Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome.
CD40L and B lymphocyte-activating factor (BAFF), members of the TNF superfamily, play critical roles in B cell survival and activation, and in the regulation of humoral immunity. We previously reported that the adaptor molecule Act1 functions as a negative regulator of CD40- and BAFF-mediated B cell survival. Here we demonstrated that mice deficient in Act1 developed systemic autoimmune disease with histological and serological features of human Sjögren's syndrome (SS), in association with systemic lupus erythematosus-like nephritis. Analyses of Act1(-/-)CD40(-/-) and Act1(-/-)BAFF(-/-) double-deficient mice revealed that Act1 regulates different stages of the disease development through its impact on both CD40- and BAFF-mediated pathways. We found that Act1 modulates the survival of autoreactive B cells mainly through its negative regulatory role in BAFF-mediated cell survival, while the effect of Act1 on autoantibody production is likely through modulation of CD40-mediated T cell-dependent antibody response. The impact of Act1 on both BAFF and CD40 pathways establishes Act1-deficient mice as a unique model to study distinct steps of autoimmunity and regulation of self tolerance.
Qian
Youcun
Y
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Giltiay
Natalia
N
Xiao
Jianhua
J
Wang
Yue
Y
Tian
Jun
J
Han
Shuhua
S
Scott
Martin
M
Carter
Robert
R
Jorgensen
Trine N
TN
Li
Xiaoxia
X
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology; D053264:B-Cell Activating Factor / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology; D005921:Glomerulonephritis / Q000209:etiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012261:Ribonucleoproteins / Q000276:immunology; D012859:Sjogren's Syndrome / Q000209:etiology*; D013363:Submandibular Gland / Q000473:pathology; D000097585:SS-B Antigen
D048868:Adaptor Proteins, Signal Transducing; D000974:Antibodies, Antinuclear; D001324:Autoantigens; D053264:B-Cell Activating Factor; D019013:CD40 Antigens; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C035356:SS-A antibodies; C505720:Tnfsf13b protein, mouse; C515963:Traf3ip2 protein, mouse