TY - JOUR
T1 - Small molecule inhibition of Rab7 impairs B cell class switching and plasma cell survival to dampen the autoantibody response in murine lupus
AU - Lam, Tonika
AU - Kulp, Dennis V.
AU - Wang, Rui
AU - Lou, Zheng
AU - Taylor, Julia
AU - Rivera, Carlos E.
AU - Yan, Hui
AU - Zhang, Qi
AU - Wang, Zhonghua
AU - Zan, Hong
AU - Ivanov, Dmitri N.
AU - Zhong, Guangming
AU - Casali, Paolo
AU - Xu, Zhenming
N1 - Publisher Copyright:
© Copyright 2016 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the classswitched IgG autoantibody response in MRL/Faslpr/lpr and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell-dependent and T cell-independent Ab responses, but it did not affect T cell-mediated clearance of Chlamydia infection, consistent with a B cell-specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class switching and survival, respectively, whereas proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-κB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-κB activation, indicated that Rab7 mediates these processes by promoting NF-κB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus.
AB - IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the classswitched IgG autoantibody response in MRL/Faslpr/lpr and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell-dependent and T cell-independent Ab responses, but it did not affect T cell-mediated clearance of Chlamydia infection, consistent with a B cell-specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class switching and survival, respectively, whereas proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-κB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-κB activation, indicated that Rab7 mediates these processes by promoting NF-κB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus.
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U2 - 10.4049/jimmunol.1601427
DO - 10.4049/jimmunol.1601427
M3 - Article
C2 - 27742832
AN - SCOPUS:84994474380
SN - 0022-1767
VL - 197
SP - 3792
EP - 3805
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -