A central role for alpha beta T cells in the pathogenesis of murine lupus.
We have previously shown that female transgenic mice expressing IFN-gamma in the epidermis, under the control of the involucrin promoter, develop inflammatory skin disease and a form of murine lupus. To investigate the pathogenesis of this syndrome, we generated female IFN-gamma transgenic mice congenitally deficient in either alpha beta or gamma delta T cells. TCR delta-/- transgenics continued to produce antinuclear autoantibodies and to develop severe kidney lesions. In contrast, TCR beta-/- IFN-gamma transgenic mice failed to produce antinucleosome, anti-dsDNA, or antihistone autoantibodies, and kidney disease was abolished. Both alpha beta- and gamma delta-deficient transgenics continued to develop IFN-gamma-associated skin disease, lymphadenopathy, and splenomegaly. The data show that the autoantibody-mediated pathology of murine lupus in IFN-gamma transgenic mice is completely alpha beta T cell dependent and that gamma delta T cells cannot drive autoantibody production. These results imply that production of antinuclear autoantibodies in IFN-gamma transgenic animals is Ag driven, and we identified clusters of apoptotic cells in the epidermis of the mice as a possible source of self Ags. Our findings emphasize the relevance of this murine lupus model to the human disease.
Seery
J P
JP
Keratinocyte Laboratory, Lymphocyte Molecular Biology Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
Wang
E C
EC
Cattell
V
V
Carroll
J M
JM
Owen
M J
MJ
Watt
F M
FM
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D004247:DNA / Q000276:immunology; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D006657:Histones / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000235:genetics; D008181:Lupus Nephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000502:physiology; D012867:Skin / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D006657:Histones; D007074:Immunoglobulin G; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma; D004247:DNA