Publications by authors named "Peter Parham"

184 Publications

Abundant CpG-sequences in human genomes inhibit KIR3DL2-expressing NK cells.

PeerJ 2021 5;9:e12258. Epub 2021 Nov 5.

Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, United States.

Killer Immunoglobulin-like Receptors (KIR) comprise a diverse, highly polymorphic family of cell-surface glycoproteins that are principally expressed by Natural Killer (NK) cells. These innate immune lymphocytes fulfill vital functions in human reproduction and immune responses to viral infection. KIR3DL2 is an inhibitory NK cell receptor that recognizes a common epitope of the HLA-A3 and HLA-A11 class I glycoproteins of the major histocompatibility complex. KIR3DL2 also binds exogenous DNA containing the CpG motif. This interaction causes internalization of the KIR-DNA. Exogenous CpG-DNA typically activates NK cells, but the specificity of KIR3DL2-DNA binding and internalization is unclear. We hypothesized that KIR3DL2 binds exogenous DNA in a sequence-specific manner that differentiates pathogen DNA from self-DNA. In testing this hypothesis, we surveyed octameric CpG-DNA sequences in the human genome, and in reference genomes of all bacteria, fungi, viruses, and parasites, with focus on medically relevant species. Among all pathogens, the nucleotides flanking CpG motifs in the genomes of parasitic worms that infect humans are most divergent from those in the human genome. We cultured KIR3DL2NKL cells with the commonest CpG-DNA sequences in either human or pathogen genomes. DNA uptake was negatively correlated with the most common CpG-DNA sequences in the human genome. These CpG-DNA sequences induced inhibitory signaling in KIR3DL2NKL cells. In contrast, KIR3DL2NKL cells lysed more malignant targets and produced more IFNγ after culture with CpG-DNA sequences prevalent in parasitic worms. By applying functional immunology to evolutionary genomics, we conclude that KIR3DL2 allows NK cells to differentiate self-DNA from pathogen DNA.
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http://dx.doi.org/10.7717/peerj.12258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574216PMC
November 2021

Following Transplantation for Acute Myelogenous Leukemia, Donor Better Protects against Relapse than .

J Immunol 2021 Jun 11. Epub 2021 Jun 11.

Department of Structural Biology, Stanford University, Stanford, CA;

In the treatment of acute myelogenous leukemia with allogeneic hematopoietic cell transplantation, we previously demonstrated that there is a greater protection from relapse of leukemia when the hematopoietic cell transplantation donor has either the / genotype or a genotype having two or more gene segments. In those earlier analyses, genotyping could only be assessed at the low resolution of gene presence or absence. To give the analysis greater depth, we developed high-resolution sequence-based typing that defines all the alleles and distinguishes the expressed alleles from those that are not expressed. We now describe and analyze high-resolution genotypes for 890 donors of this human transplant cohort. and are the common haplotypes, with having evolved from by deletion of the , , , and genes. We observed a consistent trend for to provide stronger protection against relapse than This correlation indicates that protection depends on the donor having inhibitory KIR2DL2 and/or activating KIR2DS2, and is enhanced by the donor lacking inhibitory KIR2DL1, 2DL3, and 3DL1. High-resolution KIR typing has allowed us to compare the strength of the interactions between the recipient's HLA class I and the KIR expressed by the donor-derived NK cells and T cells, but no clinically significant interactions were observed. The trend observed between donor and reduced relapse of leukemia points to the value of studying ever larger transplant cohorts.
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http://dx.doi.org/10.4049/jimmunol.2100119DOI Listing
June 2021

High-Resolution Characterization of Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity.

Front Immunol 2021 7;12:674778. Epub 2021 May 7.

Department of Neurology, University of California, San Francisco, CA, United States.

The ) region is characterized by structural variation and high sequence similarity among genes, imposing technical difficulties for analysis. We undertook the most comprehensive study to date of genetic diversity in a large population sample, applying next-generation sequencing in 2,130 United States European-descendant individuals. Data were analyzed using our custom bioinformatics pipeline specifically designed to address technical obstacles in determining genotypes. Precise gene copy number determination allowed us to identify a set of uncommon gene-content haplotypes accounting for 5.2% of structural variation. In this cohort, is the framework gene that most varies in copy number (6.5% of all individuals). We identified phased high-resolution alleles in large multi-locus insertions and also likely founder haplotypes from which they were deleted. Additionally, we observed 250 alleles at 5-digit resolution, of which 90 have frequencies ≥1%. We found sequence patterns that were consistent with the presence of novel alleles in 398 (18.7%) individuals and contextualized multiple orphan dbSNPs within the complex. We also identified a novel KIR2DL1 variant, Pro151Arg, and demonstrated by molecular dynamics that this substitution is predicted to affect interaction with HLA-C. No previous studies have fully explored the full range of structural and sequence variation of as we present here. We demonstrate that pairing high-throughput sequencing with state-of-art computational tools in a large cohort permits exploration of all aspects of variation including determination of population-level haplotype diversity, improving understanding of the system, and providing an important reference for future studies.
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http://dx.doi.org/10.3389/fimmu.2021.674778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137979PMC
October 2021

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Mol Biol Evol 2021 05;38(6):2582-2596

Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.
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http://dx.doi.org/10.1093/molbev/msab053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136484PMC
May 2021

In Memoriam: Peter Hartmann (1946-2020), publisher, colleague, and friend.

Traffic 2020 12 11;21(12):749-750. Epub 2020 Oct 11.

Stanford University, Stanford, California, USA.

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http://dx.doi.org/10.1111/tra.12767DOI Listing
December 2020

Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease.

J Immunol 2020 09 24;205(5):1323-1330. Epub 2020 Jul 24.

Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158;

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated -allelic polymorphism to interrogate the role of NK cells in PD. We sequenced genes from 1314 PD patients and 1978 controls using next-generation methods and identified genotypes using custom bioinformatics. We examined associations of with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: /HLA-Bw4 from rigidity ( = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and HLA-Bw4i from gait difficulties (p = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity ( = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.
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http://dx.doi.org/10.4049/jimmunol.2000144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484130PMC
September 2020

HLAs, TCRs, and KIRs, a Triumvirate of Human Cell-Mediated Immunity.

Annu Rev Biochem 2020 06;89:717-739

Department of Structural Biology and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA; email:

In all human cells, human leukocyte antigen (HLA) class I glycoproteins assemble with a peptide and take it to the cell surface for surveillance by lymphocytes. These include natural killer (NK) cells and γδ T cells of innate immunity and αβ T cells of adaptive immunity. In healthy cells, the presented peptides derive from human proteins, to which lymphocytes are tolerant. In pathogen-infected cells, HLA class I expression is perturbed. Reduced HLA class I expression is detected by KIR and CD94:NKG2A receptors of NK cells. Almost any change in peptide presentation can be detected by αβ CD8 T cells. In responding to extracellular pathogens, HLA class II glycoproteins, expressed by specialized antigen-presenting cells, present peptides to αβ CD4 T cells. In comparison to the families of major histocompatibility complex (MHC) class I, MHC class II and αβ T cell receptors, the antigenic specificity of the γδ T cell receptors is incompletely understood.
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http://dx.doi.org/10.1146/annurev-biochem-011520-102754DOI Listing
June 2020

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

Front Immunol 2020 2;11:556. Epub 2020 Apr 2.

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, United States.

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, polymorphism associates with infection control and multiple autoimmune and pregnancy syndromes. Here we analyze 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 alleles, including 11 not previously characterized. We also identified 170 centromeric and 94 telomeric haplotypes, and 15 different haplotypes carrying either a deletion or duplication encompassing one or more complete 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 in Iran than any other population, and the highest frequency of HLA-B51, a Bw4-containing allotype that acts as a strong educator of NK cells. Compared to Europeans, the Iranians we studied also have a reduced frequency of , 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 haplotypes characterized do not express a functional activating receptor. By contrast, the most frequent haplotype in Iran expresses only one functional inhibitory KIR and the maximum number of activating KIR. This first complete, high-resolution, characterization of the locus of Iranians will form a valuable reference for future clinical and population studies.
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http://dx.doi.org/10.3389/fimmu.2020.00556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142237PMC
March 2021

Dimorphism in the TCRγ-chain repertoire defines 2 types of human immunity to Epstein-Barr virus.

Blood Adv 2020 04;4(7):1198-1205

Department of Structural Biology and.

Humans form 2 groups based on their innate immunity to Epstein-Barr virus (EBV). Group 1 makes a strong natural killer (NK)-cell and γδ T-cell response, whereas group 2 makes a strong NK-cell response, but a weak γδ T-cell response. To investigate the underlying basis for this difference in γδ T-cell immunity to EBV, we used next-generation sequencing to compare the γδ T-cell receptor (TCR) repertoires of groups 1 and 2. In the absence of EBV, group 1 TCRγ chains are enriched for complementarity determining region 3 (CDR3s) containing JγP, whereas group 2 TCRγ chains are enriched for CDR3s containing Jγ2. In group 1 donors, EBV activates many γδ T cells expressing Vγ9JγP, inducing proliferation that produces a large population of activated effector cells. The TCRs using Vγ9JγP are closely related to the TCRs of γδ T cells that respond to phosphoantigens. In group 2 donors, EBV activates a small subpopulation of γδ T cells, most expressing Vγ9JγP. In conclusion, we find that differences in the TCRγ-chain repertoire underlie the differential response of group 1 and group 2 to EBV.
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http://dx.doi.org/10.1182/bloodadvances.2019001179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160271PMC
April 2020

KIR B donors improve the outcome for AML patients given reduced intensity conditioning and unrelated donor transplantation.

Blood Adv 2020 02;4(4):740-754

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN.

Natural killer (NK) cell recognition and killing of target cells are enhanced when inhibitory killer immunoglobulin-like receptors (KIR) are unable to engage their cognate HLA class I ligands. The genes of the KIR locus are organized into either KIR B haplotypes, containing 1 or more activating KIR genes or KIR A haplotypes, which lack those genes. Analysis of unrelated donor (URD) hematopoietic cell transplants (HCT), given to acute myeloid leukemia (AML) patients between 1988 and 2009, showed that KIR B haplotype donors were associated with better outcomes, primarily from relapse protection. Most of these transplants involved marrow grafts, fully myeloablative (MAC) preparative regimens, and significant HLA mismatch. Because the practice of HCT continues to evolve, with increasing use of reduced intensity conditioning (RIC), peripheral blood stem cell grafts, and better HLA match, we evaluated the impact of URD KIR genotype on HCT outcome for AML in the modern era (2010-2016). This analysis combined data from a prospective trial testing URD selection based on KIR genotypes (n = 243) with that from a larger contemporaneous cohort of transplants (n = 2419). We found that KIR B haplotype donors conferred a significantly reduced risk of leukemia relapse and improved disease-free survival after RIC, but not MAC HCT. All genes defining KIR B haplotypes were associated with relapse protection, which was significant only in transplant recipients expressing the C1 epitope of HLA-C. In the context of current HCT practice using RIC, selection of KIR B donors could reduce relapse and improve overall outcome for AML patients receiving an allogeneic HCT.
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http://dx.doi.org/10.1182/bloodadvances.2019001053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042994PMC
February 2020

Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy.

Nat Commun 2020 01 20;11(1):381. Epub 2020 Jan 20.

Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, CB2 0SW, UK.

During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal cells and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: decidual NK cells (dNK)1-3, ILC3s and proliferating NK cells. Following stimulation, dNK2 and dNK3 produce more chemokines than dNK1 including XCL1 which can act on both maternal dendritic cells and fetal EVT. In contrast, dNK1 express receptors including Killer-cell Immunoglobulin-like Receptors (KIR), indicating they respond to HLA class I ligands on EVT. Decidual NK have distinctive organisation and content of granules compared with peripheral blood NK cells. Acquisition of KIR correlates with higher granzyme B levels and increased chemokine production in response to KIR activation, suggesting a link between increased granule content and dNK1 responsiveness. Our analysis shows that dILCs are unique and provide specialised functions dedicated to achieving placental development and successful reproduction.
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http://dx.doi.org/10.1038/s41467-019-14123-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971012PMC
January 2020

Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors.

Sci Signal 2019 12 17;12(612). Epub 2019 Dec 17.

Manchester Collaborative Centre for Inflammation Research, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.

Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primary human NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance, there was a greater proportion of KIRs in clusters. Upon receptor triggering, a structured interface called the immune synapse assembles, which facilitates signal integration and controls NK cell responses. Here, triggering of low-abundance receptors resulted in less phosphorylation of the downstream phosphatase SHP-1 but more phosphorylation of the adaptor protein Crk than did triggering of high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated NK cell spreading during activation. Thus, genetic variation modulates both the abundance and nanoscale organization of inhibitory KIRs. That is, as well as the number of receptors at the cell surface varying with genotype, the way in which these receptors are organized in the membrane also varies. Essentially, a change in the average surface abundance of a protein at the cell surface is a coarse descriptor entwined with changes in local nanoscale clustering. Together, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and, unexpectedly, the formation of activating immune synapses.
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http://dx.doi.org/10.1126/scisignal.aaw9252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944503PMC
December 2019

Nomenclature report for killer-cell immunoglobulin-like receptors (KIR) in macaque species: new genes/alleles, renaming recombinant entities and IPD-NHKIR updates.

Immunogenetics 2020 02 29;72(1-2):37-47. Epub 2019 Nov 29.

Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288, GJ, Rijswijk, The Netherlands.

The Killer-cell Immunoglobulin-like Receptors (KIR) are encoded by a diverse group of genes, which are characterized by allelic polymorphism, gene duplications, and recombinations, which may generate recombinant entities. The number of reported macaque KIR sequences is steadily increasing, and these data illustrate a gene system that may match or exceed the complexity of the human KIR cluster. This report lists the names of quality controlled and annotated KIR genes/alleles with all the relevant references for two different macaque species: rhesus and cynomolgus macaques. Numerous recombinant KIR genes in these species necessitate a revision of some of the earlier-published nomenclature guidelines. In addition, this report summarizes the latest information on the Immuno Polymorphism Database (IPD)-NHKIR Database, which contains annotated KIR sequences from four non-human primate species.
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http://dx.doi.org/10.1007/s00251-019-01135-8DOI Listing
February 2020

Correction to: Nomenclature report 2019: major histocompatibility complex genes and alleles of great and small ape and old and new world monkey species.

Immunogenetics 2020 02;72(1-2):131-132

Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288, GJ, Rijswijk, The Netherlands.

The original version of this article contained a spelling error in the Acknowledgments regarding the name of the funding organisation supporting GM and JAH. UKRI-BBSCR should have been UKRI-BBSRC, as is now indicated correctly below.
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http://dx.doi.org/10.1007/s00251-019-01146-5DOI Listing
February 2020

In vitro education of human natural killer cells by KIR3DL1.

Life Sci Alliance 2019 12 13;2(6). Epub 2019 Nov 13.

Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA

During development, NK cells are "educated" to respond aggressively to cells with low surface expression of HLA class I, a hallmark of malignant and infected cells. The mechanism of education involves interactions between inhibitory killer immunoglobulin-like receptors (KIRs) and specific HLA epitopes, but the details of this process are unknown. Because of the genetic diversity of HLA class I genes, most people have NK cells that are incompletely educated, representing an untapped source of human immunity. We demonstrate how mature peripheral KIR3DL1 human NK cells can be educated in vitro. To accomplish this, we trained NK cells expressing the inhibitory KIR3DL1 receptor by co-culturing them with target cells that expressed its ligand, Bw4HLA-B. After this training, KIR3DL1 NK cells increased their inflammatory and lytic responses toward target cells lacking Bw4HLA-B, as though they had been educated in vivo. By varying the conditions of this basic protocol, we provide mechanistic and translational insights into the process NK cell education.
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http://dx.doi.org/10.26508/lsa.201900434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856763PMC
December 2019

Nomenclature report 2019: major histocompatibility complex genes and alleles of Great and Small Ape and Old and New World monkey species.

Immunogenetics 2020 02 17;72(1-2):25-36. Epub 2019 Oct 17.

Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ, Rijswijk, The Netherlands.

The major histocompatibility complex (MHC) is central to the innate and adaptive immune responses of jawed vertebrates. Characteristic of the MHC are high gene density, gene copy number variation, and allelic polymorphism. Because apes and monkeys are the closest living relatives of humans, the MHCs of these non-human primates (NHP) are studied in depth in the context of evolution, biomedicine, and conservation biology. The Immuno Polymorphism Database (IPD)-MHC NHP Database (IPD-MHC NHP), which curates MHC data of great and small apes, as well as Old and New World monkeys, has been upgraded. The curators of the database are responsible for providing official designations for newly discovered alleles. This nomenclature report updates the 2012 report, and summarizes important nomenclature issues and relevant novel features of the IPD-MHC NHP Database.
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http://dx.doi.org/10.1007/s00251-019-01132-xDOI Listing
February 2020

KIR3DL1/S1 Allotypes Contribute Differentially to the Development of Behçet Disease.

J Immunol 2019 09 12;203(6):1629-1635. Epub 2019 Aug 12.

Clinical and Diagnostic Oral Sciences, Queen Mary University of London, Blizard Institute, E1 2AT London, United Kingdom;

Behçet disease is a chronic, relapsing-remitting autoinflammatory syndrome with a strong association. In this paper, we describe a human cohort of 267 individuals with Behçet disease and 445 matched controls from a tertiary referral center in the U.K. was confirmed as a genetic risk factor in this group ( = 0.0006, Bonferroni-Dunn correction for multiple testing [] = 0.0192, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.33-2.76). KIR3DL1/S1 allele-level analysis indicated that low-expressing KIR3DL1/S1 alleles in combination with KIR3DS1 increased the risk of developing Behçet disease (KIR3DL1/KIR3DS1: = 0.0004, = 0.0040, OR 2.47, 95% CI 1.43-4.25), whereas high-expressing KIR3DL1/S1 alleles in combination with a null-expressing KIR3DL1 reduced the risk of disease (KIR3DL1/KIR3DL1: = 0.0035, = 0.0350, OR 0.53, 95% CI 0.33-0.87). Behçet disease can manifest as a purely mucocutaneous disease or can involve other organ systems such as the eyes. In the U.K. cohort studied in this study, KIR3DL1/KIR3DS1 increased the risk of ophthalmic disease ( = 1.2 × 10, OR 3.92, 95% CI 2.06-7.47), whereas KIR3DL1/KIR3DL1 reduced the risk of having purely mucocutaneous disease ( = 0.0048, OR 0.45, 95% CI 0.25-0.81). To our knowledge, this is the first analysis of KIR3DL1/S1 allelic variation in Behçet disease and may provide insight into the pathogenic role of and its interaction with KIR3DL1/S1.
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http://dx.doi.org/10.4049/jimmunol.1801178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731450PMC
September 2019

A natural killer cell receptor takes sharp aim at the world of bacteria.

Authors:
Peter Parham

Proc Natl Acad Sci U S A 2019 06 7;116(26):12601-12603. Epub 2019 Jun 7.

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;

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http://dx.doi.org/10.1073/pnas.1907937116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601266PMC
June 2019

Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism.

Elife 2019 06 4;8. Epub 2019 Jun 4.

Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, United Kingdom.

CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining , strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22's role in metabolism and have potential to differentially influence the human insulin response.
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http://dx.doi.org/10.7554/eLife.41517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548504PMC
June 2019

Diversity of KIR, HLA Class I, and Their Interactions in Seven Populations of Sub-Saharan Africans.

J Immunol 2019 05 27;202(9):2636-2647. Epub 2019 Mar 27.

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;

and sequences were determined for Dogon, Fulani, and Baka populations of western Africa, Mbuti of central Africa, and Datooga, Iraqw, and Hadza of eastern Africa. Study of 162 individuals identified 134 alleles (41 , 60 , and 33 ). Common to all populations are three alleles (, , and ) but no or Unexpectedly, no novel was identified in these previously unstudied and anthropologically distinctive populations. In contrast, of 227 detected, 22 are present in all seven populations and 28 are novel. A high diversity of haplotypes was observed. In six populations, most haplotypes are represented just once. But in the Hadza, a majority of haplotypes occur more than once, with 2 having high frequencies and 10 having intermediate frequencies. The centromeric () part of the locus exhibits an even balance between and in all seven populations. The telomeric () part has an even balance of to in East Africa, but this changes across the continent to where is vestigial in West Africa. All four KIR ligands (A3/11, Bw4, C1, and C2) are present in six of the populations. haplotypes of the Iraqw and Hadza encode two KIR ligands, whereas the other populations have an even balance between haplotypes encoding one and two KIR ligands. Individuals in these African populations have a mean of 6.8-8.4 different interactions between KIR and HLA class I, compared with 2.9-6.5 for non-Africans.
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http://dx.doi.org/10.4049/jimmunol.1801586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690726PMC
May 2019

A specific amino acid motif of mediates risk and interacts with smoking history in Parkinson's disease.

Proc Natl Acad Sci U S A 2019 04 25;116(15):7419-7424. Epub 2019 Mar 25.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA 94158.

Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to , but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V ( = 10; odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V ( = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.
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http://dx.doi.org/10.1073/pnas.1821778116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462083PMC
April 2019

Two to Tango: Co-evolution of Hominid Natural Killer Cell Receptors and MHC.

Front Immunol 2019 19;10:177. Epub 2019 Feb 19.

Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, United States.

Natural killer (NK) cells have diverse roles in hominid immunity and reproduction. Modulating these functions are the interactions between major histocompatibility complex (MHC) class I molecules that are ligands for two NK cell surface receptor types. Diverse killer cell immunoglobulin-like receptors (KIR) bind specific motifs encoded within the polymorphic MHC class I cell surface glycoproteins, while, in more conserved interactions, CD94:NKG2A receptors recognize MHC-E with bound peptides derived from MHC class I leader sequences. The hominid lineage presents a choreographed co-evolution of KIR with their MHC class I ligands. , and are present in all great apes with species-specific haplotypic variation in gene content. The Bw4 epitope recognized by lineage II KIR is restricted to MHC-B but also present on some gorilla and human MHC-A. Common to great apes, but rare in humans, are MHC-B possessing a C1 epitope recognized by lineage III KIR. arose from duplication of and is fixed in all great apes except orangutan, where it exists on approximately 50% of haplotypes and all allotypes are C1-bearing. Recent study showed that gorillas possess yet another intermediate organization compared to humans. Like orangutans, but unlike the species, duplication of occurred. However, is fixed, and the MHC-C C2 epitope (absent in orangutans) emerges. The evolution of MHC-C drove expansion of its cognate lineage III KIR. Recently, position -21 of the MHC-B leader sequence has been shown to be critical in determining NK cell educational outcome. In humans, methionine (-21M) results in CD94:NKG2A-focused education whereas threonine (-21T) produces KIR-focused education. This is another dynamic position among hominids. Orangutans have exclusively -21M, consistent with their intermediate stage in lineage III KIR-focused evolution. Gorillas have both -21M and -21T, like humans, but they are unequally encoded by their duplicated genes. Chimpanzees have near-fixed -21T, indicative of KIR-focused NK education. Harmonious with this observation, chimpanzee KIR exhibit strong binding and, compared to humans, smaller differences between binding levels of activating and inhibitory KIR. Consistent between these MHC-NK cell receptor systems over the course of hominid evolution is the evolution of polymorphism favoring the more novel and dynamic KIR system.
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http://dx.doi.org/10.3389/fimmu.2019.00177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389700PMC
January 2020

Casting a wider net: Immunosurveillance by nonclassical MHC molecules.

PLoS Pathog 2019 02 21;15(2):e1007567. Epub 2019 Feb 21.

Laboratory of Viral Diseases, NIAID, Bethesda, Maryland, United States of America.

Most studies of T lymphocytes focus on recognition of classical major histocompatibility complex (MHC) class I or II molecules presenting oligopeptides, yet there are numerous variations and exceptions of biological significance based on recognition of a wide variety of nonclassical MHC molecules. These include αβ and γδ T cells that recognize different class Ib molecules (CD1, MR-1, HLA-E, G, F, et al.) that are nearly monomorphic within a given species. Collectively, these T cells can be considered "unconventional," in part because they recognize lipids, metabolites, and modified peptides. Unlike classical MHC-specific cells, unconventional T cells generally exhibit limited T-cell antigen receptor (TCR) repertoires and often produce innate immune cell-like rapid effector responses. Exploiting this system in new generation vaccines for human immunodeficiency virus (HIV), tuberculosis (TB), other infectious agents, and cancer was the focus of a recent workshop, "Immune Surveillance by Non-classical MHC Molecules: Improving Diversity for Antigens," sponsored by the National Institute of Allergy and Infectious Diseases. Here, we summarize salient points presented regarding the basic immunobiology of unconventional T cells, recent advances in methodologies to measure unconventional T-cell activity in diseases, and approaches to harness their considerable clinical potential.
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http://dx.doi.org/10.1371/journal.ppat.1007567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383864PMC
February 2019

Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates.

Front Immunol 2019 28;10:24. Epub 2019 Jan 28.

Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United States.

Natural killer (NK) cell functions are modulated by polymorphic killer cell immunoglobulin-like receptors (KIR). Among 13 human genes, which vary by presence and copy number, is ubiquitously present in every individual across diverse populations. No ligand or function is known for KIR3DL3, but limited knowledge of expression suggests involvement in reproduction, likely during placentation. With 157 human alleles, KIR3DL3 is also highly polymorphic and we show heterozygosity exceeds that of HLA-B in many populations. The external domains of catarrhine primate KIR3DL3 evolved as a conserved lineage distinct from other KIR. Accordingly, and in contrast to other KIR, we show the focus of natural selection does not correspond exclusively to known ligand binding sites. Instead, a strong signal for diversifying selection occurs in the D1 Ig domain at a site involved in receptor aggregation, which we show is polymorphic in humans worldwide, suggesting differential ability for receptor aggregation. Meanwhile in the cytoplasmic tail, the first of two inhibitory tyrosine motifs (ITIM) is conserved, whereas independent genomic events have mutated the second ITIM of KIR3DL3 alleles in all great apes. Together, these findings suggest that KIR3DL3 binds a conserved ligand, and a function requiring both receptor aggregation and inhibitory signal attenuation. In this model KIR3DL3 resembles other NK cell inhibitory receptors having only one ITIM, which interact with bivalent downstream signaling proteins through dimerization. Due to the extensive conservation across species, selection, and other unusual properties, we consider elucidating the ligand and function of to be a pressing question.
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http://dx.doi.org/10.3389/fimmu.2019.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360152PMC
December 2019

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis.

Biol Blood Marrow Transplant 2019 05 27;25(5):949-954. Epub 2018 Dec 27.

Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511301PMC
May 2019

HLA-B57 micropolymorphism defines the sequence and conformational breadth of the immunopeptidome.

Nat Commun 2018 11 8;9(1):4693. Epub 2018 Nov 8.

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.

Immunophenotypic differences between closely related human leukocyte antigen (HLA) alleles have been associated with divergent clinical outcomes in infection, autoimmunity, transplantation and drug hypersensitivity. Here we explore the impact of micropolymorphism on peptide antigen presentation by three closely related HLA molecules, HLA-B*57:01, HLA-B*57:03 and HLA-B*58:01, that are differentially associated with the HIV elite controller phenotype and adverse drug reactions. For each allotype, we mine HLA ligand data sets derived from the same parental cell proteome to define qualitative differences in peptide presentation using classical peptide binding motifs and an unbiased statistical approach. The peptide repertoires show marked qualitative overlap, with 982 peptides presented by all allomorphs. However, differences in peptide abundance, HLA-peptide stability, and HLA-bound conformation demonstrate that HLA micropolymorphism impacts more than simply the range of peptide ligands. These differences provide grounds for distinct immune reactivity and insights into the capacity of micropolymorphism to diversify immune outcomes.
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http://dx.doi.org/10.1038/s41467-018-07109-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224591PMC
November 2018

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.

Hum Immunol 2018 Dec 12;79(12):825-833. Epub 2018 Oct 12.

Histocompatibility, Centro de Transfusión de la Comunidad de Madrid, Madrid, Spain.

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3 ∼ KIR3DL1/S1 ∼ KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.
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http://dx.doi.org/10.1016/j.humimm.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322681PMC
December 2018

High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia.

J Immunol 2018 11 24;201(9):2593-2601. Epub 2018 Sep 24.

Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, United Kingdom;

Killer-cell Ig-like receptor (KIR) genes are inherited as haplotypes. They are expressed by NK cells and linked to outcomes of infectious diseases and pregnancy in humans. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. In this article, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected in both peripheral blood and uterine NK cells. Using this new method, we demonstrate that both blood and uterine NK cells codominantly express KIR2DL1A and KIR2DL1B allotypes but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that , not , associates with increased disease risk. This method will facilitate our understanding of how individual allelic variants affect NK cell function and contribute to disease risk.
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http://dx.doi.org/10.4049/jimmunol.1800860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258046PMC
November 2018

KIR Donor Selection: Feasibility in Identifying better Donors.

Biol Blood Marrow Transplant 2019 01 24;25(1):e28-e32. Epub 2018 Aug 24.

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.

We previously reported that acute myelogenous leukemia (AML) transplants using killer cell immunoglobulin-type receptor (KIR) B haplotype better or best (≥2 B activating gene loci ± Cen B/B) unrelated donors (URDs) yield less relapse and better survival. In this prospective trial we evaluated 535 AML searches from 14 participating centers with centralized donor KIR genotyping for donor selection. This represented 3% to 48% of all AML searches (median 20%) per center, totaling 3 to 172 patients (median 22) per center. Donor KIR genotype was reported at a median of 14 days after request (≤26 days for 76% of searches). In 535 searches, 2080 donors were requested for KIR genotyping (mean 4.3 per search); and a median of 1.8 (range, 0 to 4.5) per search were KIR typed. Choosing more donors for confirmatory HLA and KIR haplotype identification enriched the likelihood of finding KIR better or best donors. The search process identified a mean of 30% KIR better or best donors; the success ranged from 24% to 38% in the 11 centers enrolling ≥8 patients. More donors requested for KIR genotyping increased the likelihood of identifying KIR better or best haplotype donors. Of the 247 transplants, 9.3% used KIR best, 19% used KIR better, and 48% used KIR neutral donors while 24% used a non-KIR-tested donor. KIR genotyping did not delay transplantation. The time from search to transplant was identical for transplants using a KIR-genotyped versus a non-KIR-genotyped donor. Prospective evaluation can rapidly identify KIR favorable genotype donors, but choosing more donors per search would substantially increase the likelihood of having a KIR best or better donor available for transplantation. Transplant centers and donor registries must both commit extra effort to incorporate new characteristics (beyond HLA, age, and parity) into improved donor selection. Deliberate efforts to present additional genetic factors for donor selection will require novel procedures.
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http://dx.doi.org/10.1016/j.bbmt.2018.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310641PMC
January 2019
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