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.

Genome‐wide gene expression profiling reveals unsuspected molecular alterations in pemphigus foliaceus

“…Interestingly, the 19q13 region includes genes whose qualitative and/or quantitative variation influences PF pathogenesis. The presence of a higher number of activating KIR genes was associated with lower susceptibility to pemphigus foliaceus . In the present study, we did not detect significant differences between patients and controls regarding KIR gene expression.…”

KIR Gene Content in Amerindians Indicates Influence of Demographic Factors

“…The combinations of KIR variants and specific variants of the cognate HLA ligands should be analyzed in future studies to refine the analysis in search of signatures of natural selection. Several examples of associations between KIR / HLA genotypes and variation of susceptibility to multifactorial diseases have been reported [37]–[41]. Some of these combined genotypes affect morbidity and mortality and thus fitness, therefore signs of natural selection could be revealed at the levels of both population and nucleotide/aminoacid sequence analyses, as reported for the KIR3DL1/S1 polymorphism [42].…”

16th IHIW: Population Global Distribution of Killer Immunoglobulin‐like Receptor (KIR) and Ligands

“…We contribute with two samples for this workshop: Curitiba ( n = 162) is from Southern Brazil (Curitiba, Parana State) of predominantly European ancestry, and its KIR diversity was already reported (Augusto et al ., ,b;); the second one, Campo Grande ( n = 205) from Western Brazil. This population is extensively mixed by European and African ancestries, but also there is a significant Amerindian component.…”