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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079683-05
Application #
9323613
Study Section
Special Emphasis Panel (ZRG1-IMM-G (02)M)
Program Officer
Nuckolls, Glen H
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
$333,561
Indirect Cost
$107,827
Name
University of North Carolina Chapel Hill
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Allard, Denise E; Wang, Yan; Li, Jian Joel et al. (2018) Schwann cell-derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment. J Clin Invest 128:4727-4741
Smith, Collin-Jamal; Allard, Denise E; Wang, Yan et al. (2018) IL-10 Paradoxically Promotes Autoimmune Neuropathy through S1PR1-Dependent CD4+ T Cell Migration. J Immunol 200:1580-1592
Zhang, Yang; Hwang, Bin-Jin; Liu, Zhen et al. (2018) BP180 dysfunction triggers spontaneous skin inflammation in mice. Proc Natl Acad Sci U S A 115:6434-6439
Zhu, Meng-Lei; Bakhru, Pearl; Conley, Bridget et al. (2016) Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun 7:11350
Thrasher, Bradly J; Hong, Lee Kyung; Whitmire, Jason K et al. (2016) Epigenetic Dysfunction in Turner Syndrome Immune Cells. Curr Allergy Asthma Rep 16:36
Bakhru, Pearl; Su, Maureen A (2016) Estrogen turns down ""the AIRE"". J Clin Invest 126:1239-41
Anderson, Mark S; Su, Maureen A (2016) AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol 16:247-58
Cook, Kevin D; Shpargel, Karl B; Starmer, Joshua et al. (2015) T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX. Immunity 43:703-14
Su, Maureen A; Anderson, Mark S (2014) Breaking through the central tolerance ceiling to unleash anticancer immune responses. Oncoimmunology 3:e950169
Whitfield-Larry, Fatima; Felton, Jamie; Buse, John et al. (2014) Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients. Clin Immunol 153:156-64

Showing the most recent 10 out of 17 publications