Association of KIR Genes and MHC Class I Ligands with Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic illness that is associated with immune dysregulation. NK cell function has previously been associated with AD. NK cells directly interact with polymorphic HLA class I ligand variants using killer cell Ig-like receptors (KIRs). The purpose of this study was to identify potential associations between NK cell function and AD by evaluating variation in the presence of KIR genes as well as KIR gene interactions with the appropriate HLA class I KIR–specific ligands. Human DNA from the genetics of AD case–control study was used to genotype HLA class I KIR–specific ligands and the presence of KIR genes. In the full cohort, an increased risk of AD was noted for KIR2DL5 (1.51 [1.13, 2.01]), KIR2DS5 (1.72 [1.26, 2.34]), and KIR2DS1 (1.41 [1.04, 1.91]). Individuals with KIR2DS5 or KIR2DS1 and the HLA-C*C2 epitope were at an increased risk of AD (1.74 [1.21, 2.51] and 1.48 [1.04, 2.12], respectively). The HLA-B*-21T (TT) leader sequence increased the risk of AD across ethnicity. African Americans with KIR2DL2, KIR2DS1, KIR2DL5, and KIR2DS5 are more likely to have AD, and the risk increased for KIR2DS1 and KIR2DS5 in the presence of appropriate HLA-C C2 epitope. The risk of AD also increased for individuals with the HLA-B*-21T leader sequence. Future studies should focus on KIR gene allelic variation as well as consider cell-based measurements of KIR and the associated HLA class I epitopes.

Association of KIR2DL5, KIR2DS5, and KIR2DS1 allelic variation and Atopic Dermatitis

“…18,20,21 We have recently shown that the KIR genes KIR2DL5, KIR2DS5, and KIR2DS1 are more frequently found in individuals with AD. 22 This is also true for the HLA-C2 epitope and HLA-B*-21T leader sequence. 22 The goal of this study was to examine allelic variation in previously associated KIR genes KIR2DL5, KIR2DS5, and KIR2DS1 with AD.…”

“…22 This is also true for the HLA-C2 epitope and HLA-B*-21T leader sequence. 22 The goal of this study was to examine allelic variation in previously associated KIR genes KIR2DL5, KIR2DS5, and KIR2DS1 with AD. This investigation is important in that previous studies have shown that KIR association with diseases such as HIV and preeclampsia is highly dependent on allelic variation and cell surface expression also varies signi cantly by KIR allotype.…”

Immunogenomics of Killer Cell Immunoglobulin-Like Receptor (KIR) and HLA Class I: Coevolution and Consequences for Human Health

“…One of the most recently identified examples is atopic dermatitis, in which distinct compound genotypes associate, respectively, with susceptibility and progression of disease. [175][176][177] These types of relationships are likely to be recapitulated in further immune-mediated diseases such as multiple sclerosis, which has established associations with KIR and HLA combinatorial diversity. 175,178 The recent confirmation that multiple sclerosis is triggered by EBV infection 179,180 places cytotoxic immune effector cells in context of both initiation and progression of the disease.…”

Atopic Dermatitis Is Associated with Preeclampsia and Endometriosis

“…KIR and HLA-C ligands have also been associated with the development of endometriosis ( Chou et al., 2020 ). A recent study revealed that KIR gene variation is associated with AD ( Margolis et al., 2021 ). Because NK cell function and KIR genes appear to be involved in the pathogenesis of AD, preeclampsia, and endometriosis, it is possible that there may be an association between these conditions.…”

“…The findings of our work and others support that nonallergic illnesses are also associated with AD ( Sinaii et al., 2002 ; Stokholm et al., 2017 ). Furthermore, the associations with preeclampsia and endometriosis are potentially related to genetic variation in KIR genes and NK cell function, revealing additional immunologic pathways that may be associated with AD ( Margolis et al., 2021 ; Nakimuli et al., 2015 ).…”