Infectious Th1 and Th2 autoimmunity in diabetes‐prone mice

Abstract

In the non-obese diabetic (NOD) mouse, a Th1-biased autoimmune response arises spontaneously against glutamic acid decarboxylase, concurrent with the onset of insulitis. Subsequently, Th1-type autoreactivity spreads intra- and intermolecularly to other beta-cell autoantigens (beta CAAs), suggesting that a spontaneous Th1 cascade underlies disease progression. Induction of Th2 immunity to a single beta CAA results in the spreading of Th2-type T-cell and humoral responses to other beta CAAs in an infectious manner. Thus, both Th1 and Th2 autoimmunity can evolve in amplificatory cascades defined by site-specific, but not antigen-specific, positive feedback circuits. Despite the continued presence of Th1 autoimmunity, the induction of Th2 spreading is associated with active tolerance to beta CAAs and reduced disease incidence. With disease progression there is an attenuation of beta CAA-inducible Th2 spreading, presumably because of a reduced availability of uncommitted beta CAA-reactive precursor T cells. We discuss the implications of these findings for the rational design of antigen-based immunotherapeutics.

Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with Type I diabetes mellitus

“…Similar to the observations in NOD mice [56,57], the present study showed that the recognition frequency in patients with Type I diabetes for some GAD epitopes, such as B2, GAD65(252±266) decreased with disease progression, whereas the responding rate to other GAD epitopes, such as B4, GAD67(212±226) seemed to increase. No significant differences were found however, in responses to beta and V peptides between recent onset and late onset patient groups.…”

“…There appears to be a drive towards relative immunodominance of some peptides but also an apparent diversification and broadening of specificity suggesting epitope spreading with disease progression. Studies in autoimmune mouse mod- A B C els show that either initial determinant or spreading determinants could be critical in the pathogenesis of autoimmune diseases [56,57]. Many instances of organ-specific autoimmunity also show such clusters of target determinants that become involved [58].…”

“…Autoimmune T-cell responses to peptide determinants of beta-cell proteins have been characterised in nonobese diabetic (NOD) mice and human patients with Type I diabetes [12, 13, 17, 18, 41, 50±57]. Studies in NOD mice showed that T-cell responses to GAD antigens arose in a sequential order and that T-cell responses to epitopes GAD65(78±97), GAD65(202± 221), GAD65(217±236), GAD65(247±266), GAD65(509±528) or GAD(524±543) might be used as staging markers for Type I diabetes progression [56,57]. At least 15 GAD65 T-cell epitopes recognised by humans with Type I diabetes have also been identified [12, 41, 50±52, 55].…”

Genetics of type 1 diabetes mellitus

“…206 IL-12 drives the differentiation of T-lymphocytes into the Th1 subset, characterised by production of cytokines leading to cell-mediated immunity. 207,208 Furthermore, in the NOD mouse, IL-12 has been shown to play a primary role in T1D induction, 206,209,210 and in addition, plays a key role in immune reactivity against infections. However, it has been shown that in the absence of infection, IL-12-induced autoreactive T cell responses might predispose to self-destructive immunity.…”

Presence of Diabetes-Inhibiting, Glutamic Acid Decarboxylase-Specific, IL-10-Dependent, Regulatory T Cells in Naive Nonobese Diabetic Mice

“…The CD4 ϩ T cells involved in the mechanisms underlying type 1 diabetes exhibit predominantly a Th1 phenotype, characterized by the secretion of high amounts of IL-2 and IFN-␥ (3)(4)(5). Conversely, CD4 ϩ T cells of the Th2 subset may exhibit regulatory functions that control the development of type 1 diabetes (5, 6).…”