Killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C) allorecognition patterns in women with endometriosis

Ya-Ching Chou,Pi-Hua Chen,Yi-Jen Chen,Mu-Hsien Yu,Ming-Jer Chen,Peng-Sheng Yang,Ching-Wen Chang,Eing-Mei Tsai,Chii-Ruey Tzeng,Shyr-Yeu Lin,Chi-Huang Chen

doi:10.1038/s41598-020-61702-y

Abstract

Endometriosis shares similarities with several autoimmune diseases. The human leukocyte antigen (HLA)-C genotype is associated with several human autoimmune diseases. HLA-C is a ligand of killer cell immunoglobulin receptors (KIRs) and is an essential regulator of natural killer cell activity, which is associated with endometriosis progression. Polymorphisms in HLA-C and KIR affect the activity of NK cells and susceptibility to several diseases. Therefore, we attempted to investigate an association between HLA-C genotype and KIR polymorphism and the occurrence of endometriosis. We tested the association of certain KIR and HLA-C combinations and the development of endometriosis by characterizing both KIR and HLA-C genes in 147 women with endometriosis and 117 controls. The HLA-C genotypes and KIR polymorphisms were analyzed via DNA-based method for higher-resolution genotyping. We found that the occurrence of HLA-C*03:03*01 was increased in endometriosis than in control groups. Analysis of various KIR haplotypes revealed differences between the endometriosis and control cohorts. The number of KIR centromeric A/A haplotypes was increased in the endometriosis group than controls. Moreover, the endometriosis cohort was characterized by reduced number of KIR2DS2-positive individuals in the Han Chinese population. Our current findings suggest that the KIR and HLA-C genotypes are associated with the pathogenesis of endometriosis.

Highlights

Endometriosis is a chronic gynecological disease with unknown etiology and is characterized by extra-uterine growth of endometrial tissue[1]
The presence of human leukocyte antigen (HLA)-C*03:03:01 significantly increased the risk of endometriosis with p = 0.0473 [Odds Ratio (OR) = 2.811, 95% confidence interval (CI) = 1.021–7.738] and the statistical power was 43.8% (Table 2)
Abnormal immune responses are recognized in endometriosis patients, including excessive inflammatory cytokine secretion, autoantibody production, and natural killer (NK) cell regulation[17,18]

Summary

Introduction

Endometriosis is a chronic gynecological disease with unknown etiology and is characterized by extra-uterine growth of endometrial tissue[1]. HLA genes are polymorphic in binding and function in presenting antigen peptides to T-cells. HLA molecules are key factors involved in regulating the specificity of T-cell-mediated immune response in autoimmune and infectious diseases[19,20,21]. HLA Class I genes encode cell-surface proteins, whose primary functions are to present antigens to cytotoxic CD8+ T-cells during the early immune responses[19,20,21]. HLA-C acts as a ligand for killer cell immunoglobulin-like receptors (KIRs), which regulate natural killer (NK) cell-mediated cytotoxicity. NK cells are lymphocytes that serve as vital components of the immune system by regulating early responses against infected or transformed cells via cytokine production and direct cytotoxicity[27]. KIR3DL3, KIR3DP1, KIR2DL4, and KIR3DL2 are framework genes and are always present in the genome[32]

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Conclusion