Abstract
The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.
Highlights
Ankylosing spondylitis (AS) is an immune-mediated arthritis in which inflammation targeting the pelvis and spine contributes to joint erosion and reactive bone deposition
We have investigated a possible role for a class of immune-cell activating and inhibitory receptors in the pathogenesis of ankylosing spondylitis (AS), a common but poorly understood inflammatory arthritis in which the immune system causes severe damage to the joints of the pelvis and spine
We identified and excluded samples with cryptic relatedness, non-Caucasian ancestry, poor killer immunoglobulin-like receptors (KIRs) locus single nucleotide polymorphisms (SNPs) clustering or poor KIR IMP imputed KIR haplotype posterior probability scores
Summary
Ankylosing spondylitis (AS) is an immune-mediated arthritis in which inflammation targeting the pelvis and spine contributes to joint erosion and reactive bone deposition. Of interest is the potential role of killer immunoglobulin-like receptors (KIRs) in disease, a diverse collection of paired signalling receptors expressed predominantly on natural killer (NK) cells (and some T-cell subpopulations) that exhibit variable specificity for class I HLA ligands [10,11,12]. Opposing inhibitory and activating signals transduced through surface KIRs buffer the threshold of activation of KIR-expressing cells, NK cells, serving to quench or promote innate killing activity as required to maintain immune homeostasis and control inflammatory responses. The hypervariable nature of KIRs and their HLA ligands bestows upon the human population a large spectrum of proficiencies in lymphocyte responses to activating stimuli and self-tolerance. KIR-HLA co-inheritance has been associated with various immune-related phenotypes, including infection outcome [13,14,15], and susceptibility to autoimmunity [16,17,18] and cancer [19, 20]
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