Immunogenetics of lupus erythematosus

Immunopathogenesis of SLESystemic Lupus Erythematosus(SLE) is a systemic autoimmune diseasewith a prevalence of approximately1/2500 in European populationsaffecting mainly females (9females:1male) (1). It's characterizedby a plethora of immunologicalandlaboratory abnormalities withmultipleorgan / tissue damage. Almostall of the key components in the immune system are involved inthe disease pathogenesis which islargely still unclear (2) .Deficiencies in the recognitionand clearance of apoptotic cells byphagocytosis have been shown inpatients with SLE (3,4). Whetherapoptosis itself is abnormal or merelyan effect of environmental triggers,suchas U.V. irradiation or viral infection,is less understood (5,6) .During necrosis or apoptosis nuclearantigens are subjected to modificationswhich allow them to be rec- ognized as non-self. Activation ofTLR7 and TLR9 by self nucleic acidsand immune complexes leads to theproduction of IFN-α and proinflammatorycytokines such as IL-6, TNF?and IL-12 (7) .IFN-α fosters autoimmunity byseveral mechanisms; It promotesdendritic cell maturation, the productionof pro-inflammatory cytokines,stimulationof Thl pathways, B-cellactivation, plasma cell differentiationandregulation of apoptosis . InSLE the type IFNα can contribute toloss of tolerance and activation ofautoreactive T and B cells with productionof autoantibodies (9). The expression of antinuclearantibodies (ANA) can be dividedto three stages: antibody induction,maintenance and elimination.Antigens involved in the first twostages may not be the same.Indeed, there is evidence thatviral and bacterial antigens can induceANA production while selfmoleculesmay mediate antibodymaintenance (10) .However, recent studies bySchroeder et al 2013 (11), Detanicoet al 2013 (12) (8) argue that ANA arise predominantly from nonautoreactiveB cells that are transformed into autoreactivecells by the process of somatichypermutation , which is normallyassociated with affinitymaturationduring the germinal centerreaction. CD4 T cell differentiation is alteredin SLE presented in the biasofTH1/TH2 balance to TH1 (13) andsubsequently transcriptional factorsT-bet /GATA3 to T-bet (14), and inthe bias of TH17 / Treg to TH17 andsubsequently transcriptional factorsROR?t/Foxp3 to RORαt (15,16). Besidesthe role of follicular helper(TFH) (17) in providing help to Bcells allowing the formation of germinalcenter (18). CD8 T cell function is impaired inperipheral blood T cells from patientswith SLE. Double-negative T cellsare also expanded and found withincellular infiltrates in kidney biopsiesof patients with lupus nephritis withsecretion of IL-1b and IL-17 (19)SLE susceptibility genesHere we summarize the con-firmed genetic risk loci placed in thecontext of major SLE disease pathways , where possible