Mechanisms controlling ABC differentiation and function in SLE

SLE 中 ABC 分化和功能的控制机制

基本信息

  • 批准号:
    10364120
  • 负责人:
  • 金额:
    $ 56.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Abnormalities in B cell subsets play a key role in SLE, a disease that, in addition to AutoAb production and multi-organ involvement, often includes upregulation of interferon stimulated genes (ISGs). One of the hallmarks of SLE is that it preferentially affects women. Both sex hormones and the X chromosome (where TLR7 is located) have been implicated in the heightened susceptibility of women to SLE and to other autoimmune disorders. Understanding the molecular mechanisms that underlie the sex-bias that accompanies SLE pathogenesis will thus provide critical information into the development of autoimmunity and help uncover novel therapeutic targets. While expansion of germinal center (GC) B cells and plasmablasts/plasma cells (PB/PC) has long been associated with SLE, recent studies have implicated a novel B cell subset, termed Age/Autoimmune-associated B cells (ABCs), in lupus pathogenesis. In addition to classical B cell markers, ABCs also express CD11c and the transcription factor T-bet. Formation of ABCs is promoted by a combination of signals that includes TLR7 or TLR9 engagement and cytokines like IFN-g and IL-21. Aberrant accumulation of ABCs is observed both in murine lupus and in SLE patients where they are major producers of autoAbs and correlate with disease activity and clinical manifestations. Our lab has had a long-standing interest in dissecting the regulation and function of IRF family members, which have emerged as key controllers of B cell responses. While identifying IRF-interacting proteins, we isolated a protein termed Def6. Def6 and its only other homologue, SWAP-70, play an important immunoregulatory role in humans and mice. Def6 is a genetic risk factor for human SLE and biallelic mutations in Def6 result in early-onset systemic autoimmunity. Furthermore, in C57BL/6 mice, the concomitant lack of Def6 and SWAP-70 (Double-knockout mice=DKOs) leads to the spontaneous development of SLE, which, similarly to humans, preferentially affects female mice. Lupus development in DKO mice is accompanied by a marked accumulation of ABCs, which is controlled by IRF5. We have recently found that, as compared to ABCs from DKO males, ABCs from DKO females expand to a greater extent, express an ISG signature, and readily produce autoAbs upon TLR7 stimulation. Furthermore, in comparison with DKO males, DKO females accumulate greater numbers of GC B cells and PB/PCs that contain CD11c+ subsets. Dysregulating TLR7 expression in DKO males results in a marked expansion of ABCs and other B cell effector lineages including CD11c-expressing B cell subsets and promotes autoAb production and disease development in DKO males. Taken together these data suggest that sexual dimorphism underlies several aspects of ABC biology in autoimmune settings. In this proposal we will investigate the hypothesis that sex- specific mechanisms control the function and differentiation of ABCs as well as characterize the developmental relationships between ABCs and other effector B cell lineages.
摘要

项目成果

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ALESSANDRA B PERNIS其他文献

ALESSANDRA B PERNIS的其他文献

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{{ truncateString('ALESSANDRA B PERNIS', 18)}}的其他基金

Mechanisms controlling ABC differentiation and function in SLE
SLE 中 ABC 分化和功能的控制机制
  • 批准号:
    10620619
  • 财政年份:
    2022
  • 资助金额:
    $ 56.96万
  • 项目类别:
FASEB SRC on Autoimmunity
关于自身免疫的 FASEB SRC
  • 批准号:
    9752917
  • 财政年份:
    2019
  • 资助金额:
    $ 56.96万
  • 项目类别:
HSS Research Institute Rheumatology Training
HSS 研究所风湿病学培训
  • 批准号:
    10615785
  • 财政年份:
    2017
  • 资助金额:
    $ 56.96万
  • 项目类别:
HSS Research Institute Rheumatology Training
HSS 研究所风湿病学培训
  • 批准号:
    10409983
  • 财政年份:
    2017
  • 资助金额:
    $ 56.96万
  • 项目类别:
Hospital for Special Surgery Research Institute Rheumatology Training
特殊外科研究所风湿科培训医院
  • 批准号:
    9921297
  • 财政年份:
    2017
  • 资助金额:
    $ 56.96万
  • 项目类别:
Regulatory Mechanisms Controlling TFH Responses in Lupus
控制狼疮 TFH 反应的调节机制
  • 批准号:
    9271861
  • 财政年份:
    2016
  • 资助金额:
    $ 56.96万
  • 项目类别:
Novel signaling pathways in lupus pathogenesis
狼疮发病机制中的新信号通路
  • 批准号:
    9190358
  • 财政年份:
    2015
  • 资助金额:
    $ 56.96万
  • 项目类别:
Novel signaling pathways in lupus pathogenesis
狼疮发病机制中的新信号通路
  • 批准号:
    9035362
  • 财政年份:
    2015
  • 资助金额:
    $ 56.96万
  • 项目类别:
Rho GTPase-mediated pathways in autoimmune arthritis
Rho GTPase 介导的自身免疫性关节炎通路
  • 批准号:
    8230157
  • 财政年份:
    2011
  • 资助金额:
    $ 56.96万
  • 项目类别:
Rho GTPase-mediated pathways in autoimmune arthritis
Rho GTPase 介导的自身免疫性关节炎通路
  • 批准号:
    8770006
  • 财政年份:
    2011
  • 资助金额:
    $ 56.96万
  • 项目类别:

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