Although T cells are intimately involved in the development of murine systemic lupus erythematosus (SLE), the understanding of their role in disease has been elusive. Our previous studies of T- cell reactivity to the Sm nuclear antigen have provided a system to investigate T-cell recognition of an antigen important in SLE. we will define the T-cell receptors utilized by Sm-reactive T cells by creating T-cell hybridomas reactive to mouse Sm, identifying the T-cell receptor V gene families, and sequencing the genes so that we can compare the hybridomas to each other and to germline genetic elements. Lpr is a single recessive gene which causes vast expansion of a population of L3T4- LYT-2- (""""""""double negative"""""""") T lymphocytes in the periphery. We wish to understand how these T cells provoke autoimmune disease and thus will explore their origin and differentiative capacity through adoptive transfer experiments using Ly 1 congenic lpr mice. We will further define this disease- related double negative lineage using monoclonal antibodies directed against thymic double negative cells. We will investigate the surface receptors and function of hybridomas generated from the lpr double negative cells to gain understanding of these cells at the clonal level. By adoptive transfer of lpr and normal marrow into doubly heterozygous lpr hosts, we will ask whether the prominent B cell and macrophage abnormalities characteristic of lpr mice are due to the action of the abnormal T cells or instead reflect intrinsic abnormalities in other bone marrow derived lineages. Finally, we will exploit the capacity of lpr to induce autoimmunity on diverse murine backgrounds to determine the influence of major histocompatibility class I and class II genes on expression of SLE.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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General Medicine A Subcommittee 2 (GMA)
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University of North Carolina Chapel Hill
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Chapel Hill
United States
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Kuan, Anita P; Cohen, Philip L (2005) p53 is required for spontaneous autoantibody production in B6/lpr lupus mice. Eur J Immunol 35:1653-60
Cohen, Philip L; Caricchio, Roberto (2004) Genetic models for the clearance of apoptotic cells. Rheum Dis Clin North Am 30:473-86, viii
Suh, Chang-Hee; Freed, John H; Cohen, Philip L (2003) T cell reactivity to MHC class II-bound self peptides in systemic lupus erythematosus-prone MRL/lpr mice. J Immunol 170:2229-35
Caricchio, Roberto; McPhie, Lenese; Cohen, Philip L (2003) Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol 171:5778-86
Freed, J H; Marrs, A; VanderWall, J et al. (2000) MHC class II-bound self peptides from autoimmune MRL/lpr mice reveal potential T cell epitopes for autoantibody production in murine systemic lupus erythematosus. J Immunol 164:4697-705
Weintraub, J P; Cohen, P L (1999) Ectopic expression of B7-1 (CD80) on T lymphocytes in autoimmune lpr and gld mice. Clin Immunol 91:302-9
Caricchio, R; Kovalenko, D; Kaufmann, W K et al. (1999) Apoptosis provoked by the oxidative stress inducer menadione (Vitamin K(3)) is mediated by the Fas/Fas ligand system. Clin Immunol 93:65-74
Caricchio, R; Cohen, P L (1999) Spontaneous and induced apoptosis in systemic lupus erythematosus: multiple assays fail to reveal consistent abnormalities. Cell Immunol 198:54-60
Fecho, K; Cohen, P L (1998) Fas ligand (gld)- and Fas (lpr)-deficient mice do not show alterations in the extravasation or apoptosis of inflammatory neutrophils. J Leukoc Biol 64:373-83
Booker, J K; Reap, E A; Cohen, P L (1998) Expression and function of Fas on cells damaged by gamma-irradiation in B6 and B6/lpr mice. J Immunol 161:4536-41

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