In organ specific autoimmune diseases, the T cell mechanism is pivotal, but the role of antibody is unclear. Also unclear is how pathogenic CD4+ T cells home to and target native autoantigens to initiate pathogenesis, since T cells only recognized antigenic peptide-MHC class II complexes on the antigen presenting cells (APC). In a murine model for human ovarian autoimmune disease (oophoritis), CD4+ T cells, specific to an ovarian protein ZP3, are sufficient to induce ovarian pathology, but antibody to ZP3 does not induce any ovarian pathology. T cells alone, however, targets only degraded ZP3 in degenerated follicles with MHC lass II/+ macrophage infiltration; normal follicles with native ZP3 are spared. We recently discovered antibody induced T cell retargeting, in which binding of IgG autoantibody to native ZP3 completely alters the location of T cell mediated inflammation from degenerated follicles to normal follicles, leading to destruction of the functional part of the ovary. This phenomenon is not only clinically relevant, but also may serve as a model to study how T cells target native antigen, and how antibody functions in the process. Based on recent progress, we hypothesize a two-phase mechanism. In Phase I, the combined effect of native ZP3-bound antibody with T cells probably cytokine(s), induces a mild antibody mediated inflammation, which results in a pro-inflammatory response in the follicles. In Phase II, the pro-inflammatory changes in turn attract T cells (maybe non-specific) and monocyte to the follicles; a T cell mediated inflammation rapidly replaces antibody-mediated inflammation. Thus, antibody brings about a full T cell mediated tissue injury in the location of native antigen.
In Specific Aim 1, cellular and molecular cascades will be investigated in detail, and inflammatory molecules possibly involved in Phase I and II will be identified;
in Specific Aim 2, we will study which cytokines or antibody isotypes are able to induce inflammation in Phase I;
in Specific Aim 3, we will investigate what pro- inflammatory changes occur in the follicles to attract T cells and monocytes, and what type of T cells are involved in targeting follicles.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD035993-01A1
Application #
2750214
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Taymans, Susan
Project Start
1999-02-01
Project End
2000-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Carlock, Colin I; Wu, Jean; Zhou, Cindy et al. (2014) Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis. J Immunol 193:161-9
Zhou, Cindy; Wu, Jean; Borillo, Jason et al. (2009) Potential roles of a special CD8 alpha alpha+ cell population and CC chemokine thymus-expressed chemokine in ovulation related inflammation. J Immunol 182:596-603
Robertson, Julie; Wu, Jean; Arends, Jon et al. (2005) Characterization of the T-cell epitope that causes anti-GBM glomerulonephritis. Kidney Int 68:1061-70
Lou, Ya-Huan (2004) Anti-GBM glomerulonephritis: a T cell-mediated autoimmune disease? Arch Immunol Ther Exp (Warsz) 52:96-103
Zhou, Cindy; Borillo, Jason; Wu, Jean et al. (2004) Ovarian expression of chemokines and their receptors. J Reprod Immunol 63:1-9
Wu, Jean; Arends, Jon; Borillo, Jason et al. (2004) A self T cell epitope induces autoantibody response: mechanism for production of antibodies to diverse glomerular basement membrane antigens. J Immunol 172:4567-74
Wu, Jean; Borillo, Jason; Glass, William F et al. (2003) T-cell epitope of alpha3 chain of type IV collagen induces severe glomerulonephritis. Kidney Int 64:1292-301
Lou, Ya-Huan; Borillo, Jason (2003) Migration of T cells from nearby inflammatory foci into antibody bound tissue: a relay of T cell and antibody actions in targeting native autoantigen. J Autoimmun 21:27-35
Wu, Jean; Hicks, John; Borillo, Jason et al. (2002) CD4(+) T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis. J Clin Invest 109:517-24
Wu, J; Hicks, J; Ou , C et al. (2001) Glomerulonephritis induced by recombinant collagen IV alpha 3 chain noncollagen domain 1 is not associated with glomerular basement membrane antibody: a potential T cell-mediated mechanism. J Immunol 167:2388-95

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