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Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus This information is current as of September 26, 2021. 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 and Zhenming Xu J Immunol 2016; 197:3792-3805; Prepublished online 14 Downloaded from October 2016; doi: 10.4049/jimmunol.1601427 http://www.jimmunol.org/content/197/10/3792 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/10/13/jimmunol.160142 Material 7.DCSupplemental References This article cites 70 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/197/10/3792.full#ref-list-1 by guest on September 26, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus Tonika Lam,*,1 Dennis V. Kulp,*,1 Rui Wang,*,1,2 Zheng Lou,* Julia Taylor,* Carlos E. Rivera,* Hui Yan,* Qi Zhang,* Zhonghua Wang,† Hong Zan,* Dmitri N. Ivanov,† Guangming Zhong,* Paolo Casali,*,3 and Zhenming Xu*,3 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/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 Downloaded from 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-kB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-kB activation, indicated that Rab7 mediates these http://www.jimmunol.org/ processes by promoting NF-kB 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. The Journal of Immunology, 2016, 197: 3792–3805. lass switch DNA recombination (CSR) in the IgH locus underlying B cell class switching and plasma cell generation/ substitutes the IgH constant (CH) region, such as Cm of maintenance targets of new lupus therapeutics. C IgM expressed in naive B cells, with Cg,Ca,orCε, thereby Similar to SHM, CSR requires activation-induced cytidine de- giving rise to IgG, IgA, or IgE Abs. Together with somatic hyper- aminase (AID, encoded by AICDA in humans and Aicda in mice). by guest on September 26, 2021 mutation (SHM), CSR is central to the maturation of the Ab response AID expression is mainly restricted in peripheral B cells activated to pathogens, as class-switched Abs display wide tissue distributions by CD154 engagement of CD40 on the B cell surface or by com- and possess diverse biological effector functions (1). These traits also plex Ags that engage both a TLR and the BCR (7). AID is elevated make IgG and IgA autoantibodies highly pathogenic and capable of in B cells of lupus patients and lupus mice, consistent with the mediating multiple organ damage in systemic lupus erythematosus heightened CSR/SHM in these B cells (8), and AID deficiency (SLE) (2, 3). Unswitched IgM autoantibodies are mostly nonpatho- abrogates IgG autoantibodies in lupus-prone MRL/Faslpr/lpr mice genic and, rather, may mediate frontline immune protection as natural (8, 9). Inhibitors of AID deaminase activity are yet to be developed, polyreactive Abs (4). Class-switched B cells further differentiate into thereby emphasizing the need for molecules that target the mech- memory B cells or plasma cells, which secrete Abs at a high rate. A anisms underlying AID induction to dampen the class-switched hallmark of active lupus is the high number of IgG+ Ab-secreting cells pathogenic autoantibody response. (ASCs) that produce autoantibodies. These are diverse but generally Ras-related in brain 7 (Rab7; encoded by RAB7A in humans and target nuclear Ags, such as DNA (5, 6), making the mechanisms Rab7 in mice) is a small GTPase that, when bound to its GTP *Department of Microbiology, Immunology and Molecular Genetics, University of Identification in Lupus Grant ALR 295955 and the Zachry Foundation Distinguished Texas School of Medicine, University of Texas Health Science Center at San Anto- Chair, D.N.I. by a Voelcker Fund Young Investigator Award, H.Z. by an Arthritis nio, San Antonio, TX 78229; and †Department of Biochemistry, University of Texas National Research Foundation research grant, and R.W. by the Xiangya School of School of Medicine, University of Texas Health Science Center at San Antonio, San Medicine, Central South University of China. Antonio, TX 78229 Address correspondence and reprint requests to Dr. Paolo Casali and Dr. Zhenming 1T.L., D.V.K., and R.W. contributed equally to this work. Xu, Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San 2Current address: Xiangya School of Medicine, Central South University of China, Antonio, 7703 Floyd Curl Drive, Mail Code 7758, San Antonio, TX 78229. E-mail Changsha, Hunan, China. addresses: [email protected] (P.C.) and [email protected] (Z.X.) 3P.C. and Z.X. jointly directed the study. The online version of this article contains supplemental material. ORCIDs: 0000-0002-6270-7234 (T.L.); 0000-0002-9048-7048 (D.V.K.); 0000-0002- Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; AID, activation- 7549-0812 (J.T.); 0000-0001-6906-107X (Z.W.); 0000-0001-7053-5009 (G.Z.); induced cytidine deaminase; ANA, anti-nuclear Ab; ASC, Ab-secreting cell; C57, 0000-0002-8982-5177 (P.C.). C57BL/6; CGG, chicken g-globulin; CSR, class switch DNA recombination; DC, Received for publication August 16, 2016. Accepted for publication September 9, dendritic cell; NMR, nuclear magnetic resonance; NP, (4-hydroxy-3-nitrophenyl)acetyl; 2016. PAS, periodic acid–Schiff; PNA, peanut agglutinin; qRT-PCR, quantitative RT-PCR; RA, retinoic acid; Rab7, Ras-related in brain 7; SLE, systemic lupus erythematosus. This work was supported by National Institutes of Health Grants AI 079705 and AI 105813 (to P.C.), AI 124172 (to Z.X.), AI 104476 (to D.N.I.), and AI 047997 (to Ó G.Z.). P.C. was also partially supported by Alliance for Lupus Research Target Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601427 The Journal of Immunology 3793 substrate, promotes endosome maturation and autophagy. As we 1067700 for 10 wk and maintained until moribund (e.g., showing signs of have shown (10), Rab7 is induced in activated B cells in vivo (i.e., in severe loss of mobility, hunched back, piloerection, ruffled fur, dyspnea, peanut agglutinin [PNA]hi germinal center B cells) and in vitro, for gasping, and weight loss), at which point they were euthanized. For other clinical, serological, cellular, and molecular analyses (see below), mice example, by CD154 and TLR ligands, the same stimuli that induce were treated for 7 wk in a double-blind manner, as their identities were AID expression and CSR. It plays a B cell–intrinsic role in Ab re- made unknown to investigators who performed these assays. sponses, as mice that conditionally knockout Rab7 in activated For immunization, C57 mice were treated with nil or CID 1067700 7 d B cells cannot mount mature Ab responses to T cell–dependent or – before i.p. injection with 100 mg of (4-hydroxy-3-nitrophenyl)acetyl (NP)– chicken g-globulin (CGG) (in average 16 molecules of NP conjugated to 1 independent Ags (10). Rab7 promotes CSR (to IgG, IgE, and IgA) molecule of CGG; Biosearch Technologies) in 100 ml of aluminum hydroxide and does so by mediating AID induction, as enforced expression of (Imject Alum; Pierce) or 25 mg of NP-LPS (0.2 NP molecule conjugated to 1 AID rescues CSR in Rab7 knockout B cells. Furthermore, Rab7 plays LPS molecule; Biosearch Technologies) in 100 ml of PBS. Mice were treated an important role in CD40- or TLR-triggered activation of NF-kB, with nil or CID 1067700 once every 3 d until being sacrificed.
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