Intermolecular Antigen Spreading Occurs During the Preclinical Period of Human Type 1 Diabetes

Department of Medicine, University of Washington, Seattle, WA 98195, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2001; 166(8):5265-70. DOI: 10.4049/jimmunol.166.8.5265
Source: PubMed


Intra- and intermolecular spreading of T cell responses to autoantigens has been implicated in the pathogenesis of autoimmune diseases. Therefore, we questioned whether T cell responses from subjects identified as at-risk (positive for autoantibody reactivity to islet proteins) for the development of type 1 diabetes, a cell-mediated autoimmune disease, would demonstrate intermolecular Ag spreading of T cell responses to islet cell proteins. Previously, we have demonstrated that by the time subjects develop type 1 diabetes, they have T cell responses to numerous islet proteins, whereas T cells from normal controls respond to a limited number of islet proteins. Initial testing of PBMC responses from 25 nondiabetic at-risk subjects demonstrated that 16 of the 25 subjects have PBMC responses to islet proteins similar to controls. Fourteen of these 16 subjects were available for follow-up. Eleven of the 14 developed T cell responses to increasing numbers of islet proteins, and 6 of these subjects developed type 1 diabetes. In the nine subjects who already demonstrated T cell Ag spreading at the initial visit, four were available for follow-up. Of these four, two had increases in T cell reactivity to islet proteins, while two maintained their initial levels of T cell reactivity. We also observed Ag spreading in autoantibody reactivity to islet proteins in nine of the 18 at-risk subjects available for follow-up. Our data strongly support the conclusion that intermolecular spreading of T cell and Ab responses to islet proteins occurs during the preclinical period of type 1 diabetes.

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    • "By the end of the study the B cell repertoire had diversified to include all four Abs. Other at risk volunteers not diagnosed with clinical type 1 diabetes also displayed evidence of intermolecular B cell epitope spreading [56]. "
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    ABSTRACT: While a variety of factors act to trigger or initiate autoimmune diseases, the process of epitope spreading is an important contributor in their development. Epitope spreading is a diversification of the epitopes recognized by the immune system. This process happens to both T and B cells, with this review focusing on B cells. Such spreading can progress among multiple epitopes on a single antigen, or from one antigenic molecule to another. Systemic lupus erythematosus, multiple sclerosis, pemphigus, bullous pemphigoid and other autoimmune diseases, are all influenced by intermolecular and intramolecular B cell epitope spreading. Endocytic processing, antigen presentation, and somatic hypermutation act as molecular mechanisms that assist in driving epitope spreading and broadening the immune response in autoimmune diseases. The purpose of this review is to summarize our current understanding of B cell epitope spreading with regard to autoimmunity, how it contributes during the progression of various autoimmune diseases, and treatment options available. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Nov 2014 · Immunology Letters
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    • "It is not dependent on major histocompatibility complex (MHC) type. In addition, a positive immunoblot response was found before the diagnosis of disease and predicted disease onset in individuals at risk (Brooks-Worrell et al. 2001). Limitations of this assay include the requirements for relatively large numbers of peripheral blood mononuclear cell cultures (PBMC) and the need for fresh (i.e., not frozen) cells (Table 2). "
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