A primary knowledge of normal mechanisms of immune tolerance, the kind of determinants recognized by tolerant and autoreactive T cells, and the nature of the tolerant and autoreactive lymphocytes themselves, are required before the immunological events leading to autoimmunity may be understood. Much has been learned about immune tolerance to membrane and secreted antigens in recent years, largely through the use of transgenic technology, but here is a gap in knowledge regarding normal mechanisms of tolerance to protein antigens of the nucleus. Yet, the majority of autoantigens, like LaJSS-B, targeted in a number of systemic autoimmune diseases including Sjogren's syndrome and systemic lupus erythematosus are composed of protein and localize to the nucleus. Pathways through which nuclear antigens become visible to the immune system are fundamentally different from previously well-studied membrane and secreted antigens. In order for tolerance and autoimmunity to nuclear antigens to be comprehended, a requirement for unraveling the etiology(ies) of systemic autoimmune disease(s), it is therefore imperative hat nuclear antigens be studied as a special class of antigen. To address these issues, the role of autoreactive T cells in tolerance and autoimmunity to the La systemic nuclear autoantigen will be studied as a paradigm for protein antigens of the nucleus. The studies will utilize a model of T cell initiated anti-nuclear autoimmunity in mice bearing the human La (hLa) transgene in its natural form. Preliminary studies reveal functional T cell tolerance to the hLa neo-antigen in this system. In the current proposal, the La T cell determinant(s) responsible for inducing this observed tolerance will be determined, and the relative roles of T cells recognizing immunodominant and subdominant determinants in tolerance and autoimmunity to the La nuclear antigen will be resolved. It will be determined whether peripheral tolerance to a nuclear antigen occurs and by what potential mechanism(s). Finally, the influence of Type 1 versus Type 2 immunity on tolerance and autoimmunity to the La nuclear antigen will be determined. These studies will advance our collective understanding of anti-nuclear autoimmunity underlying a constellation of systemic autoimmune disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048097-05
Application #
6855161
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Esch, Thomas R
Project Start
2001-04-15
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$240,000
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Pan, Z-J; Horton, C G; Lawrence, C et al. (2016) Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B. Clin Exp Immunol 186:18-29
Edgar, Contessa E; Terrell, Deirdra R; Vesely, Sara K et al. (2015) Ribosomal and immune transcripts associate with relapse in acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura. PLoS One 10:e0117614
Yaciuk, Jane C; Pan, Yujun; Schwarz, Karen et al. (2015) Defective selection of thymic regulatory T cells accompanies autoimmunity and pulmonary infiltrates in Tcra-deficient mice double transgenic for human La/Sjögren's syndrome-B and human La-specific TCR. J Immunol 194:1514-22
Maier-Moore, Jacen S; Horton, Christopher G; Mathews, Shirley A et al. (2014) Interleukin-6 deficiency corrects nephritis, lymphocyte abnormalities, and secondary Sjögren's syndrome features in lupus-prone Sle1.Yaa mice. Arthritis Rheumatol 66:2521-31
Andrews, Sarah F; Zhang, Qingzhao; Lim, Samuel et al. (2013) Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity. J Exp Med 210:125-42
Charles, Elizabeth; Joshi, Sunil; Ash, John D et al. (2010) CD4 T-cell suppression by cells from Toxoplasma gondii-infected retinas is mediated by surface protein PD-L1. Infect Immun 78:3484-92
Pan, Zi-jian; Maier, Shannon; Schwarz, Karen et al. (2010) Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells. Ann Rheum Dis 69:1195-9
Horton, Christopher G; Pan, Zi-jian; Farris, A Darise (2010) Targeting Toll-like receptors for treatment of SLE. Mediators Inflamm 2010:
Maeda, Kenichiro; Malykhin, Alex; Teague-Weber, Brittany N et al. (2009) Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals. Blood 113:4534-40
Semsei, Imre; Maier, Shannon; Workman-Azbill, Jennifer et al. (2007) Detection of a rare oligo(A) repeat tract mutation (8As-->7As) in the sequence encoding the La/SS-B autoantigen. Anal Biochem 370:47-53

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