Publication Date:
2016-11-05
Description:
IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the class-switched IgG autoantibody response in MRL/ Fas lpr/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-B activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-B activation, indicated that Rab7 mediates these processes by promoting NF-B 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.
Print ISSN:
0022-1767
Electronic ISSN:
1550-6606
Topics:
Medicine
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