Genetics of human lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by immune complex formation with multi-organ manifestations. Lupus nephritis (LN) is one of the most severe types of organ damage in SLE, and it clearly contributes to increased morbidity and mortality due to SLE. LN occurs more frequently and is more severe in non-European ancestral backgrounds, although the cause of this disparity remains largely unknown. Genetic factors play an important role in the pathogenesis of SLE. Although many SLE susceptibility genes have been identified, the genetic basis of LN is not as well understood. While some of the established general SLE susceptibility genes are associated with LN, recent discoveries highlight a number of genes with renal functions that are specifically associated with LN. Some of these genes associated with LN help to explain the disparity in the prevalence of nephritis between individuals with SLE, and also partially explain differences in LN between ancestral backgrounds. Moreover, not only the gene mutations, but also post-translational modifications seem to play important roles in the pathogenesis of LN. Overall it seems likely that a combination of general SLE susceptibility genes cooperate with LN specific risk genes to result in the genetic propensity for LN. In this review, we will outline the genetic contribution to LN and describe possible roles of LN susceptibility genes.

Keywords: APOL1; Genetics; HAS2; Lupus nephritis; PDGFR; Systemic lupus erythematosus.

Figure 1. Interactions between multiple factors predisposing to LN

Interactions between genetic factors and environmental factors predispose to SLE and LN. LN, lupus nephritis; SLE, systemic lupus erythematosus

Figure 2. SLE and LN susceptibility genes

Venn diagram of SLE and LN susceptibility genes. LN, lupus nephritis; SLE, systemic lupus erythematosus

Figure 3. Genetic contribution to immune system in the pathogenesis of LN

Altered functions of complement receptors (Mac-1) and FcgR will result in defective clearance of apoptotic cells and move towards secondary necrosis. Phagocyted nuclear antigens will activate TLRs and altered IRF5 leads to increased production of IFN alpha. Co-stimulatory factors (i.e. HLA and OX40L) activate T cells and result in IFN gamma production via STAT4 activation. Altered ABIN1 function, caused by TNIP1 variant leads to dysregulation of NF-kappaB activation. Auto-antibodies will be produced by B cells with the help of activated T cells. IFNs will induce APOL1 expression in the kidney. IL-1 beta, secreted by activated APC (e.g. macrophages) and the signal of PDGF via PDGFR will eventually lead to increased expression of HA via HAS2. ABIN1, A20 binding and inhibitor of NF-kappaB 1; APC, antigen presenting cell; APOL1, apolipoprotein L-1; FCGR, Fc gamma receptor; HA, hyaluronan; HAS2, hyaluronan synthase 2; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; IRF5, interferon regulatory factor 5; ITGAM, integrin alpha M; OX40L, OX40 ligand; PDGFRA, platelet-derived growth factor receptor alpha; STAT4, signal transducers and activators of transcription 4; TLRs, Toll-like receptors; TNFSF4, tumor necrosis factor super family 4; * Susceptible genes.