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Genes and Immunity (2009) 10, 390–396 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene

REVIEW

Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation H Kanta1,2 and C Mohan1,2 Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA and Department of Immunology, University of Texas Southwestern Medical School, Dallas, TX, USA

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Although the etiology of systemic lupus erythematosus (SLE) remains to be fully elucidated, it is now apparent that multiple genetic and environmental factors are at play. Over the past decade, several studies have helped uncover genetic associations and susceptibility loci in human and murine lupus. In particular, recent genome-wide association studies have uncovered a large number of associated genes in human SLE. Given this plethora of candidate genes, the next challenge for lupus biologists is to fathom how these different genes operate to engender lupus. In this context, recent genetic studies in mouse models of lupus have been particularly informative. The purpose of this review is to overview three key genetically determined checkpoints in lupus development that have emerged from studies of NZM2410-derived congenic strains bearing individual lupus susceptibility loci. These three events include a breach in central tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune response by the innate immune system and local processes in the target organ that facilitate end-organ disease. Collectively, murine congenic dissection studies provide a framework for understanding and analyzing the steady stream of gene candidates that are currently emerging from human lupus studies. Genes and Immunity (2009) 10, 390–396; doi:10.1038/gene.2009.6; published online 5 March 2009 Keywords: SLE; genetics; autoantibodies; kidney disease

Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology in both humans and animal models, characterized by the presence of widespread immunological abnormalities and multiorgan injury. The hallmark of SLE is the production of high titers of autoantibodies directed against nuclear antigens such as double-strand DNA and chromatin, which result ultimately in autoantibody-mediated end-organ damage. Although the etiology of SLE remains to be fully elucidated, it is now apparent that multiple genetic and environmental factors are at play. Over the past decade, several studies have helped uncover genetic associations and susceptibility loci in human and murine lupus.1–4 In particular, recent genome-wide association studies have uncovered a large number of associated genes in human SLE. Given this plethora of candidate genes, the next challenge for lupus geneticists is to fathom how these different genes operate to engender lupus. In this context, recent genetic studies in mouse models of lupus have been particularly informative. The purpose of this Correspondence: Dr C Mohan, Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Mail Code 8884, Y8.204, Dallas, TX 75390-8884, USA. E-mail: [email protected] Received 15 December 2008; revised and accepted 21 January 2009; published online 5 March 2009

review is to overview three key genetically determined checkpoints in lupus development: breach in central tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune response by the innate immune system and local processes in the target organ that facilitate end-organ disease.

Genetic dissection of murine lupus The NZM2410 mouse strain is a New Zealand black/ white (NZB/NZW)-derived inbred strain that spontaneously develops lupus nephritis that is very similar to human SLE.5 Through linkage analysis, several non-H2 chromosomal intervals, notably, Sle1z on chromosome 1, Sle2z on chromosome 4 and Sle3z on chromosome 7 have been found to confer lupus susceptibility in this mouse model.6 By introgressing these different chromosomal intervals onto the healthy C57BL/6 (B6) background, congenic strains bearing Sle1z, Sle2z and Sle3z have been generated for functional analysis.7,8 Hence, for the first time, researchers have been able to study ‘monogenic’ models of lupus as opposed to studying ‘polygenic’ strains. This genetic simplification through ‘congenic dissection’ has been instrumental in demonstrating that each lupus susceptibility locus in this model infringes a different checkpoint in disease development. The B6.Sle1z congenic strain exhibited a breach of immune tolerance to nuclear antigens, resulting in the production of autoantibodies to chromatin, autoreactive

Checkpoints in murine lupus H Kanta and C Mohan

T cells responding to histone epitopes, with increased expression of activation markers on T and B cells.8–10 B6.Sle2z mice exhibited B-cell hyperactivity and elevated B1 cell numbers, leading to polyclonal and/or polyreactive hypergammaglobulinemia.11–13 B6 mice bearing the Sle3z disease interval exhibited phenotypes affecting primarily the T-cell compartment, as well as modest levels of antinuclear IgG antibodies and nephritis.14,15 Of particular note is the observation that Sle1z Sle2z or Sle3z in isolation was not sufficient for the development of fatal lupus but only elicited modest serological and cellular features of autoreactivity. In contrast, the epistatic interaction of these loci with each other and other loci such as Faslpr and Yaa led to highly penetrant glomerulonephritis (GN).16–20 The above ‘congenic dissection’ studies illustrate that the genesis of fatal lupus is the end result of multiple genes and pathways acting in concert. Though the above studies had originated with the NZM2410 model of lupus, parallel findings have also been reported in other mouse models of lupus, as reviewed.21 Collectively, these studies have revealed that both the innate and adaptive arms of the immune systems have to be dysregulated for full-blown lupus to ensue. Additional studies have also indicated that further checkpoints may be operative within the end organs in lupus. This review discusses recent evidence indicating that murine lupus susceptibility genes may infringe all of the above checkpoints in lupus development, as captioned in Figure 1.

Checkpoint I: aberrant adaptive immunity in lupus

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B cells that are generated in the bone marrow (BM) and T cells that are generated in the thymus populate and constitute the adaptive arm of the immune system. The adaptive immune system produces antibodies and T cells that are highly specific for a particular pathogen (or antigen). The relative specificity of SLE sera to a select subset of nuclear antigens (as opposed to reacting to the whole universe of antigens) suggests that lupus genes must be impacting adaptive immunity, at some level. Our recent genetic dissection studies have indicated that Sle1z may be one such locus/gene (Figure 1). The Sle1z interval, located on distal chromosome 1, is perhaps one of the most extensively studied chromosomal intervals in murine lupus, because it confers disease susceptibility in multiple spontaneous lupus models including the BWF1, SNF1, BXSB and NZM2410 strains of mice. The Sle1z interval is home to three subloci: Sle1az, Sle1bz and Sle1cz22 Among these, the NZM2410/NZWderived ‘z’ allele of Sle1bz leads to the highest levels and penetrance of antinuclear autoantibodies (ANAs).23,24 Studies employing crosses to HEL-reactive B-cell receptor (BCR) transgenic models have demonstrated that Sle1z could breach tolerance among B cells with lowavidity but not high-avidity reactivity to self-antigens.24 Though the mature B cells from these mice were

Figure 1 Three key steps in lupus pathogenesis, as indicated by congenic dissection studies in mice. Checkpoint I patrols central immune tolerance in the adaptive arm of the immune system, ensuring that anti-self B cells and T cells are censored in the bone marrow (BM) and thymus, respectively. Ly108 (the candidate gene within the Sle1/Sle1b lupus susceptibility interval on chromosome 1) is an example of a gene that can breach the first checkpoint. Checkpoint II patrols the innate arm of the immune system. When this checkpoint is breached, peripheral amplification of the autoimmune response results in the generation of potentially pathogenic autoantibodies and effector lymphocytes. The Sle3 lupus susceptibility locus on murine chromosome 7 is an example of a locus that can breach checkpoint II. Yaa/Tlr7 is a second example of a locus/gene that profoundly impacts checkpoint II. The consequence of this breach is the emergence of hyperactive, pro-inflammatory myeloid cells, which can secondarily impact the activation of autoreactive lymphocytes. It is envisioned that a final checkpoint might be operative in the end organs, where autoantibodies, T cells and myeloid cells mediate pathology. Congenic dissection of lupus nephritis in mouse models has recently suggested that kallikreins may be renoprotective in immune-mediated nephritis and may constitute candidate genes for the disease. The coordinate activation of disease susceptibility genes at all three checkpoints appears to be necessary for full-blown disease in murine models. Indicated in the right margin are candidate disease genes that have recently been implicated in human systemic lupus erythematosus (SLE), largely through genome-wide association studies. On the basis of the known properties of these human genes (as briefly referenced in the text), the disease checkpoints they are most likely to influence are also highlighted. Genes and Immunity

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functionally normal, immature B cells from the Sle1z- and Sle1bz-bearing BM exhibited a profound reduction in calcium flux, RAG expression and cell death following BCR cross-linking, revealing that the Sle1bz lupus susceptibility locus significantly dampened central B-cell tolerance.24 Through a meticulous positional cloning approach, Wakeland and co-workers23 demonstrated the SLAM family of costimulatory molecules to be the candidate genes for Sle1bz. Among this family of molecules, one member, Ly108, exhibited interesting expression differences associated with functional consequences when immature B cells from B6 and B6.Sle1bz mice were compared.24 The normal ‘b’ allele of Ly108 encodes predominantly the Ly108.2 isoform (bearing three intracellular immunotyrosine switch motif (ITSM) signaling motifs); in contrast, the lupus-associated ‘z’ allele of Ly108 encodes predominantly the Ly108.1 isoform (bearing two intracellular ITSM motifs) due to splice-site polymorphisms. Importantly, immature B cells transfected with the lupus-associated Ly108.1 isoform showed impaired calcium flux, apoptotic cell loss and BCR editing, compared to transfectants bearing the normal Ly108.2 isoform. The normal Ly108.2 isoform appears to render immature B cells sensitive to BCR cross-linking, effectively facilitating the operation of several tolerance mechanisms including receptor editing and deletion, whereas the lupus-associated isoform, Ly108.1, may be functioning by blocking these processes.24 Collectively, the above studies reveal that polymorphisms in the SLAM family gene Ly108 can infringe key checkpoints in central B-cell tolerance, hence leading to the emergence of self-reactive antibodies. Recent work from the Wakeland laboratory indicates that the same polymorphisms in Ly108 may also breach thymic tolerance in B6.Sle1bz mice (submitted). Hence, Ly108 is the prototype of a class of genes that can infringe central tolerance in both the B- and T-cell compartments that constitute the adaptive arm of the immune system. Whether similar genes may also be operative in human SLE is discussed further below. In addition to Sle1bz it is worth noting that the more distal locus on murine chromosome 1, Sle1cz, may also harbor genes that breach B-cell tolerance either centrally or peripherally, including Cr2.25–28

Checkpoint II: aberrant innate immunity in lupus The innate immune system is a universal and ancient form of host defense presumably designed to fight infection. Before launching an effective adaptive immune response, the host must deal with acute assaults, sense the presence of pathogens, distinguish infectious nonself from noninfectious self and mount an effective immune response against invading organisms rapidly. Myeloid cells, interferons (IFN) and Toll-like receptors (TLRs) all are important in innate immune responsiveness.29–31 Unfortunately, when innate immune responses are misdirected to components of self, autoimmunity can ensue. Recent genetic studies in mice have yielded at least two examples of loci/genes that could potentially contribute to lupus by dysregulating innate immunity, as diagrammed in Figure 1, and discussed further below. Genes and Immunity

Genetic dissection studies in murine models of lupus have uncovered a lupus susceptibility locus on midchromosome 7 similarly positioned in several strains of mice, including the NZM2410, NZB/NZW and MRL/ lpr.6,14,32–34 This locus has been termed Sle3z in the NZM2410 model. B6.Sle3z congenics exhibit low levels of ANAs and several lymphocyte phenotypes.14 Importantly, Sle3z-bearing T cells were spontaneously activated and exhibited elevated CD4/CD8 ratios and impaired activation-induced cell death.1,14,35 To explore the cellular origin of the Sle3z-associated phenotypes, Sobel et al.15 transferred BM from allotype-marked B6 and B6.Sle3 congenic mice into B6 hosts. In these chimeras, T cells of both origins (that is, with or without Sle3z) exhibited elevated CD4/CD8 ratios and spontaneous T-cell activation, phenotypes that have been attributed to Sle3z These studies demonstrated that the Sle3z-associated phenotypes may not be encoded in a T-cell-intrinsic fashion, although they were BM transferable. Likewise, the same study also revealed that autoantibody production in the chimeras was also not contingent upon the intrinsic expression of Sle3z within B cells.15 Consistent with the above findings, the Sle3z-associated phenotypes arise from the intrinsic impact of this locus on myeloid cells.35 Dendritic cells (DCs) and macrophages isolated from B6.Sle3z spleens, lymph nodes and BM exhibited increased surface levels of CD40, CD80, CD86, CD54, CD106 (VCAM-1) and FcR (CD16/32) and increased expression levels of proinflammatory cytokines such as interleukin (IL)-12, IL-1b and tumor necrosis factor-a (TNF-a).35 Also, when Sle3z-bearing DCs were ovalbumin (OVA)-pulsed and cocultured with OVA-specific T-cell receptor Tg T cells, the T cells demonstrated greater expansion and reduced apoptosis, compared to T cells cocultured with B6 DCs.35 Most importantly, after adoptive transfer into young B6 hosts, Sle3z-bearing DCs led to elevated splenic CD4/ CD8 ratios and serum autoantibody levels. These findings indicated that Sle3z-bearing DCs were sufficient to recreate the Sle3z-associated lupus phenotypes. More recently, the subinterval within Sle3z that may be responsible for these phenotypes has been narrowed to a sublocus termed Sle3b (Wakeland EK et al., unpublished). The candidate gene(s) within this locus that may be responsible for these myeloid cell phenotypes remain to be decoded. It is of interest to note that similar myeloid cell abnormalities have also been described in human SLE.36,37 A more recent breakthrough in murine lupus genetics that has highlighted the importance of the innate immune system revolves around the Yaa lupus susceptibility locus derived from the BXSB lupus strain, which was originally derived from the SB/Le and C57BL/6 (B6) parental strains.38–41 The male bias in BXSB lupus has clearly been shown to be encoded by the BXSB Y chromosome, and the putative locus on Y chromosome has been termed Yaa or Y chromosome autoimmunity accelerating locus. Interestingly, the Yaa locus leads to different degrees of autoimmunity on different genetic backgrounds, in epistasis with other lupus susceptibility loci.39–42 Defined about 30 years ago, it was only recently that the identity of Yaa was elucidated—two independent groups identified Tlr7 as the candidate gene for Yaa.19,43 Finally, another lupus susceptibility gene identified in mice with spontaneous lupus is Ifi202, a gene that

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may not only facilitate IFN-I-driven peripheral amplification of the autoimmune response, but may also impact cellular apoptosis in a variety of cell types.44–46 Collectively, the above studies suggest that dysregulated expression or function of DCs, the TLRs they bear (for example, TLR7) and cytokines they express (for example, IFN-I) can profoundly impact lupus pathogenesis. Though the breach in checkpoint I in the adaptive arm of the immune system may suffice for autoreactive B and T cells to emerge in the periphery, these may not be sufficient to induce disease. A breach in the innate arm of the immune system (that is, checkpoint II) may be necessary for the ‘amplification’ of the autoimmune response and the generation of pathogenic effector molecules, including pathogenic antibodies, effector T cells and pro-inflammatory myeloid cells, all of which may be responsible for the ensuing end-organ pathology (Figure 1). Although checkpoint II has been described as being focused on the innate immune system, genes that amplify T-cell/B-cell collaboration such as Roquin47 and major histocompatibility complex (MHC) can also be expected to have critical functions in amplifying the autoimmune response in the periphery. Indeed, the MHC locus has consistently emerged as the strongest susceptibility factor for murine lupus in multiple murine models.48,49 Though this locus (referred to Sle4 or Sles1 in NZM2410 mice) has been phenotypically very well characterized, definitive evidence indicating that the H2 genes are indeed the disease genes within this locus is still elusive.

Checkpoint III: genetically determined events in the end organs that dictate pathology The consequence of breaching checkpoints I and II in the adaptive and innate arms of the immune system, respectively, is the generation of potentially pathogenic mediators, including autoantibodies, immune complexes, T cells and myeloid cells. However, leads from the literature indicate that an additional set of genes/ molecules may have the potential to modulate the severity of the end-organ disease that ensues. Discordance between serum ANAs and GN have been documented in murine as well as in human lupus, as reviewed.50,51 Strongly nephrophilic seropositivity can be uncoupled from renal disease, in experimental models where key molecular mediators (for example, FcR, MCP1, complement, TNF-a, ICAM-1) are deficient.52–56 In addition, genetic mapping studies have uncovered loci that are strongly linked to nephritis, but not autoantibodies.49,57,58 Reports of familial clustering of primary/ idiopathic GN59–61 and of GN following lupus, diabetes and hypertension62–65 further support the potential importance of Genetics in determining intrinsic susceptibility to renal disease in lupus as well as in other diseases. A valuable tool for uncovering key molecular determinants in lupus nephritis is the anti-glomerular basement membrane (GBM) experimentally induced model of nephritis. The ability of heterologous ‘anti-kidney’ (or anti-GBM) sera to inflict nephritis was first recognized by Masugi in 1934.66 In contrast to spontaneous lupus

nephritis, proteinuria, azotemia, glomerular and tubulointerstitial disease all ensue with a rapid and predictable time course in the experimentally induced models. Over the past decade, researchers have assessed the functions of 425 different molecules (including various complement proteins and TLR ligands, FcR, B7/CD28/CTLA4, LFA1/ICAM1, P-selectin, TNF-a, IL1, IL-6, IL-12, IL-18, IFN-g, M-CSF, PDGF, MCP-1 and NO) in the pathogenesis of spontaneous lupus nephritis as well as experimental anti-GBM disease. Importantly, the molecules that have been studied thus far have shown excellent concordance in how they affect both disease settings, as recently reviewed.67 In other words, molecules known to influence the progression of experimental anti-GBM disease also impacted the development of spontaneous lupus nephritis in the same direction. Thus, although experimental anti-GBM nephritis and spontaneous lupus nephritis may differ in the nature of the inciting antibodies and the localization of the immune deposits, a shared network of downstream molecular pathways is likely to be mediating disease in both settings. Indeed, when different strains were challenged with anti-GBM serum, it became evident that B6 mice bearing the Sle3 congenic interval at chromosome 7 exhibited significantly increased renal disease.58 Mapping using recombinant congenics revealed that a sublocus harboring the kallikrein gene complex on chromosome 7 was responsible for this phenotype.68 Functional studies indicated that increased renal kallikrein had a protective function in immune-mediated nephritis.68 Collectively these studies allude to a third checkpoint in the development of lupus nephritis that could potentially modulate the degree of end-organ disease, in the face of potentially pathogenic autoantibodies and autoaggressor lymphocytes (Figure 1).

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Relevance of the three-checkpoint model to human SLE genetics Though the three-checkpoint model depicted in Figure 1 may be an oversimplification of the molecular events that lead to murine lupus, it provides us with a working framework for classifying and understanding the large number of likely human lupus genes that have recently been reported, as reviewed in.69 On the basis of the known function of these molecules one can readily identify gene candidates that may potentially infringe each of the three checkpoints, as indicated on the right margin of Figure 1. Genes such as Bank1, Blk and the complement molecules are candidates that could be envisioned to breach checkpoint I, based on the published properties of these molecules.70–74 In fact, there is already functional evidence from repertoire monitoring studies indicating that early B-cell tolerance checkpoints may also be infringed in human SLE.75,76 A relatively extensive subset of the genes implicated in human SLE could be envisioned to upregulate myeloid cell activity or enhance T-cell/B-cell or DC/T-cell interactions, leading in essence to a breach of checkpoint II, as captioned in Figure 1. Once again, these proposed assignments to the respective checkpoints are based on the published properties of these molecules.77–82 Finally, genes such as ITGAM, complement, and the various FcR Genes and Immunity

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molecules could potentially have a function at checkpoint III in lupus development, to regulate the degree of end-organ inflammation, again based on the published properties of these molecules.52–55,83–86 Clearly, these provisional assignments to the respective checkpoints may have to be revised once we learn more about the functional attributes of these genes.

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Conclusion ‘Genetic dissection’ using congenic strains has clarified some of the mystery enshrouding murine lupus pathogenesis. It appears that there are at least three distinct events leading to disease. The first involves a tolerance breach in the adaptive arm of the immune system, as exemplified by Sle1bz/Ly108z. The second involves a dysregulation of innate immunity, as can happen in the context of Sle3z-bearing pro-inflammatory DCs, heightened TLR7 activity or increased IFN-I production. A final checkpoint may be operative in the end organs, serving to modulate the severity of clinical disease. Coordinate dysregulation of all checkpoints may be necessary for full-blown lupus nephritis to ensue. The challenges ahead are to study and catalog various human SLE genes according to the specific checkpoints they breach, to uncover additional checkpoints and mechanisms that could lead to lupus and to eventually devise effective therapies targeting each of the key checkpoints in the pathogenic cascade leading to SLE.

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