Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by a striking preponderance in females, multisystem involvement, and autoantibodies directed primarily against nuclear antigens. Pathogenic mechanisms have been partly elucidated and defects in immune complex clearance, B-cell tolerance, and T-cell function have all been described. Little, however, is known about predisposing factors and mechanisms leading to disease induction. Through a variety of study designs, a strong genetic predisposition has been shown. For example, studies of affected probands estimate the sibling recurrence risk (λs) to be approximately 20. Twin studies have demonstrated concordance rates among monozygotic twins of 24-65%, compared with 2-9% in dizygotic twins [1]. SLE is a complex, polygenic trait with contributions from MHC and non-MHC genes, and up to 100 genes may be involved in disease susceptibility [1]. The study of SLE genetics is at an exciting and rapidly advancing stage. This review aims to update our current understanding of this area.

Genetic analyses in the mouse have provided some important insights into the pathogenic processes mediating disease in experimental models of SLE. Linkage analysis and congenic dissection have provided insights into the genetic basis for susceptibility in the classic lupus-prone mouse strains. These studies have delineated specific genetic pathways that are critical to the development of severe lupus nephritis and have identified allele-specific, suppressive modifiers capable of dramatically influencing disease progression. The 'synthesis' of mouse models of systemic autoimmunity via the production of targeted gene disruptions has also helped identify specific genes and gene combinations capable of causing and modifying disease.

The chromosomal locations of genes mediating susceptibility to lupus nephritis or systemic autoimmunity in the NZB/W, MRL, and BXSB mouse models have been determined through genome scans [2,3,4,5]. These studies show that lupus susceptibility is inherited in a complex fashion involving both genetic interactions and additive effects of individual genes. In all, 31 different gene designations have been defined thus far, distributed among 21 nonoverlapping 20-cM genome intervals (Table 1). Other investigators have mapped loci affecting a variety of component phenotypes associated with systemic autoimmunity [6]. The genomic segments on murine chromosomes 1, 4, and 7 are associated with disease susceptibility in multiple strain combinations, suggesting that these intervals contain genes or gene clusters that strongly influence autoimmunity. The Sle1, Sle2, and Sle3 loci have been individually identified as the major SLE susceptibility loci in NZM2410 mice [2] and their immunophenotypes have been characterised. Sle1 mediates loss of tolerance to nuclear antigens, Sle2 lowers the activation threshold of B cells, and Sle3 mediates dysregulation of CD4⁺ T cells [2]. The combination of Sle1 with any one of Sle2, Sle3, or Yaa (autoimmune accelerating gene) on the B6 genetic background results in the development of systemic autoimmunity with variably penetrant glomerulonephritis culminating in renal failure and death. In contrast, two-loci combinations of any of Sle2, Sle3, or Yaa did not mediate fatal disease. These results identify Sle1 as a strategic locus in SLE pathogenesis [7]. The NZW genome also has four epistatic modifiers, SLE suppressors (Sles1-Sles4), which suppress autoimmunity. The most potent, Sles1, switches off the Sle1 immunophenotype and can suppress the entire autoimmune pathological process [8]. Recent fine-mapping analysis of the Sle1 locus has identified a cluster of functionally related loci (Sle1a-d). These loci share a common pathway leading to loss of tolerance to chromatin but differ by various other serological and cellular phenotypes [9]. This potent susceptibility locus is syntenic with the 1q23-42 segment of the human chromosome.

Other models of intense interest are those supporting an apoptosis-related autoantigen clearance defect, for example C1q knockout, DNase1-deficient, and serum-amyloid-P-deficient mice. These models have shown several important pathogenic abnormalities, including reduced macrophage clearance of apoptotic cells and increased concentrations of apoptotic bodies, in tissue samples associated with development of glomerulonephritis [10,11,12,13].

The traditional approach for locating a disease gene in humans is linkage analysis. Results from mouse models of SLE presented the first evidence for genetic linkage to an area of chromosome 1 in the mouse that is syntenic to human chromosome 1q23-42. In 1997, Tsao et al [14] published linkage evidence on the long arm of chromosome 1q41-42, using 43 families with 52 affected sibling pairs of mixed origin. Several additional linkage studies have been performed using sib-pairs and extended family pedigrees [15,16,17,18,19]. The parameters and test populations for each study as well as the genomic intervals detected in at least two mapping studies are summarised in Tables 2 and 3.

As Table 2 shows, there are many sources of variation between these studies, including ethnic mix, sample size, specific markers used, and analytic models used. Another source of variation may relate to clinical phenotypes of the affected individuals. Localisation of genes with modest effects by linkage analysis is difficult and such variations may further limit the power of such studies. Despite these important limitations, there is some agreement as regards regions providing evidence of linkage. Several areas on chromosome 1 have been detected (1p36, 1q21-23 and 1q41-42) [15,16,17,18,19] that contain genes of immunological importance, some of which may have direct relevance to pathogenic processes in SLE (Table 4). The importance of using well-defined populations is emphasised by recent studies of Nordic multi-case families in which a susceptibility locus at chromosome 2q37 (SLEB2) has been reported [19]. A study of single-case Swedish families confirmed association with further markers in this region but, in contrast, there was no linkage to this area in 13 Mexican families [20].

Many individual genes have been studied in SLE and a comprehensive analysis of these is beyond the scope of this review. Recent studies do, however, illustrate important points that are likely to apply to other genes in SLE.

The past decade has witnessed major advances in our understanding of the immunopathogenesis of SLE. Intensive study of several mouse models has allowed significant progress towards understanding the genetic contribution to the development and expression of the disease. The observed genetic synteny between human and murine loci provides valuable clues to the origins of human SLE, and future studies will make possible a clearer understanding of the role of genetic factors in disease susceptibility. The next challenge will be to focus on genetic and molecular pathways that determine an individual's particular phenotype as an aid to prognostication and early intervention to prevent complications.

Fc = crystallizable fragment [of antibody]; FcγR = Fc IgG receptor; IL = interleukin; SLE = systemic lupus erythematosus; TNF = tumour necrosis factor.