Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most common acquired chronic autoimmune neuropathy and is characterized by demyelination and immune cell infiltration of the peripheral nervous system (PNS). CIDP is associated with progressive Weaknesses, paresthesias, and sensory dysfunction and is the chronic counterpart of Guillain-Barre Syndrome. Current treatments for CIDP have non-specific mechanisms of action and are ineffective in one-third of patients. Understanding the immune tolerance defects that result in PNS autoimmunity is critical for developing more effective, mechanism-based therapies. CIDP has recently been reported in rare patients with mutations in the Autoimmune Regulator (AIRE) gene. In parallel, we reported that mice with a dominant Aire G228W patient mutation on the autoimmune-prone NOD background (NOD.AireGW/+ mice) spontaneously develop autoimmune peripheral neuropathy that shares multiple features with sporadic CIDP. Together, these findings suggest that Aire plays an important role in preventing PNS autoimmunity in both mice and humans. Aire is a putative thymic transcription factor which promotes immune tolerance by upregulating thymic self-antigen expression and negative selection of self- reactive T cells, enhancing regulatory T cell development, and preventing B cell activation and autoantibody production. We hypothesize that these immunoregulatory mechanisms affected by Aire are also those important in maintaining immune tolerance towards the PNS. The NOD.AireGW/+ mouse therefore represents a valuable model for determining the immune tolerance defects underlying PNS autoimmunity. To this end, we propose to utilize our Aire-deficient model to: 1) identify the primary inciting PNS autoantigen(s) expressed in the thymus, 2) determine how Aire-deficiency alters the development of regulatory T cells important in suppressing PNS autoimmunity, and 3) determine the role of autoantibodies in Aire-mediated PNS autoimmunity. Because Aire affects tolerance mechanisms that are also disrupted in common autoimmune diseases, findings from this study will be applicable not only to the minority of patients with Aire mutations and CIDP, but also to sporadic CIDP patients who do not have Aire mutations. Additionally, findings from these studies will contribute to a broader understanding of how Aire functions to prevent autoimmunity.

Public Health Relevance

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a devastating condition resulting from destruction of the peripheral nervous system (PNS) by the body's own immune system. We have recently developed a new mouse strain with an altered Autoimmune Regulator (Aire) gene which spontaneously manifests autoimmunity against the PNS. We will use this novel model of PNS autoimmunity to define which PNS proteins are primary target(s) of autoimmune attack and which components of the immune system contribute to the autoimmune response against the PNS. A better understanding of how the immune system destroys the PNS will inform us on how the immune system can be modulated for the prevention and treatment of CIDP!

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Gwinn, Katrina
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University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Medicine
Chapel Hill
United States
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Waterfield, Michael; Khan, Imran S; Cortez, Jessica T et al. (2014) The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat Immunol 15:258-65
Misumi, Ichiro; Alirezaei, Mehrdad; Eam, Boreth et al. (2013) Differential T cell responses to residual viral antigen prolong CD4+ T cell contraction following the resolution of infection. J Immunol 191:5655-68
Zeng, Xiaopei L; Nagavalli, Anil; Smith, Colin-Jamal et al. (2013) Divergent effects of T cell costimulation and inflammatory cytokine production on autoimmune peripheral neuropathy provoked by Aire deficiency. J Immunol 190:3895-904