Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage
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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Targeting DAMPs with nucleic acid scavengers to treat lupus
2022, Translational ResearchIsotype-specific outcomes in Fc gamma receptor targeting of PspA using fusion proteins as a vaccination strategy against Streptococcus pneumoniae infection
2020, VaccineCitation Excerpt :Crosslinking of FcγRIIB with the B-cell receptor (BCR) or activating FcγR provides a contrasting cascade that limits the development of excessive inflammation and autoimmunity. Consequently, an FcγRIIB loss of function polymorphism has been identified as a causative agent of systemic lupus erythematosus in some individuals, due in part to the loss of inhibitory function on B-cells [17]. The mechanisms by which FcγRIIB controls autoimmunity can also play a meaningful role in regulation of humoral and cellular immunity in response to invasive pathogen.
Interleukin-1 single nucleotide polymorphisms and risk of systemic lupus erythematosus among Iraqi patients
2020, Meta GeneCitation Excerpt :Further, genome-wide associations studies identified a growing number of risk loci that exceeded 50 in SLE. The majority of the identified SLE susceptibility genes encode products of innate and adaptive immunity, especially those involved in immunological pathways of SLE pathogenesis such as cytokines (Dai et al., 2014; Julià et al., 2018). Cytokines are important regulators of immune response and play active roles in activation, differentiation, and maturation of immune cells, and imbalance between pro- and anti-inflammatory cytokines is considered as important characteristic of SLE.
Mechanisms of renal damage in systemic lupus erythematosus
2020, Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects
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These authors contributed equally to this review.