Small molecule inhibition of Rab7 impairs B cell class switching and plasma cell survival to dampen the autoantibody response in murine lupus

Tonika Lam, Dennis V. Kulp, Rui Wang, Zheng Lou, Julia Taylor, Carlos E. Rivera, Hui Yan, Qi Zhang, Zhonghua Wang, Hong Zan, Dmitri N. Ivanov, Guangming Zhong, Paolo Casali, Zhenming Xu

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3792-3805
Number of pages14
JournalJournal of Immunology
Volume197
Issue number10
DOIs
StatePublished - Nov 15 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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