Autoantibodies and associated T-cell responses to determinants within the 831-860 region of the autoantigen IA-2 in Type 1 diabetes.
ABSTRACT B-cells influence T-cell reactivity by facilitating antigen presentation, but the role of autoantibody-secreting B-cells in regulating T-cell responses in Type 1 diabetes is poorly defined. The aims of this study were to characterise epitopes on the IA-2 autoantigen for three monoclonal antibodies from diabetic patients by amino acid substitutions of selected residues of IA-2, establish contributions of these epitopes to binding of serum antibodies in Type 1 diabetes and relate B- and T-cell responses to overlapping determinants on IA-2. The monoclonal antibodies recognised overlapping epitopes, with residues within the 831-860 region of IA-2 contributing to binding; substitution of Glu836 inhibited binding of all three antibodies. Monoclonal antibody Fab fragments and substitution of residues within the 831-836 region blocked serum antibody binding to an IA-2 643-937 construct. IL-10-secreting T-cells responding to peptides within the 831-860 region were detected by cytokine-specific ELISPOT in diabetic patients and responses to 841-860 peptide were associated with antibodies to the region of IA-2 recognised by the monoclonal antibodies. The study identifies a region of IA-2 frequently recognised by antibodies in Type 1 diabetes and demonstrates that these responses are associated with T-cells secreting IL-10 in response to a neighbouring determinant.
Article: Autoimmunity in 2009.[Show abstract] [Hide abstract]
ABSTRACT: The number of 2009 publications in indexed journals dealing with 'autoimmunity' has maintained its increasing trend compared to the previous five years. Numerous developments have been proposed in our understanding of systemic and organ-specific autoimmune diseases (particularly multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis) and of basic autoimmunity mechanisms (particularly Th17, T regulatory cells, and autoantibodies). Both these lines of evidence share a significant potential to be translated into new therapeutic options to impact clinical practice. This article will discuss selected publications from prominent scientific journals dedicated to immunology and autoimmunity and ultimately include some expectations in branches of autoimmunity that appear promising for future developments.Autoimmunity reviews 10/2010; 9(12):795-800. · 6.37 Impact Factor
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ABSTRACT: This review focuses on genes that control β-cell targeting in autoimmune, type 1-dependent, diabetes (T1D) and on insulin as the major autoantigen recognized by T lymphocytes throughout the disease process. T1D associates with multiple gene variants. Beyond genes that predispose to general failure of immune tolerance to self, loci identified by the analysis of crosses between non-obese diabetic (NOD) and conventional mouse strains harbour genes that control β-cell targeting or the deviation of autoimmunity towards other tissues. We report here the role of genes encoding co-activation molecules involved in the activation of T lymphocytes, ICOS and ICOS ligand (B7RP1). NOD mice which are deficient in either of these two molecules are protected from diabetes, but instead develop a neuromuscular autoimmune disease. We also report the characterization in humans of T lymphocytes that are specific for major β-cell autoantigens, especially insulin. This opens the way towards new bioassays in the diagnosis of autoimmunity and towards autoantigen-specific immunotherapy in T1D. In order to develop a new preclinical model of T1D that would allow testing insulin epitopes to induce immune tolerance in vivo, we developed a mouse that is deficient in endogenous major histocompatibility complex class I and class II genes and deficient for the two murine insulin genes and that express human class I, class II and insulin genes.Diabetes Obesity and Metabolism 10/2013; 15(suppl 3):89-97. · 5.18 Impact Factor
Article: Pearls in autoimmunity[Show abstract] [Hide abstract]
ABSTRACT: This manuscript does a review of the more frequent issues published at Autoimmunity Reviews, Journal of Autoimmunity and Autoimmunity in the period of January–December 2009. The following topics were commented: (1) multiple sclerosis (MS) and its relationships with Epstein Barr infection, with vitamin D polymorphism and the new modalities of MS treatment. (2) Type 1 diabetes and genetic discovers, studies with GAD 65 and IA-2 autoantigen and the association T1D and autoimmune organ-specific diseases. (3) Autoimmune thyroid disorders and its association with susceptibility genes and polymorphisms. (4) Multiplex autoantibody profiling approaches in MS and rheumatoid arthritis. (5) Th17 cytokine in primary biliary cirrhosis, experimental autoimmune encephalomyelitis and celiac disease. (6) Vitamin D and experimental autoimmune prostatitis and pulmonary alveolar proteinosis. KeywordsAutoimmunity–Multiple sclerosis–Diabetes–Thyroid disorders–Vitamin D–Autoantibodies01/2011; 2(1):1-4.