Abstract

Guillain-Barre Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) are autoimmune diseases characterized by inflammatory demyelinating lesions of the peripheral nervous system that cause devastating neurological deficits and paralysis. We have developed the first model of spontaneous autoimmune disease of the peripheral nervous system, called Spontaneous Autoimmune Peripheral Polyneuropathy (SAPP). NOD mice deficient in the co-stimulatory molecule B7-2 exhibit a progressive and generalized limb paralysis associated with severe demyelination and axonal damage due to massive inflammation of the peripheral nervous system. Adoptive transfer experiments showed that the disease is mediated, at least in part, by CD4+ T cells. The course of the disease and its pathophysiological features are strikingly similar to human GBS and CIDP. SAPP is observed in mice of the autoimmune-prone NOD background, which has been widely recognized as a valuable animal model of autoimmunity in humans. Furthermore, B7-2-deficient NOD mice do not develop diabetes. Thus, this animal model will provide insight into the influence of the co-stimulatory milieu on the polarization of autoimmunity towards different tissues and the development of distinct diseases in individuals presenting a general susceptibility to autoimmunity. The following specific aims are proposed to study this disease:
Specific aim #1 : To determine the antigen(s) targeted by autoreactive T cells in the peripheral nerves.
Specific aim #2 : To understand the influence of B7 costimulation on the polarization of autoimmunity in nod mice.
Specific aim #3 : To determine the immunopathology of SAPP, particularly the cell subsets and the effector mechanisms involved in the disease.
Specific aim #4 : To analyze the genetic control of SAPP. We propose to study the hypothesis that SAPP shares a subset of immunological and genetic attributes similar to those associated with the other autoimmune syndromes in the NOD strain. Our results will allow us to define genetic and immunological characteristics that determine the general susceptibility of individuals to autoimmunity and identify distinct mechanisms that lead to spontaneous destructive immune response in the nervous system versus the pancreas.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI050834-01
Application #
6419144
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
2001-12-15
Project End
2006-11-30
Budget Start
2001-12-15
Budget End
2002-11-30
Support Year
1
Fiscal Year
2002
Total Cost
$289,325
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Xu, Pinglong; Bailey-Bucktrout, Samantha; Xi, Ying et al. (2014) Innate antiviral host defense attenuates TGF-? function through IRF3-mediated suppression of Smad signaling. Mol Cell 56:723-37
Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142
Bailey-Bucktrout, Samantha L; Martinez-Llordella, Marc; Zhou, Xuyu et al. (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949-62
Yadav, Mahesh; Stephan, Stephen; Bluestone, Jeffrey A (2013) Peripherally induced tregs - role in immune homeostasis and autoimmunity. Front Immunol 4:232
Herold, Kevan C; Vignali, Dario A A; Cooke, Anne et al. (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243-56
Bour-Jordan, Hélène; Thompson, Heather L; Giampaolo, Jennifer R et al. (2013) Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background. J Autoimmun 45:58-67
Yadav, Mahesh; Louvet, Cedric; Davini, Dan et al. (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209:1713-22, S1-19
Bour-Jordan, Hélène; Esensten, Jonathan H; Martinez-Llordella, Marc et al. (2011) Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/?B7 family. Immunol Rev 241:180-205
Bour-Jordan, Hélène; Bluestone, Jeffrey A (2009) Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells. Immunol Rev 229:41-66
Louvet, Cédric; Kabre, Beniwende G; Davini, Dan W et al. (2009) A novel myelin P0-specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy. J Exp Med 206:507-14

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