Home About us Contact
|
Home About us Contact | ||
|
|
||
Autoimmunity
Kinds of Autoimmunity Selected AbstractsRisk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registryARTHRITIS & RHEUMATISM, Issue 9 2010J.-E. Gottenberg Objective The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. Methods The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. Results Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3,7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3,6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6,15.2], P = 0.005) were significantly associated with increased risk of a severe infection. Conclusion The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG. [source] Safety and efficacy of rituximab in systemic lupus erythematosus: Results from 136 patients from the French autoimmunity and rituximab registryARTHRITIS & RHEUMATISM, Issue 8 2010Benjamin Terrier Objective A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice. Methods We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX. Results One hundred thirty-six patients received treatment for SLE. The mean ± SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 ± 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA,SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX. Conclusion Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE. [source] Autoimmunity as a prognostic factor in melanoma patients treated with adjuvant low-dose interferon alphaINTERNATIONAL JOURNAL OF CANCER, Issue 11 2007Imke Satzger Abstract Interferon alpha is used for the adjuvant treatment of malignant melanoma at different dosages (high-, intermediate-, low-dose therapy). Only a minority of patients might benefit from this therapy, and markers to identify such patients are missing. A recent study suggested that melanoma patients developing autoantibodies or clinical manifestations of autoimmunity during adjuvant high-dose interferon alpha treatment had a significant survival benefit. We retrospectively reviewed 134 melanoma patients from our institution treated with adjuvant low-dose interferon alpha therapy and correlated the development of autoimmune diseases with prognosis. Interferon (IFN) therapy was routinely monitored by history, physical examination and laboratory tests before, after the first month and then after every 3 months of therapy. During a median follow up of 46.0 months (8.5,79.0 months) 28 patients (20.9%) suffered from recurrences and melanoma related deaths occurred in 16 patients (11.9%). In 20 patients (14.9%) autoimmune thyroiditis (AIT) was diagnosed during IFN therapy, one of these 20 patients developed rheumatoid arthritis later while continuing IFN therapy. Other autoimmune diseases were not observed. In 2 patients (one with AIT and one with arthritis) the autoimmune disease led to discontinuation of IFN therapy, in the other patients AIT remained subclinical or responded well to treatment while IFN therapy was continued. Kaplan,Meier analyses revealed a significant better recurrence free survival and a trend for a better overall survival for patients with AIT. Thus, autoimmunity triggered by low-dose IFN therapy appears to indicate an improved prognosis and should encourage continuation of IFN therapy. © 2007 Wiley-Liss, Inc. [source] Autoimmunity as an aetiological factor in vitiligoJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 7 2007N Rezaei Abstract Vitiligo is a common dermatological disorder characterized by the presence on the skin of depigmented macules resulting from the destruction of cutaneous melanocytes. Autoimmunity is an important hypothesis with regard to vitiligo aetiology and the evidence for autoimmune responses being involved in the pathogenesis of this disorder will be discussed in the present review. All immune system compartments, including innate and adaptive immunity have been implicated in vitiligo development. Particularly relevant are autoantibodies and autoreactive T cells in vitiligo patients that have cytotoxic effects upon pigment cells. Furthermore, predisposition to vitiligo appears to be associated with certain alleles of the major histocompatibility complex class II antigens as well as with other autoimmune-susceptibility genes. Moreover, the association of vitiligo with autoimmune disorders, the animal models of the disease, and the positive response to immunosuppressive therapeutic agents emphasize the role of autoimmunity in the development of this disorder. [source] Bullous Lupus: An Unusual Initial Presentation of Systemic Lupus Erythematosus in an Adolescent GirlPEDIATRIC DERMATOLOGY, Issue 4 2010Monica Tincopa B.S Autoimmunity in bullous systemic lupus erythematosus is characterized by the presence of circulating anti-type VII collagen antibodies. We report here a case of a child whose initial systemic lupus erythematosus presentation was a diffuse bullous eruption. [source] Autoimmunity, spontaneous tumourigenesis, and IL-15 insufficiency in mice with a targeted disruption of the tumour suppressor gene Fus1,THE JOURNAL OF PATHOLOGY, Issue 5 2007AV Ivanova Abstract The Fus1 gene resides in the critical 3p21.3 human chromosomal region deleted in lung and breast cancers. Recently, the tumour suppressor properties of Fus1 were confirmed experimentally by intra-tumoural administration of Fus1 that suppressed experimental lung metastasis in mice. We generated Fus1 -deficient mice that were viable, fertile, and demonstrated a complex immunological phenotype. Animals with a disrupted Fus1 gene developed signs of autoimmune disease, such as vasculitis, glomerulonephritis, anaemia, circulating autoantibodies, and showed an increased frequency of spontaneous vascular tumours. Preliminary analysis of immune cell populations revealed a consistent defect in NK cell maturation in Fus1 null mice that correlated with changes in the expression of IL-15. Injection of IL-15 into Fus1 knockout mice completely rescued the NK cell maturation defect. Based on these results, we propose the hypothesis that Fus1 deficiency affects NK cell maturation through the reduction of IL-15 production but does not directly alter their developmental capacity. Since acquired immunity was not affected in Fus1 -deficient animals, we suggest a relationship between the Fus1 protein and the regulation of innate immunity via IL-15 production. The increased frequency of spontaneous cancers and the development of an autoimmune syndrome in Fus1 null mice imply that these mice could serve as a model for studying molecular mechanisms of anti-tumour immunity and autoimmunity. Published in 2007 by John Wiley & Sons, Ltd. [source] Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis,ARTHRITIS & RHEUMATISM, Issue 9 2010Jason R. Kolfenbach Objective To determine whether antibodies against peptidyl arginine deiminase type 4 (PAD-4) are present in the preclinical phase of rheumatoid arthritis (RA) and to compare the timing and extent of their appearance with those of other preclinical autoantibodies. Methods Prediagnosis serum samples from 83 patients with RA were evaluated for the presence of anti,PAD-4 antibody, anti,cyclic citrullinated peptide (anti-CCP) antibody, and rheumatoid factor. In addition, a control cohort (n = 83) matched by age, sex, race, number of serum samples, and duration of serum storage was tested for the presence of anti,PAD-4 antibody to determine its sensitivity and specificity for the subsequent development of RA. Results Fifteen of 83 patients with RA (18.1%) had at least 1 prediagnosis sample positive for anti,PAD-4. One of 83 control subjects (1.2%) had at least 1 positive sample, resulting in a sensitivity and specificity of 18.1% and 98.8%, respectively, of anti,PAD-4 for the future development of RA. The mean duration of anti,PAD-4 positivity prior to clinical diagnosis was 4.67 years. Anti,PAD-4 positivity was associated with anti-CCP positivity (odds ratio 5.13 [95% confidence interval 1.07,24.5]). In subjects with prediagnosis samples that were positive for both antibodies, anti-CCP positivity predated anti,PAD-4 positivity in 9 of 13 cases (69%). Conclusion Autoantibodies to PAD-4 are present during the preclinical phase of RA in a subset of patients and are associated with anti-CCP positivity. Further exploration is needed regarding the timing of appearance and disease-related effects of PAD-4 autoimmunity. [source] Gonadotrophin receptor blocking antibodies measured by the use of cell lines stably expressing human gonadotrophin receptors are not detectable in women with 46,XX premature ovarian failureCLINICAL ENDOCRINOLOGY, Issue 3 2004Massimo Tonacchera Summary background, Premature ovarian failure (POF) is defined by cessation of ovarian function after puberty and before the age of 40. The syndrome is characterized by amenorrhoea, oestrogen deficiency and elevated levels of gonadotrophins. Autoimmunity has been proposed as a mechanism for some cases of destruction or malfunction of ovarian follicles. POF is often associated with type I and type II polyglandular autoimmune syndromes. It has also been postulated that receptors such as the LH and FSH receptors might become targets for blocking antibodies and such antibodies could be a cause of ovarian failure. patients and methods, Sixty-nine patients with POF isolated or associated with other endocrine autoimmune diseases (autoimmune thyroid diseases, Addison's disease, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis) were studied. All the patients had secondary amenorrhoea. The patient group had a median age of 33·1 years (range 15,57). Ovarian failure had been diagnosed at a median age of 29 years (range 15,39). The median time since diagnosis was almost 1 year but in six patients gonadal insufficiency had appeared 10,30 years earlier. All had a normal chromosomal karyotype (46, XX). Patients with POF were characterized by duration of amenorrhoea > 1 year, with elevated FSH and LH levels and undetectable or low oestrogen levels. Cell lines stably expressing recombinant human LH (CHO-LHr) and FSH (CHO-FSHr) receptors were prepared and used to search for antibodies able to inhibit LH- or FSH-stimulated cAMP production. Immunoglobulins extracted from sera of patients with POF were incubated with CHO-LHr and CHO-FSHr in the presence of human recombinant CG and FSH, respectively. results and conclusions, None of the immunoglobulin G (IgG) preparations from patients with POF was able to inhibit the activity of the FSH- and CG-stimulated cAMP production. [source] Strategies to prevent type 1 diabetesDIABETES OBESITY & METABOLISM, Issue 10 2009S. L. Thrower Type 1 diabetes is a chronic autoimmune condition resulting from T cell,mediated destruction of the insulin-producing cells in the islets of Langerhans. Its primary cause remains unknown, but it has been established that the clinical presentation is preceded by a long prodrome. This enables individuals at high risk of disease to be identified and offers the possibility of intervention to prevent clinical disease. Many groups are working in this field, concentrating on manipulation of environmental exposures that are potential triggers of autoimmunity and on immunomodulation strategies that aim to prevent destruction of ,-cells. Some interventions have shown promising results in early trials, but effective disease prevention remains elusive. This article reviews current progress in the field. [source] New prospects for immunotherapy at diagnosis of type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2009Paolo Pozzilli Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring ,-cell mass and function. Recent clinical trials of non-specific and of antigen-specific immune therapies have demonstrated the feasibility of modulation of islet-specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area. Copyright © 2009 John Wiley & Sons, Ltd. Insulin therapy in type 1 diabetes (T1D) rescues the patient from a certain death but not cure the disease. The goal of any therapeutic intervention in T1D is the preservation of insulin-secreting cells; this is achieved by the abrogation of pathogenic reactivity to beta cell autoantigens while preserving full capacity to generate a normal immune response against foreign antigens. Although several therapeutic candidates have been investigated in experimental models of T1D many of which showed promising results, a successful extrapolation of these findings to human T1D has proved to be difficult. In part, this failure results from the considerable disease heterogeneity associated with diverse genetic and non-genetic disease determinants and the spectrum of clinical phenotype at diagnosis. Thus, a younger age at onset is associated with stronger genetic susceptibility, more intense immune response to ,-cell antigens, shorter duration of symptoms, more severe metabolic derangement at diagnosis and a more rapid rate of ,-cell-destruction 1,3. Therefore, designing therapies that would be effective in all clinical settings is definitely challenging. In this issue five different approaches are discussed ranging from antigen-specific therapies [DiaPep277 and glutamic acid decarboxylase(GAD)], to non-antigen-specific immunoregulation (anti-CD3) and to anti-inflammatory (anti-IL1 receptor antagonist). These approaches are currently being tested in large international multicenter trials, and all of them use very similar outcome in terms of a beneficial effect (C-peptide secretion as evidence of a therapeutic effect on restoration of ,-cell function). The authors have been asked to follow a similar format in presenting their approaches so that the reader can easily compare them in terms of rationale and therapeutic goals. [source] Genetic and perinatal factors as risk for childhood type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2004Karin Larsson Abstract The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10 000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase,related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright © 2004 John Wiley & Sons, Ltd. [source] Enteroviruses and type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2003Ruben Varela-Calvino Abstract The development of type 1 diabetes mellitus (T1DM) has been linked to exposure to environmental triggers, with Enteroviruses (EV) historically considered the prime suspects. Early serological studies suggested a link between EV infections and the development of T1DM and, though controversial, have been bolstered by more recent studies using more sensitive techniques such as direct detection of the EV genome by RT-PCR in peripheral blood. In this review, we consider the weight of evidence that EV can be considered a candidate trigger of T1DM, using three major criteria: (1) is EV infection associated with clinical T1DM, (2) can EV trigger the development of autoimmunity and (3) what would explain the putative association? Copyright © 2003 John Wiley & Sons, Ltd. [source] A role for innate immunity in type 1 diabetes?DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2003H. Beyan Abstract Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and ,, T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes. Copyright © 2002 John Wiley & Sons, Ltd. [source] A new look at viruses in type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2003Hee-Sook Jun Abstract Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell-specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus-induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein-Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed. Copyright © 2002 John Wiley & Sons, Ltd. [source] New potential treatments for protection of pancreatic B-cell function in Type 1 diabetesDIABETIC MEDICINE, Issue 11 2008S. Cernea Abstract Type 1 diabetes mellitus results from the progressive and specific autoimmune destruction of insulin-secreting pancreatic B-cells, which develops over a period of years and continues after the initial clinical presentation. The ultimate goal of therapeutic intervention is prevention or reversal of the disease by the arrest of autoimmunity and by preservation/restoration of B-cell mass and function. Recent clinical trials of antigen-specific or non-specific immune therapies have proved that modulation of islet specific autoimmunity in humans and prevention of insulin secretion loss in the short term after the onset of disease is achievable. The identification of suitable candidates for therapy, appropriate dosage and timing, specificity of intervention and the side-effect profile are crucial for the success of any approach. Considering the complexity of the disease, it is likely that a rationally designed approach of combined immune-based therapies that target suppression of B-cell specific autoreactivity and maintenance of immune tolerance, coupled with islet regeneration or replacement of the destroyed B-cell mass, will prove to be most effective in causing remission/reversal of disease in a durable fashion. [source] Islet autoimmunity and genetic mutations in Chinese subjects initially thought to have Type 1B diabetesDIABETIC MEDICINE, Issue 1 2006D. Zhang Abstract Aims To explore the contribution of islet autoimmunity and genetic mutations in Chinese patients initially thought to have Type 1B diabetes. Methods A group of 33 Chinese patients with newly diagnosed Type 1B diabetes, were identified by the absence of autoantibodies to glutamic acid decarboxylase (GAD), IA-2, insulin, thyroid globulin or thyroid peroxidase, or high-risk HLA-DQ haplotypes. The cohort was further characterized by measurement of autoantibodies to carboxypeptidase H (CPH) and SOX13 using radioligand assays, and testing for genetic mutations associated with MODY3/MODY6 and mitochondrial diabetes. Mutations of HNF-1, (MODY3) and neuroD1/,2 (MODY6) genes were screened using the single-strand conformation polymorphism (SSCP) technique and sequencing. Mitochondrial DNA mutations were analysed with polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP). Results Within the cohort, we found one patient with a novel mutation, R321H (CGC,CAC) in exon 5 of the HNF-1, gene, one with ND1 mt3316 G,A mutation in mitochondrial DNA, five with Ala45Thr polymorphisms in the neuroD1/,2 gene, and two patients with autoantibodies to SOX13. Conclusions Some of the Chinese patients originally thought to have Type 1B diabetes do have other evidence of islet autoimmunity and genetic mutations involved in the underlying aetiology. This suggests that more rigorous screening for these conditions is needed before classifying subjects as having Type 1B diabetes. [source] Prospective screening for biopsy proven coeliac disease, autoimmunity and malabsorption markers in Belgian subjects with Type 1 diabetesDIABETIC MEDICINE, Issue 7 2005M. Buysschaert Abstract Aims To determine prospectively the prevalence of biopsy proven coeliac disease (CD) in an adult Type 1 diabetic population from Belgium with regards to associated auto-immunity and malabsorption. Methods and results Determination in 400 Type 1 diabetic patients of serum anti-endomysial and/or anti-transglutaminase auto-antibodies. All subjects with abnormal serology underwent an intestinal biopsy. Ten patients (2.5%) had positive antibodies. Diagnosis of CD was confirmed by an intestinal biopsy. Eight patients were symptom-free, although laboratory findings suggesting malabsorption were prominent in the presence of CD [microcytic anaemia, iron and folate deficiencies, low levels of 25(OH)vitamin D3, calcium and cholesterol]. Other auto-immune conditions, especially vitiligo, were found in patients with CD. Conclusions Asymptomatic coeliac disease occurs frequently in adult Type 1 diabetic patients, and is often associated with subclinical malabsorption. Screening should be part of routine evaluation, to implement life-long dietary gluten avoidance. [source] Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 haplotype in Type 1 diabetes mellitusDIABETIC MEDICINE, Issue 8 2000C. E. M. De Block SUMMARY Aims To assess the prevalence of thyrogastric autoimmunity in relation to age, sex, ,-cell antibody status and HLA DQ haplotypes in Type 1 diabetes mellitus. Methods One hundred and seventy-one patients with Type 1 diabetes mellitus were studied (male/female 86/85; mean age 19 ± 11 years; duration of diabetes 5 ± 4 years). Islet cell antibodies (ICA) and parietal cell antibodies (PCA) were measured using indirect immunofluorescence; glutamic acid decarboxylase-65 antibodies (GADA) by radiobinding assay and thyroid peroxidase antibodies (TPO) with an immunoradiometric assay (IRMA). Results The majority of subjects (81.3%) showed one or more autoantibodies. The prevalence rates were: GADA 64.9%, ICA 46.2%, PCA 19.9% and TPO 19.3%. Patients with ICA+ , 3 years after diagnosis had a higher prevalence of GADA (P = 0.03, odds ratio (OR) 2.66) and thyrogastric antibodies (P = 0.05, OR 2.23) than subjects ICA, after 3 years. PCA+ patients were older (P = 0.04), had a higher prevalence of GADA (P = 0.005, OR 3.89) and TPO (P = 0.05, OR 2.50) than PCA, subjects. Logistic regression analysis showed that PCA status was determined by the HLA DQA1*0501-DQB1*0301 haplotype (, = 2.94, P = 0.04) and GADA status (, = 2.44, P = 0.041). Conclusions Thyrogastric antibodies are highly prevalent in Type 1 diabetes mellitus, especially in patients with persisting ICA. Screening for gastric autoimmunity is particularly advised in patients who are positive for GADA and for the HLA DQA1*0501-DQB1*0301 haplotype. [source] Prospects for therapeutic vaccination with glatiramer acetate for neurodegenerative diseases such as Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 2 2002Michal Schwartz Abstract Neurodegenerative diseases, whatever their primary causes, are characterized by certain common features, one of which is their self-perpetuating nature. The ongoing progression of the disorder is due to the effects of destructive self-compounds, whose presence in the tissues is an outcome of the early phase of the disease and which gradually destroy remaining functional neurons. Studies in our laboratory have led to the recent formulation of a novel concept of protective autoimmunity as the body's mechanism of defense against these destructive self-compounds. This autoimmune response to central nervous system (CNS) insults is mediated by T-cells and presumably operates by activating and regulating local microglia and infiltrating macrophages (inflammatory response) to carry out their function of clearing destructive material from the tissue at risk. We suggest that a well-controlled autoimmunity counteracts and overcomes the destructive effects of the potentially harmful self-compounds, at the cost of some loss of tissue. An additional risk to the individual is the induction of an autoimmune disease, which is likely to occur if the autoimmune response is malfunctioning. An optimal balance of the various factors will lead to an outcome of maximal benefit at minimal cost to the tissue. A procedure for safely boosting the autoimmune response, by vaccination with a weak self-crossreactive antigen such as glatiramer acetate (also known as Cop-1) was found to protect rats from glutamate toxicity, a major mediator of the spread of damage and a well-known causative factor in neurodegenerative disorders. Cop-1, when administered according to a different regimen, is an FDA-approved drug for the treatment of multiple sclerosis. Different formulations of the same drug can therefore be used to treat two extreme manifestations of chronic degenerative diseases of the CNS. Drug Dev. Res. 56:143,149, 2002. © 2002 Wiley-Liss, Inc. [source] Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Jean-Marie Ramirez Abstract Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-,, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4+ T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4+ T cells to produce IL-22 without IL-17 and IFN-,. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161+ Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4+ T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. [source] Revisiting the role of IL-2 in autoimmunityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Hans Dooms Abstract IL-2 was discovered as a T-cell growth factor that promoted T-cell-dependent immune responses; however, more recent studies suggest that the essential role of IL-2 is to maintain functional Treg and thus control immune responses. These results are leading to new ideas about the potential of IL-2 as a therapeutic strategy in autoimmune diseases. In this issue of the European Journal of Immunology, a study further examines the role of IL-2 in immune regulation and shows for the first time that IL-2 complexes can ameliorate autoantibody-mediated autoimmunity. This commentary examines the current findings in relation to what we already know about IL-2 complexes. [source] MAPK3 deficiency drives autoimmunity via DC armingEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010Ivo Bendix Abstract DC are professional APC that instruct T cells during the inflammatory course of EAE. We have previously shown that MAPK3 (Erk1) is important for the induction of T-cell anergy. Our goal was to determine the influence of MAPK3 on the capacity of DC to arm T-cell responses in autoimmunity. We report that DC from Mapk3,/, mice have a significantly higher membrane expression of CD86 and MHC-II and , when loaded with the myelin oligodendrocyte glycoprotein , show a superior capacity to prime naïve T cells towards an inflammatory phenotype than Mapk3+/+ DC. Nonetheless and as previously described, Mapk3,/, mice were only slightly but not significantly more susceptible to myelin oligodendrocyte glycoprotein-induced EAE than WT littermate mice. However, Mapk3+/+ mice engrafted with Mapk3,/, BM (KO,WT) developed a severe form of EAE, in direct contrast to WT,KO mice, which were even less sick than control WT,WT mice. An infiltration of DC and accumulation of Th17 cells was also observed in the CNS of KO,WT mice. Therefore, triggering of MAPK3 in the periphery might be a therapeutic option for the treatment of neuroinflammation since absence of this kinase in the immune system leads to severe EAE. [source] IL-15 is critical for the maintenance and innate functions of self-specific CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2009Momoe Itsumi Abstract IL-15 is a pleiotropic cytokine involved in host defense as well as autoimmunity. IL-15-deficient mice show a decrease of memory phenotype (MP) CD8+ T cells, which develop naturally in naïve mice and whose origin is unclear. It has been shown that self-specific CD8+ T cells developed in male H-Y antigen-specific TCR transgenic mice share many similarities with naturally occurring MP CD8+ T cells in normal mice. In this study, we found that H-Y antigen-specific CD8+ T cells in male but not female mice decreased when they were crossed with IL-15-deficient mice, mainly due to impaired peripheral maintenance. The self-specific TCR transgenic CD8+ T cells developed in IL-15-deficient mice showed altered surface phenotypes and reduced effector functions ex vivo. Bystander activation of the self-specific CD8+ T cells was induced in vivo during infection with Listeria monocytogenes, in which proliferation but not IFN-, production was IL-15-dependent. These results indicated important roles for IL-15 in the maintenance and functions of self-specific CD8+ T cells, which may be included in the naturally occurring MP CD8+ T-cell population in naïve normal mice and participate in innate host defense responses. [source] CTLA-4 co-receptor impacts on the function of Treg and CD8+ T-cell subsetsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Christopher E. Rudd Abstract CTLA-4 has potent regulatory effects on the threshold of T-cell signalling and, in the process, guards against the development of hyper-proliferation and autoimmunity. Despite this, the role of CTLA-4 on specific T-cell subsets has been unclear. Such studies could shed light on both the function of CTLA-4, and on the contribution of the subsets to the disease phenotype of the Ctla4,/, mouse. Recently, a role for this co-receptor in the function of Treg has been outlined and, in this issue of the European Journal of Immunology, the selective targeting of the T-box transcription factor Eomes by CTLA-4 in the regulation of CD8+ cytolytic T-cell (CTL) effector function is shown. Together, these papers shed light on the role of CTLA-4 in different T-cell subsets. [source] Activating and inhibitory Fc, receptors can differentially modulate T cell-mediated autoimmunityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Mirentxu Abstract The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although Fc,R have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (Fc,RIII) and inhibitory (Fc,RIIb) Fc,R can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While Fc,RIIb,/, mice showed a significant increase in EAE severity, an Fc,RIII deficiency protected mice from disease. In addition, Fc,RIIb,/, mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, Fc,RIII,/, mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for Fc,RIII,/, mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory Fc,R signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression. [source] MR1-restricted V,19i T cells , a second population recognizing lipid antigens?EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Jens Schümann Abstract There is increasing evidence that T cells recognizing lipid antigens contribute to the immunological regulation of different disease conditions including autoimmunity. The best-known subset is CD1d-restricted lipid-reactive T cells characterized by the expression of an invariant TCR, chain. Much less is known about the biology of another invariant T cell subset, which is restricted to the MHC class I-like molecule MR1. A beneficial role of MR1-restricted T cells has been suggested in a mouse EAE model. However, the nature of antigens that can be presented by MR1 to this invariant T cell subset remained largely unclear. An article in this issue of the European Journal of Immunology presents strong indications that derivatives of ,-mannosyl ceramide (,-ManCer), i.e. glycolipids, can serve as ligands for MR1-restricted invariant T cells. In addition to that, the structure of the ,-ManCer sphingosine chain influences the Th1-Th2 polarization of the cytokine response. These important new findings will foster further research on the identity of physiological ligands for MR1-restricted T cells and on their relation with immunoregulation. See accompanying article: http://dx.doi.org/10.1002/eji.200636689 [source] Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infectionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Martin Abstract IL-2 is a cytokine with multiple and even divergent functions; it has been described as a key cytokine for in vitro T cell proliferation but is also essential for down-regulating T cell responses by inducing activation-induced cell death as well as regulatory T cells. The in vivo analysis of IL-2 function in regulating specific T cell responses has been hampered by the fact that mice deficient in IL-2 or its receptors develop lymphoproliferative diseases and/or autoimmunity. Here we generated chimeric mice harboring both IL-2R-competent and IL-2R-deficient T cells and assessed CD8+ T cell induction, function and maintenance after acute or persistent viral infections. Induction and maintenance of CD8+ T cells were relatively independent of IL-2R signaling during acute/resolved viral infection. In marked contrast, IL-2 was crucial for secondary expansion of memory CD8+ T cells and for the maintenance of virus-specific CD8+ T cells during persistent viral infections. Thus, depending on the chronicity of antigen exposure, IL-2R signaling is either essential or largely dispensable for induction and maintenance of virus-specific CD8+ T cell responses. [source] Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus-prone miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007Abstract We have determined that abnormal DNA methylation in T cells coincides with the development of autoimmunity, using a mouse model that exhibits an age-dependent lupus-like disease (MRL/lpr mice). Splenic CD4+ T cells were isolated from these mice at 5 and 16,wk of age (before and after autoimmunity is established) and the expression of DNA methyltransferase,1 (Dnmt1) and the methylation-sensitive gene Tnfsf7 (CD70) was measured. Bisulfite DNA sequencing was used to monitor the methylation status of the Tnfsf7 gene. We found that Dnmt1 steady-state mRNA levels were significantly lower in 16-wk-old MRL/lpr mice, which had established autoimmunity, compared to the 5-wk-old MRL/lpr mice. Furthermore, the expression of CD70 was higher in MRL/lpr mice at 16,wk. CD70 was overexpressed in MRL/lpr mice compared to age- and sex-matched MRL+/+ controls. Bisulfite DNA sequencing of the Tnfsf7 gene in MRL/lpr mice revealed that at 16,wk, CG pairs were hypomethylated compared to 5-wk-old mice, and that Tnfsf7 from MRL/lpr mice was hypomethylated at 16,wk relative to age-matched MRL+/+ controls. Our data indicate that decreased expression of Dnmt1 and the corresponding T cell DNA hypomethylation correlate with the development of age-dependent autoimmunity in MRL/lpr mice. [source] Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007Heather Wojcik Abstract Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage. [source] Generalized multi-organ autoimmunity in CCR7-deficient miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2007Abstract Development of autoimmunity is a multi-factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7-deficient mice are prone to develop generalized multi-organ autoimmunity. The autoimmune phenotype of CCR7,/, mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue-specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7-deficient mice show increased susceptibility to streptozotocin-induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity. [source] | ||||||||||||||||||||||||||||||||||||||||