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 1Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA and 2Department of Immunology, University of Texas Southwestern Medical School, Dallas, TX, USA 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 review is to overview three key genetically determined checkpoints in lupus development: breach in central Systemic lupus erythematosus (SLE) is a chronic auto- tolerance in the adaptive arm of the immune system, immune disease of complex etiology in both humans and peripheral amplification of the autoimmune response by animal models, characterized by the presence of wide- the innate immune system and local processes in the spread immunological abnormalities and multiorgan target organ that facilitate end-organ disease. 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 Genetic dissection of murine lupus ultimately in autoantibody-mediated end-organ damage. Although the etiology of SLE remains to be fully The NZM2410 mouse strain is a New Zealand black/ elucidated, it is now apparent that multiple genetic and white (NZB/NZW)-derived inbred strain that sponta- environmental factors are at play. Over the past decade, neously develops lupus nephritis that is very similar to human SLE.5 Through linkage analysis, several non-H2 several studies have helped uncover genetic associations z 1–4 chromosomal intervals, notably, Sle1 on chromosome 1, and susceptibility loci in human and murine lupus. In z z particular, recent genome-wide association studies have Sle2 on chromosome 4 and Sle3 on chromosome 7 have been found to confer lupus susceptibility in this mouse uncovered a large number of associated genes in human 6 SLE. Given this plethora of candidate genes, the next model. By introgressing these different chromosomal challenge for lupus geneticists is to fathom how these intervals onto the healthy C57BL/6 (B6) background, congenic strains bearing Sle1z, Sle2z and Sle3z have been different genes operate to engender lupus. In this 7,8 context, recent genetic studies in mouse models of lupus generated for functional analysis. Hence, for the first have been particularly informative. The purpose of this time, researchers have been able to study ‘monogenic’ models of lupus as opposed to studying ‘polygenic’ strains. This genetic simplification through ‘congenic Correspondence: Dr C Mohan, Division of Rheumatology, Depart- dissection’ has been instrumental in demonstrating that ment of Internal Medicine, University of Texas Southwestern each lupus susceptibility locus in this model infringes a Medical Center, 5323 Harry Hines Boulevard, Mail Code 8884, different checkpoint in disease development. Y8.204, Dallas, TX 75390-8884, USA. z E-mail: [email protected] The B6.Sle1 congenic strain exhibited a breach of Received 15 December 2008; revised and accepted 21 January 2009; immune tolerance to nuclear antigens, resulting in the published online 5 March 2009 production of autoantibodies to chromatin, autoreactive Checkpoints in murine lupus H Kanta and C Mohan 391 T cells responding to histone epitopes, with increased Checkpoint I: aberrant adaptive immunity expression of activation markers on T and B cells.8–10 in lupus B6.Sle2z mice exhibited B-cell hyperactivity and elevated B1 cell numbers, leading to polyclonal and/or polyreactive B cells that are generated in the bone marrow (BM) and T hypergammaglobulinemia.11–13 B6 mice bearing the Sle3z cells that are generated in the thymus populate and disease interval exhibited phenotypes affecting primarily constitute the adaptive arm of the immune system. The the T-cell compartment, as well as modest levels of anti- adaptive immune system produces antibodies and T cells nuclear IgG antibodies and nephritis.14,15 Of particular note that are highly specific for a particular pathogen (or is the observation that Sle1z Sle2z or Sle3z in isolation was antigen). The relative specificity of SLE sera to a select not sufficient for the development of fatal lupus but only subset of nuclear antigens (as opposed to reacting to the elicited modest serological and cellular features of auto- whole universe of antigens) suggests that lupus genes reactivity. In contrast, the epistatic interaction of these loci must be impacting adaptive immunity, at some level. with each other and other loci such as Faslpr and Yaa led to Our recent genetic dissection studies have indicated that highly penetrant glomerulonephritis (GN).16–20 Sle1z may be one such locus/gene (Figure 1). The above ‘congenic dissection’ studies illustrate that The Sle1z interval, located on distal chromosome 1, is the genesis of fatal lupus is the end result of multiple perhaps one of the most extensively studied chromoso- genes and pathways acting in concert. Though the above mal intervals in murine lupus, because it confers disease studies had originated with the NZM2410 model of susceptibility in multiple spontaneous lupus models lupus, parallel findings have also been reported in other including the BWF1, SNF1, BXSB and NZM2410 strains mouse models of lupus, as reviewed.21 Collectively, these of mice. The Sle1z interval is home to three subloci: Sle1az, studies have revealed that both the innate and adaptive Sle1bz and Sle1cz22 Among these, the NZM2410/NZW- arms of the immune systems have to be dysregulated for derived ‘z’ allele of Sle1bz leads to the highest levels and full-blown lupus to ensue. Additional studies have also penetrance of antinuclear autoantibodies (ANAs).23,24 indicated that further checkpoints may be operative Studies employing crosses to HEL-reactive B-cell recep- within the end organs in lupus. This review discusses tor (BCR) transgenic models have demonstrated that recent evidence indicating that murine lupus suscept- Sle1z could breach tolerance among B cells with low- ibility genes may infringe all of the above checkpoints in avidity but not high-avidity reactivity to self-antigens.24 lupus development, as captioned in Figure 1. 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