Type I Diabetes and Multiple Sclerosis Patients Target Islet Plus Central Nervous System Autoantigens; Nonimmunized Nonobese Diabetic Mice Can Develop Autoimmune Encephalitis

Abstract

Type I diabetes and multiple sclerosis (MS) are distinct autoimmune diseases where T cells target either islet or CNS self-proteins. Unexpectedly, we found that autoreactive T cells in diabetic patients, relatives with high diabetes risk, nonobese diabetic (NOD) mice, and MS patients routinely target classical islet as well as CNS autoantigens. The pathogenic potential of CNS autoreactivity was testable in NOD mice. Pertussis holotoxin, without additional Ags or adjuvants, allowed development of an NOD mouse-specific, autoimmune encephalitis with variable primary-progressive, monophasic, and relapsing-remitting courses. T cells from diabetic donors transferred CNS disease to pertussis toxin-pretreated NOD.scid mice, with accumulation of CD3/IFN-γ transcripts in the brain. Diabetes and MS appear more closely related than previously perceived. NOD mouse-specific, autoimmune encephalitis provides a new MS model to identify factors that determine alternative disease outcomes in hosts with similar autoreactive T cell repertoires.

Islet-infiltrating B-Cells in Nonobese Diabetic Mice Predominantly Target Nervous System Elements

“…These results lend strong support to the idea that B-cell responses against islet-associated nervous elements may be an early event in diabetogenesis. This observation is consistent with a recent publication indicating that development of type 1 diabetes in both mice and humans is accompanied by T-cell responses against pancreatic nervous system tissue elements (7) and might account for some of the neurological pathologies that have been described in pre-diabetic humans and mice (35)(36)(37). The mechanisms underlying this predominant anti-nervous tissue-specific B-cell response in type 1 diabetes are unclear.…”

Distinct Effector Mechanisms in the Development of Autoimmune Neuropathy versus Diabetes in Nonobese Diabetic Mice

“…Autoimmune responses targeting the PNS in our model result from chronic presentation of multiple autoantigens and are likely to be very different from strong immune responses facilitated by adjuvants and induced by high doses of a single PNS Ag. Furthermore, autoimmune B and T cell responses targeting the nervous system in the NOD mouse have been described (7,8), and Setoguchi et al (9) recently described that NOD mice treated with anti-IL-2 mAbs developed an autoimmune peripheral neuropathy similar to the neuropathy that occurs in NOD-B7-2KO mice. Finally, these findings raise the possibility that autoimmune neuropathy, such as that observed in NOD and NOD-B7-2KO mice, may reflect some features of diabetic neuropathy seen in humans.…”

Prevalence of Diabetes Type 1 in Patients Suffered From Multiple Sclerosis

“…Considering that both MS and TID are autoimmune diseases, similarity of immunological patterns of these diseases could also be involved in their correlation (11). Both diseases are caused by T-helper lymphocytes attacking body tissues, and studies by Winer et al show that pancreatic and nervous system auto-antigens are both affected by T-helper cells, and thus some existing auto-antibodies against both tissues may be the same (13). Given that TID is a multi-factorial disease, thus, incidence of this disease may be intensified under the influence of factors other than MS autoimmune disease.…”