State of the Art REVIEW
lupus erythematosus susceptibility. However, the relative contribution of, and exact mechanisms by which, gene overexpression due to escape from X chromosome inactivation leads to autoimmunity remain poorly understood. Although not yet directly shown to be subject to aberrant inactivation, the gene TSC22D3 , encoding the glucocorticoid induced leucine zipper (GILZ) protein, is also located on the X chromosome 50 ; GILZ deficiency results in spontaneous B cell hyperactivation and a lupus-like phenotype in mice, 51 while GILZ also restrains Th17 and type I interferon pathways. 52-54 Sex hormones having a role in sexual dimorphism in systemic lupus erythematosus is supported by the more prominent female to male ratio in patients during their reproductive years, increased flares in high estrogen settings such as pregnancy, and higher risk of developing systemic lupus erythematosus in postmenopausal women after estrogen administration. 55 56 In addition, estrogens have been shown to accelerate or worsen disease in murine models of lupus 57 58 and have several immunomodulatory effects. 59 Estrogens have been shown to upregulate Bcl-2 and anti-B cell activating factor (BAFF) and potentiate the survival, activation, and differentiation of B cells into antibody producing cells. 60-64 Estrogens have been shown to increase type I interferon induced gene expression in human cells in vitro, and exert a number of proinflammatory activities on the innate immune system. 65 66 Estrogens can also modulate the immune response via epigenetic modifications, inducing changes in DNA methylation patterns and regulating the expression of microRNAs. 67-69 Overall, it seems likely that the strong female skewing in systemic lupus erythematosus represents the convergence of multiple genetic, epigenetic, hormonal, and environmental factors. Importantly from a clinical perspective, a prospective placebo controlled study of 183 patients showed that oral contraception containing estrogen does not exacerbate systemic lupus erythematosus. 70 Epigenetics and systemic lupus erythematosus Epigenetics, or the sum of genome wide chromatin modifications that do not change DNA sequences, includes DNA methylation, histone modification, microRNA regulation, and 2D chromatin interactions, all of which can alter chromatin accessibility and transcription factor binding. 69 70 Importantly, both genetic and environmental factors—particularly during early development—can influence epigenetic modifications, therefore, the epigenome can mediate disease associated gene-environment interactions. 71 This relatively new area of research could help to explain how environmental factors affect systemic lupus erythematosus risk. The most robustly studied epigenetic modification in rheumatic diseases is DNA methylation, a process by which genomic cytosine nucleotides positioned near adjacent guanine nucleotides (CpG sites) are methylated by DNA methyltransferases. 72 Multiple
erythematosus cases and 5908 controls revealed relatively short range linkage disequilibrium with a strong, narrow signal at the HLA class II region. The most significantly associated HLA haplotypes in European ancestry and African ancestry participants were HLA-DQB*02:01 and HLA-DRB1*15:03, respectively. 32 While some genetic risk factors appear to be common across populations, clear examples of ancestry specific associations exist as well. It seems likely that these differences reflect functional variation in immune genes in ancestral populations caused by infectious evolutionary pressures. One such example is the APOL1 gene. Two coding change variants APOL1 identified exclusively in sub- Saharan African genomes are thought to have been evolutionarily conserved by conferring protection against Trypanosoma brucei , the parasite that causes African trypanosomiasis. 33 However, the APOL1 high risk genotype is associated with risk of end stage kidney disease in patients with lupus nephritis, as well as several other adverse renal phenotypes. 34 35 Correspondingly, a missense polymorphism in PTPN22 is highly associated with autoimmune conditions, including systemic lupus erythematosus in European ancestry, but not clearly in African- American or Asian-American populations. 36 Variants in the promoter region of the IRF5 gene have been associated with systemic lupus erythematosus across populations, but a separate, Neanderthal derived haplotype is also prevalent in populations with Neanderthal admixture. 37 38 These data highlight the importance of inclusivity in genetic research in systemic lupus erythematosus. Sex bias in systemic lupus erythematosus Although the biological basis of the 9:1 female to male ratio of systemic lupus erythematosus incidence remains largely unexplained, accumulating evidence implicates the X chromosome. Patients with an extra X chromosome, such as those with Klinefelter syndrome (47,XXY) 39 and trisomy X syndrome (47,XXX), 40 have a higher prevalence of systemic lupus erythematosus. Men with Klinefelter syndrome are estimated to have a 14-fold higher risk of systemic lupus erythematosus than karyotypically normal men (46,XY), 39 whereas women with trisomy X syndrome have a prevalence of systemic lupus erythematosus that is about 2.5 times higher than in karyotypically normal women (46,XX), 40 an effect that seems to be largely independent of circulating sex hormones. Furthermore, many genes that regulate the immune response are located on the X chromosome, several of which escape X chromosome inactivation 41 or can be demethylated and expressed in the inactive X chromosome. These include genes that directly regulate the innate and adaptive immune responses such as IRAK1, CD40LG, TLR7, BTK, and CXorf21/ TASL. 42-48 This process has been shown to be dynamic in human B cell lineages. 49 Taken together, these findings support the concept of a gene-dose effect from the X chromosome as a contributor to systemic
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doi: 10.1136/bmj-2022-073980 | BMJ 2023;383:073980 | the bmj
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