Retargeting T cell-mediated inflammation: a new perspective on autoantibody action.
To understand the pathogenesis of organ-specific autoimmune disease requires an appreciation of how the T cell-mediated inflammation is targeted, and how the organ function is compromised. In this study, autoantibody was documented to influence both of these parameters by modulating the distribution of T cell-mediated inflammation. The murine autoimmune ovarian disease is induced by immunization with the ZP3330-342 peptide of the ovarian zona pellucida 3 glycoprotein, ZP3. Passively transferred or actively induced Ab to ZP3335-342 bound to the zona pellucida in the functional and degenerative ovarian follicles, and the ovaries remained histologically normal. Transfer of ZP3330-342 peptide-specific T cells targeted the degenerative follicles and spared the functional follicles, and the resultant interstitial oophoritis was associated with unimpaired ovarian function. Unexpectedly, the coexistence of ZP3330-342 peptide-specific T cells and zona-bound autoantibody led to a dramatic translocation of the ovarian inflammation to the growing and mature ovarian follicles, with destruction of the ovarian functional unit. Ab retargeted both Th1-induced mononuclear inflammation and Th2-induced eosinophilic inflammation, and retargeting was induced by murine and rat polyclonal Abs to multiple distinct native B cell determinants of the zona pellucida. Therefore, by reacting with the native determinants in tissue Ag, Ab alters the distribution of T cell-mediated inflammation, and results in destruction of the functional units of the target organ. We propose that this is a clinically important and previously unappreciated element of Ab action in autoimmune disease.
Lou
Y H
YH
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. ylou@mail.db.uth.tmc.edu
Park
K K
KK
Agersborg
S
S
Alard
P
P
Tung
K S
KS
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001284:Atrophy; D001323:Autoantibodies / Q000008:administration & dosage / Q000502:physiology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000502:physiology; D004527:Egg Proteins / Q000008:administration & dosage / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009869:Oophoritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D009928:Organ Specificity / Q000276:immunology; D006080:Ovarian Follicle / Q000276:immunology / Q000473:pathology; D011956:Receptors, Cell Surface; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D015044:Zona Pellucida / Q000276:immunology / Q000473:pathology; D000072216:Zona Pellucida Glycoproteins
D001323:Autoantibodies; D016207:Cytokines; D004527:Egg Proteins; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C000606517:ZP3 protein, human; D000072216:Zona Pellucida Glycoproteins; C000606521:Zp3 protein, mouse