Role of endogenous 4-1BB in the development of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against nuclear antigens including nucleosomes and DNA. To determine the role of T-cell costimulatory molecule 4-1BB in the regulation of SLE, MRL-Fas(lpr) (lpr) mice deficient in 4-1BB (lpr/4-1BB(-/-)) were generated and their disease phenotype was compared to that of control lpr mice. The main finding of this study is that the lpr/4-1BB(-/-) mice had more pronounced skin lesions which appeared earlier, increased lymphadenopathy, increased renal damage, and higher mortality than 4-1BB-intact control lpr mice. The increased severity of lesions in lpr/4-1BB(-/-) mice was closely associated with increases in CD4(+) T, CD3(+) B220(+) double-negative T cells, serum immunoglobulin, anti-dsDNA autoantibodies, and tissue immunoglobulin deposits. These data suggest that the 4-1BB-4-1BB ligand signalling pathway plays an important role in SLE and that deletion of 4-1BB confers susceptibility to lpr mice, leading to accelerated induction of disease and early mortality.
Vinay
Dass S
DS
LSU Eye Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA, USA.
Choi
Jae H
JH
Kim
Jung D
JD
Choi
Beom K
BK
Kwon
Byoung S
BS
D000208:Acute Disease; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology; D008206:Lymphatic Diseases / Q000276:immunology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D012871:Skin Diseases / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology; D013163:Splenomegaly / Q000276:immunology; D016019:Survival Analysis; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000276:immunology*
D001323:Autoantibodies; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9