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Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called \u201ceducation\u201d to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression (\u201cMissing-self\u201d hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1\/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1<jats:sup>+<\/jats:sup>C2<jats:sup>+<\/jats:sup>Bw4<jats:sup>+<\/jats:sup>) was not associated with MM occurrence. However, MM patients were more likely to be C1<jats:sup>-<\/jats:sup>\/C2<jats:sup>+<\/jats:sup>\/Bw4<jats:sup>+<\/jats:sup> (<jats:italic>p<\/jats:italic> = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (<jats:italic>p<\/jats:italic> = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2\/KIR2DL1 and Bw4\/KIR3DL1 (<jats:italic>p<\/jats:italic> = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.<\/jats:p>","DOI":"10.1007\/s00251-024-01336-w","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T20:05:59Z","timestamp":1710360359000},"page":"155-164","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["HLA class I NK-epitopes and KIR diversities in patients with multiple myeloma"],"prefix":"10.1007","volume":"76","author":[{"given":"Nicky A.","family":"Beelen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan J. 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