Autoantibody responses and pathology regulated by B7-1 and B7-2 costimulation in MRL/lpr lupus.
The activation of T lymphocytes requires both Ag-mediated signaling through the TCR as well as costimulatory signals transmitted through B7-1 and/or B7-2 with CD28. The interference of B7-mediated costimulatory signals has been proposed as one immunotherapeutic intervention for the prevention autoimmune disease. This study has examined autoantibody responses and autoimmune pathology in a murine model of human systemic lupus erythematosus (SLE), the MRL-lpr/lpr mouse, genetically deficient in B7-1 or B7-2, or in mice treated with B7-1/B7-2 blocking Abs. In contrast to other studies of murine models of SLE, MRL-lpr/lpr mice treated with B7 blocking Abs exhibit strong anti-small nuclear ribonucleoprotein (snRNP) and anti-DNA autoantibody responses with some changes in isotype switching as compared with untreated animals. All MRL-lpr/lpr mice deficient in B7-1 or B7-2 produce anti-snRNP and anti-DNA titers with isotypes virtually identical with wild-type animals. However, the absence of B7-2 costimulation did interfere with the spontaneous activation and the accumulation of memory CD4+ or CD8+ T lymphocytes characteristic of wild-type MRL-lpr/lpr mice. IgG and C3 complement deposition was less pronounced in the kidneys of B7-2 deficient MRL-lpr/lpr mice, reflecting their lessor degree of glomerulonephritis. By comparison, B7-1-deficient MRL-lpr/lpr mice had more severe IgG and C3 deposits in glomeruli.
Liang
B
B
Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06510, USA.
Kashgarian
M J
MJ
Sharpe
A H
AH
Mamula
M J
MJ
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis*; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D015415:Biomarkers; D003176:Complement C3 / Q000378:metabolism; D004247:DNA / Q000276:immunology; D007074:Immunoglobulin G / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr / Q000276:immunology; D018345:Mice, Knockout; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D001323:Autoantibodies; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015415:Biomarkers; C497965:Cd86 protein, mouse; D003176:Complement C3; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D017411:Ribonucleoproteins, Small Nuclear; D004247:DNA