Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases,such as systemic lupus erythematosus(SLE).Currently,both the phenotypic features and functional regulation of ...Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases,such as systemic lupus erythematosus(SLE).Currently,both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear.In this study,we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A(IL-17)stimulation in SLE patients and lupus mice.Using a humanized lupus mouse model,we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs.Moreover,long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+subsets among IL-17 receptor-expressing plasma cells.Lupus mice deficient in IL-17 or IL-17 receptor C(IL-17RC)exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage,while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice.In reconstituted chimeric mice,IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells.Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization.Together,our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis,which may provide new therapeutic strategies for the treatment of SLE.展开更多
Dear Editor,Primary Sjogren's syndrome(pSS)is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands(SG)and lacrimal glands.Currently,pSS patients are suf...Dear Editor,Primary Sjogren's syndrome(pSS)is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands(SG)and lacrimal glands.Currently,pSS patients are suffering from a lack of effective therapies.Many studies have revealed dysregulated immune responses during pSS development,in which Th17 cells are considered as the key driver in disease initiation and perpetuation.展开更多
基金funded by grants from the National Natural Science Foundation of China(Nos.81771761,91842304,and 81901635)Chongqing International Institute for Immunology(2020YJC10)Sanming Project of Medicine in Shenzhen(SZSM201512019)。
文摘Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases,such as systemic lupus erythematosus(SLE).Currently,both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear.In this study,we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A(IL-17)stimulation in SLE patients and lupus mice.Using a humanized lupus mouse model,we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs.Moreover,long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+subsets among IL-17 receptor-expressing plasma cells.Lupus mice deficient in IL-17 or IL-17 receptor C(IL-17RC)exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage,while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice.In reconstituted chimeric mice,IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells.Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization.Together,our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis,which may provide new therapeutic strategies for the treatment of SLE.
基金This work was supported by Chongqing International Institute for Immunology(2020YJC10)National Natural Science Foundation of China(82071817,82171771,82004171,81971542)+4 种基金Shenzhen Science and Technology Program(YCYJ20210324114602008)Young Elite Scientist Sponsorship Program by CACM(CACM-2020-QNRC2-05)Hong Kong Research Grants Council(17113319,17103821)RGC Theme-based Research Scheme(TRS)(T12-703/19-R)the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission,The Government of Hong Kong SAR,China.
文摘Dear Editor,Primary Sjogren's syndrome(pSS)is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands(SG)and lacrimal glands.Currently,pSS patients are suffering from a lack of effective therapies.Many studies have revealed dysregulated immune responses during pSS development,in which Th17 cells are considered as the key driver in disease initiation and perpetuation.