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Pathways of Antigen-Driven Differentiation B Cell Tolerance B Cell Tolerance Checkpoints That Restrict Pathways of Antigen-Driven Differentiation Jacqueline William, Chad Euler, Nicole Primarolo and Mark J. Shlomchik This information is current as of September 23, 2021. J Immunol 2006; 176:2142-2151; ; doi: 10.4049/jimmunol.176.4.2142 http://www.jimmunol.org/content/176/4/2142 Downloaded from References This article cites 84 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/176/4/2142.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 by guest on September 23, 2021 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology B Cell Tolerance Checkpoints That Restrict Pathways of Antigen-Driven Differentiation1 Jacqueline William,* Chad Euler,† Nicole Primarolo,† and Mark J. Shlomchik2*,† Autoreactive B cells can be regulated by deletion, receptor editing, or anergy. Rheumatoid factor (RF)-expressing B lymphocytes in normal mice are not controlled by these mechanisms, but they do not secrete autoantibody and were presumed to ignore self-Ag. Surprisingly, we now find that these B cells are not quiescent, but instead are constitutively and specifically activated by self-Ag. In BALB/c mice, RF B cells form germinal centers (GCs) but few Ab-forming cells (AFCs). In contrast, autoimmune mice that express the autoantigen readily generate RF AFCs. Most interestingly, autoantigen-specific RF GCs in BALB/c mice appear defective. B cells in such GCs neither expand nor are selected as efficiently as equivalent cells in autoimmune mice. Thus, our data establish two novel checkpoints of autoreactive B cell regulation that are engaged only after initial autoreactive B cell activation: one that allows GCs but prevents AFC formation and one that impairs selection in the GC. Both of these checkpoints fail in Downloaded from autoimmunity. The Journal of Immunology, 2006, 176: 2142–2151. igh autoantibody titers are a hallmark of systemic auto- syndrome, mixed cryoglobulinemia, and SLE (2, 20, 21), and by immune diseases such as rheumatoid arthritis (RA)3 and Fas-deficient lpr mice (22). H systemic lupus erythematosus (SLE) (1, 2). This must To study RF B cells, we have used AM14 H chain Tg mice. represent a breakdown of tolerance mechanisms that normally reg- When this H chain is paired with a Tg-encoded or endogenous http://www.jimmunol.org/ ulate autoreactive B cells. Central tolerance prevents the develop- V␬8 L chain, the result is an Ab that binds the Fc portion of ment of high-affinity self-reactive B cells. Mechanisms of central IgG2aa, but not IgG2ab (23). The AM14 Tg mouse is an ideal tolerance, such as deletion, anergy, and receptor editing, were model because it combines specificity for a disease-related autoan- demonstrated using mice with Ig transgenes (Tg) specific for ar- tigen and the ability to study the regulation of the B cells in the tificial autoantigens, like hen egg lysozyme or MHC class I pro- presence or absence of autoantigen (in IgHa or IgHb congenic teins (3–6). There are also peripheral tolerance mechanisms for B mice). This Tg system uniquely allows for measurement and con- cells (7), but these are much less well defined. To initiate systemic trol of the presence or absence of a disease-related autoantigen. autoimmunity, either central tolerance mechanisms must be over- This ability is useful for distinguishing specific from nonspecific B come or mechanisms that regulate peripheral B cells must by guest on September 23, 2021 cell activation. We have found that B cells in autoantigen-positive break down. (IgHa) BALB/c mice Tg for both the AM14 H and L chains were Our laboratory and others have used Ig-Tg models to study how neither anergized nor deleted during development (23, 24). How- B cells specific for disease-related self-Ags are regulated (8–15). ever, in Fas-deficient H and HL Tg mice, RF B cells differentiated In SLE, only certain Ags efficiently elicit autoreactive B cells: into numerous Ab-forming cells (AFCs). The formation of AFCs chromatin, ribonucleoproteins, and IgG (2, 16). These autoanti- was autoantigen-driven, because IgHb congenic mice that lacked gens must have special properties that render them preferred tar- gets when immune regulation is abnormal. These properties, which the autoantigen failed to produce RF AFCs (25). We have recently include the ability to provide an endogenous ligand for certain further investigated the fates of RF B cells in autoimmune-prone Toll-like receptors (17, 18), are currently being elucidated. It is mice, revealing a dominant short-lived plasmablast response (26, thus important to study B cells specific for relevant autoantigens. 27). However, the differences between RF B cell fates as revealed We have focused on the regulation of rheumatoid factor (RF)- by our recent studies of MRL/lpr mice and our earlier work on expressing B cells that bind to the constant region of Ig (19). RFs BALB/c mice (23, 24) indicated the presence of additional mech- are prevalent in RA patients but are also produced by patients with anisms that regulate naive but fully developed RF B cells. These a number of other systemic autoimmune diseases such as Sjogren’s mechanisms are presumably intact in BALB/c mice but are breached in MRL/lpr mice. In this study, we have used the AM14 model to identify these *Section of Immunobiology and †Department of Laboratory Medicine, Yale Univer- sity School of Medicine, New Haven, CT 06520 mechanisms by comparing the regulation of RF B cells in MRL/lpr Received for publication July 7, 2005. Accepted for publication November 28, 2005. to the BALB/c and MRL ϩ/ϩ strains. We found that normal The costs of publication of this article were defrayed in part by the payment of page BALB/c mice do not have RF AFCs; at this level, the mice remain charges. This article must therefore be hereby marked advertisement in accordance apparently self-tolerant. However, we were surprised to find that with 18 U.S.C. Section 1734 solely to indicate this fact. despite the lack of RF AFCs, RF B cells are not quiescent in 1 This work was supported by National Institute of Health Grants P01 AI36529 and BALB/c mice. Rather, they actively participate in germinal centers R01 AR44077. 2 (GCs). Importantly, this activation of RF B cells is autoantigen- Address correspondence and reprint requests to Dr. Mark J. Shlomchik, Department b of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, Box specific, because it is absent in the autoantigen-negative IgH 208035, New Haven, CT 06520-8035. E-mail address: [email protected] strains. Furthermore, RF B cells undergo somatic hypermutation in 3 Abbreviations used in this paper: RA, rheumatoid arthritis; SLE, systemic lupus GCs of BALB/c mice, which could potentially lead to the gener- erythematosus; Tg, transgene; RF, rheumatoid factor; AFC, Ab-forming cell; GC, germinal center; PNA, peanut agglutinin; TNP, trinitrophenol; KLH, keyhole limpet ation of high-affinity autoantibodies. Nonetheless, analysis of so- hemocyanin; MLN, mesenteric lymph node; IC, immune complex; LN, lymph node. matic hypermutation patterns of V regions from RF B cells in Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 2143 BALB/c mice compared with those from autoimmune mice re- mune-prone/Fas-deficient (MRL/lpr) mice, spleens and mesenteric vealed a failure to efficiently select and expand RF B cell clones. lymph nodes (MLNs) of IgHa and IgHb Tg mice of ages ranging Overall, our data show that Ag-specific autoimmunity can proceed from 10 to 44 wk were examined by histology and FACS. Unex- much further than originally thought even in normal animals, but pectedly, we found that RFϩ (i.e., 4-44ϩ) GCs were common in that diversion from AFC production and regulation in the GC can the follicles of most normal Tg BALB/c spleens (Fig. 1G, M). GCs prevent the pathologic consequences. were also found in MRL ϩ/ϩ spleens (Fig. 1, H, J, N, and P). In contrast, CB.17 (IgHb) and IgHb MRL ϩ/ϩ congenic strains that Materials and Methods lacked the autoantigen had very few 4-44ϩ cells and no detectable Mice 4-44ϩ GCs (Fig. 1, E, F, K, L, Q, and R). The absence of RFϩ GCs b ϩ AM14 H Tg MRL ϩ/ϩ mice were made by backcrossing Tg BALB/c mice in the IgH mice demonstrates that the RF GCs in BALB/c and (23) at least 10 generations to MRL ϩ/ϩ mice (The Jackson Laboratory). MRL ϩ/ϩ mice were spontaneously induced by self-Ag. These Congenic Tg BALB/c IgHb mice (CB.17) were made by crossing AM14Tg data are quantitated in Fig. 2A and corroborated by FACS data BALB/c to CB.17 mice (Taconic). Tg MRL ϩ/ϩ IgHb mice were made by presented below. similar crosses between the AM14 Tg MRL ϩ/ϩ mice and MRL ϩ/ϩ b ϩ ϩ b Although both normal BALB/c and autoimmune-prone MRL IgH mice.
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