Cellular and Genetic Mechanisms of Autoimmune Diabetes Associated Neuritis

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PROJECT SUMMARY Type 1 diabetes (T1D) is often accompanied by other autoimmune disorders, including autoimmune neuropathies. Findings in both NOD mice and patients have revealed potential overlap between immune responses targeting pancreatic b-cells and nerves. We hypothesized that lymphocyte populations involved in T1D pathogenesis targeting proteins co-expressed in the nervous system may be the earliest responders causing initial damage to peripheral nerves. These first responders provide the necessary trigger to expand immune responses against myelin and other nervous system components traditionally studied in existing mouse models of autoimmune neuritis. A vast majority of islet-infiltrating B-lymphocytes in NOD mice respond to the nervous-system protein peripherin. Antibodies against phosphorylated peripherin have been identified in T1D patients. We recently created a new mouse model (NOD-PerIg) in which B-lymphocytes transgenically express the immunoglobulin molecule from the peripherin-reactive B-cell clone H280 isolated from islets. T1D is accelerated in NOD-PerIg mice. T-cells from NOD-PerIg, but not NOD mice, transfer an autoimmune neuritis similar to chronic demyelinating polyneuropathy (CIDP) to NOD.scid recipients. This new NOD-PerIg à NOD.scid model of T1D-associated autoimmune neuritis provides an experimental system to directly dissect the discreet stages of nerve cell infiltration and damage. We originally hypothesized that insulitis expanded T- cells capable of causing neuritis. However, we have recently determined that T-cells derived from islets or sciatic nerves in primary NOD.scid recipients are only capable of infiltrating the organ from which they were derived. Therefore, experiments in Aim 1 will address the current unknowns regarding the discrete temporal and spatial steps leading to cellular recruitment into peripheral nerves. We have also found that in addition to the presence of IFNg and TNFa producing CD4+ T-cells, there is paradoxically an expansion of T-cells negative for traditional Th1, Th2, and Th17 cytokines within sciatic nerves. An additional open question is whether peripherin remains the antigen towards which T-cells are responding or whether there has been an expansion of responses against other neuronal antigens. Therefore, studies in Aim 2 will dissect the mechanisms by which T-cells destroy peripheral nerves and how an immune response against one shared b- cell/neuronal antigen can spill over to a wider neuronal response. Finally, in large NOD colonies, spontaneous clinical neuritis can be occasionally observed. We have found that at baseline, NOD mice (around the age of T1D onset) already have sciatic nerve infiltrating T-cells. These T-cells are not observed in non-autoimmune prone C57BL/6 mice. This indicates the likelihood that NOD harbors genetic loci contributing to spontaneous nerve infiltration that can lead to spontaneous neuritis. Whether these loci are distinct or overlapping with loci contributing to T1D is unknown. Therefore, studies in Aim 3 will map genes associated with spontaneous nerve infiltration allowing future genetic screening of patients at risk for developing autoimmune neuropathy.