Defective autoimmune regulator-dependent central tolerance to myelin protein zero is linked to autoimmune peripheral neuropathy

MA Su, D Davini, P Cheng, K Giang, U Fan… - The Journal of …, 2012 - journals.aai.org
MA Su, D Davini, P Cheng, K Giang, U Fan, JJ DeVoss, K Johannes, L Taylor, AK Shum…
The Journal of Immunology, 2012journals.aai.org
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 Ags, 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-Ags and deletion of self-reactive T cells. In this study, we
used mice with hypomorphic Aire function and two patients with Aire mutations to define how …
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 Ags, 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-Ags and deletion of self-reactive T cells. In this study, we used mice with hypomorphic Aire 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, an Ag for which 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-γ in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to myelin protein zero initiates an autoimmune Th1 effector response toward peripheral nerves.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common acquired chronic autoimmune neuropathy and affects 1 in 10,000 individuals (1). The pathogenic steps resulting in immune destruction of the peripheral nervous system (PNS) are not well understood, 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-Ags in medullary thymic epithelial cells (mTECs)(3) and promoting the negative selection of developing thymocytes that recognize these Ags with high affinity (4). NOD. Aire GW/+ mice have hypomorphic Aire function in that mTECs express tissue-specific self-Ags at∼ 10% of normal levels (2). NOD. Aire GW/+ mice are protected from early lethal autoimmune diseases (eg, exocrine pancreatitis, pneumonitis) but remain susceptible to a distinct set of autoimmune diseases that include autoimmune peripheral neuropathy.
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