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      KIR Variation in Iranians Combines High Haplotype and Allotype Diversity With an Abundance of Functional Inhibitory Receptors

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          Natural killer (NK) cells are innate lymphocytes that eliminate infected and transformed cells. They discriminate healthy from diseased tissue through killer cell Ig-like receptor (KIR) recognition of HLA class I ligands. Directly impacting NK cell function, KIR polymorphism associates with infection control and multiple autoimmune and pregnancy syndromes. Here we analyze KIR diversity of 241 individuals from five groups of Iranians. These five populations represent Baloch, Kurd, and Lur, together comprising 15% of the ethnically diverse Iranian population. We identified 159 KIR alleles, including 11 not previously characterized. We also identified 170 centromeric and 94 telomeric haplotypes, and 15 different KIR haplotypes carrying either a deletion or duplication encompassing one or more complete KIR genes. As expected, comparing our data with those representing major worldwide populations revealed the greatest similarity between Iranians and Europeans. Despite this similarity we observed higher frequencies of KIR3DL1 * 001 in Iran than any other population, and the highest frequency of HLA-B *51, a Bw4-containing allotype that acts as a strong educator of KIR3DL1 * 001 + NK cells. Compared to Europeans, the Iranians we studied also have a reduced frequency of 3DL1 * 004, which encodes an allotype that is not expressed at the NK cell surface. Concurrent with the resulting high frequency of strong viable interactions between inhibitory KIR and polymorphic HLA class I, the majority of KIR-A haplotypes characterized do not express a functional activating receptor. By contrast, the most frequent KIR-B haplotype in Iran expresses only one functional inhibitory KIR and the maximum number of activating KIR. This first complete, high-resolution, characterization of the KIR locus of Iranians will form a valuable reference for future clinical and population studies.

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          Most cited references 58

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          Phylogenetic Analysis: Models and Estimation Procedures

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            Human diversity in killer cell inhibitory receptor genes.

            The presence and expression of killer inhibitory receptor (KIR) and CD94:NKG2 genes from 68 donors were analyzed using molecular typing techniques. The genes encoding CD94:NKG2 receptors were present in each person, but KIR gene possession varied. Most individuals expressed inhibitory KIR for the three well-defined HLA-B and -C ligands, but noninhibitory KIR genes were more variable. Twenty different KIR phenotypes were defined. Two groups of KIR haplotypes were distinguished and occurred at relatively even frequency. Group A KIR haplotypes consist of six genes: the main inhibitory KIR, one noninhibitory KIR, and a structurally divergent KIR. Allelic polymorphism within five KIR genes was detected. Group B comprises more noninhibitory KIR genes and contains at least one additional gene not represented in group A. The KIR locus therefore appears to be polygenic and polymorphic within the human population.
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              The shaping of modern human immune systems by multiregional admixture with archaic humans.

              Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                02 April 2020
                : 11
                1Department of Immunology, IRCCS Bambino Gesù Children's Hospital , Rome, Italy
                2Department of Structural Biology, Stanford University School of Medicine , Stanford, CA, United States
                3Department of Microbiology and Immunology, Stanford University School of Medicine , Stanford, CA, United States
                4Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences , Tehran, Iran
                5School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences , Shiraz, Iran
                6Division of Immunology, Department of Pathology, University of Cambridge , Cambridge, United Kingdom
                7Department of Neurology, University of California, San Francisco , San Francisco, CA, United States
                8Blood Center of Zhejiang Province , Hangzhou, China
                9Division of Personalized Medicine, Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus , Aurora, CO, United States
                Author notes

                Edited by: Martin Maiers, National Marrow Donor Program, United States

                Reviewed by: Ketevan Gendzekhadze, City of Hope National Medical Center, United States; Johannes Schetelig, Universitätsklinikum Carl Gustav Carus, Germany

                *Correspondence: Paul J. Norman paul.norman@

                This article was submitted to NK and Innate Lymphoid Cell Biology, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Copyright © 2020 Alicata, Ashouri, Nemat-Gorgani, Guethlein, Marin, Tao, Moretta, Hollenbach, Trowsdale, Traherne, Ghaderi, Parham and Norman.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 71, Pages: 12, Words: 6928
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R01 AI017892
                Funded by: European Research Council 10.13039/501100000781
                Original Research


                immune diversity, nk cells, kir, hla class i, iranian populations


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