Elsevier

Current Opinion in Immunology

Volume 31, December 2014, Pages 87-96
Current Opinion in Immunology

Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage

https://doi.org/10.1016/j.coi.2014.10.004Get rights and content

Highlights

  • GWA studies that identify candidate genes in human lupus are summarized.

  • Examples of the identification of candidate genes are provided.

  • Human and murine genes conferring end organ resistance to damage are discussed.

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder. Considerable progress has been made to delineate the genetic control of this complex disorder. In this review, selected aspects of human and mouse genetics related to SLE are reviewed with emphasis on genes that contribute to both innate and adaptive immunity and to genes that contribute directly to susceptibility to end organ damage. It is concluded that the interactions among these two major pathways will provide further insight into the pathogenesis of SLE. An interactive model of the two major pathways is proposed without emphasis on the importance of breaking tolerance to autoantigens.

Section snippets

Overview of human SLE genetics

The initial approaches, including linkage analysis and candidate gene association studies, identified and confirmed a limited number of SLE-associated loci (e.g. HLA-DR2/DR3). The genome-wide association study (GWAS) approach to screen hundreds of thousands of single nucleotide polymorphisms (SNPs) across the genome in a hypothesis-free manner has advanced our understanding of genetic basis of SLE. Since 2007, eight GWAS in SLE (four in European-derived [3, 4, 5, 6] and four in Asian

Clearance of apoptotic cells and ICs

Inefficient clearance of apoptotic cells and ICs that may result in autoantigens accumulation promote initiation and maintenance of autoimmune responses in SLE. Deficiencies or polymorphisms in genes encoding components required for this process confer susceptibility to SLE (reviewed in [13]). For example, ITGAM encodes the α-chain of αMβ2 integrin that functions in phagocytosis of complement-coated particles and ICs as well as regulation of leukocyte apoptosis, adhesion and migration via

T cell signaling and function

Genes involved in T cell functions have been associated with SLE. The importance of highly conserved and extended haplotypes bearing the class II HLA-DR2 and HLA-DR3 alleles in SLE susceptibility has been well recognized [13]. HLA class II molecules are critical in mediating host defense responses through antigen presentation and immune tolerance by self/non-self recognition. Given of their roles in T-cell dependent antibody and effector responses, cumulative evidence supports association of

SLE susceptibility genes with other functions

In addition to immune signaling, several SLE susceptibility genes with functions linked to the other pathways contribute to the pathogenesis of SLE. For example, NCF2 encodes a subunit of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex involved in the ROS generation. Overproduction of ROS may lead to oxidative stress that stimulates autoimmune responses. A surprising finding of the SLE-risk variant in human NCF2 gene leading to low NADPH oxidase activity and reduced ROS

Emergence of genes controlling susceptibility to end organ damage

Since non-muscle myosin heavy chain 9 (MYH9) has been implicated in focal segmental glomerulosclerosis, HIV-associated nephropathy, hypertensive end-stage renal disease (ESRD) and diabetes and non-diabetic ESRD, its role in lupus nephritis was investigated together with the closely-linked gene APOL1 [37]. No significant association was found in EA, AA, Asians, Amerindians or Hispanics. However, a recent study published in Arthritis & Rheumatology by Freedman et al. indicates that APOL1 G1/G2

NZM2410

The contributions to our understanding of the pathogenesis of SLE by studies in animal models have been extensively reviewed by Hahn and Kono [40]. The recent studies on the NZM strains have enhanced our understanding of the complexity of lupus genetics. The two most studied strains are NZM2410 and NZM2328. L. Morel has summarized the studies on NZM2410 [41••]. Because of the approach taken by her and her colleagues by generating congenic lines with Sle1-3 on B6 background and the lack of

Future directions

The implication of our findings in NZM2328 has been discussed in two review papers [45••, 46]. The findings reviewed here provide us a frame-work for future investigation on the pathogenesis of SLE. Figure 3 summarizes our working model for the pathogenesis of SLE. It is important to note that this model has a general application to other autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, type I diabetes mellitus, etc.

Future challenges in understanding SLE genetics

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work is supported by grants from NIH P50-AR04522, R01-AR047988, and R01-AR049449 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, R01-AI079621 from the National Institute of Allergy and Infectious Diseases and grants from Alliance for Lupus Research to SMF, a grant from National Human Genome Research Institute, R01-HG006693 to AQ and grants from NIH R01-AR043814 and R21-AR065626 and the Alliance for Lupus Research to BPT.

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