Overview of the pathogenesis of systemic lupus erythematosus

Genetics

Genetics plays a critical role in predisposing to the development of SLE, as discussed in Chapters 11, 12, and 34. This is best exemplified by the finding that siblings of affected individuals have up to 20-fold higher risk to develop SLE than individuals without a family history of SLE, and monozygotic twins of lupus patients present a 10-fold higher risk than dizygotic twins, and ∼30% concordance.

Although SLE has mostly a polygenic inheritance, it can also occur in association with homozygotic single gene mutations ( C1q, TREX1, DNASE1 , and ACP5 polymorphisms). However, in most cases, SLE patients appear to have inherited multiple predisposing genes that, alone, might not predict the illness. In this sense, certain genetic variants in SLE are common with other autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, suggesting the possibility of common genetic influencers of autoimmune responses.

In SLE, single nucleotide polymorphism (SNP) genotyping and genome-wide association studies (GWAS) have identified multiple risk loci and confirmed previously described associations with defined alleles. More than 60 genetic regions have been recognized as robustly associated with the disease, as discussed in Chapter 11. In some cases, such as for C4 or TLRs , altered gene copy numbers rather than the genes themselves appear to be relevant in conferring predisposition to SLE.

According to function, the predisposing genetic regions can be grouped into modulators of immunological pathways and tissue homing ( ITGAM/CD11B ), clearance of immune complexes (ICs) and apoptotic cells ( C1Q, C2, C4, CR2, FCGRs ), cell signaling, and innate ( STAT4, IRF5, IRF7, TNFAIP3 ) and adaptive immune responses ( BLK, BANK1, ETS1, IL-10, IL-21, LYN, PTPN22 ). GWAS have also unveiled genes involved in immune cell regulation and DNA epigenetic modifications, although the roles of some genes in the disease have not yet been fully characterized ( Table 9.1 ). Additionally, although some gene polymorphisms associated with SLE clearly influence immunological and hematological mechanisms (e.g., STAT4 , HLA , ITGAM , and IRF5 ), gene–gene interactions have also to be taken into account as additive or epistatic contributors [the latter being proposed for human leukocyte antigen ( HLA ) and CTLA4 , ITGAM and IRF5 , STAT4 and IRF5 , BLK and TNFSF4 ]. This is because the identification of SLE-associated loci through genetic discovery represents only an initial step in the process of understanding the underlying mechanisms of disease. Subsequent evaluation of the effects of structural variations and their link to clinical features and phenotypes require mechanistic studies that can clarify the role of specific gene products in the disease pathogenesis.

In any case, strongest GWAS associations with SLE are found with the HLA genes—some shared among ethnical groups (such as the HLA-DR2 and DR3 alleles among Europeans, and HLA-DR4 and DR8 among nonEuropeans) and some common to multiple races ( IRF7 , TLR7/8 , TNFS4 ). Some associations have been linked to defined traits, that is, HLA-DR3 and -DQ2 (that are in linkage disequilibrium) have been associated with renal disease (and to antiRo/La autoantibodies), -DR4 to antiphospholipid antibodies, and polymorphism of APOL1 has been associated with kidney failure in African–Americans.

Polymorphisms of IL-10 and TNFS4 have been described in European, Hispanic American, and Asian populations, and polymorphisms of STAT4 have been correlated with early onset and more severe SLE.

Of interest, Asians and Africans have an FCGR2B SNP associated with SLE and a reduced susceptibility to malaria infection, and other SLE risk loci ( PTPN22 , TNFSF4 , ITGAM , BLK ) provide evolutionary advantage during infection, leading to the consideration that certain genes involved in the handling of infection could play a role in the pathogenesis of SLE. In this sense, genetic heterogeneity could provide evolutionary advantage in certain groups—positively selecting certain genotypes rather than others and partly defying a frequency expected from stochastic variations, thus creating grounds for genetic predisposition. In other words, some infectious agents might facilitate the initial steps leading to disease development, and additive or cumulative factors would ultimately promote the development of the disease.

Epigenetics

Epigenetic modifications help to partly explain the missing genetic heritability, as discussed in Chapter 32. For example, chromatin structure and DNA methylation, which are both sensitive to environmental factors, significantly influence gene expression.

In SLE patients, DNA hypomethylation—which causes increased gene expression and is favored by UV light, lupus-inducing drugs and microRNAs (miRNAs)—has been correlated in CD4 ⁺ T cells with autoreactivity, with ITGAL , LFA1, CD70 , and TNFS5 found as significantly affected by hypomethylation. Also in CD4 ⁺ T cells from SLE patients with active disease, demethylation of the perforin gene has been observed in concomitance with acute flares, as well as hypomethylation of genes of the type 1 interferon (IFN-I) pathway.

Other epigentic modifiers that influence gene expression are the miRNAs—small noncoding molecules that modulate target messenger RNA expression, as discussed in Chapter 30. In lupus CD4 ⁺ T cells, overexpression of miR-126, miR-148a, and miR-21 inhibits the expression of DNA methyltransferase 1, enhancing DNA hypomethlylation. miR-21 also increases IL-10 levels in CD4 ⁺ T cells, whereas miR-31 hyperactivity reduces IL-2 secretion and negatively regulates Foxp3 expression in regulatory T cells (Tregs). In B cells, the overexpression of miR-30a and miR-181b promotes cell proliferation and antibody diversification, respectively, while miR-182 in T cells reduces IL-2 levels by inhibiting Foxo1 activation. For miR-146, a suppressive role in autoimmunity  has been proposed. Upregulation of miR-146 mediated by Toll-like receptor (TLR)2, 4, and 5 increases the expression of STAT1, IRF5, IRAK1, and TRAF6, while and a reduced expression of this miRNA associates with TLR7/9 activation in plasmacytoid dendritic cells (pDCs) that sustain inflammation through IFN-α production (Chapter 18). Also acting on type I IFN production in pDCs is miR-155, which also promotes T-cell-dependent antibody production, somatic hypermutation, and autoantibody class switch in B cells.