Monogenic forms of systemic lupus erythematosus: new insights into SLE pathogenesis

Primary complement defects, especially in early components of the classical pathway, can lead to an increased susceptibility to SLE [3]. However, less than 1% of SLE cases are associated with complement deficiencies, and conversely complement deficiencies are not always associated to SLE [4]. C1q, C1s and C1r complete deficiencies are rare and associated with a high risk to develop pediatric SLE (estimated to 93% for C1q and 66% for C1s/r). C1q deficiency is associated with cutaneous rash in 90% of case and glomerulonopehritis in around 1/3 of cases [5]. Notably, the incidence of anti–double-stranded DNA antibodies "(anti-dsDNA)"is low. C4 deficiency is also strongly associated with SLE development (around 75%) [6‐8] (Table 1). Homozygous C2 deficiency, which is the most frequent hereditary deficiency in classical pathway complement components (1/10,000 to 1/30,000 among caucasians), is associated with SLE in only 10 to 30% of the cases, suggesting that exogenous factors may be also involved. In all cases, early-onset disease and association with recurrent pyogenic or neisserial infections should evoke the diagnosis.

Complement deficiencies demonstrate the crucial role of complement in maintenance of tolerance (Figure 1). Early components of the classical pathway (especially C1q) help clearing apoptotic cells, thus decreasing the number of autoantigens [9]. Another role of complement is to process antibodies and eliminate circulating immune complexes, thus decreasing or avoiding vascular deposition. Interestingly, complement plays a role in T and B cell activation as well, and complement deficiency may upset the balance of lymphoid cell activation[10]. Finally, C1q has also been shown to inhibit in vitro interferon IFN-α production by plasmacytoid dendritic cells [11], and its deficiency can lead to defective suppression of IFN-α in response to immune complex-containing nucleoproteins [12].

Apoptosis defects are thought to be involved in SLE pathogenesis as autoreactive B and/or T cells might survive death signals when they are ongoing central or peripheral tolerance. Nevertheless, to date there is no evidence that apoptosis-related gene defects involving B or T cell tolerance are directly involved in the pathogenesis of SLE. Autoimmune lymphoproliferative syndrome (ALPS) is the human counterpart of the lpr mouse, a widely explored model of murine lupus. Molecular mechanisms of ALPS are related to deficiencies of T cell apoptosis. Mutations in the Fas/FasL pathway underlie ALPS, which is characterized by lymphoproliferation in lymphoid organs associated with multiple autoimmunity [13]. One single case has been reported with classical features of SLE [14].

Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced transcripts [15]. In addition, large-scale genetic analyses have demonstrated that genes involved in IFN-α pathway such as IRF5 IRF7 both expressed downstream of the endosomal TLR or STAT-4, transcriptional factor induced by Interferon type I were associated with SLE [16]. In the last years, studies on early-onset SLE and familial SLE led to the identification of new genes involved in IFN-α production (Table 2). This all started with the identification of the genes responsible for Aicardi-Goutieres syndrome (AGS) [17]. AGS is a rare genetic disorder occurring within the first few weeks of life that can mimic maternofetal infections, with an inflammatory encephalopathy. This autosomal recessive disease is associated with high IFN-α production [18]. Some children with AGS develop an early-onset form of SLE [19, 20].

Nucleic acid are able to initiate an immune response, activating membrane receptors such as Toll-like receptors (TLR) or cytosolic sensors, involved in IFN-α production [21]. Defective clearance of self-derived nucleic acids can cause severe IFN-associated autoimmunity (Figure 1). One major mechanism by which these extracellular nucleic acids cause autoimmunity is through activation of TLR7 and TLR9 on autoreactive B cells [22, 23]. Recently, it has been shown that TREX1 deficiency results in endogenous DNA accumulation and IFN-α production, independently from TLRs [24].

CGD is characterized by recurrent life-threatening infections by bacteria and fungi, due to severely impaired phagocyte intracellular destruction. CGD is caused by defects of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase system, which is responsible for the generation of superoxide and other reactive oxygen species in phagocytic cells. The X-linked form, caused by mutations of the CYBB gene, accounts for more than 75% of the cases [42]. In the large U.S. series of 368 CGD patients, ten (2.7%) affected patients presented concomitantly discoid lupus (DLE) and 2 (0.5%) SLE. A large number of first-degree female relatives were also reported as having SLE or discoid lupus, while infection susceptibility was not increased. Cale et al. [43] investigated 19 mothers who carried the X-linked CGD allele for the presence of lupus manifestations. Remarkably, 12 of them presented photosensitivity, seven arthralgia, and eight had mouth ulcers. Anti-nuclear antibodies were positive in five, one had anti-dsDNA and another a lupus anticoagulant. The link between CYBB mutation and lupus may arise from the apoptosis defect of neutrophils in CGD patients, characterized by an impaired exposure of phosphatidyl serine on neutrophil membrane [44]. Moreover, in CGD neutrophil apoptosis is associated to diminished production of anti-inflammatory mediators [5]. Of note, neutrophils are now have been shown to be important in lupus pathogenesis, especially since mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs) which contain DNA as well as large amounts of proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid dendritic cells [45]. Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and Toll-like receptor 9-dependent manner.

Altogether, these data might suggest that CYBB and other CGD-related genes could be lupus-susceptibility genes.