Defective Aire-Dependent Central Tolerance to P0 Is Linked to Autoimmune Peripheral Neuropathy

Chronic Inflammatory Demyelinating Polyneuropathy is a debilitating autoimmune disease characterized by peripheral nerve demyelination and dysfunction. How the autoimmune response is initiated, identity of provoking antigens, and pathogenic effector mechanisms are not well-defined. The Autoimmune Regulator (Aire) plays a critical role in central tolerance by promoting thymic expression of self-antigens and deletion of self-reactive T cells. Here, we utilized mice with hypomorphicAire function and two patients with Aire mutations to define how Aire deficiency results in spontaneous autoimmune peripheral neuropathy. Autoimmunity against peripheral nerves in both mice and humans targets Myelin Protein Zero (P0), an antigen whose expression is Aire-regulated in the thymus. Consistent with a defect in thymic tolerance, CD4+ T cells are sufficient to transfer disease in mice and produce IFN-gamma in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to P0 initiates an autoimmune Th1 effector response toward peripheral nerves. in part because of the scarcity of robust animal models. We recently reported that spontaneous autoimmune peripheral neuropathy develops in NOD mice harboring a G228W point mutation in the Autoimmune Regulator (Aire) gene (NOD.Aire GW/+ mice) (2). Aire plays a critical role in central tolerance by upregulating the ectopic expression of a wide array of tissue-specific self-antigens in medullary thymic epithelial cells (mTECs) (3) and promoting the negative selection of developing thymocytes that recognize these antigens with high affinity (4). NOD.Aire GW/+ mice have hypomorphicAire function in that mTECs