Association of Killer Cell Immunoglobulin- Like Receptor Genes in Iranian Patients with Rheumatoid Arthritis

Abstract

ObjectivesRheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by persistent synovitis, ultimately leading to cartilage and bone degeneration. Natural Killer cells and CD28 null T-cells are suspected as role players in RA pathogenesis. These cells are similar in feature and function, as they both exert their cytotoxic effect via Killer Cell Immunoglobulin- Like Receptors (KIR) on their surface. KIR genes have either an inhibitory or activating effect depending on their intracytoplasmic structure. Herein we genotyped 16 KIR genes, 3 pseudo genes and 6 HLA class І genes as their corresponding ligands in RA patients and control subjects.MethodsIn this case-control study, KIR and HLA genes were genotyped in 400 RA patients and 372 matched healthy controls using sequence-specific primers (SSP-PCR). Differences in the frequency of genes and haplotypes were determined by χ² test.Results KIR2DL2, 2DL5a, 2DL5b and activating KIR: KIR2DS5 and 3DS1 were all protective against RA. KIR2DL5 removal from a full Inhibitory KIR haplotype converted the mild protection (OR = 0.56) to a powerful predisposition to RA (OR = 16.47). Inhibitory haplotype No. 7 comprising KIR2DL5 in the absence of KIR2DL1 and KIR2DL3 confers a 14-fold protective effect against RA.ConclusionIndividuals carrying the inhibitory KIR haplotype No. 6 have a high potential risk for developing RA.

Role of KIR gene cluster in susceptibility to rheumatoid arthritis

“…Moreover, it was found that the incidence of inhibitory gene KIR3DL1 was higher in frequency among the RA patients than the controls in the study population (P value-0.0446, OR-2.8141, 95% CI-1.0965 to 7.2222). The protective functionality of KIR genes in RA as reported in different populations [8][9][10][11][12][13] was not observed in this study group. Distribution of the KIR genes in patient and control group in terms of frequency of occurrences has been illustrated in Figure 2.…”

“…9 In Polish population, 10 it has been found that frequencies of KIRs in patients with RA are similar to the frequencies in controls whereas in Iranian population KIR2DL2, KIR2DL5, KIR2DS5 and KIR3DS1 are found to be protective against RA. 8 In North Indian population also KIR association with RA has been studied where they observed KIR3DS1 and KIR2DS2 have risk association however KIR2DL2, KIR2DL3 and KIR3DL1 have protective function. 13 Another observation was made where KIR3DL1, which is normally classified under inhibitory signaling genes, 8 has been found to be higher in patients than in controls, thus contraindicating its inhibitory role in the population in Assam.…”

“…8 In North Indian population also KIR association with RA has been studied where they observed KIR3DS1 and KIR2DS2 have risk association however KIR2DL2, KIR2DL3 and KIR3DL1 have protective function. 13 Another observation was made where KIR3DL1, which is normally classified under inhibitory signaling genes, 8 has been found to be higher in patients than in controls, thus contraindicating its inhibitory role in the population in Assam. Other KIR genes viz., KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS2, KIR3DL2, KIR3DL3, KIR3DS1, KIR2DP1, KIR3DP1 were found to have similar frequencies in both cases and controls and their relationship with RA could not be statistically proven.…”

“…6 Natural killer (NK) cells, which are bone marrow derived large granular lymphocytes, mount early immune responses in an antigen independent manner by direct cytotoxicity. 7 [8][9][10][11][12][13] Studies on the relationship of KIR and RA are inconsistent and contradictory. 14 In the Northeastern parts of India, only a few studies related to association of genetic factors related to RA, have been done.…”

The shortening telomere length of T lymphocytes maybe associated with hyper‑function in servere aplastic anemia

“…CD70 is the immunoglobulin superfamily member, which CD70 is similar with TNF family members and can regard as the co-stimulatory signaling molecule of T leukomonocytes regulating the activation of B leukomonocytes ( 28 , 29 ). In normal, T cells hardly express CD70 and CD158, but when the organism undergone a series of allergic reaction or autoimmune response, the activated T lymphocytes increased expression of CD70 and CD158, which indicates that they play a important role in pathological damage caused by immune disorders ( 30 , 31 ). The high level of effector molecules has the additional effect of lowering the T cell activation threshold, enhanced cytotoxicity and display suppressive functions, finally, it would progress into an autoimmune disease, e.g., rheumatoid arthritis (RA), multiple sclerosis, Wegener's granulomatosis, Graves' disease, or Ankylosing spondylitis ( 32 , 33 ).…”