Table 2: Mechanisms implicated by susceptible genes for SLE.

Characteristics of the geneGenes/lociImmunological effects

Genes related to innate immune responseIRF5
TNFAIP3
IRAK1
STAT4
TREX1
(i) IRF5 is the most consistent non-MHC gene in SLE and is important for transactivation of type 1 IFN and production of proinflammatory cytokines (IL6, IL12, TNF α, IL10).
(ii) Other genes also involved in pathways of type 1 IFN production.

Genes related to adaptive immune response (T-cell signaling)HLA-DR
PTPN22
STAT4
PDCD1
IRAK1
TNFSF4
(i) HLA region at 6p21.3 has shown strongest association with SLE. MHC class II genes influence antigen presentation by interacting with T cell receptor (TCR), and susceptible HLA haplotype contributes to abnormal response to self antigens.
(ii) Other genes are involved in hyperactivity of T cells and failure of multiple immunoregulatory circuits to down-regulate those responses.

Genes related to adaptive immune response (B-cell signaling)HLA-DR
BLK
BANK1
LYN
These genes are involved in hyperactivity of B cells and failure of multiple immunoregulatory circuits to downregulate those responses.

Genes related to immune complex clearingComplements
(C1q, C2, C4)
FCGR2A
FCGR3A
CRP
ITGAM
(i) These genes are associated with dysregulated and inadequate immune complex clearance in SLE.
(ii) ITGAM encodes integrin α M (complement receptor type 3) and is involved in immune complex clearance, leukocyte activation, phagocytosis, and adhesion to endothelia through interaction with multiple ligands, for examples, ICAM-1, C3bi, fibrinogen, glycoprotein Iba. ITGAM gene plays a key role in SLE pathogenesis, especially through endothelial injury.
(iii) FCGR2A and FCGR3A genes code the IgG Fc receptor IIA and IIIA. The lupus predisposing polymorphisms in these genes relate to poor binding to IgG and phagocytosis of immune complexes.

Other genes in SLE pathogenesisMECP2
ATG5
(i) MECP2 is involved in DNA methylation.
(ii) ATG5 is involved in apoptosis.