T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus.
(NZB x NZW) F1 (BWF1) mice develop spontaneous T cell autoimmunity to VH region determinants of syngeneic anti-DNA before the onset of clinical disease. In this study, we characterized the immunogenicity, MHC binding, and lymphokine secretion patterns induced by T cell determinants from the VH region of one such anti-DNA mAb (A6.1) and examined their role in the regulation of autoimmunity. Determinants were identified by proliferation of syngeneic splenic T cells from young, unprimed BWF1 mice in response to overlapping 12-mer peptides representing the entire VH region sequence. Immunization of young BWF1 mice with any of three determinants (A6H 34-45 [p34], A6H 58-69 [p58], and A6H 84-95 [p84]) elicited proliferative responses upon in vitro recall. Upon immunization with the whole A6.1 molecule, however, proliferative responses could be recalled only to the p58 peptide, defining this as immunodominant. The other two peptides (p34 and p84) elicited minimal or no proliferation and could be termed cryptic. Proliferative responses elicited by the cryptic determinants were restricted by a single class II (I-Ed for p34 and I-Au for p84), whereas the immunodominant p58 determinant was restricted by both I-Ed and I-Eu. The cryptic p34 and p84 bound strongly to I-Ed and I-Au, respectively, whereas the immunodominant p58 peptide bound poorly to I-Ed. A6H p84 elicited T cells that secreted lymphokines in a pattern consistent with a Th1-like phenotype, whereas p58 induced a Th2-like cytokine pattern. Immunization with p34 or p84, or adoptive transfer of a p84-reactive T cell line to young BWF1 mice significantly increased IgG anti-DNA levels, accelerated nephritis, and decreased survival. In conclusion, in BWF1 mice, autoreactive T cells recognizing both cryptic and dominant self-determinants on anti-DNA autoantibodies escape deletion or anergy induction. Furthermore, since these cells are spontaneously activated before the onset of clinical disease, they may be involved in the development of the autoimmune process.
Singh
R R
RR
Department of Medicine/Rheumatology, University of California, Los Angeles 90024, USA.
Kumar
V
V
Ebling
F M
FM
Southwood
S
S
Sette
A
A
Sercarz
E E
EE
Hahn
B H
BH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology*; D000939:Epitopes / Q000276:immunology / Q000494:pharmacology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007376:Interleukin-2; D007371:Interferon-gamma; D004247:DNA