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Autoantibodies
Kinds of Autoantibodies Terms modified by Autoantibodies Selected AbstractsGlutamic acid decarboxylase and IA-2 autoantibodies in type 1 diabetes: comparing sample substrates for autoantibody determinationsPEDIATRIC DIABETES, Issue 1 2000C Wasserfall Large-scale programs designed to assess risk for type 1 diabetes through serologic assessment of autoantibodies to recombinant ,-cell autoantigens are hampered by several limitations, including the methods for sample collection and assay performance, as well as the volume required for autoantibody determinations. The present study was designed to develop a low sample-volume, primary screening method for autoantibody detection of high specificity and sensitivity, and to determine the feasibility of dried blood spots collected on filter paper in serving as vehicles for such determinations. Autoantibodies to glutamic acid decarboxylase (GAD) and ICA512bdc (IA-2), both individually and in combination, were determined in persons with type 1 diabetes, healthy controls, or individuals with other autoimmune disorders. Autoantibody results for serum, plasma, and dried blood spots were compared. GAD, IA-2, and combined GAD/IA-2 autoantibodies were concordant in their measurement from minimal volumes of serum, plasma, and whole blood extracted from dried filter paper. The autoantibody levels from the dried blood spots were, however, lower than corresponding serum samples, and, as currently designed, failed to detect low-titer autoantibodies. Despite this limitation, screening for diabetes risk can be performed using small volumes of whole blood, serum, or plasma collected onto filter paper. These methodological improvements should simplify matters, reduce costs, and increase the efficacy of screening programs for type 1 diabetes. Further development of better substrates/methods for blood-specimen collection seems necessary to exploit the full potential of this and other autoantibody measurement strategies for screening large populations. [source] Autoantibody to heterogeneous nuclear ribonucleoprotein-A2 (RA33) in juvenile idiopathic arthritis: Clinical significancePEDIATRICS INTERNATIONAL, Issue 2 2009Hoda Y. Tomoum Abstract Background:, Objective biomarkers are needed for early diagnosis of juvenile idiopathic arthritis (JIA). Anti-A33 antibodies are considered good markers for adult rheumatoid arthritis (RA), but little information is available on their occurrence in JIA. The aim of the present study was therefore to investigate the value of anti-RA33 for diagnosis of JIA (both early and established disease), and its relation to markers of disease activity, and bone resorption. Subjects:, This case,control study was conducted on 34 children with JIA. Ten patients with arthritis of short duration (<6 weeks) were included, as undifferentiated arthritis. Forty-four age- and sex- matched healthy children served as controls. Beside evaluation and assessment of disease activity, urinary calcium, serum parathyroid hormone and serum anti-RA33 were measured in included subjects. Joints were examined radiologically and modified Larsen index (LI) was estimated. Results:, During follow up, eight of the patients with undifferentiated arthritis were diagnosed as having early JIA. Patients with JIA (early and established cases) had higher anti-RA33 levels than the control group (z = 6.04, 3.95, respectively). A total of 66.7% of the patients were positive for anti-RA33, results were comparable in early and established cases. Anti-RA33 values were correlated to disease activity (clinical and laboratory), to laboratory markers (urinary calcium, parathyroid hormone levels) and radiological evidence (LI) of bone resorption (r = 0.95, 0.63, 0.94, respectively). Conclusion:, Anti-RA33 is detected in two-thirds of JIA patients and occurs with comparable frequency early in the disease. Its levels are correlated to disease activity and markers of bone resorption and it seems to convey diagnostic and prognostic insights for appropriate management. [source] Clinical, electrophysiological, and serological overlap between Miller Fisher syndrome and acute sensory ataxic neuropathyACTA NEUROLOGICA SCANDINAVICA, Issue 5 2002H. Shimamura We report a patient with severe sensory ataxia, areflexia, and ophthalmoplegia with preservation of limb muscle strength. Electrophysiological examinations revealed peripheral sensory nerve involvement. A serological examination showed the elevation of IgG antibodies to various b-series gangliosides as well as GT1a. These indicated that this case is an overlap between acute sensory ataxic neuropathy and Miller Fisher syndrome. Autoantibody is implicated as potential pathogenic agents in some cases of acute sensory ataxic neuropathy. [source] Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosisCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2004C. NISHIJIMA SUMMARY Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence, or, levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover. [source] Diabetes classification: grey zones, sound and smoke: Action LADA 1DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 7 2008R. D. G. Leslie Abstract Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes. KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area. Copyright © 2008 John Wiley & Sons, Ltd. [source] Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodiesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2005Bernd Franke Abstract The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only ,-cell specific antibodies. There is general consensus that the presence of multiple Aab (, 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA. Copyright © 2005 John Wiley & Sons, Ltd. [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] The DPT-1 trial: a negative result with lessons for future type 1 diabetes preventionDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2002Professor Paolo Pozzilli Abstract The author comments on the DPT-1 Trial and why the observed negative outcome in preventing diabetes in first-degree relatives of type 1 diabetic patients by parenteral insulin administration may have occurred and what can be gathered from this large study. There were three main lessons to be learned from the DPT-1 Trial as follows. (1) Large preventive trials of type 1 diabetes are feasible in first-degree relatives of type 1 diabetic patients and other preventive approaches may be now envisaged. (2) The natural history of type 1 diabetes, at least in its final years before clinical onset, has been elucidated and reiterates the relevance of our present predictive tools (autoantibodies) for identifying individuals at risk for the disease. (3) Strict follow-up of enrolled subjects in trials permits an earlier diagnosis of the disease with less frequency of ketoacidosis and implementation of insulin therapy when higher C-peptide levels are present. DPT-1 has paved the way on how to proceed and new trials will be planned benefiting from such experience. Copyright © 2002 John Wiley & Sons, Ltd. [source] Islet autoantibodies in cord blood: maternal, fetal, or neither?DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2002Marian Rewers Abstract In high-risk type 1 diabetes populations, up to 3% of the general population newborns may express islet autoantibodies in cord blood and the vast majority of those appear to be maternal autoantibodies that disappear usually before the age of 9 months. Despite recent progress in standardization of autoantibody assays, some of the findings appear to be artifacts or non-IgG-mediated binding phenomena. It remains unclear whether transplacentally transmitted maternal autoantibodies play any role in protecting the offspring of diabetic women from diabetes. The evidence for fetal production of islet autoantibodies is very limited and remains to be validated in large prospective studies currently underway. Copyright © 2002 John Wiley & Sons, Ltd. [source] Autoimmune gestational diabetes mellitus: a distinct clinical entity?DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2001Dídac Mauricio Abstract This review gives an update of the present knowledge on what is defined here as autoimmune gestational diabetes mellitus (GDM). Autoimmune phenomena associated with type 1 diabetes mellitus (DM) can be detected in a subgroup of women with GDM. Islet autoantibodies are present in sera from women with GDM with variable frequency. Distinct phenotypic and genotypic features may be recognised in this subset of women with GDM, which are representative of a distinct clinical entity. Furthermore, these women are at increased risk of developing type 1,DM after pregnancy. However, the eventual progression of the autoimmune destruction of beta-cells in these subjects may follow different time-course patterns thus leading to variable forms of presentation of autoimmune DM. As a high-risk group for type 1 diabetes, women with previous autoimmune GDM may be candidates for potential immune intervention strategies. Copyright © 2001 John Wiley & Sons, Ltd. [source] The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitusDIABETIC MEDICINE, Issue 2 2008A. W. Van Deutekom Abstract Latent autoimmune diabetes in the adult (LADA) is a slowly progressive form of autoimmune diabetes, characterized by diabetes-associated autoantibody positivity. A recent hypothesis proposes that LADA consists of a heterogeneous population, wherein several subgroups can be identified based on their autoimmune status. A systematic review of the literature was carried out to appraise whether the clinical characteristics of LADA patients correlate with the titre and numbers of diabetes-associated autoantibodies. We found that the simultaneous presence of multiple autoantibodies and/or a high-titre anti-glutamic acid decarboxylase (GAD),compared with single and low-titre autoantibody,is associated with an early age of onset, low fasting C-peptide values as a marker of reduced pancreatic B-cell function, a high predictive value for future insulin requirement, the presence of other autoimmune disorders, a low prevalence of markers of the metabolic syndrome including high body mass index, hypertension and dyslipidaemia, and a high prevalence of the genotype known to increase the risk of Type 1 diabetes. We propose a more continuous classification of diabetes mellitus, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes. Future studies should focus on determining optimal cut-off points of anti-GAD for differentiating clinically relevant diabetes mellitus subgroups. [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] Autoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetesDIABETIC MEDICINE, Issue 3 2003T. M. E. Davis Abstract Aims The autoantigen SOX-13 of the SRY-related high mobility group box is a low-frequency reactant in sera from patients with Type 1 diabetes. We further investigated the potential diagnostic role of anti-SOX-13, and in particular its ability to distinguish Type 1 from Type 2 diabetes, in two large, well-characterized cohorts. Methods SOX-13 autoantibody status was ascertained using a radioimmunoprecipitation assay in (i) a random sample of 546 participants in an Australian community-based study (the Fremantle Diabetes Study; FDS) of whom 119 had Type 1 and 427 Type 2 diabetes, and (ii) a sample of 333 subjects with Type 2 diabetes from the United Kingdom Prospective Diabetes Study (UKPDS) stratified by age, anti-glutamic acid decarboxylase (GAD) and islet cell antibody (ICA) status, and requirement for insulin therapy within 6 years of diagnosis. Results The frequencies of anti-SOX-13 in the FDS subjects were 16.0% and 14.8% for Type 1 and Type 2 patients, respectively, and levels were similar. In the UKPDS subjects, the frequency was 4.5%. In a logistic regression model involving demographic, anthropometric and metabolic variables, only diabetes duration was significantly associated with anti-SOX-13 positivity, especially for duration > 5 years (P < 0.002). When the coexistence of autoantibodies was assessed in the two study samples, there were no significant associations between anti-SOX-13 and ICA, anti-GAD or ICA512/IA-2. Conclusions Whilst the frequency of anti-SOX-13 may be increased in some populations of diabetic patients, this reactivity does not usefully distinguish Type 1 from Type 2 diabetes. However, the association with diabetes duration suggests that anti-SOX-13 may be a non-specific marker of tissue damage associated with chronic hyperglycaemia. Diabet. Med. 20, 198,204 (2003) [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] Laparoscopic findings of liver cirrhosis due to non-alcoholic steatohepatitisDIGESTIVE ENDOSCOPY, Issue 4 2003Teruki Miyake A 42-year-old Japanese man was admitted to our hospital for investigation of abnormal liver function tests. He had no history of drug use, and drank little alcohol. Body mass index was 30. Serum was negative for viral markers and autoantibodies. Laparoscopy revealed diffuse small nodules on the liver surface. Liver biopsy revealed small nodules with pericellular fibrosis and macrovesicular fat deposition throughout the acini. Some inflammatory changes were observed. Liver cirrhosis due to non-alcoholic steatohepatitis (NASH) was diagnosed. NASH displays similar histological and laparoscopic characteristics to alcoholic liver diseases. [source] The magnocellular theory of developmental dyslexiaDYSLEXIA, Issue 1 2001John Stein Abstract Low literacy is termed ,developmental dyslexia' when reading is significantly behind that expected from the intelligence quotient (IQ) in the presence of other symptoms,incoordination, left,right confusions, poor sequencing,that characterize it as a neurological syndrome. 5,10% of children, particularly boys, are found to be dyslexic. Reading requires the acquisition of good orthographic skills for recognising the visual form of words which allows one to access their meaning directly. It also requires the development of good phonological skills for sounding out unfamiliar words using knowledge of letter sound conversion rules. In the dyslexic brain, temporoparietal language areas on the two sides are symmetrical without the normal left-sided advantage. Also brain ,warts' (ectopias) are found, particularly clustered round the left temporoparietal language areas. The visual magnocellular system is responsible for timing visual events when reading. It therefore signals any visual motion that occurs if unintended movements lead to images moving off the fovea (,retinal slip'). These signals are then used to bring the eyes back on target. Thus, sensitivity to visual motion seems to help determine how well orthographic skill can develop in both good and bad readers. In dyslexics, the development of the visual magnocellular system is impaired: development of the magnocellular layers of the dyslexic lateral geniculate nucleus (LGN) is abnormal; their motion sensitivity is reduced; many dyslexics show unsteady binocular fixation; hence poor visual localization, particularly on the left side (left neglect). Dyslexics' binocular instability and visual perceptual instability, therefore, can cause the letters they are trying to read to appear to move around and cross over each other. Hence, blanking one eye (monocular occlusion) can improve reading. Thus, good magnocellular function is essential for high motion sensitivity and stable binocular fixation, hence proper development of orthographic skills. Many dyslexics also have auditory/phonological problems. Distinguishing letter sounds depends on picking up the changes in sound frequency and amplitude that characterize them. Thus, high frequency (FM) and amplitude modulation (AM) sensitivity helps the development of good phonological skill, and low sensitivity impedes the acquisition of these skills. Thus dyslexics' sensitivity to FM and AM is significantly lower than that of good readers and this explains their problems with phonology. The cerebellum is the head ganglion of magnocellular systems; it contributes to binocular fixation and to inner speech for sounding out words, and it is clearly defective in dyslexics. Thus, there is evidence that most reading problems have a fundamental sensorimotor cause. But why do magnocellular systems fail to develop properly? There is a clear genetic basis for impaired development of magnocells throughout the brain. The best understood linkage is to the region of the Major Histocompatibility Complex (MHC) Class 1 on the short arm of chromosome 6 which helps to control the production of antibodies. The development of magnocells may be impaired by autoantibodies affecting the developing brain. Magnocells also need high amounts of polyunsaturated fatty acids to preserve the membrane flexibility that permits the rapid conformational changes of channel proteins which underlie their transient sensitivity. But the genes that underlie magnocellular weakness would not be so common unless there were compensating advantages to dyslexia. In developmental dyslexics there may be heightened development of parvocellular systems that underlie their holistic, artistic, ,seeing the whole picture' and entrepreneurial talents. Copyright © 2001 John Wiley & Sons, Ltd. [source] Prevalence of Anti-cardiolipin, Anti-,2 Glycoprotein I, and Anti-prothrombin Antibodies in Young Patients with EpilepsyEPILEPSIA, Issue 1 2002R. Cimaz Summary: ,Purpose: To measure anti-cardiolipin (aCL), anti-,2 glycoprotein I (anti-,2GPI), and anti-prothrombin (aPT) antibodies in young patients with epilepsy, and to correlate their presence with demographic data, clinical diagnoses, laboratory and neuroradiologic findings, and antiepileptic drugs (AEDs). Methods: Sera from one hundred forty-two consecutive patients with epilepsy with a median age of 10 years were tested for aCL and anti-,2GPI autoantibodies by solid-phase assays. aPT antibodies also were assayed in sera from 90 patients. Positive results were confirmed after a minimum of 6 weeks. Antinuclear antibodies (ANAs) and antibodies against extractable nuclear antigens (ENAs) also were tested. Results: An overall positivity of 41 (28.8%) of 142 sera was found. Fifteen patients were positive for aCL, 25 for anti-,2GPI, and 18 for aPT antibodies. Several patients (12%) displayed more than one specificity in their serum. Only one of these patients had a concurrent positivity for ANAs and ENAs. A predominance of younger patients was found in the antibody-positive group. All types of epilepsy were represented in the positive group. No relation between antibody positivity and AEDs was found. Diffuse ischemic lesions at computed tomography (CT)/magnetic resonance imaging (MRI) scans were present in higher percentages in patients who were antibody positive. No positive patient had a history of previous thrombosis or other features related to systemic lupus erythematosus (SLE), and no patient was born of a mother with SLE. Conclusions: Our study suggests a relation between epilepsy and aPL in young patients. A pathogenetic role for these autoantibodies cannot be excluded, and their determination might prove useful even from a therapeutic point of view. [source] Immunopathogenesis of cholestatic autoimmune liver diseasesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2001J. Medina Primary biliary cirrhosis and primary sclerosing cholangitis are well recognized chronic cholestatic liver diseases that are considered to have an autoimmune basis. Recent progress in the study of autoimmune liver diseases has improved the recognition and characterization of these conditions. An important component of this progress has been the identification of liver disease-associated autoantibodies and their respective target antigens, and the development of specific assays for these autoantibodies. In addition, some nonhumoral immunological findings imply an involvement of specific immunopathogenic mechanisms in the development of these conditions. Furthermore, immunogenetic factors associated with increased susceptibility to some of these diseases have been identified. This article reviews the most relevant information relating to the postulated autoimmune pathogenesis of these diseases, with special emphasis on their associated humoral and cellular immunological abnormalities and immunopathogenetic factors. Some of the remaining important unresolved issues relating to the pathogenesis of these diseases, that need to be addressed in further research, are highlighted. [source] Fulminant thrombotic thrombocytopenic purpura in two patients with systemiclupus erythematosus and phospholipid autoantibodiesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2000M. Osman Musa No abstract is available for this article. [source] Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Rogier Kersseboom Abstract B-cell receptor (BCR)-mediated signals provide the basis for B-cell differentiation in the BM and subsequently into follicular, marginal zone, or B-1 B-cell subsets. We have previously shown that B-cell-specific expression of the constitutive active E41K mutant of the BCR-associated molecule Bruton's tyrosine kinase (Btk) leads to an almost complete deletion of immature B cells in the BM. Here, we report that low-level expression of the E41K or E41K-Y223F Btk mutants was associated with reduced follicular B-cell numbers and significantly increased proportions of B-1 cells in the spleen. Crosses with 3-83,, and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca2+ mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM+ plasma cells in spleen and BM and significantly elevated serum IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are essential for appropriate regulation of B-cell activation. [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] Peripheral B cell receptor editing may promote the production of high-affinity autoantibodies in CD22-deficient miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2006Yuval Yarkoni Abstract CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22,/, mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with V,1-J,1 or V,8-J,5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age- and sex-dependent. High-affinity IgG autoantibodies were largely dependent on the selection of B cells with a particular H/L combination, in which a non-transgenic, endogenous L,chain was assembled by secondary rearrangements through the mechanism of receptor editing. Moreover, we present evidence that these secondary rearrangements are very prominent in splenic peripheral B cells. Since CD22 is primarily expressed on the surface of peripheral B cells, we propose a model for the development of a lupus-like autoimmune disease by a combination of peripheral receptor editing and abnormal B cell activation. [source] Toll-like receptor engagement stimulates anti-snRNP autoreactive B cells for activationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2006Chuanlin Ding Abstract Autoreactive B cells are the source of pathogenic autoantibodies (autoAb) in systemic lupus erythematosus (SLE). Previous studies have demonstrated that anti-small nuclear ribonucleoprotein particles (snRNP) B cells from normal background mice tolerize T cells in the periphery and do not secrete autoAb. In this study, we examined whether these anti-snRNP B cells can be activated for autoAb production by the engagement of Toll-like receptors (TLR). Anti-snRNP B cells proliferated vigorously and secreted abundant anti-snRNP autoAb upon exposure to CpG or polyriboinosinic polyribocytidylic acid [poly,(I:C)] in vitro. In addition, the costimulatory molecules CD80 and CD86 were up-regulated. While both anti-snRNP B cells and wild-type B cells produced similar levels of IL-6 and IL-10, anti-snRNP B cells secreted predominately IFN-, in response to CpG or poly,(I:C) stimulation. Furthermore, we showed that in vivo engagement of TLR stimulated immature anti-snRNP B cells to further differentiate and produce autoAb and form germinal centers. The activated anti-snRNP B cells became expanded and migrated into the T-B cell interface. Moreover, TLR engagement directly or indirectly activated autoreactive B cells via a CD4 T cell-independent manner. These results provide in vitro and in vivo evidence that BCR/TLR co-engagement promotes the activation of anti-snRNP B cells for autoAb production. [source] A crucial role for macrophages in the pathology of K/B,×,N serum-induced arthritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2005Samuel Solomon Abstract Autoantibodies in the form of immune complexes are known to be crucial mediators in initiating inflammation in a variety of autoimmune diseases. This has been well documented in the anti-collagen,II antibody-induced arthritis animal model for a long time now. Recently, in the K/B,×,N mouse model (the F1 of the TCR-transgenic KRN and the diabetic NOD mice), anti-glucose-6-phosphate isomerase (GPI) autoantibodies have been shown to induce arthritis. Experimental work in the K/B,×,N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and Fc,RIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-,, finally leading to joint destruction. The presence of high amounts of inflammatory cytokines and matrix-degrading proteases at sites of inflammation obviously put the cytokine-producing macrophages as the next target for investigation in this model. Here, we show that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/B,×,N serum-induced arthritis. Reconstituting clodronate liposome-treated mice with macrophages from naive animals could reverse this resistance. Also, we found that deficiencies in the Wiskott-Aldrich syndrome protein and CD40, which are both implicated in macrophage activation, chemotaxis and phagocytosis, are not essential in serum-induced arthritis. Mast cell degranulation was seen in arthritogenic serum-treated mice even in the absence of macrophages, possibly suggesting that mast cell degranulation/activation acts hierarchically before macrophages in the inflammatory cascade of anti-GPI antibody-induced arthritis. [source] Isolation and characterization of human anti-acetylcholine receptor monoclonal antibodies from transgenic mice expressing human immunoglobulin lociEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2005Evdokia Protopapadakis Abstract The isolation of human antibodies against muscle acetylcholine receptor (AChR), the autoantigen involved in myasthenia gravis (MG), is important for the development of therapeutically useful reagents. Monovalent antibody fragments from monoclonal antibodies against the main immunogenic region (MIR) of AChR protect the receptor from the destructive activity of MG autoantibodies. Human anti-AChR ,-subunit antibody fragments with therapeutic potential have been isolated using phage display antibody libraries. An alternative approach for obtaining human mAb has been provided by the development of humanized mice. In this report, we show that immunization of transgenic mouse strains with the extracellular domain of the human AChR ,-subunit results in antibody responses and isolation of hybridomas producing human mAb. Four specific IgM mAb were isolated and analyzed. mAb170 recognized the native receptor the best and was capable of inducing AChR antigenic modulation, suggesting its specificity for a pathogenic epitope. Moreover, the recombinant antigen-binding (Fab) fragment of this mAb competed with an anti-MIR mAb, revealing that its antigenic determinant lies in or near the MIR. Finally, Fab170 was able to compete with MG autoantibodies and protect the AChR against antigenic modulation induced by MG sera. This approach will be useful for isolating additional mAb with therapeutic potential against the other AChR subunits. [source] Restoration of C1q levels by bone marrow transplantation attenuates autoimmune disease associated with C1q deficiency in miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Josefina Cortes-Hernandez Abstract C1q deficiency in both humans and mice is strongly associated with autoimmunity. We have previously shown that bone marrow transplantation (BMT) restored C1q levels in C1q-deficient (C1qa,/,) mice. Here, we studied the effect of BMT on autoimmunity in C1qa,/, mice. Following irradiation, young C1qa,/, or wild-type MRL/Mp mice received bone marrow cells (BMC) from strain-matched wild-type or C1qa,/, animals. C1q levels increased rapidly when C1qa,/, mice received BMC from wild-type mice. Conversely, they decreased slowly in wild-type mice transplanted with C1qa,/, BMC. C1qa,/, animals transplanted with C1qa,/, BMC demonstrated accelerated disease when compared with wild-type mice given wild-type BMC. In contrast, a significant delay in the development of autoantibodies and glomerulonephritis was observed in C1qa,/, mice reconstituted with wild-type BMC, and the impaired clearance of apoptotic cells, previously described in C1qa,/, mice, was rectified. Moreover, the autoimmune disease was accelerated in wild-type mice given C1qa,/, BMC compared to animals transplanted with wild-type cells. These results provide supporting evidence that BMT may be a therapeutic option in the treatment of autoimmunity associated with human C1q deficiency. [source] An MHC anchor-substituted analog of myelin oligodendrocyte glycoprotein,35,55 induces IFN-, and autoantibodies in the absence of experimental autoimmune encephalomyelitis and optic neuritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2004Mandy Abstract Previous strategies to ameliorate experimental autoimmune encephalitis (EAE) include the treatment of autoreactive T,cells with altered peptide ligands, which contain amino acid substitutions at TCR contact residues. We recently showed that a variant of myelin oligodendrocyte glycoprotein (MOG),35,55 possessing low affinity for MHC (45D) induced anergy in MOG,35,55-specific T,cells and reduced their encephalitogenicity upon adoptive transfer. Here we investigate the characteristics of the primary immune response to this MHC anchor-substituted peptide. Overall, we observed that immunization with 45D resulted in the production of IFN-, and anti-MOG,35,55 autoantibodies at levels similar to those of MOG,35,55-immunized mice with active EAE. However, no symptoms of clinical or histological EAE or overt histological optic neuritis were observed in 45D-immunized mice. Consistent with this finding, 45D-immunized mice did not exhibit CD4+ infiltrates into the CNS. Therefore, MOG,35,55-specific precursors stimulated with a weak ligand (45D) mediate some EAE-associated effector functions but are unable to fully initiate the inflammatory process in the central nervous system that leads to clinical manifestation of EAE. [source] Idiotype-specific CD4+CD25+ T suppressor cells prevent, by limiting antibody diversity, the occurrence of anti-dextran antibodies crossreacting with histone H3EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2003Christoph Specht Abstract CD25+ suppressor T cells regulate the immune response against the type-2 "thymus independent" bacterial polysaccharide antigen ,(1,3)dextran (Dex) in BALB/c mice. These T cells, represented by the clone 178-4 Ts, restrict the Dex-specific IgG antibody repertoire such that the J558 idiotype dominates. Antibodies with other structures in the heavy-chain variable region (VH region), predominantly within the CDR3 domain, occur when the T cell control fails. This increase of antibody diversity caused by a lack of CD25+ Ts cells, e.g. in nude mice, does not result in the appearance of antibodies with enhanced affinity to the antigen Dex, but often leads to a crossreactivity with autologous proteins. Twenty-two out of sixty Dex-specific hybridomas from nude mice, but no hybridomas from euthymic mice, crossreact with a nuclear protein, as tested by ELISA. This nuclear protein was identified as histone H3. Ten of the sixty hybridomas from nude mice were sequenced and show VH sequences that deviate from the original J558 sequence. Three of these ten hybridomas crossreact with the histone H3. Adoptive transfer of CD25+ Ts cells to nude mice leads to a marked increase of antibodies carrying the original J558 idiotype within the IgG pool after immunization with Dex. Our data demonstrate a CD25+ Ts cell-mediated restriction of VH usage, which prevents the appearance of crossreactive autoantibodies. [source] Fc,RIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune diseaseEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2003Kaori Yajima Abstract MRL.Faslpr/lpr mice, a model for systemic lupus erythematosus (SLE) and arthritis in humans, have a Fas mutation that results in spontaneous development of systemic autoimmune diseases and a short life span. Half of them die by 5,6,months of age due to massive progression of systemic autoimmune diseases, such as lupus nephritis. However, C57BL/6 (B6).Faslpr/lpr strain does not develop such disorders within the normal life span, indicating that suppressor gene(s) in B6 mice may control the onset and exacerbation of disease. Here, we show that the gene for a unique inhibitory Fc receptor for IgG (Fc,RIIB) is a critical SLE suppressor. Fc,RIIB-deficient B6.Faslpr/lpr (B6.IIB,/,Faslpr/lpr) mice developed systemic autoimmune diseases, including anti-DNA and anti-type,II collagen autoantibodies and cryoglobulin production, immune complex glomerulonephritis and arthritis. They were short-lived, due to enhanced autoantibody production by B cells culminating in fatal lupus nephritis. Thus, Fc,RIIB deletion with Fas mutation is sufficient for the development of systemic autoimmunity in B6 mice. The inhibitory signaling cascade via Fc,RIIB may be critical for suppressing SLE in humans. [source] Autoantibodies in alcoholic liver diseaseADDICTION BIOLOGY, Issue 2 2000Ian G. McFarlane Despite many decades of research, the reasons why only a relatively small proportion of individuals who consume excessive quantities of alcohol develop clinically significant liver disease remain unknown. The association with features of autoimmune diseases, including hypergammaglobulinaemia, circulating autoantibodies, inheritance of certain immunogenetic (HLA) markers and response to corticosteroid therapy in some patients has led to a persistent impression that altered immune regulation with a relative loss of self-tolerance underlies susceptibility to the development of the more severe forms of alcoholic liver disease (alcoholic hepatitis and/or cirrhosis). However, review of the data from the numerous studies that have been conducted over the past 30 years fails to reveal sufficiently convincing evidence that autoimmunity plays a primary role in alcohol-related liver damage. In particular, most of the wide range of circulating autoantibodies that have been reported in patients are found mainly at low titres, are not confined to those with severe liver injury, and are probably more likely to be a response to the hepatic insult than causally related to liver damage. Additionally, an association with various HLA phenotypes has not been confirmed by meta-analysis. Interpretation is complicated by evidence that alcohol may have direct effects on some components of the immune system but, if there is an immunogenetic basis for alcoholic liver disease, the present evidence suggests that this might be related more to cytokine gene polymorphisms than to a predisposition to autoimmunity per se. [source] | ||||||||||||||||||||||||||||||||||||||||||||||