Enforced Bcl-2 expression in B lymphocytes induces rheumatoid factor and anti-DNA production, but the Yaa mutation promotes only anti-DNA production.
The presence of rheumatoid factors (RF) is a characteristic feature of patients with rheumatoid arthritis, but not systemic lupus erythematosus. In this study, we have explored the role of the anti-apoptotic Bcl-2 protein and the Y-linked autoimmune acceleration (Yaa) mutation in the production of IgG RF in comparison with IgG anti-DNA autoimmune responses. Analysis in C57BL/6 mice, in their F1 hybrids with lupus-prone NZW mice, and in bone marrow chimeras containing mixtures of C57BL/6 bcl-2-transgenic and BXSB non-transgenic cells demonstrated that an enforced Bcl-2 expression in B cells promoted the induction of IgG anti-DNA production in these mice, while significant IgG RF responses were observed only in mice developing high levels of gp70-anti-gp70 immune complexes and lethal glomerulonephritis. Moreover, in contrast to a synergistic interaction between the Yaa mutation and Bcl-2 overexpression on IgG anti-DNA production, the Yaa mutation failed to enhance the production of IgG RF induced in bcl-2-transgenic mice. Our results reveal that defects in the regulation of B cell apoptosis play a critical role in the production of IgG RF, and that the Yaa mutation differentially modulates RF and anti-DNA autoimmune responses, likely related to the nature of autoantigens involved in each autoimmune response.
Kuroki
Aki
A
Department of Pathology, CMU, Geneva, Switzerland.
Moll
Thomas
T
López-Hoyos
Marcos
M
Fossati-Jimack
Liliane
L
Ibnou-Zekri
Nabila
N
Kikuchi
Shuichi
S
Merino
Jesús
J
Merino
Ramón
R
Izui
Shozo
S
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000097:blood; D017209:Apoptosis / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002678:Chimera; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012217:Rheumatoid Factor / Q000276:immunology*
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D019253:Proto-Oncogene Proteins c-bcl-2; D012217:Rheumatoid Factor