Abstract
Genetic studies in the last 5 years have greatly facilitated our understanding of how the dysregulation of diverse components of the innate immune system contributes to pathophysiology of SLE. A role for macrophages in the pathogenesis of SLE was first proposed as early as the 1980s following the discovery that SLE macrophages were defective in their ability to clear apoptotic cell debris, thus prolonging exposure of potential autoantigens to the adaptive immune response. More recently, there is an emerging appreciation of the contribution both monocytes and macrophages play in orchestrating immune responses with perturbations in their activation or regulation leading to immune dysregulation. This paper will focus on understanding the relevance of genes identified as being associated with innate immune function of monocytes and macrophages and development of SLE, particularly with respect to their role in (1) immune complex (IC) recognition and clearance, (2) nucleic acid recognition via toll-like receptors (TLRs) and downstream signalling, and (3) interferon signalling. Particular attention will be paid to the functional consequences these genetic associations have for disease susceptibility or pathogenesis.
Highlights
This study found that the odds ratios (ORs) for the development of Systemic lupus erythematosus (SLE) among individuals with the T/T and I/T genotypes versus the I/I genotype were 2.3 and 1.1, respectively
Consistent with results seen by Tao et al investigating Toll-Like Receptor 9 (TLR9), the exonic region rs352139A/G single nucleotide polymorphism (SNP) has been mildly associated with SLE (P = 0.040), with genetic analysis in a Japanese population indicating that carrying the G allele of this polymorphism predisposes individuals to an increased risk of SLE through the downregulation of TLR9 expression levels in reporter gene assays [28]
The only known functional polymorphism in IRF7 is the nonsynonymous SNP rs1131665 which encodes a protein carrying a Q to R mutation at position 412 [30]. This variant has been shown to be associated with SLE patients of Asian and European American ancestry (P = 6.18 × 10−6), and functional analysis of the mutated protein revealed its enhanced transcriptional activation of an ISRE-dependent promoter. This is in keeping with the hypothesis that SLEassociated IRF7 polymorphisms may lead to the expression of proteins with increased activity downstream of the toll-like receptors (TLRs), leading to overproduction of type I IFN characteristic of the disease
Summary
Systemic lupus erythematosus (SLE) is a multisystem chronic autoimmune disease, which affects approximately 0.1% of the population, with women being approximately nine times more likely to develop the disease than men [1]. Recently attention has shifted to the role of the innate immune system and myeloid cells in disease Both monocytes and macrophages are phenotypically altered in SLE, with SLE macrophages demonstrated to have reduced uptake of apoptotic cells, enhanced activatory status, an altered skew of proinflammatory and anti-inflammatory macrophages and an overproduction of inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL6), interleukin-10 (IL-10), and antiviral type I interferons (IFNs) (Figure 1) [3,4,5]. Whilst the focus of this paper is the involvement of these candidate genes in macrophage function and their contribution to SLE pathology, it must be stressed that many of the candidate genes discussed below, those that regulate type I IFN production, play an important role in dendritic cell-driven autoimmune pathology [15, 16]
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