Recent advances in the genetics of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of antinuclear autoantibodies and the inflammatory infiltration of many organ systems. SLE is a complex disorder in which multiple genetic variants, together with environmental and hormonal factors, contribute to disease risk. In this article, we summarize our current understanding of the genetic contribution to SLE in light of recent genome-wide association studies, which have brought the total number of confirmed SLE susceptibility loci to 29. In the second section, we explore the functional implications of these risk loci and, in particular, highlight the role that many of these genes play in the Toll-like receptor and type I interferon signaling pathways. Finally, we discuss the genetic overlap between SLE and other autoimmune and inflammatory conditions as several risk loci are shared among multiple disorders, suggesting common underlying pathogenic mechanisms.

Figure 1. Many SLE risk loci function in the Toll-like receptor/IFN-I signaling pathway

Nucleic acid-sensing TLRs, which include TLR-3, -7, -8 and -9, are localized to endosomal compartments. SLE immune complexes that contain nucleic acids are bound by FCGR2A on the surface of dendritic cells and are subsequently internalized where they gain access to the endosome and activate TLRs. TLR7, TLR8 and TLR9 signal through the adaptor protein MyD88, the kinases IRAK1 and IRAK4, and the E3 ubiquitin ligase TRAF6. Upon stimulation, the IRF family members IRF5 and IRF7 are phosphorylated, dimerize and translocate to the nucleus where they induce transcription of IFN-I. IRF5 is also critical for the induction of proinflammatory cytokines in response to TLR stimulation. TLR signaling activates the NF-κB transcription factor, which promotes the induction of many proinflammatory cytokines and other inflammatory genes. TNFAIP3 is a negative regulator of TRAF6 and inhibits the activation of NFκB. IFN-Is, which include many subtypes of IFN-α and a single subtype of IFN-β, bind to their receptor, which is composed of two chains, IFNAR1 and IFNAR2. Signaling through the receptor results in the activation of receptor-associated Janus kinases, JAK1 and TYK2, which in turn promote the phosphorylation of the STAT family members STAT1, STAT2 and STAT4. Upon activation, STAT proteins dimerize, translocate to the nucleus and induce the expression of IFN-I-inducible genes. In many cases, the evidence supporting certain functions is preliminary or inconclusive, as indicated by the ‘?’and as described in the main text. ATG: Autophagy-specific gene; BDCA: Blood dendritic cell antigen; ETS1: v-ets erythroblastosis virus E26 oncogene homolog 1; FCGR2A: Fc fragment of IgG receptor IIa; IFN-I: Type I interferon; IFNAR: IFN (α and β) receptor; IKZF1: Ikaros family zinc finger 1; IRAK: IL-1 receptor-associated kinase; IRF: Interferon regulatory factor; ITGAM: Integrin α M; JAK: Janus kinase; LYN: v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog; MyD88: Myeloid differentiation primary response gene 88; NCF2: Neutrophil cytosolic factor 2; PRDM1: PR domain containing 1; STAT: Signal transducer and activator of transcription; TLR: Toll-like receptor; TNFAIP: TNF-α-induced protein; TNFSF4: TNF ligand superfamily 4; TRAF6: TNF receptor-associated factor 6; TYK2: Tyrosine kinase 2; UBE2L3: Ubiquitin-conjugating enzyme E2L3.