Systemic lupus erythematosus (SLE) is characterized by IgG autoantibodies to certain intracellular components, including chromatin and ribonucleoproteins. Several inbred mouse strains also develop spontaneous lupus, with the same spectrum of autoantibodies. Certain of these specificities are pathogenic, including those against chromatin that induce immune-complex glomerulonephritis. Autoantibodies in lupus arise as a consequence of autoantigen-specific alpha/beta CD4+ T cell help, including T cells specific for peptides of chromatin-associated proteins. Such autoreactive T cells bypass normal tolerance mechanisms in the periphery; however, the mechanism of activation of T cells responsive to self peptides in lupus is unknown, as are the tissue source(s) of such peptides and the events leading to autoreactive CD4+ T cell-B cell collaboration with resultant pathogenic autoantibody production. In this proposal, an in vivo approach will be used to dissect the mechanisms that lead to peripheral T cell tolerance abrogation and T cell help for autoantibody production in lupus. It is hypothesized that these events arise in two stages: first, that lupus T cells have intrinsic (genetic) defects that render them susceptible to activation after contact with the ubiquitous self peptide-class II MI-IC complexes that are sufficient for CD4+ T cell survival in normal animals; second, that such activation, initiating tolerance loss with polyclonal expansion of autoreactive T cells, leads to oligoclonal T-B cell collaboration in the setting of specific autoantigen presentation by autoreactive B cells. The hypothesis will be addressed in two aims. First, it will be determined if normally displayed (ubiquitous) MHC-self peptide complexes can activate autoreactive T cells from Fas-intact mice MRL/+Fas-lpr mice, in comparison to non-autoimmune control T cells. Second, it will be determined if T cells from MRL/+Fas-lpr mice can provide B cell help in the setting of autoantigen presentation by autoreactive B cells, an event that leads to antigen-specific expansion of cells from both lineages. These objectives fit well within the overall context of this IRPO proposal centered around developing a better understanding of T cell-B cell interactions during the development and maintenance of systemic autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044076-07
Application #
6511875
Study Section
Special Emphasis Panel (ZRG1-ALY (03))
Program Officer
Gretz, Elizabeth
Project Start
1996-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
7
Fiscal Year
2002
Total Cost
$408,750
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ray, John P; Marshall, Heather D; Laidlaw, Brian J et al. (2014) Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40:367-77
Weinstein, Jason S; Bertino, Sarah A; Hernandez, Sairy G et al. (2014) B cells in T follicular helper cell development and function: separable roles in delivery of ICOS ligand and antigen. J Immunol 192:3166-79
Look, Michael; Saltzman, W Mark; Craft, Joe et al. (2014) The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus. Biomaterials 35:1089-95
Kumamoto, Yosuke; Linehan, Melissa; Weinstein, Jason S et al. (2013) CD301b? dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39:733-43
Look, Michael; Stern, Eric; Wang, Qin A et al. (2013) Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice. J Clin Invest 123:1741-9
Craft, Joseph E (2012) Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol 8:337-47
Choi, Jinyoung; Kim, Sang Taek; Craft, Joe (2012) The pathogenesis of systemic lupus erythematosus-an update. Curr Opin Immunol 24:651-7
Jog, Neelakshi R; Frisoni, Lorenza; Shi, Qin et al. (2012) Caspase-activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens. Arthritis Rheum 64:1247-56
Weinstein, Jason S; Hernandez, Sairy G; Craft, Joe (2012) T cells that promote B-Cell maturation in systemic autoimmunity. Immunol Rev 247:160-71
Rankin, Andrew L; Guay, Heath; Herber, Deborah et al. (2012) IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice. J Immunol 188:1656-67

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