Unexpected development of autoimmunity in BAFF-R-mutant MRL-lpr mice.
BAFF-R is the predominant receptor that mediates B-cell activating factor (BAFF)-dependent B-cell signalling and plays a critical role in late-stage B-cell maturation and survival. BAFF has been implicated in the development of autoimmunity and systemic lupus erythematosus (SLE). To define the role of BAFF-R in autoimmunity and SLE, we crossed A/WySnJ mice with MRL-lpr mice and generated BAFF-R-mutant MRL-lpr mice. The BAFF-R mutation markedly impaired the development of immature, mature and marginal zone B cells in the spleens of MRL-lpr mice. Unexpectedly, the BAFF-R mutation in MRL-lpr mice did not result in decreased autoantibody production, hypergammaglobulinaemia or immune complex-mediated glomerulonephritis. Rather, the ability of BAFF-R-mutant lpr splenic B cells to produce immunoglobulins in vitro was not decreased, although germinal centre formation, antibody response and B-cell proliferation were impaired. Further studies found increased numbers of B cells in the bone marrow of BAFF-R-mutant MRL-lpr mice compared to the BAFF-R-intact lupus mice. ELISPOT analysis revealed that BAFF-R-mutant MRL-lpr mice had more antibody-secreting cells in their bone marrow than the control mice. Thus, these findings could explain the development of autoimmunity and hypergammaglobulinaemia observed in BAFF-R-mutant MRL-lpr mice.
Ju
Zhong L
ZL
Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China. zlju@sibs.ac.cn
Shi
Gui Y
GY
Zuo
Jin X
JX
Zhang
Jing W
JW
D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000276:immunology; D007105:Immune Complex Diseases / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009154:Mutation; D013154:Spleen / Q000276:immunology
D001323:Autoantibodies; D053265:B-Cell Activation Factor Receptor; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C486662:Tnfrsf13c protein, mouse