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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Available from: Vivian Gersuk, Oct 05, 2015
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    • "Initiation of the diabetogenic response involves T cell recognition of a limited number of β cell autoantigens. As β cell autoimmunity progresses, several autoantigens are targeted due to intra- and inter-molecular epitope spread, resulting in the expansion of multiple clonotypes of pathogenic β cell-specific effector T cells (Teff) [11]–[18]. The latter is evident by a T cell receptor (TCR) repertoire marked by expression of multiple TCR variable (V) genes by islet resident T cells [19]–[21], and β cell-specific T cell clones [19], [22]–[26]. "
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    ABSTRACT: Islet transplantation provides a "cure" for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4(+) and CD8(+) T cells. Insight into the T cell receptor (TCR) repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ) chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4(+) and CD8(+) T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8(+) T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4(+) T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8(+) T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4(+) T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4(+) and CD8(+) T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4(+) and CD8(+) T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.
    PLoS ONE 12/2012; 7(12):e52054. DOI:10.1371/journal.pone.0052054 · 3.23 Impact Factor
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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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    ABSTRACT: Type 1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is a chronic disorder that results from autoimmune destruction of insulin-producing β cells in the islets of Langerhans within the pancreas ( Atkinson and Maclaren 1994). This disease becomes clinically apparent only after significant destruction of the β-cell mass, which reduces the ability to maintain glycemic control and metabolic function. In addition, it continues for years after clinical onset until, generally, there is complete destruction of insulin secretory capacity. Because prevention and therapy strategies are targeted to this pathologic process, it becomes imperative to have methods with which it can be monitored. This work discusses current research-based approaches to monitor the autoimmunity and metabolic function in T1D patients and their potential for widespread clinical application.
    Cold Spring Harbor Perspectives in Medicine 06/2012; 2(6):a007708. DOI:10.1101/cshperspect.a007708 · 9.47 Impact Factor
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    ABSTRACT: München, Univ., Diss., 2005 (Nicht für den Austausch).
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