Activating KIR and HLA Bw4 ligands are associated to decreased susceptibility to pemphigus foliaceus, an autoimmune blistering skin disease

Abstract

The KIR genes and their HLA class I ligands have thus far not been investigated in pemphigus foliaceus (PF) and related autoimmune diseases, such as pemphigus vulgaris. We genotyped 233 patients and 204 controls for KIR by PCR-SSP. HLA typing was performed by LABType SSO reagent kits. We estimated the odds ratio, 95% confidence interval and performed logistic regression analyses to test the hypothesis that KIR genes and their known ligands influence susceptibility to PF. We found significant negative association between activating genes and PF. The activating KIR genes may have an overlapping effect in the PF susceptibility and the presence of more than three activating genes was protective (OR=0.49, p=0.003). A strong protective association was found for higher ratios activating/inhibitory KIR (OR=0.44, p=0.001). KIR3DS1 and HLA-Bw4 were negatively associated to PF either isolated or combined, but higher significance was found for the presence of both together (OR=0.34, p<10(-3)) suggesting that the activating function is the major factor to interfere in the PF pathogenesis. HLA-Bw4 (80I and 80T) was decreased in patients. There is evidence that HLA-Bw4(80T) may also be important as KIR3DS1 ligand, being the association of this pair (OR=0.07, p=0.001) stronger than KIR3DS1-Bw4(80I) (OR=0.31, p=0.002). Higher levels of activating KIR signals appeared protective to PF. The activating KIR genes have been commonly reported to increase the risk for autoimmunity, but particularities of endemic PF, like the well documented influence the environmental exposure in the pathogenesis of this disease, may be the reason why activated NK cells probably protect against pemphigus foliaceus.

Figure 1. Frequency of the number of activating and inhibitory KIR genes in patients and controls.

Only the Euro population was considered. (A) KIR2DL4 was counted as activating gene and the deleted KIR2DS4 was not counted as activating or inhibitory. Significant negative association was found for the presence of more than 3 activating genes (OR  = 0.49; 95% CI = 0.30–0.79; p = 0.003). (B) KIR3DL3 was not included as inhibitory. (C) Significant negative association was found for the ratio higher than 0.75 (OR  = 0.44; 95% CI  = 0.27–0.73; p = 0.001).

Figure 2. Association analyzes for the combinations KIR x HLA ligands.

The bars indicate the 95% confidence interval and the black spot indicates the OR. The results for the Euro sample are shown. The results for the two population strata and the complete information about KIR and HLA combinations are found in Table S2. *at least one Bw4 epitope (80I from HLA-A or HLA-B loci or 80T).