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Barr virus modulates the impact of these alleles. 25 This possibility is intriguing, given epidemiological data supporting Epstein Barr virus as a causal factor in systemic lupus erythematosus. 26 While over 91 gene loci have been implicated as common risk factors in systemic lupus erythematosus, 27 we still do not know the function of most of them. Studies have suggested, for example, that the protein tyrosine phosphatase non-receptor type 22 (PTPN22) variant alters lymphocyte function in complex ways. 28 Risk loci for the type I interferon pathway appear to confer gain of function in that pathway 29 ; a recent study suggested that some risk loci for interferon pathway systemic lupus erythematosus are protective against death from acute covid-19. 30 These data support the idea that genetic risk factors for autoimmune disease have endured owing to positive selection pressure relating to effects on immunity against pathogens. 30 Functional studies of the known risk loci for systemic lupus erythematosus could provide pathological insight, as well as new targets for treatment. Ancestry While genetic studies have assessed multiple populations, non-European ancestry populations are less well studied, and thus less is known about their genetic susceptibility to systemic lupus erythematosus. The HLA region encodes multiple genes essential to immune function, 31 and has been most strongly associated with risk of systemic lupus erythematosus in European and Chinese populations. The HLA region is also associated with systemic lupus erythematosus in Amerindian and African American populations, but with a different pattern of association and different alleles implicated. For example, a recent fine mapping of the HLA region in 1494 African American systemic lupus
be strongest among patients with systemic lupus erythematosus possessing the type 1 interferon signature 18 (see below), and other studies have also suggested that the common systemic lupus erythematosus risk alleles could be specifically associated with this patient subgroup. 19 Single gene mutations of large effect can also cause systemic lupus erythematosus. Recessive C1q deficiency has long been known as a monogenic cause of systemic lupus erythematosus, and several other monogenic causes have been discovered, such as mutations in DNAse1L3, TREX1, and TLR7. 20 21 In general, these mutations are in genes that function in the immune system or DNA processing, consistent with our concept of systemic lupus erythematosus as an autoimmune disease with an antinucleic acid response. These monogenic variants are each very rare, and even if many more are discovered it seems that only a small percentage of systemic lupus erythematosus will be attributable to monogenic causes. A greater proportion of monogenic versus polygenic systemic lupus erythematosus is present in childhood onset disease, 20 as might be expected, and polygenic childhood systemic lupus erythematosus is associated with more known common risk variants. 22 23 Despite advances in our understanding of the genetic risk factors underlying systemic lupus erythematosus, much of the heritability remains unexplained. Additive genetic models still do not account for the majority of the heritability of systemic lupus erythematosus, 24 and gene-gene and gene-environment interactions (see below) probably contribute (it being unlikely that all genetic risk factors work in complete isolation). For example, a recent paper showed that Epstein Barr virus proteins occupy approximately 50% of the promoter regions of common risk loci for systemic lupus erythematosus in B cells, suggesting that Epstein
Table 1 | Summary of settled science and unanswered questions in pathogenesis of systemic lupus erythematosus Settled science Evidence Unanswered questions Role of innate immunity/type 1 interferon Incredibly reproducible interferon signature in blood, tissues Positive phase 3 trials, resulting in regulatory approval Cellular source(s) of interferon are not clear Stimulus of innate immunity:
many different nucleic acid types and sources seem possible, including nucleic acid immune complexes, nucleic acid sensors; sources could include apoptotic debris, NETs from NETosis, viruses, etc. Why do so many people have antinuclear antibody but not a disease? What are the pathological consequences of different autoantibody specificities (eg Sm, Ro), are they involved in pathogenesis or simply markers of disease? The underlying biological and environmental factors are not well understood, and differences between populations are likely due to a combination of factors Despite the large sex differential in disease, the biological basis is incompletely understood Not enough X chromosome risk factors that could explain the data on Klinefelter syndrome Function of risk genes in the immune system (and other organ systems) is largely unknown, gene-gene and gene-environment interactions probably exist but have been difficult to identify Whether these epigenetic events occur before or after disease onset is not clear
Role of humoral immunity
Prominence of autoantibodies in patients led to use in diagnostic criteria (although now that could be seen as self-fulfilling) Efficacy of belimumab in systemic lupus erythematosus and nephritis Clear evidence across multiple studies that patients of non- European ancestry with systemic lupus erythematosus are both more frequently and more severely affected Clear female sex skewing which is more prominent in reproductive years Additional X chromosome in Klinefelter syndrome increases risk of lupus Familial predilection to systemic lupus erythematosus and other autoimmune diseases Well validated risk loci (both HLA and non-HLA) Epigenetic programs can be detected in patients, such as the interferon signature
Ancestral variation in clinical phenotype Sex prevalence (9:1 female to male ratio)
Genetics
Epigenetics
NET=neutrophil extracellular trap.
the bmj | BMJ 2023;383:073980 | doi: 10.1136/bmj-2022-073980
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