disease.

Vestergaard, Peter; St?en, Ole-Gunnar; Swenson, Jon E.; Mosekilde, Leif; Heickendorff, Lene; Frobert, Ole



Assembly of the Prothrombinase Complex on the Surface of Human Foreskin Fibroblasts: Implications for Connective Tissue Growth Factor  

PubMed Central

Activated factor X (FXa) and thrombin can up-regulate gene expression of connective tissue growth factor (CTGF/CCN2) on fibroblasts. Since tissue factor (TF) is expressed on these cells, we hypothesized that they may assemble the prothrombinase complex leading to CTGF/CCN2 upregulation. In addition, the effect of thrombospondin-1 (TSP1) on this reaction was evaluated. Human foreskin fibroblasts were incubated with purified factor VII (FVII), factor X (FX), factor V (FV), prothrombin and calcium in the presence and absence of TSP1. Generation of FXa and of thrombin were assessed using chromogenic substrates. SMAD pathway phosphorylation was detected via Western-blot analysis. Pre-incubation of fibroblasts with FVII led to its auto-activation by cell-surface expressed TF, which in turn in the presence of FX, FVa, prothrombin and calcium led to FXa (9.7 ± 0.8 nM) and thrombin (7.9 ± 0.04 U/mL × 10-3) generation. Addition of TSP1 significantly enhanced thrombin (23.3 ± 0.7 U/mL × 10-3) but not FXa (8.5 ± 0.6 nM) generation. FXa and thrombin generation leads to upregulation of CTGF/CCN2. TSP1 alone upregulated CTGF/CCN2, an effect mediated via activation of transforming growth factor beta (TGF?) as showed by phosphorylation of the SMAD pathway an event blunted by using a TGF? receptor I inhibitor (TGF?RI). FXa- and thrombin-induced upregulation of CTGF/CCN2 was not blocked by TGF?RI. In summary, assembly of the prothrombinase complex occurs on fibroblast’s surface leading to serine proteases generation, an event enhanced by TSP1 and associated with CTGF/CCN2 upregulation. These mechanisms may play an important role in human diseases associated with fibrosis.

Rico, Mario C.; Rough, James J.; Manns, Joanne M.; Carpio-Cano, Fabiola Del; Safadi, Fayez F.; Kunapuli, Satya P.; Cadena, Raul A DeLa



Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate.  


Peritoneal fibrosis (PF) is an important complication of peritoneal dialysis (PD) therapy that often occurs in association with peritoneal high transport rate and ultrafiltration failure (UFF). To study the possible pathogenic role of connective tissue growth factor (CTGF) in the relationship of PF and UFF, dialysate CTGF contents (n = 178) and tissue CTGF expression (n = 61) were investigated by ELISA, real-time PCR, immunohistochemistry, and in situ hybridization. CTGF production with and without TGF-beta1 stimulation in human peritoneal mesothelial cells (HPMC) from the spent patients' peritoneal dialysate (n = 32) was studied in vitro. The dialysate-to-plasma ratio for creatinine (D/P Cr) was positively correlated to dialysate CTGF concentration and estimated local peritoneal production of CTGF. CTGF mRNA expression was 11.4-fold higher in peritoneal membranes with UFF than in pre-PD renal failure peritoneum and was correlated with thickness of the peritoneum. CTGF protein and mRNA were detected in mesothelium and in fibroblast-like cells. In cultured HPMC, TGF-beta(1)-induced expression of CTGF mRNA was increased at 12 and 24 h and was correlated with D/P Cr. In contrast, bone morphogenic protein-4 mRNA expression was inversely correlated with D/P Cr. Our results suggest that high peritoneal transport state is associated with fibrosis and increased peritoneal CTGF expression and production by mesothelial cells, which can be stimulated by TGF-beta1. Dialysate CTGF concentration could be a biomarker for both peritoneal fibrosis and membrane function. Functional alteration of mesothelial cells may be involved in progression of peritoneal fibrosis in high transport state. PMID:20015945

Mizutani, Makoto; Ito, Yasuhiko; Mizuno, Masashi; Nishimura, Hayato; Suzuki, Yasuhiro; Hattori, Ryohei; Matsukawa, Yoshihisa; Imai, Masaki; Oliver, Noelynn; Goldschmeding, Roel; Aten, Jan; Krediet, Raymond T; Yuzawa, Yukio; Matsuo, Seiichi



Histomorphometrical and clinical study of connective tissue around titanium dental implants with porous surfaces in a canine model.  


Connective tissue (CT) reactions and collagen fiber orientation were evaluated on titanium implants with porous surfaces made by a laser method. Three groups in which the diameters of pores were 10 ± 5 µm, 40 ± 5 µm, and 70 ± 5 µm were involved in this test, together with a machined group as control. A total of 24 implants were randomly placed in mandibles after 3 months of premolars and the first molar extraction in beagle dogs. All the implants were firmly anchored in the bone after 3-month insertion. Histological sections showed that the gingival tissue was attached tightly to implant surface and there was no significant difference in inflammatory cell invasion and probing depth among all groups (p > 0.05). Histomorphometric analysis demonstrated that no significant difference in total CT length was observed among four groups (p > 0.05), however, the gingival recession in the 40 ± 5 µm and 70 ± 5 µm porous groups was less than in the 10 ± 5 µm porous group and control group (p < 0.05). Collagen fibers at the inner zone of the CT around the 40 ± 5 µm and 70 ± 5 µm porous implants aligned mostly in an oblique orientation, while there was a mainly parallel fiber direction around the 10 ± 5 µm porous and control implants. It was noted that some fibroblasts and fibers in the 70 ± 5 µm porous group was inserted into the pores of implant surface, indicating that pores of a proper size on the implant surface could induce the insertion of CT and prevent gingival recession. PMID:22210806

Zhao, Bao Hong; Cui, Fu Zhai; Liu, Yang; Deng, Chun Fu



Toxicology of Autoimmune Diseases  

PubMed Central

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.



Understanding Autoimmune Diseases  


... 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 ...


Cell-to-cell interactions in the secretion of enzymes of connective tissue breakdown, collagenase and proteoglycan-degrading neutral proteases. A review  

Microsoft Academic Search

Cell and tissue culture techniques provide valuable tools for investigating cell-to-cell interactions leading to the secretion of connective-tissue degrading enzymes, collagenase and proteoglycan-degrading neutral proteases, in inflammatory situations. These interactions, which might constitute a major regulatory mechanism, are reviewed here. Taken together, the available data strongly suggest that fibroblasts and related mesenchymal cells (such as chondrocytes, fibroblast-like or type B

Gilbert Vaes



The Architecture of the Connective Tissue in the Musculoskeletal System--An Often Overlooked Functional Parameter as to Proprioception in the Locomotor Apparatus  

PubMed Central

The architecture of the connective tissue, including structures such as fasciae, sheaths, and membranes, is more important for understanding functional meaning than is more traditional anatomy, whose anatomical dissection method neglects and denies the continuity of the connective tissue as integrating matrix of the body. The connective tissue anatomy and architecture exhibits two functional tendencies that are present in all areas of the body in different ways and relationships. In body cavities, the “disconnecting” quality of shaping space enables mobility; between organs and body parts, the “connecting” dimension enables functional mechanical interactions. In the musculoskeletal system, those two features of the connective tissue are also present. They cannot be found by the usual analytic dissection procedures. An architectural description is necessary. This article uses such a methodologic approach and gives such a description for the lateral elbow region. The result is an alternative architectural view of the anatomic substrate involved in the transmission and conveyance of forces over synovial joints. An architectural description of the muscular and connective tissue organized in series with each other to enable the transmission of forces over these dynamic entities is more appropriate than is the classical concept of “passive” force-guiding structures such as ligaments organized in parallel to actively force-transmitting structures such as muscles with tendons. The discrimination between so-called joint receptors and muscle receptors is an artificial distinction when function is considered. Mechanoreceptors, also the so-called muscle receptors, are arranged in the context of force circumstances—that is, of the architecture of muscle and connective tissue rather than of the classical anatomic structures such as muscle, capsules, and ligaments. In the lateral cubital region of the rat, a spectrum of mechanosensitive substrate occurs at the transitional areas between regular dense connective tissue layers and the muscle fascicles organized in series with them. This substrate exhibits features of type and location of the mechanosensitive nerve terminals that usually are considered characteristic for “joint receptors” as well as for “muscle receptors.” The receptors for proprioception are concentrated in those areas where tensile stresses are conveyed over the elbow joint. Structures cannot be divided into either joint receptors or muscle receptors when muscular and collagenous connective tissue structures function in series to maintain joint integrity and stability. In vivo, those connective tissue structures are strained during movements of the skeletal parts, those movements in turn being induced and led by tension in muscular tissue. In principle, because of the architecture, receptors can also be stimulated by changes in muscle tension without skeletal movement, or by skeletal movement without change in muscle tension. A mutual relationship exists between structure (and function) of the mechanoreceptors and the architecture of the muscular and regular dense connective tissue. Both are instrumental in the coding of proprioceptive information to the central nervous system.

van der Wal, Jaap



Autoimmune Polyglandular Syndrome Type 2  

Microsoft Academic Search

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


Adenovirus conducted connective tissue growth factor on extracellular matrix in trabecular meshwork and its role on aqueous humor outflow facility.  


Deposition of extracellular matrix (ECM) in trabecular meshwork, such as fibronectin, collagen IV, elastin. leads to increased resistance of trabecular meshwork in primary open angle glaucoma (POAG). Connective tissue growth factor (CTGF) is known to regulate the ECM deposits. In this study, we detect the effect of adenovirus conducted CTGF (Adv-CTGF) transfection on either the expression of ECM components or aqueous humor outflow facility. Adv-CTGF was used to transfect rat trabecular meshwork cells in vivo and in vitro. Aqueous humor outflow facility was test by microbeads perfusion. Protein expression of CTGF, fibronectin, and collagen IV was determined using Western blot. In the Adv-CTGF group, the outflow facility displayed a significant decrease from baseline. It appears as though the transfection with Adv-CTGF significantly affects the aqueous humor outflow pattern. A negative correlation between IOP and PEFL indicated that a decrease in the area of bead deposition corresponded to an overall decrease of outflow, leading to an elevated IOP. Adv-CTGF can enhance the expression of CTGF, fibronectin and collagen IV. CTGF is the novel target for treatment of POAG. It is necessary to further study to test inhibition of CTGF expression for treatment of POAG. PMID:24052232

Su, Ying; Cheng, Jingli; Liu, Hongtao; Wang, Feng; Zhao, Shiguang



Efficacy of intermittent etidronate therapy for corticosteroid-induced osteoporosis in patients with diffuse connective tissue disease.  


We conducted a one-year comparative study of 25 patients with corticosteroid-induced osteoporosis associated with diffuse connective tissue disease. The patients were randomly divided into 2 groups: group A (9 patients), monotherapy with active vitamin D3 (V.D3); and group B (16 patients), combination therapy with V.D3 and etidronate. Four markers were employed: as an bonegenic marker, serum alkaline phosphatase (ALP); as a bone resorption marker, urinary deoxypyridinoline (DPD); as a bone salt minerals assay level, young adult mean (YAM); and bonefracture ratio. Results showed that: ALP decreased in both groups with no significant difference between groups; DPD increased significantly from baseline (p < 0.05) in group A, but it decreased significantly from baseline (p < 0.05) in group B, but again without a significant difference between groups; YAM resulted in no significant improvement in group A, but a significant improvement from baseline (p < 0.01) was shown in group B, with a significant difference between groups (p < 0.05); and a new spinal compression fracture ratio was extremely lower in group A than in group B. The findings indicated cyclical/intermittent etidronate therapy is effective in preventing corticosteroid-induced osteoporosis. PMID:11059223

Jinnouchi, Y



CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes  

PubMed Central

The matricellular protein CCN2 (Connective Tissue Growth Factor; CTGF) is an essential mediator of ECM composition, as revealed through analysis of Ccn2 deficient mice. These die at birth due to complications arising from impaired endochondral ossification. However, the mechanism(s) by which CCN2 mediates its effects in cartilage are unclear. We investigated these mechanisms using Ccn2?/? chondrocytes. Expression of type II collagen and aggrecan were decreased in Ccn2?/? chondrocytes, confirming a defect in ECM production. Ccn2?/? chondrocytes also exhibited impaired DNA synthesis and reduced adhesion to fibronectin. This latter defect is associated with decreased expression of ?5 integrin. Moreover, CCN2 can bind to integrin ?5?1 in chondrocytes and can stimulate increased expression of integrin ?5. Consistent with an essential role for CCN2 as a ligand for integrins, immunofluorescence and Western blot analysis revealed that levels of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK)1/2 phosphorylation were reduced in Ccn2?/? chondrocytes. These findings argue that CCN2 exerts major effects in chondrocytes through its ability to (1) regulate ECM production and integrin ?5 expression, (2) engage integrins and (3) activate integrin-mediated signaling pathways.

Nishida, Takashi; Kawaki, Harumi; Baxter, Ruth M.; DeYoung, R. Andrea; Takigawa, Masaharu



Mechanically relevant consequences of the composite laminate-like design of the abdominal wall muscles and connective tissues.  


Together, three abdominal wall muscles (external oblique, internal oblique and transversus abdominis) form a tightly bound muscular sheet that has been likened to a composite-laminate structure. Previous work has demonstrated the ability of force generated by these three muscles to be passed between one another through connective tissue linkages. Muscle fibres in each muscle are obliquely oriented with respect to its neighbouring muscles. It is proposed here is that this unique morphology of the abdominal wall muscles functions, through the application of constraining forces amongst the muscles, to increase force- and stiffness-generating capabilities. This paper presents a mathematical formulation of the stress-strain relationship for a transversely isotropic fibrous composite, and establishes a strengthening and stiffening effect when stress can be transferred between the fibrous layers. Application of empirical mechanical properties to this formulation demonstrates this effect for the abdominal wall muscles and, in greater proportion, for the anterior aponeurosis of the abdominal wall. This has implications for increasing the stiffness and passive load bearing ability of the abdominal wall muscles, and has the potential to modulate the whole muscle force-length and force-velocity relationships during contraction. PMID:22137674

Brown, Stephen H M



Connective Tissue Growth Factor (CTGF) Inactivation Leads to Defects in Islet Cell Lineage Allocation and ?-Cell Proliferation during Embryogenesis  

PubMed Central

The factors necessary for normal pancreatic islet morphogenesis have not been well characterized. Here we report that connective tissue growth factor (CTGF) is involved in the establishment of normal islet endocrine cell ratio and architecture. CTGF is a secreted protein known to modulate several growth factor-signaling pathways including TGF-?, BMP, and Wnt. Although its role in pancreatic diseases such as pancreatitis and pancreatic cancer are well documented, a role for CTGF in normal pancreas development and function has heretofore not been examined. Using a lacZ-tagged CTGF allele, we describe for the first time the expression pattern of CTGF in the developing pancreas and the requirement of CTGF for normal islet morphogenesis and embryonic ?-cell proliferation. CTGF is highly expressed in pancreatic ductal epithelium and vascular endothelium, as well as at lower levels in developing insulin+ cells, but becomes down-regulated in ?-cells soon after birth. Pancreata from CTGF null embryos have an increase in glucagon+ cells with a concomitant decrease in insulin+ cells, and show defects in islet morphogenesis. Loss of CTGF also results in a dramatic decrease in ?-cell proliferation at late gestation. Unlike CTGF null embryos, CTGF heterozygotes survive past birth and exhibit a range of islet phenotypes, including an intermingling of islet cell types, increased number of glucagon+ cells, and ?-cell hypertrophy.

Crawford, Laura A.; Guney, Michelle A.; Oh, Young Ah; DeYoung, R. Andrea; Valenzuela, David M.; Murphy, Andrew J.; Yancopoulos, George D.; Lyons, Karen M.; Brigstock, David R.; Economides, Aris; Gannon, Maureen



Finite Element Model of Subsynovial Connective Tissue Deformation due to Tendon Excursion in the Human Carpal Tunnel  

PubMed Central

Carpal Tunnel Syndrome (CTS) is a nerve entrapment disease which has been extensively studied by the engineering and medical community. Although the direct cause is unknown, in vivo and in vitro medical research has shown that tendon excursion creates micro tears in the subsynovial connective tissue (SSCT) surrounding the tendon in the carpal tunnel. One proposed mechanism for the SSCT injury is shearing which is believed to cause fibrosis of the SSCT. Few studies have reported quantitative observations of SSCT response to mechanical loading. Our proposed model is a 2-D section that consists of an FDS tendon, interstitial SSCT and adjacent stationary tendons. We believe that developing this model will allow the most complete quantitative observations of SSCT response to mechanical loading reported thus far. Boundary conditions were applied to the FEA model to simulate single finger flexion. A velocity was applied to the FDS tendon in the model to match loading conditions of the documented cadaver wrist kinematics studies. The cadaveric and FEA displacement results were compared to investigate the magnitude of stiffness required for the SSCT section of the model. The relative motions between the model and cadavers matched more closely than the absolute displacements. Since cadaveric models do not allow identification of the SSCT layers, an FEA model will help determine the displacement and stress experienced by each SSCT layer. Thus, we believe this conceptual model is a first step in understanding how the SSCT layers are recruited during tendon excursion.

Henderson, Jacqueline; Thoreson, Andrew; Yoshii, Yuichi; Zhao, Kristin D.; Amadio, Peter C.; An, Kai-Nan



Finite element model of subsynovial connective tissue deformation due to tendon excursion in the human carpal tunnel.  


Carpal tunnel syndrome (CTS) is a nerve entrapment disease, which has been extensively studied by the engineering and medical community. Although the direct cause is unknown, in vivo and in vitro medical research has shown that tendon excursion creates microtears in the subsynovial connective tissue (SSCT) surrounding the tendon in the carpal tunnel. One proposed mechanism for the SSCT injury is shearing, which is believed to cause fibrosis of the SSCT. Few studies have reported quantitative observations of SSCT response to mechanical loading. Our proposed model is a 2-D section that consists of an FDS tendon, interstitial SSCT and adjacent stationary tendons. We believe that developing this model will allow the most complete quantitative observations of SSCT response to mechanical loading reported thus far. Boundary conditions were applied to the FEA model to simulate single finger flexion. A velocity was applied to the FDS tendon in the model to match loading conditions of the documented cadaver wrist kinematics studies. The cadaveric and FEA displacement results were compared to investigate the magnitude of stiffness required for the SSCT section of the model. The relative motions between the model and cadavers matched more closely than the absolute displacements. Since cadaveric models do not allow identification of the SSCT layers, an FEA model will help determine the displacement and stress experienced by each SSCT layer. Thus, we believe this conceptual model is a first step in understanding how the SSCT layers are recruited during tendon excursion. PMID:20887993

Henderson, Jacqueline; Thoreson, Andrew; Yoshii, Yuichi; Zhao, Kristin D; Amadio, Peter C; An, Kai-Nan



Root Surface Biomodification with Nd:YAG Laser for the Treatment of Gingival Recession with Subepithelial Connective Tissue Grafts  

PubMed Central

Abstract Background/Aim: Root surface biomodification has been used to treat gingival recession and periodontitis. The principle for this procedure is that removing the smear layer from the root surfaces exposes collagen fibers, which leads to improved healing. Clinical studies generally have failed to find any improvement in clinical parameters when using such procedures, however. The aim of this study was to evaluate and compare the outcome of gingival recession therapy using the subepithelial connective tissue graft (SCTG) with or without Nd:YAG laser application for root surface biomodification. Materials and Methods: Thirty-four teeth in 17 patients with Miller Class 1 and 2 recession were treated with SCTG with (test group) or without (control group) the application of Nd:YAG laser (1?W, 10?Hz, 100?mj, 60?s, 1064?nm). Clinical attachment level (CAL), recession depth (RD), recession width (RW), and probing depth (PD) were measured at baseline and six months postsurgery. Results: Both treatments yielded significant improvements in terms of RD and RW decrease and CAL gain compared to baseline values. For test and control groups, the average root coverage was 33% and 77%, respectively (p?

Aydin, Tugba; Canakci, Varol; Cicek, Yasin



Root Surface Biomodification with an Er:YAG Laser for the Treatment of Gingival Recession with Subepithelial Connective Tissue Grafts  

PubMed Central

Abstract Background/Aim: Root surface biomodification has been used to treat gingival recession and periodontitis. The principle for this procedure is that removing the smear layer from the root surfaces exposes collagen fibers, which leads to improved healing. Clinical studies generally have failed to find any improvement in clinical parameters when using such agents. The aim of this study was to evaluate and compare the outcome of gingival recession therapy using the subepithelial connective tissue graft (SCTG) with or without Er:YAG laser application for root surface biomodification. Materials and Methods: Twenty-four teeth in 12 patients with Miller class I and II recession were treated with SCTG with (test group) or without (control group) the application of an Er:YAG laser (2?Hz, 60?mJ/pulse, 40?s, with air spray). Clinical attachment level (CAL), recession depth (RD), recession width (RW), and probing depth (PD) were measured at baseline and 6 months postsurgery. Results: There were no significant differences between test and control groups (p?>?0.05). Postoperatively, significant root coverage, gains in CAL, and highly significant increases in the RW were observed in both groups. For test and control groups, the average root coverage was 80% and 86%, respectively (p?>?0.05), and complete root coverage was 75% and 67%, respectively. Conclusions: The present study showed that root surface conditioning with an Er:YAG laser does not enhance the results achieved when SCTG was performed alone.

Aydin, Tugba; Yavuz, M. Selim



Successful laparoscopic Nissen fundoplication in a patient with mixed connective tissue disease with a short esophagus: report of a case.  


A 51-year-old female with esophageal stricture was referred to our hospital. She was diagnosed to have mixed connective tissue disease and had been placed on steroid and immunosuppressant treatment. She presented with passage disturbance and free reflux of the gastric contents when in the supine position. Pneumatic dilatation and medication resulted in partial relief of her symptoms. Preoperative imaging studies demonstrated a shortened esophagus with severe stricture of the esophagogastric junction and a moderate hiatal hernia. A DeMeester's score of 140.1 was noted on 24-h pH monitoring. Under a diagnosis of stricturing reflux esophagitis, surgical treatment was indicated. Laparoscopic transhiatal mediastinal dissection with crural repair and fundoplication was offered instead of thoracotomy and/or laparotomy, since she had a high risk due to immunosuppression. The esophagus was extensively dissected through the hiatus up to the level of the tracheal bifurcation, and fundoplication was completed without Collis gastroplasty. Her postoperative course was rapid and uneventful. Postoperatively, her clinical symptoms were resolved with anatomical/functional improvement. PMID:24122051

Nakajima, Kiyokazu; Takahashi, Tsuyoshi; Takiguchi, Shuji; Miyata, Hiroshi; Yamasaki, Makoto; Kurokawa, Yukinori; Mori, Masaki; Doki, Yuichiro



CCN2/Connective Tissue Growth Factor Is Essential for Pericyte Adhesion and Endothelial Basement Membrane Formation during Angiogenesis  

PubMed Central

CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor ? (TGF?) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes.

Huang, Bau-Lin; van Handel, Ben; Hofmann, Jennifer J.; Chen, Tom T.; Choi, Aaron; Ong, Jessica R.; Benya, Paul D.; Mikkola, Hanna; Iruela-Arispe, M. Luisa; Lyons, Karen M.



Antiproliferative factor regulates connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells  

PubMed Central

Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis (IC)—a chronic, painful bladder disease of unknown etiology. APF inhibits the proliferation of normal bladder epithelial and T24 bladder carcinoma cells in vitro by binding to cytoskeleton-associated protein 4 (CKAP4) and altering the transcription of genes involved in proliferation, cellular adhesion, and tumorigenesis; however, specific molecular mechanisms and effector genes that control APF's antiproliferative effects are unknown. In this study, we found that there was a 7.5-fold up-regulation of connective tissue growth factor (CTGF/CCN2) expression in T24 bladder carcinoma cells treated with APF. Western blot revealed a dose-dependent increase in CCN2 protein levels, with secretion into the culture medium after APF treatment. CCN2 overexpression enhanced APF's antiproliferative activity, whereas CCN2 knockdown diminished APF-induced p53 expression. Using a luciferase reporter construct, we found that APF treatment resulted in fivefold activation of the CCN2 proximal promoter and, of importance, that small interfering RNA–mediated knockdown of CKAP4 inhibited CCN2 upregulation. In addition, we demonstrate that CKAP4 translocates to the nucleus and binds to the CCN2 proximal promoter in an APF-dependent manner, providing evidence that CCN2 regulation by APF involves CKAP4 nuclear translocation and binding to the CCN2 promoter.

Matika, Christina A.; Wasilewski, Melissa; Arnott, John A.; Planey, Sonia Lobo



Inhibition of collagen production in scleroderma fibroblast cultures by a connective tissue glycoprotein extracted from normal dermis  

SciTech Connect

It was shown in a previous paper that a connective tissue glycoprotein (CTGP) extracted from normal rabbit dermis was able to inhibit total protein and collagen syntheses by normal dermis fibroblast cultures. In the present study, the effects of CTGP on scleroderma fibroblasts were investigated. (/sup 14/C)Proline incorporation into total proteins of the supernatant was not significantly different from that found in controls. By contrast, the amount of collagen, expressed as percentage of total secreted protein, was far higher in scleroderma cultures than in normal ones (14.4% +/- 6.0% vs 4.6% +/- 0.9%). Addition of CTGP to the medium induced a concentration-dependent inhibition of (/sup 14/C)proline incorporation into proteins from both control and scleroderma cells. In control cultures, no significant decrease of the percentage of collagen was observed, but over 60 micrograms/ml, both cytotoxic effects and inhibition of protein synthesis occurred. In scleroderma cultures, the inhibition was twice as effective on collagen as on noncollagen protein synthesis. The inhibition of collagen secretion was not related either to changes in collagen hydroxylation or to the intracellular catabolism of newly synthesized procollagen.

Maquart, F.X.; Bellon, G.; Cornillet-Stoupy, J.; Randoux, A.; Triller, R.; Kalis, B.; Borel, J.P.



Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner  

PubMed Central

Connective tissue growth factor (CTGF), a downstream mediator of transforming growth factor-?1, mediates mesangial cell/fibroblast proliferation and extracellular matrix production by renal cells. Here, we show that renal tubular epithelial cells from patients with minimal change nephritic syndrome produced CTGF after glucocorticoid treatment. In addition, the glucocorticoid dexamethasone (DEX) increased CTGF mRNA levels in the kidneys of C57B6 but not SJL mice and produced intermediate CTGF mRNA levels in the kidneys of F1 (C57B6 × SJL) mice, midway between the levels found for parental strains. DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA. Transient transfection experiments using luciferase reporter constructs bearing CTGF promoter fragments revealed that the ?897- to ?628-bp fragment contained DEX-responsive positive regulatory elements, which were active in mProx24 but not MCT cells. Long-term DEX treatment resulted in fibronectin deposition in the kidneys of C57B6 but not SJL mice, and this effect was inhibited by co-administration of CTGF anti-sense oligodeoxynucleotides. Thus, glucocorticoid-induced renal fibrogenesis seems to be influenced by genetic background, with the critical DEX-responsive elements in the ?897- to ?628-bp region of the CTGF promoter.

Okada, Hirokazu; Kikuta, Tomohiro; Inoue, Tsutomu; Kanno, Yoshihiko; Ban, Shinichi; Sugaya, Takeshi; Takigawa, Masaharu; Suzuki, Hiromichi



Smell and autoimmunity: a comprehensive review.  


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



Differentiation-dependent expression of connective tissue growth factor and lysyl oxidase messenger ribonucleic acids in rat granulosa cells.  


Searching for novel genes involved in tissue remodeling during ovarian folliculogenesis, we carried out differential display RT-PCR (DDRT-PCR) on RNA from gonadotropin-stimulated rat granulosa cells (GC). GC from preantral and early antral follicles in immature rat ovaries were cultured in serum-free medium containing no hormone (control), recombinant human FSH (10 ng/ml), 5alpha-dihydrotestosterone (DHT; 10(-6) M), or FSH plus DHT. Total cellular RNA was extracted from cells at 6, 12, 24, and 48 h of treatment for DDRT-PCR analysis, corresponding to an estimated 60% saturation of the messenger RNA (mRNA) population. Six distinct complementary DNA clones were obtained that reproduced the DDRT-PCR profile on a Northern blot of the corresponding RNA samples. Two of these clones detected transcripts that were strongly down-regulated by FSH. One corresponded to connective tissue growth factor (CTGF), a cysteine-rich secreted protein related to platelet-derived growth factor that is implicated in mitogenesis and angiogenesis, and a second was identical to lysyl oxidase (LO), a key participant in extracellular matrix deposition. In detailed expression studies, Northern analysis revealed a single, approximately 2.5-kb CTGF transcript maximally suppressed within 3 h of exposure to FSH with or without DHT and two LO transcripts ( approximately 3.8 and approximately 5.2 kb) maximally suppressed at 6 h. DHT alone did not affect CTGF mRNA, but strongly enhanced LO mRNA relative to the control value. In vivo, CTGF and LO transcripts were significantly suppressed in GC 48 h after equine CG injection (10 IU, ip) compared with untreated controls and were further reduced 12 h after administration of additional 10 IU hCG to induce luteinization. In situ hybridization confirmed GC in preantral/early antral follicles as principal sites of CTGF and LO mRNA expression. We conclude that expression of CTGF and LO mRNAs is inversely related to GC differentiation. The encoded proteins probably have roles in the regulation of tissue remodeling and extracellular matrix formation during early follicular development. PMID:11181522

Slee, R B; Hillier, S G; Largue, P; Harlow, C R; Miele, G; Clinton, M



HIV and autoimmunity  

Microsoft Academic Search

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



Non-marfan idiopathic medionecrosis (cystic medial necrosis) presenting with multiple visceral artery aneurysms and diffuse connective tissue fragility: Two brothers  

Microsoft Academic Search

Two brothers with multiple visceral artery aneurysms or dilatations and diffuse connective tissue fragility who did not have clinical features of Marfan syndrome are reported. One presented with retroperitoneal hemorrhage during angiography, and idiopathic medionecrosis was proved by resection of the aneurysms. These cases belong to the heterogeneous group of Marfan syndrome. The angiographical features (multiple dilation of visceral arteries)

Jun Kubota; Mami Tsunemura; Shigeko Amano; Shigemi Tokizawa; Susumu Oowada; Hiroko Shinkai; Yasunobu Maehara; Keigo Endo



miR133 and miR30 Regulate Connective Tissue Growth Factor Implications for a Role of MicroRNAs in Myocardial Matrix Remodeling  

Microsoft Academic Search

The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosis. Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target. Regulation of CTGF expression at the promoter level has

R. F. Duisters; A. J. Tijsen; B. Schroen; J. J. Leenders; V. Lentink; Made van der I; V. Herias; Leeuwen van R. E; M. W. Schellings; P. Barenbrug; J. G. Maessen; S. Heymans; Y. M. Pinto; E. E. Creemers



Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis.  


Transforming growth factor (TGF)-beta(1), -beta(2), and -beta(3) are involved in control of wound repair and development of fibrosis. Connective tissue growth factor (CTGF) expression is stimulated by all TGF-beta isoforms and is abundant in glomerulosclerosis and other fibrotic disorders. CTGF is hypothesized to mediate profibrotic effects of TGF-beta(1) or to facilitate interaction of TGF-beta(1) with its receptor, but its interactions with TGF-beta isoforms in nonpathological conditions are unexplored so far. Tissue repair and remodeling may recapitulate gene transcription at play in organogenesis. To further delineate the relationship between CTGF and TGF-beta, we compared expression patterns of CTGF and TGF-beta isoforms in rat and human glomerulogenesis and in various human glomerulopathies. CTGF mRNA was present in the immediate precursors of glomerular visceral and parietal epithelial cells in the comma- and S-shaped stages, but not in earlier stages of nephron development. During the capillary loop and maturing glomerular stages and simultaneous with the presence of TGF-beta(1), -beta(2), and -beta(3) protein, CTGF mRNA expression was maximal and present only in differentiating glomerular epithelial cells. CTGF protein was also present on precursors of mesangium and glomerular endothelium, suggesting possible paracrine interaction. Concomitant with the presence of TGF-beta(2) and -beta(3) protein, and in the absence of TGF-beta(1), CTGF mRNA and protein expression was restricted to podocytes in normal adult glomeruli. However, TGF-beta(1) and CTGF were again coexpressed, often with TGF-beta(2) and -beta(3), in particular in podocytes in proliferative glomerulonephritis and also in mesangial cells in diabetic nephropathy and IgA nephropathy (IgA NP). Coordinated expression of TGF-beta isoforms and of CTGF may be involved in normal glomerulogenesis and possibly in maintenance of glomerular structure and function at adult age. Prolonged overexpression of TGF-beta(1) and CTGF is associated with development of severe glomerulonephritis and glomerulosclerosis. PMID:20576680

Ito, Yasuhiko; Goldschmeding, Roel; Kasuga, Hirotake; Claessen, Nike; Nakayama, Masahiro; Yuzawa, Yukio; Sawai, Akiho; Matsuo, Seiichi; Weening, Jan J; Aten, Jan



Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61).  


Connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61) are prototypical members of the CCN family which also contains nephroblastoma overexpressed (NOV) and Wnt-induced secreted proteins-1, -2 and -3 (WISP-1, -2, -3). These proteins function as extracellular matrix (ECM)-associated signaling molecules that contain structural modules allowing them to bind directly with other moieties in the pericellular environment. Although multiple target cell types have been identified for CCN proteins, there is strong evidence supporting a role for CTGF and CYR61 in the regulation of endothelial cell function and angiogenesis. Both CTGF and CYR61 can promote endothelial cell growth, migration, adhesion and survival in vitro and at least some of these effects are mediated through cell surface integrins. Both proteins are transcriptionally activated in endothelial cells in response to basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF), and endothelial cell proliferation and migration in vitro is reduced by antagonists of CTGF production or action. The expression pattern of CTGF and CYR61 in endothelial cells of vessels in situ supports a role for these molecules in normal endothelial homeostasis, as well as participating in the angiogenic process during embryonic development, placentation, tumor formation, fibrosis, and wound healing. CTGF or CYR61 knockout mice exhibit vascular defects during embryogenesis and fetal development. Both CTGF and CYR61 are intrinsically active in in vivo asssays for angiogenic activity. However, they can also regulate the production and/or activity of other angiogenic molecules (e.g. bFGF, VEGF) as well molecules that affect the integrity or stability of the ECM (e.g. collagen, matrix metalloproteases (MMPs), tissue inhibitors of MMPs (TIMPs)). Therefore, through their paracrine action as products of cells such as fibroblasts or smooth muscle cells or through their autocrine action as products of endothelial cells, CTGF and CYR61 participate in a variety of direct and indirect mechanisms by which angiogenesis is regulated at multiple control points. PMID:12831056

Brigstock, David R



Capillaroscopic pattern in systemic lupus erythematosus and undifferentiated connective tissue disease: what we still have to learn?  


In rheumatology, specific is the capillaroscopic pattern in systemic sclerosis (SSc), the so-called "scleroderma type". Capillaroscopic pattern in systemic lupus erythematosus (SLE) is less specific and includes a wide range of microvascular changes-"SLE-type" capillaroscopic pattern, non-specific findings and in a small percentage "scleroderma-like" pattern. The latter finding is currently associated with a potential subclinical overlap with SSc. Various microvascular changes have been observed in a different proportion of patients with undifferentiated connective tissue disease (UCTD). The aim of the study was to evaluate the capillaroscopic changes in SLE and UCTD. Patients from the following groups were included in the study: 30 female patients with SLE (mean age, 49 ± 15.4 years), 31 patients with UCTD (mean age, 50 ± 17 years; 30 females and 1 male); 34 age- and sex-matched healthy volunteers were examined as a control group. Nailfold capillaroscopy was performed using videocapillaroscope Videocap 3.0 (DS Medica). Capillaroscopic findings were compared with clinical and laboratory data of the patients. At capillaroscopic examination, the most frequent capillaroscopic changes in SLE patients were the presence of elongated capillaries in 43 % (13/30), an increased tortuosity in 70 % (21/30) and a prominent subpapillary plexus in 60 % (18/30) of the cases. In 80 % (24/30) of the patients, dilated capillaries were found; in 6.6 % (2/30), giant capillary loops; and in 16.6 % (5/30), haemorrhages. In 50 % of the patients, an "SLE-type" capillaroscopic pattern was found. In 30 % (9/30) of the cases the capillaroscopic examination revealed "non-specific changes", in 6.6 % (2/30) of the patients it was found a normal capillaroscopic pattern and in 13.3 % (4/30) a "scleroderma-like" pattern. Positive tests for ANA were detected in 73.3 % (11/15) of the patients with "SLE-type" capillaroscopic pattern. In all the patients with "scleroderma-like" capillaroscopic finding, positive autoantibodies with a high titre were found, without signs for overlap with other connective tissue disease (CTD). In two out of four patients with such capillaroscopic findings, a vasculitis of peripheral vessels was evident and in the other two secondary RP and high immunologic activity. A "scleroderma-like" pattern was found in 38 % (12/31) of the patients with UCTD. In 51 % (16/31) of the patients from this group, "non-specific" capillaroscopic findings were observed. For the evaluation of the predictive value of capillaroscopic pattern for the development of a distinct rheumatic disorder in patients with UCTD, a longer period of follow-up is necessary. In SLE patients, it has been found that capillaroscopic examination reveals microvascular changes also in the absence of RP. Here, the results from the study illustrate the correlation between capillaroscopic changes and immunological profile. "Scleroderma-like" capillaroscopic pattern may be observed in the context of active vasculitis of peripheral vessels as well as in patients with secondary RP and high immunologic activity. It does not have an obligatory association with an overlap syndrome with other CTD. Capillaroscopic findings in UCTD are heterogeneous. The potential of capillaroscopic examination in UCTD for evaluating the prognosis of the disease needs to be revealed through long-term follow-up. PMID:22527142

Lambova, Sevdalina Nikolova; Müller-Ladner, Ulf



Relationship of one form of human histamine-releasing factor to connective tissue activating peptide-III.  

PubMed Central

We have previously reported purification of three forms of histamine-releasing factors (HRFs) from mixtures of streptokinase-streptodornase stimulated human mononuclear cells and platelets with apparent molecular masses of 10-12, 15-17, and 40-41 kD (1989. J. Clin. Invest. 83:1204-1210). We have also prepared mouse MAbs against the 10-12-kD HRF (1989. J. Allergy Clin. Immunol. 83:281). Affinity-purified 10-12-kD HRF appears as a broad band upon polyacrylamide gel electrophoresis in the presence of SDS. We determined the NH2-terminal amino acid sequence of the top and bottom halves of this broad band. Sequence analysis revealed striking homology between this HRF and connective tissue activating peptide-III (CTAP-III), a platelet-derived 8-10-kD protein known to cause mitogenesis and extracellular matrix formation in fibroblast cultures. 19 of 21 NH2-terminal residues in the top half of the HRF band were identical to the NH2-terminal sequence of CTAP-III. 20 of 21 NH2-terminal residues in the bottom half were identical to the NH2-terminal sequence of neutrophil-activating peptide-2, which is derived from CTAP-III by proteolytic cleavage between residues 15 and 16. Purified CTAP-III also released histamine from basophils. Rabbit antiserum raised against either native or recombinant CTAP-III recognized affinity-purified HRF in immunodot blot assays, and MAb against HRF recognized CTAP-III in both dot blot and microtiter plate based immunoassays. These data demonstrate the first structural, functional, and immunologic relationship between one form of human HRF and a previously described cell product. Images

Baeza, M L; Reddigari, S R; Kornfeld, D; Ramani, N; Smith, E M; Hossler, P A; Fischer, T; Castor, C W; Gorevic, P G; Kaplan, A P



Serum proteins and paraproteins in women with silicone implants and connective tissue disease: a case-control study  

PubMed Central

Prior studies have suggested abnormalities of serum proteins, including paraproteins, in women with silicone implants but did not control for the presence of connective-tissue disease (CTD). This retrospective case–control study, performed in tertiary-care academic centers, assessed possible alterations of serum proteins, including paraproteins, in such a population. Seventy-four women with silicone implants who subsequently developed CTD, and 74 age-matched and CTD-matched women without silicone implants, were assessed in the primary study; other groups were used for additional comparisons. Routine serum protein determinations and high-sensitivity protein electrophoresis and immunofixation electrophoresis were performed for detection of paraproteins. Women with silicone implants, either with or without CTD, had significantly lower serum total protein and ?1-globulin, ?2-globulin, ?-globulin, ?-globulin, and IgG levels compared with those without silicone implants. There was no significant difference, however, in the frequency of paraproteinemia between women with silicone implants and CTD (9.5%) and age-matched and CTD-matched women without silicone implants (5.4%) (odds ratio, 1.82; 95% confidence interval, 0.51–6.45). Paraprotein isotypes were similar in the two groups, and the clinical characteristics of the 13 women with paraproteinemia were comparable with an independent population of 10 women with silicone breast implants, CTD, and previously diagnosed monoclonal gammopathies. In summary, this first comprehensive study of serum proteins in women with silicone implants and CTD found no substantially increased risk of monoclonal gammopathy. Women with silicone implants, however, had unexpectedly low serum globulin and immunoglobulin levels, with or without the subsequent development of CTD. The causes and clinical implications of these findings require further investigation.

Csako, Gyorgy; Costello, Rene; Shamim, Ejaz A; O'Hanlon, Terrance P; Tran, Anthony; Clauw, Daniel J; Williams, H James; Miller, Frederick W



Connective Tissue Growth Factor with a Novel Fibronectin Binding Site Promotes Cell Adhesion and Migration During Rat Oval Cell Activation  

PubMed Central

Oval cell activation, as part of the regenerative process after liver injury, involves considerable cell-matrix interaction. The matricellular protein, connective tissue growth factor (CTGF), has been shown to be critical for oval cell activation during liver regeneration following N-2-acetylaminofluorene/partial hepatectomy. To understand the mode of action of CTGF during this process, N-terminal CTGF was used as bait to screen a yeast two-hybrid complementary DNA library specific for regenerating livers with massive oval cell presence. Fibronectin (FN), a prominent component of hepatic extracellular matrix (ECM), was found to specifically bind to a new site on CTGF. In addition to module IV, this study showed that module I of CTGF was sufficient for binding to FN in both solid-phase in vitro binding assays and immunoprecipitation. Immunofluorescent staining revealed a dynamic ECM remodeling characterized by an FN-concentrated provisional matrix during oval cell–aided liver regeneration. Abundant CTGF protein was colocalized with FN in the provisional matrix. When expressed as recombinant proteins and immobilized on plastic surfaces, modules I and IV of CTGF were selectively adhesive to thymus cell antigen 1–positive (Thy1+) oval cells, stellate cells, and sinusoidal endothelial cells but not to hepatocytes. The adhesion of these two modules on Thy1+ oval cells required heparan sulfate proteoglycan and integrin ?5?1. Recombinant CTGF promoted an integrin ?5?1–dependent migration but not proliferation on Thy13 oval cells. Conclusion: Modules I and IV enabled the linkage of CTGF to FN and activated hepatic cells. Through these bindings, CTGF on the FN-concentrated provisional matrix promoted cell adhesion and migration, thereby facilitating oval cell activation.

Pi, Liya; Ding, Xiaodong; Jorgensen, Marda; Pan, Jen-Jung; Oh, Seh-Hoon; Pintilie, Dana; Brown, Alicia; Song, Wen-Yuan; Petersen, Bryon E.



Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-{beta} responsiveness  

SciTech Connect

Background: The matricellular protein connective tissue growth factor (CCN2) has been implicated in pathological fibrosis, but its physiologic role remains elusive. In vitro, transforming growth factor-{beta} (TGF-{beta}) induces CCN2 expression in mesenchymal cells. Because CCN2 can enhance profibrotic responses elicited by TGF-{beta}, it has been proposed that CCN2 functions as an essential downstream signaling mediator for TGF-{beta}. To explore this notion, we characterized TGF-{beta}-induced activation of fibroblasts from CCN2-null (CCN2{sup -/-}) mouse embryos. Methods: The regulation of CCN2 expression was examined in vivo in a model of fibrosis induced by bleomycin. Cellular TGF-{beta} signal transduction and regulation of collagen gene expression were examined in CCN2{sup -/-} MEFs by immunohistochemistry, Northern, Western and RT-PCR analysis, immunocytochemistry and transient transfection assays. Results: Bleomycin-induced skin fibrosis in the mouse was associated with substantial CCN2 up-regulation in lesional fibroblasts. Whereas in vitro proliferation rate of CCN2{sup -/-} MEFs was markedly reduced compared to wild type MEFs, TGF-{beta}-induced activation of the Smad pathways, including Smad2 phosphorylation, Smad2/3 and Smad4 nuclear accumulation and Smad-dependent transcriptional responses, were unaffected by loss of CCN2. The stimulation of COL1A2 and fibronectin mRNA expression and promoter activity, and of corresponding protein levels, showed comparable time and dose-response in wild type and CCN2{sup -/-} MEFs, whereas stimulation of alpha smooth muscle actin and myofibroblast transdifferentiation showed subtle impairment in MEFs lacking CCN2. Conclusion: Whereas endogenous CCN2 plays a role in regulation of proliferation and TGF-{beta}-induced myofibroblast transdifferentiation, it appears to be dispensable for Smad-dependent stimulation of collagen and extracellular matrix synthesis in murine embryonic fibroblasts.

Mori, Yasuji; Hinchcliff, Monique; Wu, Minghua; Warner-Blankenship, Matthew [Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E Huron Street, Chicago, IL 60611 (United States); Lyons, Karen M. [OH/UCLA Department of Orthopedic Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA (United States); Varga, John [Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E Huron Street, Chicago, IL 60611 (United States)], E-mail:




PubMed Central

Connective Tissue Growth Factor (CTGF), a member of the Cyr 61, CTGF, Nov (CCN) family of proteins, regulates multiple cellular functions. Overexpression of CTGF in vivo causes osteopenia, but in vitro CTGF can induce osteoblastogenesis. To investigate mechanisms involved in the effects of CTGF on osteoblastic cell differentiation, we examined whether CTGF modifies the activity of nuclear factor of activated T cells (NFATc) 1, a transcription factor that cooperates with osterix in the formation of new bone. CTGF increased the transactivation of a transiently transfected reporter construct, where 9 NFAT binding sites direct the expression of luciferase (9xNFAT-Luc) and the activity of the Regulators of calcineurin 1 exon 4 (Rcan1.4) promoter, an NFAT target gene. We postulated that CTGF could modify the phosphorylation of NFAT by regulating glycogen synthase kinase 3? (GSK3?). CTGF increased the mRNA levels of Protein kinase cyclic guanosine monophosphate (GMP) dependent type II (Prkg2), the gene encoding for cGMP dependent protein kinase II (CGKII) which phosphorylates GSK3?. Accordingly, CTGF induced GSK3? phosphorylation and decreased the active pool of GSK3?, a kinase that phosphorylates NFAT and leads to its nuclear export. As a consequence, CTGF favored the nuclear localization of NFATc1. Down regulation of PRKG2 by RNA interference reversed the effect of CTGF on the transactivation of the 9xNFAT reporter construct and the Rcan 1.4 promoter, confirming the role of cGKII in the activation of NFAT by CTGF. In conclusion, CTGF enhances NFAT signaling through the induction of cGKII and the phosphorylation of GSK3?.

Smerdel-Ramoya, Anna; Zanotti, Stefano; Canalis, Ernesto



Clinical and biometrical evaluation of socket preservation using demineralized freeze-dried bone allograft with and without the palatal connective tissue as a biologic membrane  

PubMed Central

Background: Alveolar ridge preservation following tooth extraction has the ability to maintain the ridge dimensions and allow the implant placement in an ideal position fulfilling both functional and aesthetic results. The aim of this study was to evaluate the efficacy of the palatal connective tissue as a biological membrane for socket preservation with demineralized freeze-dried bone allograft (DFDBA). Materials and Methods: Twelve extraction sites were treated with DFDBA with (case group) and without (control group) using autogenous palatal connective tissue membrane before placement of implants. Alveolar width and height, amount of keratinized tissue, and gingival level were measured at pre-determined points using a surgical stent at two times, the time of socket preservation surgery Results: In both groups a decrease in all socket dimensions was found. The average decrease in socket width, height, keratinized tissue, and gingival level in case group was 1.16, 0.72, 3.58, and 1.27 mm, and in control group was 2.08, 0.86, 4.52, and 1.58 mm respectively. Statistical analysis showed that decrease in socket width (P = 0.012), keratinized tissue (P ? 0.001), and gingival level (P = 0.031) in case group was significantly lower than that of the control group. Results showed no meaningful difference in socket height changes when compared with case and control groups (P = 0.148). Conclusion: Under the limits of this study, connective tissue membrane could preserve socket width, amount of keratinized tissue, and the gingival level more effectively than DFDBA alone.

Moghaddas, Hamid; Amjadi, Mohammad Reza; Naghsh, Narges



Gastrointestinal Manifestations in Systemic Autoimmune Diseases  

PubMed Central

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



Immunopathogenic mechanisms of systemic autoimmune disease.  


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



Autoimmune diseases and autoimmunity post-bone marrow transplantation  

Microsoft Academic Search

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



Autoimmune encephalitis in children.  


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

Erol, I



Utility of a simplified ultrasound assessment to assess interstitial pulmonary fibrosis in connective tissue disorders - preliminary results  

PubMed Central

Introduction Interstitial pulmonary fibrosis (IPF) is a frequent manifestation in patients with connective tissue disorders (CTD). Recently the ultrasound (US) criterion validity for its assessment has been proposed; however, the US scoring systems adopted include the study of several lung intercostal spaces (LIS), which could be time-consuming in daily clinical practice. The aim of this study was to investigate the utility of a simplified US B-lines scoring system compared with both the US comprehensive assessment and the high-resolution computed tomography (HRCT) findings of IPF in CTD patients. Methods Thirty-six patients with a diagnosis of CTD were enrolled. Each patient underwent chest HRCT and lung US by an experienced radiologist and rheumatologist, respectively. Both comprehensive and simplified US B-lines assessments were scanned. The comprehensive US assessment was performed at 50 LIS level, whereas the simplified US assessment included bilaterally 14 LIS; for the anterior chest: the second LIS along the para-sternal lines, the fourth LIS along the mid-clavear, anterior axillary and mid-axillary lines; for the posterior chest: the eighth LIS along the paravertebral, sub-scapular and posterior axillary lines. For criterion validity, HRCT was considered the gold standard. Feasibility, inter and intra-observer reliability was also investigated. Results A highly significant correlation between comprehensive and simplified US assessment was found (P = 0.0001). A significant correlation was also found between the simplified US assessment and HRCT findings (P = 0.0006). Kappa values for the inter-observer simplified US assessment were in a range from 0.769 to 0.885, whereas the concordance correlation coefficient values for the intra-observer were from 0.856 to 0.955. There was a relevant difference in time spent on comprehensive (mean 23.3 ± SD 4.5 minutes) with respect to the simplified US assessment (mean 8.6 ± SD 1.4) (P < 0.00001). Conclusions Our results provide a new working hypothesis in favor of the utility of a simplified US B-lines assessment as an adjunct method to assess IPF in patients with CTD.



[Multiple autoimmune syndromes].  


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



Latent Epstein–Barr virus (EBV) infection and cytomegalovirus (CMV) infection in synovial tissue of autoimmune chronic arthritis determined by RNA and DNA-in situ hybridization  

Microsoft Academic Search

In rheumatoid arthritis (RA) viral triggers, especially Epstein–Barr virus (EBV) and cytomegalovirus (CMV), have been suggested. By PCR analysis DNA of several viruses among which EBV, CMV, and parvovirus B19 (B19) has been detected in RA synovial fluid and synovial tissue. In 63 synovial tissues of 29 rheumatoid arthritis (RA), 6 psoriatic arthritis (PsA), 26 reactive arthritis\\/synovitis (rA\\/S), and two

Yasmin Mehraein; Carsten Lennerz; Sandra Ehlhardt; Klaus Remberger; Andreas Ojak; Klaus D Zang; med. Y Mehraein



Autoimmune esophagitis: IgG4-related tumors of the esophagus.  


We present a case of a 23-year-old gentleman who presented with dysphagia, weight loss, and recurrent esophageal strictures requiring multiple dilatations. An endoscopic ultrasound with esophagogastroduodenoscopy revealed a mass present in the distal esophagus. Fine needle aspiration suggested that the mass in the lower esophagus resembled a gastrointestinal stromal tumor. After surgical resection, final pathologic analysis revealed that the tumor was comprised of benign-appearing fibroinflammatory cells with an increase and predominance of IgG4-positive plasma cells. The microscopic appearance was consistent with a benign condition as a result of an IgG4-related process. He did not, however, have any other symptoms indicative of systemic autoimmune disease or connective tissue disorders. We present the pre-operative imaging, operative management, pathologic diagnosis, and literature review of this rare condition and the first known report of autoimmune esophagitis as part of the IgG4 spectrum of diseases. PMID:20195914

Lopes, James; Hochwald, Steven N; Lancia, Nicholas; Dixon, Lisa R; Ben-David, Kfir



Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture  

SciTech Connect

Thioglycollate-elicited mouse peritoneal macrophages were cultured in contact with the mixture of extracellular matrix proteins produced by rat smooth muscle cells in culture. Both live macrophages and their conditioned media hydrolyzed glycoproteins, elastin, and collagen. Live macrophages also degraded extracellular connective tissue proteins secreted by endothelial cells and fibroblasts. The glycoproteins in the matrix markedly inhibited the rate of digestion of the other macromolecules, particularly elastin. When plasminogen was added to the matrix, activation of plasminogen to plasmin resulted in the hydrolysis of the glycoprotein components, which then allowed the macrophage elastase easier access to its substrate, elastin. Thus, although plasmin has no direct elastinolytic activity, its presence accelerated the rate of hydrolysis of elastin and therefore the rate of matrix degradation. These findings may be important in an understanding of disease states, such as emphysema and atherosclerosis, that are characterized by the destruction of connective tissue.

Jones, P.A. (Univ. of Southern California, Los Angeles); Werb, Z.



Non-marfan idiopathic medionecrosis (cystic medial necrosis) presenting with multiple visceral artery aneurysms and diffuse connective tissue fragility: Two brothers  

Microsoft Academic Search

Two brothers with multiple visceral artery aneurysms or dilatations and diffuse connective tissue fragility who did not have\\u000a clinical features of Marfan syndrome are reported. One presented with retroperitoneal hemorrhage during angiography, and idiopathic\\u000a medionecrosis was proved by resection of the aneurysms. These cases belong to the heterogeneous group of Marfan syndrome.\\u000a The angiographical features (multiple dilation of visceral arteries)

Jun Kubota; Mami Tsunemura; Shigeko Amano; Shigemi Tokizawa; Susumu Oowada; Hiroko Shinkai; Yasunobu Maehara; Keigo Endo



Irbesartan Ameliorates Diabetic Nephropathy by Reducing the Expression of Connective Tissue Growth Factor and Alpha-Smooth-Muscle Actin in the Tubulointerstitium of Diabetic Rats  

Microsoft Academic Search

The effect of irbesartan on the expression of connective tissue growth factor (CTGF) and ?-smooth-muscle actin (?-SMA) in the renal tubulointerstitium of diabetic rats was investigated in our study. Diabetes was induced in male Wistar rats by intraperitoneal administration of streptozotocin (STZ), 60 mg·kg–1 body weight. The rats were then randomized to a diabetic group (DM) and an irbesartan therapy

Xiaojun Ren; Guangju Guan; Gang Liu; Gaohong Liu



Isolation of connective-tissue-specific genes involved in Xenopus intestinal remodeling: thyroid hormone up-regulates Tolloid\\/BMP1 expression  

Microsoft Academic Search

To clarify connective-tissue-specific genes involved in adult epithelial development during amphibian intestinal remodeling, we have isolated 16 cDNA clones derived from the anterior part of Xenopus laevis intestine cultured in vitro by using subtractive suppression hybridization. Among four genes identified, the expression of Xtld, a Xenopus homolog of Drosophila Tolloid closely related to bone morphogenic protein-1 (BMP-1), was most remarkably

Katsuhiko Shimizu; Atsuko Ishizuya-Oka; Tosikazu Amano; Katsutoshi Yoshizato; Shuichi Ueda



Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomaslies not linked to the Fibrillin genes  

SciTech Connect

The authors describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly), respectively. To test whether one of these genes was also implicated in this French family, the authors performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fib15) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of [minus]11.39 (for Fib15) and [minus]13.34 (for Fib5), at 0 = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome. 33 refs., 1 fig. 2 tabs.

Boileau, C.; Coulon, M.; Alexandre, J.-A.; Junien, C. (Laboratorie Central de Biochimie et de Genetique Moleculaire (France)); Jondeau, G.; Delorme, G.; Dubourg, O.; Bourdarias, J.-P. (CHU Ambroise Pare, Boulogne (France)); Babron, M.-C.; Bonaieti-Pellie, C. (INSERM, Chateau de Longchamp, Paris (France)); Sakai, L. (Shriners' Hospital for Crippled Children, Portland, OR (United States)); Melki, J. (Hopital Necker-Enfants Malades, Paris (France))



Autoimmune manifestations in acquired idiopathic splenic atrophy: A puzzling association.  


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



Neuroendocrinology of autoimmunity  

Microsoft Academic Search

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

Michael Harbuz



Autoimmune Pancreatitis – Recent Advances  

Microsoft Academic Search

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



Infections and autoimmune diseases  

Microsoft Academic Search

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

Jean-François Bach



The morphology and connectivity of dissociated and reaggregated fetal tectal tissue transplanted to the midbrain of newborn rats  

Microsoft Academic Search

Tectal tissue from E15 or E16 Wistar rat embryos was dissociated and reaggregated (DR) prior to transplantation on to the midbrain of newborn host rats. We wished to determine how complete disruption of the donor tissue (i) affected the subsequent morphological development of the grafts in the host brain, and (ii) whether this procedure affected the selectivity with which host

Brett M. Bairstow; Alan R. Harvey



Sex hormones and autoimmunity.  


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



Progesterone and autoimmune disease.  


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



Mesenchymal stem cells in autoimmune disease.  


Autoimmune diseases afflict more than 3% of the U.S. population. Current therapy for mild to moderate cases is symptomatic, however advanced cases suffer high morbidity and mortality. Advanced patients have benefited from stem cell therapy in the form of bone marrow transplantation in conjunction with high-dose cytotoxic therapy. Broader application of stem cell therapy requires better understanding of how adult stem cells affect development and foster treatment of autoimmune pathologies, and of better ways to manipulate the host immune responses. While extensive research documents the role of hematopoietic stem cells (HSCs) in autoimmune disease, few studies have addressed if and how mesenchymal stem cells (MSCs) contribute to their etiopathology. Recent characterization of MSCs and their role in hematopoiesis and immune modulation suggest that their potential for cell therapy extends beyond their traditional accessory function in HSC engraftment. MSCs contribute significantly to tissue restructuring and immune functioning, in addition to facilitating durable, long-lasting stem cell engraftment. MSCs are relatively easy to obtain and expand in in vitro cultures, rendering them a prime candidate for genetic manipulations for stem cell therapy. They have the potential to differentiate into multiple lineages such as osteoblasts, adipose tissue, cartilage, tendon, and stromal cells. The role of MSCs for autoimmune disease therapy could thus be based both on immune function modulation and contribution to hematopoiesis. In this review, we examine the biology of MSCs, and their potential for cell therapy of autoimmune disease. PMID:15588504

El-Badri, Nagwa S; Maheshwari, Akhil; Sanberg, Paul R



Alternatively activated macrophages in infection and autoimmunity  

PubMed Central

Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy to evade the immune system. M2 are particularly efficient at scavenging self tissues following injury through receptors like the mannose receptor and scavenger receptor-A. Thus, M2 may increase autoimmune disease by presenting self tissue to T cells. M2 may also exacerbate immune complex (IC)-mediated pathology and fibrosis, a hallmark of autoimmune disease in women, due to the release of profibrotic factors such as interleukin (IL)-1?, transforming growth factor-?, fibronectin and matrix metalloproteinases. We have found that M2 comprise anywhere from 30% to 70% of the infiltrate during acute viral or experimental autoimmune myocarditis, and shifts in M2 populations correlate with increased IC-deposition, fibrosis and chronic autoimmune pathology. Thus, women may be at an increased risk of M2-mediated autoimmunity due to estrogen’s ability to increase Th2 responses.

Fairweather, DeLisa; Cihakova, Daniela



Cell Damage and Autoimmunity: A Critical Appraisal  

PubMed Central

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.



Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen XIII play a role?  

PubMed Central

Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease, is a complex inflammatory disorder of the eye that, as its name implies, is associated with thyroid disease. TAO can be divided into three subtypes: ocular myopathy, congestive myopathy and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TAO remains unclear it is likely to reflect an autoimmune reaction involving sensitized T-cells and autoantibodies directed against a thyroid and orbital tissue shared antigen. One well studied candidate in this immune reaction is the thyroid-stimulating hormone receptor (TSH-r), expressed in the orbital fibroblast and pre adipocyte. In our studies of TAO, we have investigated the nature and significance of antibodies targeting other eye muscle and orbital connective tissue (OCT) antigens. Our findings suggest that autoimmunity against the eye muscle antigen calsequestrin and the OCT antigen collagen XIII plays a role in the pathogenesis of TAO. We propose that ocular myopathy and chronic eyelid retraction are due to autoimmunity against skeletal muscle calsequestrin in the extraocular and eyelid muscles, respectively. This may be initiated in the thyroid where calsequestrin expression is upregulated, possibly due to a stimulatory effect of TSH-r antibodies. We also propose that congestive ophthalmopathy results from a reaction against the TSH-r or collagen XIII in orbital fibroblast cell membranes. Further insight into the role of eye muscle and OCT antigens in the pathogenesis of TAO may allow for the development of new therapies to treat the eye disorder and reduce patient morbidity.

Lahooti, Hooshang; Parmar, Kishan R; Wall, Jack R



Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen XIII play a role?  


Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease, is a complex inflammatory disorder of the eye that, as its name implies, is associated with thyroid disease. TAO can be divided into three subtypes: ocular myopathy, congestive myopathy and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TAO remains unclear it is likely to reflect an autoimmune reaction involving sensitized T-cells and autoantibodies directed against a thyroid and orbital tissue shared antigen. One well studied candidate in this immune reaction is the thyroid-stimulating hormone receptor (TSH-r), expressed in the orbital fibroblast and pre adipocyte. In our studies of TAO, we have investigated the nature and significance of antibodies targeting other eye muscle and orbital connective tissue (OCT) antigens. Our findings suggest that autoimmunity against the eye muscle antigen calsequestrin and the OCT antigen collagen XIII plays a role in the pathogenesis of TAO. We propose that ocular myopathy and chronic eyelid retraction are due to autoimmunity against skeletal muscle calsequestrin in the extraocular and eyelid muscles, respectively. This may be initiated in the thyroid where calsequestrin expression is upregulated, possibly due to a stimulatory effect of TSH-r antibodies. We also propose that congestive ophthalmopathy results from a reaction against the TSH-r or collagen XIII in orbital fibroblast cell membranes. Further insight into the role of eye muscle and OCT antigens in the pathogenesis of TAO may allow for the development of new therapies to treat the eye disorder and reduce patient morbidity. PMID:20505833

Lahooti, Hooshang; Parmar, Kishan R; Wall, Jack R



Autoimmunity in Coxsackievirus B3 induced myocarditis: role of estrogen in suppressing autoimmunity  

PubMed Central

SUMMARY Picornaviruses are small, non-enveloped, single stranded, positive sense RNA viruses which cause multiple diseases including myocarditis/dilated cardiomyopathy, type 1 diabetes, encephalitis, myositis, orchitis and hepatitis. Although picornaviruses directly kill cells, tissue injury primarily results from autoimmunity to self antigens. Viruses induce autoimmunity by: aborting deletion of self-reactive T cells during T cell ontogeny; reversing anergy of peripheral autoimmune T cells; eliminating T regulatory cells; stimulating self-reactive T cells through antigenic mimicry or cryptic epitopes; and acting as an adjuvant for self molecules released during virus infection. Most autoimmune diseases (SLE, rheumatoid arthritis, Grave’s disease) predominate in females, but diseases associated with picornavirus infections predominate in males. T regulatory cells are activated in infected females because of the combined effects of estrogen and innate immunity.



Epstein-Barr Virus in Systemic Autoimmune Diseases  

PubMed Central

Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation.

Duus, Karen; Houen, Gunnar



[The repair of traumatic cerebrospinal fluid leak using temporal loose areolar connective tissue insertion into the frontal sinus and pericranial flap covering: a case report].  


We report a case of cerebrospinal fluid (CSF) leak repair using loose areolar connective tissue insertion into the frontal sinus and pericranial flap covering. A 61-years-old man suffered from skull fracture including frontal sinus fracture in violence inflicted by others. Fifty days later, he presented rhinorrhea and pneumocephalus caused by a bone defect site of the frontal sinus and anterior skull base. We performed CSF leak repair with insertion of pedunculated loose areolar connective tissue into his frontal sinus, covering the leak point using pericranial flap. In general, frontal sinus obliteration has been accomplished with autologous grafts such as fat, muscle, or bone. These avascular grafts carry an increased risk of resorption and infection. The use of loose areolar tissue insertion into the frontal sinus was able to increase stability of the construct and caused no cosmetic troubles in our short follow up period. The combined use of these two autologous materials may be useful for repair of CSF leak from an anterior skull base fracture. PMID:21799229

Kamoshima, Yuuta; Terasaka, Shunsuke; Hamauchi, Shuji; Kaneko, Sadahiro; Murakami, Hiroki; Houkin, Kiyohiro



Different forms of 130 kD connective tissue protein are specific for boundaries in the nervous system and basement membrane of muscle cells in leech.  


The nervous system and muscle tissue of the leech express two different organ-specific forms of connective tissue protein. The nervous system-specific form appears in regional boundaries separating cell bodies, axonal tracts and areas of the neuropile during late embryogenesis. In contrast, the muscle-specific form appears earlier during development in the basement membrane of muscle cells. In extraction experiments both forms behave like extracellular matrix proteins and because of their molecular weight, are considered members of a group of cell type-specific 130 kD proteins (leech gp130s). However, the two forms differ in their posttranslational modification. As determined by Con A and lentil lectin affinity chromatography, only the nervous system-specific, but not the muscle-specific form, has fucosylated and high mannose N-linked carbohydrates. These differences in the developmental onset and glycosylation suggest that nervous system-specific and muscle-specific connective tissue proteins are regulated differently and participate in different molecular interactions. PMID:8283187

Thorey, I; Zipser, B



Autoimmunity and the outer retina.  


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



Human adipose CD34+ CD90+ stem cells and collagen scaffold constructs grafted in vivo fabricate loose connective and adipose tissues.  


Stem cell based therapies for the repair and regeneration of various tissues are of great interest for a high number of diseases. Adult stem cells, instead, are more available, abundant and harvested with minimally invasive procedures. In particular, mesenchymal stem cells (MSCs) are multi-potent progenitors, able to differentiate into bone, cartilage, and adipose tissues. Human adult adipose tissue seems to be the most abundant source of MSCs and, due to its easy accessibility; it is able to give a considerable amount of stem cells. In this study, we selected MSCs co-expressing CD34 and CD90 from adipose tissue. This stem cell population displayed higher proliferative capacity than CD34(-) CD90(-) cells and was able to differentiate in vitro into adipocytes (PPAR?(+) and adiponectin(+)) and endothelial cells (CD31(+) VEGF(+) Flk1(+)). In addition, in methylcellulose without VEGF, it formed a vascular network. The aim of this study was to investigate differentiation potential of human adipose CD34(+) /CD90(+) stem cells loaded onto commercial collagen sponges already used in clinical practice (Gingistat) both in vitro and in vivo. The results of this study clearly demonstrate that human adult adipose and loose connective tissues can be obtained in vivo, highlighting that CD34(+) /CD90 ASCs are extremely useful for regenerative medicine. PMID:23129214

Ferraro, Giuseppe A; De Francesco, Francesco; Nicoletti, Gianfranco; Paino, Francesca; Desiderio, Vincenzo; Tirino, Virginia; D'Andrea, Francesco



Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice.  

PubMed Central

Tolerance to peripheral antigens is thought to result from the inability of parenchymal tissue to stimulate T cells--an inability that is believed to relate to the lack of expression of the costimulatory signal(s) required for T-cell activation. To test this model, we generated transgenic mice expressing costimulatory molecule B7-1 on the B cells of the pancreas. We find that islets from these transgenic mice are immunogenic for naive T cells in vitro and in vivo. Nonetheless, mice expressing the costimulator B7-1 specifically on beta cells do not develop diabetes, suggesting that expression of the B7-1 costimulator is not sufficient to abrogate the tolerance to peripheral antigens. We have reported that tumor necrosis factor alpha subunit (TNF-alpha) expressed by beta cells leads to a local inflammation but no islet destruction. Strikingly, however, the combination of a local inflammation due to the expression of the cytokine TNF-alpha and the expression of B7-1 results in tissue destruction and diabetes. Images

Guerder, S; Picarella, D E; Linsley, P S; Flavell, R A



Mesenchymal stem cells and progenitor cells in connective tissue engineering and regenerative medicine: is there a future for transplantation?  

Microsoft Academic Search

Purpose  Transplantation surgery suffers from a shortage of donor organs worldwide. Cell injection and tissue engineering (TE), thus\\u000a emerge as alternative therapy options. The purpose of this article is to review the progress of TE technology, focusing on\\u000a mesenchymal stem cells (MSC) as a cell source for artificial functional tissue.\\u000a \\u000a \\u000a \\u000a \\u000a Results  MSC from many different sources can be minimally invasively harvested: peripheral

Andres Hilfiker; Cornelia Kasper; Ralf Hass; Axel Haverich



The Protein Precursors of Peptides That Affect the Mechanics of Connective Tissue and/or Muscle in the Echinoderm Apostichopus japonicus  

PubMed Central

Peptides that cause muscle relaxation or contraction or that modulate electrically-induced muscle contraction have been discovered in the sea cucumber Apostichopus japonicus (Phylum Echinodermata; Class Holothuroidea). By analysing transcriptome sequence data, here the protein precursors of six of these myoactive peptides (the SALMFamides Sticho-MFamide-1 and -2, NGIWYamide, stichopin, GN-19 and GLRFA) have been identified, providing novel insights on neuropeptide and endocrine-type signalling systems in echinoderms. The A. japonicus SALMFamide precursor comprises eight putative neuropeptides including both L-type and F-type SALMFamides, which contrasts with previous findings from the sea urchin Strongylocentrotus purpuratus where L-type and F-type SALMFamides are encoded by different genes. The NGIWYamide precursor contains five copies of NGIWYamide but, unlike other NG peptide-type neuropeptide precursors in deuterostomian invertebrates, the NGIWYamide precursor does not have a C-terminal neurophysin domain, indicating loss of this character in holothurians. NGIWYamide was originally discovered as a muscle contractant, but it also causes stiffening of mutable connective tissue in the body wall of A. japonicus, whilst holokinins (PLGYMFR and derivative peptides) cause softening of the body wall. However, the mechanisms by which these peptides affect the stiffness of body wall connective tissue are unknown. Interestingly, analysis of the A. japonicus transcriptome reveals that the only protein containing the holokinin sequence PLGYMFR is an alpha-5 type collagen. This suggests that proteolysis of collagen may generate peptides (holokinins) that affect body wall stiffness in sea cucumbers, providing a novel perspective on mechanisms of mutable connective tissue in echinoderms.

Elphick, Maurice R.



Autoimmunity, polyclonal B-cell activation and infection.  


It is widely believed that autoimmunity is an integral part of the immune system, and that genetic, immunologic, hormonal, environmental and other factors contribute to the pathogenesis of autoimmune disease. Thus, autoimmune disease may represent an abnormal expression of immune functions instead of loss of tolerance to self, and it can be organ specific or systemic in its manifestations. We review the various factors that contribute to the development of autoimmune disease; we also review the mechanisms of polyclonal B-cell activation, with emphasis on the role of infectious agents. We consider systemic lupus erythematosus in humans and in experimental animals as prototypic autoimmune disease, and we summarize data to indicate that polyclonal B-cell activation is central to the pathogenesis of systemic autoimmune disease. The effect of polyclonal B-cell activation, brought about by injections of a B-cell activator-lipopolysaccharide from Gram-negative bacteria-is sufficient to cause autoimmune disease in an immunologically normal host. In fact, autoimmune disease can be arrested if excessive polyclonal B-cell activation is suppressed; alternatively, autoimmune disease can be exacerbated if polyclonal B-cell activation is enhanced. We explore the mechanism of tissue injury when autoimmune disease is induced or exacerbated, and we consider the pathogenic roles of autoantibodies, immune complexes, complement, the blood cell carrier system, and the mononuclear phagocyte system. Although polyclonal B-cell activation may be the mechanism whereby various factors can cause or exacerbate systemic autoimmune disease, polyclonal B-cell activation may cause autoimmune disease on its own. PMID:1301966

Granholm, N A; Cavallo, T



Autoimmune liver disease panel  


... 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 ...


Preliminary observations on differences in the Raman spectra of cancerous and noncancerous cells and connective tissue of human skin  

Microsoft Academic Search

A less invasive method of reliably detecting skin cancers is required. Raman spectroscopy is just one of several spectroscopic methods that look promising, but are not yet sufficiently reliable. More information is needed on how and why the Raman spectra of cancerous skin tissue is different from its normal counterpart. We have used confocal micro-Raman spectroscopy with a spatial resolution

Michael A. Short; Harvey Lui; David I. McLean; Haishan Zeng; Abdulmajeed Alajlan; Michael X. Chen