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1.  Common subclinical hypothyroidism during Whipple’s disease 
BMC Infectious Diseases  2014;14:370.
Classic Whipple’s disease is caused by T. whipplei and likely involves genetic predispositions, such as the HLA alleles DRB1*13 and DQB1*06, that are more frequently observed in patients. T. whipplei carriage occurs in 2-4% of the general population in France. Subclinical hypothyroidism, characterized by high levels of TSH and normal free tetra-iodothyronine (fT4) dosage, has been rarely associated with specific HLA factors.
We retrospectively tested TSHus in 80 patients and 42 carriers. In cases of dysthyroidism, we tested the levels of free-T4 and anti-thyroid antibodies, and the HLA genotypes were also determined for seven to eight patients.
In this study, 72-74% of patients and carriers were male, and among the 80 patients, 14 (17%) individuals had a high level of TSH, whereas none of the carriers did (p < 0 · 01). In the 14 patients with no clinical manifestations, the T4 levels were normal, and no specific antibodies were present. Four patients treated with antibiotics, without thyroxine supplementation, showed normal levels of TSHus after one or two years. One patient displayed a second episode of subclinical hypothyroidism during a Whipple’s disease relapse five years later, but the subclinical hypothyroidism regressed after antibiotic treatment. HLA typing revealed nine alleles that appeared more frequently in patients than in the control cohort, but none of these differences reached significance due to the small size of the patient group.
Regardless of the substratum, classic Whipple’s disease could lead to subclinical hypothyroidism. We recommend systematically testing the TSH levels in patients with Whipple’s disease.
PMCID: PMC4099391  PMID: 24996424
Tropheryma whipplei; Whipple’s disease; Subclinical hypothyroidism; HLA
2.  African Relapsing Fever Borreliae Genomospecies Revealed by Comparative Genomics 
Background: Relapsing fever borreliae are vector-borne bacteria responsible for febrile infection in humans in North America, Africa, Asia, and in the Iberian Peninsula in Europe. Relapsing fever borreliae are phylogenetically closely related, yet they differ in pathogenicity and vectors. Their long-term taxonomy, based on geography and vector grouping, needs to be re-apprised in a genomic context. We therefore embarked into genomic analyses of relapsing fever borreliae, focusing on species found in Africa.
Results: Genome-wide phylogenetic analyses group Old World Borrelia crocidurae, Borrelia hispanica, B. duttonii, and B. recurrentis in one clade, and New World Borrelia turicatae and Borrelia hermsii in a second clade. Accordingly, average nucleotide identity is 99% among B. duttonii, B. recurrentis, and B. crocidurae and 96% between latter borreliae and B. hispanica while the similarity is 86% between Old World and New World borreliae. Comparative genomics indicates that the Old World relapsing fever B. duttonii, B. recurrentis, B. crocidurae, and B. hispanica have a 2,514-gene pan genome and a 933-gene core genome that includes 788 chromosomal and 145 plasmidic genes. Analyzing the role that natural selection has played in the evolution of Old World borreliae species revealed that 55 loci were under positive diversifying selection, including loci coding for membrane, flagellar, and chemotaxis proteins, three categories associated with adaption to specific niches.
Conclusion: Genomic analyses led to a reappraisal of the taxonomy of relapsing fever borreliae in Africa. These analyses suggest that B. crocidurae, B. duttonii, and B. recurrentis are ecotypes of a unique genomospecies, while B. hispanica is a distinct species.
PMCID: PMC4157404  PMID: 25229054
Borrelia; relapsing fever; genomics; phylogeny; speciation
3.  Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans 
PLoS Genetics  2013;9(10):e1003938.
Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1–14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.
Author Summary
Natural killer cells are white blood cells with critical roles in human health that deliver front-line immunity against pathogens and nurture placentation in early pregnancy. Controlling these functions are cell-surface receptors called KIR that interact with HLA class I ligands expressed on most cells of the body. KIR and HLA are both products of complex families of variable genes, but present on separate chromosomes. Many HLA and KIR variants and their combinations associate with resistance to specific infections and pregnancy syndromes. Previously we identified basic components of the system necessary for individual and population survival. Here, we explore the system at its most genetically diverse by studying the Ga-Adangbe population from Ghana in West Africa. Co-evolution of KIR receptors with their HLA targets is ongoing in the Ga-Adangbe, with every one of 235 individuals studied having a unique set of KIR receptors and HLA class I ligands. In addition, one critical combination of receptor and ligand maintains alternative forms that either can or cannot interact with their ‘partner.’ This balance resembles that induced by malfunctioning variants of hemoglobin that confer resistance to malaria, a candidate disease for driving diversity and co-evolution of KIR and HLA class I in the Ga-Adangbe.
PMCID: PMC3814319  PMID: 24204327
4.  Computational Analyses of an Evolutionary Arms Race between Mammalian Immunity Mediated by Immunoglobulin A and Its Subversion by Bacterial Pathogens 
PLoS ONE  2013;8(9):e73934.
IgA is the predominant immunoglobulin isotype in mucosal tissues and external secretions, playing important roles both in defense against pathogens and in maintenance of commensal microbiota. Considering the complexity of its interactions with the surrounding environment, IgA is a likely target for diversifying or positive selection. To investigate this possibility, the action of natural selection on IgA was examined in depth with six different methods: CODEML from the PAML package and the SLAC, FEL, REL, MEME and FUBAR methods implemented in the Datamonkey webserver. In considering just primate IgA, these analyses show that diversifying selection targeted five positions of the Cα1 and Cα2 domains of IgA. Extending the analysis to include other mammals identified 18 positively selected sites: ten in Cα1, five in Cα2 and three in Cα3. All but one of these positions display variation in polarity and charge. Their structural locations suggest they indirectly influence the conformation of sites on IgA that are critical for interaction with host IgA receptors and also with proteins produced by mucosal pathogens that prevent their elimination by IgA-mediated effector mechanisms. Demonstrating the plasticity of IgA in the evolution of different groups of mammals, only two of the eighteen selected positions in all mammals are included in the five selected positions in primates. That IgA residues subject to positive selection impact sites targeted both by host receptors and subversive pathogen ligands highlights the evolutionary arms race playing out between mammals and pathogens, and further emphasizes the importance of IgA in protection against mucosal pathogens.
PMCID: PMC3760800  PMID: 24019941
5.  Mutation at Positively Selected Positions in the Binding site for HLA-C Shows KIR2DL1 is a More Refined but Less Adaptable NK cell Receptor than KIR2DL31 
Through recognition of HLA class I, killer cell immunoglobulin-like receptors (KIR) modulate NK cell functions in human immunity and reproduction. Although a minority of HLA-A and –B allotypes are KIR ligands, HLA-C allotypes dominate this regulation, because they all carry either the C1 epitope recognized by KIR2DL2/3 or the C2 epitope recognized by KIR2DL1. The C1 epitope and C1-specific KIR evolved first, followed several million years later by the C2 epitope and C2-specific KIR. Strong, varying selection pressure on NK cell functions drove the diversification and divergence of hominid KIR, with six positions in the HLA class I binding site of KIR being targets for positive selection. Introducing each naturally occurring residue at these positions into KIR2DL1 and KIR2DL3, produced 38 point mutants that were tested for binding to 95 HLA- A, -B and –C allotypes. Modulating specificity for HLA-C is position 44, whereas positions 71 and 131 control cross reactivity with HLA-A*11:02. Dominating avidity modulation is position 70, with lesser contributions from positions 68 and 182. KIR2DL3 has lower avidity and broader specificity than KIR2DL1. Mutation can increase the avidity and change the specificity of KIR2DL3, whereas KIR2DL1 specificity was resistant to mutation and its avidity could only be lowered. The contrasting inflexibility of KIR2DL1 and adaptability of KIR2DL3 fits with C2-specific KIR having evolved from C1-specific KIR, and not vice versa. Substitutions restricted to activating KIR all reduced the avidity of KIR2DL1 and KIR2DL3, further evidence that activating KIR function often becomes subject to selective attenuation.
PMCID: PMC3439511  PMID: 22772445
Natural Killer Cells; MHC; Epitopes; Comparative Immunology/Evolution
6.  Immunogenetics of Human Placentation 
Placenta  2011;33(0):S71-S80.
Natural killer (NK) cells are a population of lymphocytes that function in both immune defense and reproduction. Diversifying NK cell phenotype and function are interactions between NK cell receptors and major histocompatibility complex (MHC) class I ligands. As a consequence of strong and variable selection these ligand-receptor systems are polymorphic, rapidly evolving, and considerably species-specific. Counterparts to the human system of HLA class I ligands and killer cell immunoglobulin-like receptors (KIR) are present only in apes and Old World monkeys. HLA-C, the dominant ligand for human KIR and the only polymorphic HLA class I expressed by trophoblast, is further restricted to humans and great apes. Even then, the human system appears qualitatively different from that of chimpanzees, in that it has evolved a genetic balance between particular groups of receptors and ligands that favor reproductive success and other groups of receptors and ligands that have been correlated with disordered placentation. Human populations that have survived successive episodes of epidemic disease and population bottlenecks maintain a breadth of diversity for KIR and HLA class I, implying that loss of such diversity disfavors long-term survival of a human population.
PMCID: PMC3677947  PMID: 22177321
HLA; natural killer cells; balancing selection; evolution; immunity; reproduction
7.  The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans 
Science (New York, N.Y.)  2011;334(6052):89-94.
Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic 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.
PMCID: PMC3677943  PMID: 21868630
8.  Natural variation at position 45 in the D1 domain of lineage III killer cell immunoglobulin-like receptors (KIR) has major effects on the avidity and specificity for MHC class I 
Immunogenetics  2011;63(8):543-547.
Alternative lysine and methionine residues at position 44 in the D1 domain determine the specificities of human lineage III killer cell immunoglobulin-like receptors (KIR) for the C1 and C2 epitopes of HLA-C. KIR having glutamate 44 are also present in orangutans (Popy2DLB) and chimpanzees (Pt-2DL9) but notably absent from humans. Popy2DLB exhibits broad specificity for both the C1 and C2 epitopes, whereas Pt-2DL9 has narrow specificity for C2. Mutation of phenylalanine 45 in Popy2DLB to the cysteine residue present in Pt-2DL9 was sufficient to narrow the Popy2DLB specificity to be like that of Pt-2DL9. In contrast, replacement of cysteine 45 in Pt-2DL9 by phenylalanine had no effect on its C2 specificity, but reduced the avidity. In a similar manner, replacement of phenylalanine 45 with cysteine in Popy2DLA, which has lysine 44 and recognizes C1, maintained this specificity while reducing avidity. Position 45 is exceptionally variable, exhibiting twelve residues that distinguish KIR of different lineages and species. Our study demonstrates the potential for variation at position 45 to modulate KIR avidity and specificity for HLA-C. The various effects of position 45 mutation are consistent with a model in which a Popy2DLB-like receptor, having glutamate 44 and broad specificity for C1 and C2, facilitated the evolution of the C2 epitope from the C1 epitope and C2-specific KIR from C1-specific KIR. With the acquisition of C2 and C2-specific receptors, the selection against this broadly specific receptor led to its loss from the human line and narrowing of its specificity on the chimpanzee line.
PMCID: PMC3160831  PMID: 21541786
KIR receptors; MHC; Non-human primates; Evolution
9.  Variable NK cell Receptors Exemplified by Human KIR3DL1/S11 
Variegated expression of variable NK cell receptors for polymorphic MHC class I broadens the range of an individual’s NK cell response, and the capacity for populations and species to survive disease epidemics and population bottlenecks. On evolutionary time-scales this component of immunity is exceptionally dynamic, unstable and short-lived, being dependent upon co-evolution of ligands and receptors subject to varying, competing selection pressures. Consequently these systems of variable NK cell receptors are largely species-specific and have recruited different classes of glycoprotein, even within the primate order of mammals. Such disparity helps explain substantial differences in NK cell biology between humans and animal models, for which the population genetics is largely ignored. KIR3DL1/S1, that recognizes the Bw4 epitope of HLA-A and –B and is the most extensively studied of the variable NK cell receptors, exemplifies how variation in all possible parameters of function is recruited to diversify the human NK cell response.
PMCID: PMC3223120  PMID: 21690332
Natural Killer Cells; MHC; Comparative Immunology/Evolution; Antigens/Peptides/Epitopes
10.  Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules 
In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity—combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands—drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species.
PMCID: PMC3267113  PMID: 22312047
natural killer cells; major histocompatibility complex; balancing selection
11.  Although Divergent in Residues of the Peptide-Binding Site, Conserved Chimpanzee Patr-AL and Polymorphic Human HLA-A*02 have Overlapping Peptide-Binding Repertoires 1 
Patr-AL is an expressed, non-polymorphic MHC class I gene carried by ∼50% of chimpanzee MHC haplotypes. Comparing Patr-AL+ and Patr-AL- haplotypes showed Patr-AL defines a unique 125kb genomic block flanked by blocks containing classical Patr-A and pseudogene Patr-H. Orthologous to Patr-AL are polymorphic orangutan Popy-A and the 5′ part of human pseudogene HLA-Y, carried by ∼10% of HLA haplotypes. Thus the AL gene alternatively evolved in these closely related species to become classical, non-classical and non-functional. Although differing by 30 amino acid substitutions in the peptide-binding α1 and α2 domains, Patr-AL and HLA-A*0201 bind overlapping repertoires of peptides; the overlap being comparable to that between the A*0201 and A*0207 subtypes differing by one substitution. Patr-AL thus has the A02 supertypic peptide-binding specificity. Patr-AL and HLA-A*0201 have similar three-dimensional structures, binding peptides in similar conformation. Although comparable in size and shape, the B and F specificity pockets of Patr-AL and HLA-A*0201 differ in both their constituent residues and contacts with peptide anchors. Uniquely shared by Patr-AL, HLA-A*0201, and other members of the A02 supertype are the absence of serine at position 9 in the B pocket and the presence of tyrosine at position 116 in the F pocket. Distinguishing Patr-AL from HLA-A*02 is an unusually electropositive upper face on the α2 helix. Stimulating PBMC from Patr-AL- chimpanzees with B cells expressing Patr-AL, produced potent alloreactive CD8 T cells with specificity for Patr-AL and no crossreactivity toward other MHC class I, including HLA-A*02. PBMC from Patr-AL+ chimpanzees are tolerant of Patr-AL.
PMCID: PMC3124313  PMID: 21209280
12.  Humans differ from other hominids in lacking an activating NK cell receptor that recognizes the C1 Epitope of MHC class I1 
Modulation of human NK cell function by killer cell immunoglobulin-like receptors (KIR) and MHC class I is dominated by the bipartite interactions of inhibitory lineage III KIR with the C1 and C2 epitopes of HLA-C. In comparison, the ligand specificities and functional contributions of the activating lineage III KIR remain poorly understood. Using a robust, sensitive assay of KIR binding and a representative panel of 95 HLA class I targets, we show that KIR2DS1 binds C2 with ∼50% the avidity of KIR2DL1, whereas KIR2DS2, 2DS3 and 2DS5 have no detectable avidity for C1, C2 or any other HLA class I epitope. In contrast, the chimpanzee has activating C1 and C2-specific lineage III KIR with strong avidity, comparable to those of their paired inhibitory receptors. One variant of chimpanzee Pt-KIR3DS2, the activating C2-specific receptor, has the same avidity for C2 as inhibitory Pt-KIR3DL4, and a second variant has ∼73% the avidity. Chimpanzee Pt-KIR3DS6, the activating C1-specific receptor, has avidity for C1 that is ∼70% that of inhibitory Pt-KIR2DL6. In both humans and chimpanzees we observe an evolutionary trend toward reducing the avidity of the activating C1- and C2-specific receptors through selective acquisition of attenuating substitutions. However, the extent of attenuation has been extreme in humans as exemplified by KIR2DS2, an activating C1-specific receptor that has lost all detectable avidity for HLA class I. Supporting such elimination of activating C1-specific receptors as a uniquely human phenomenon is the presence of a high avidity activating C1-specific receptor (Gogo-KIR2DSa) in gorilla.
PMCID: PMC3124310  PMID: 20802150
Natural Killer Cells; Cell Surface Molecules; Comparative Immunology/ Evolution; MHC
13.  Co-evolution of Killer Cell Immunoglobulin-like Receptors with HLA-C to Become The Major Variable Regulators of Human NK cells1 
Interactions between HLA class I and killer cell immunoglobulin-like receptors (KIR) diversify human NK cell responses. Dominant KIR ligands are the C1 and C2 epitopes of MHC-C, a young locus restricted to humans and great apes. C1 and C1-specific KIR evolved first, being present in orangutan and functionally like their human counterparts. Orangutans lack C2 and C2-specific KIR, but have a unique C1+C2 specific KIR that binds equally to C1 and C2. Such a receptor was likely the mechanism by which C2-KIR interaction evolved from C1-KIR while avoiding a non-functional intermediate: either orphan receptor or ligand. Orangutan inhibitory MHC-C reactive KIR pair with activating receptors of identical avidity and specificity, contrasting with the selective attenuation of human activating KIR. The orangutan C1-specific KIR reacts or cross-reacts with all four polymorphic epitopes (C1, C2, Bw4, and A3/11) recognized by human KIR, revealing their structural commonality. Saturation mutagenesis at specificity-determining position 44, demonstrates that KIR are inherently restricted to binding just these four epitopes, either individually or in combination. This restriction frees the majority of HLA-A and –B variants to be dedicated T-cell receptor ligands, not subject to conflicting pressures from the NK cell and T cell arms of the immune response.
PMCID: PMC3124317  PMID: 20805421
14.  Primate-Specific Regulation of Natural Killer Cells 
Journal of medical primatology  2010;39(4):194-212.
Natural killer (NK) cells are circulating lymphocytes that function in innate immunity and placental reproduction. Regulating both development and function of NK cells is an array of variable and conserved receptors that interact with major histocompatibility complex (MHC) class I molecules. Families of lectin-like and immunoglobulin-like receptors are determined by genes in the natural killer (NKC) and leukocyte receptor (LRC) complexes, respectively. As a consequence of the strong, varying pressures on the immune and reproductive systems, NK cell receptors and their MHC class I ligands evolve rapidly, are highly diverse, and exhibit dramatic species-specific differences. The variable, polymorphic family of killer cell immunoglobulin-like receptors (KIR) that regulate human NK cell development and function evolved recently, from a single-copy gene during the evolution of simian primates. Our studies of KIR and MHC class I genes in representative species show how these two unlinked but functionally intertwined genetic complexes have co-evolved. In humans, combinations of KIR and HLA class I factors are associated with infectious diseases, including HIV/AIDS, autoimmunity, reproductive success and the outcome of therapeutic transplantation. The extraordinary, and unanticipated, divergence of human NK cell receptors and MHC class I ligands from their mouse counterparts can in part explain the difficulties experienced in finding informative mouse models for human diseases. Non-human primate models have far greater potential, but to realize their promise will first require more complete definition of the genetics and function of KIR and MHC variation in non-human primate species, at a level comparable to that achieved for the human species.
PMCID: PMC2921375  PMID: 20618586
Non-human primates; NK cells; KIR; MHC; innate immunity
15.  A Small, Variable and Irregular Killer Cell Ig-Like Receptor Locus Accompanies the Absence of MHC-C and MHC-G in Gibbons1 
The killer cell Ig-like receptors (KIR) of natural killer (NK) cells recognize major histocompatibility complex (MHC) class I ligands and function in placental reproduction and immune defense against pathogens. During the evolution of monkeys, great apes and humans, an ancestral KIR3DL gene expanded to become a diverse and rapidly evolving gene family of four KIR lineages. Characterising the KIR locus are three framework regions, defining two intervals of variable gene-content. By analysis of four KIR haplotypes from two species of gibbon, we find that the smaller apes do not conform to these rules. Although diverse and irregular in structure, the gibbon haplotypes are unusually small, containing only two to five functional genes. Comparison with the predicted ancestral hominoid KIR haplotype indicates that modern gibbon KIR haplotypes were formed by a series of deletion events, which created new hybrid genes as well as eliminating ancestral genes. Of the three framework regions, only KIR3DL3 (lineage V), defining the 5’ end of the KIR locus, is present and intact on all gibbon KIR haplotypes. KIR2DL4 (lineage I) defining the central framework region has been a major target for elimination or inactivation, correlating with the absence of its putative ligand, MHC-G, in gibbons. Similarly, the MHC-C driven expansion of lineage III KIR genes in great apes has not occurred in gibbons because they lack MHC-C. Our results indicate that the selective forces shaping the size and organisation of the gibbon KIR locus differed from those acting upon the KIR of other hominoid species.
PMCID: PMC3017126  PMID: 20026738
Comparative Immunology/Evolution; Reproductive Immunology; Natural Killer Cells; Cell Surface Molecules; MHC
16.  Different Patterns of Evolution in the Centromeric and Telomeric Regions of Group A and B Haplotypes of the Human Killer Cell Ig-Like Receptor Locus 
PLoS ONE  2010;5(12):e15115.
The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ∼6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ∼1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region.
PMCID: PMC3012066  PMID: 21206914
17.  Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells 
PLoS Genetics  2010;6(11):e1001192.
Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these functions within individuals and populations are rapidly-evolving interactions between highly polymorphic major histocompatibility complex (MHC) class I ligands and variable NK cell receptors. Specific to simian primates is the family of Killer cell Immunoglobulin-like Receptors (KIR), which recognize MHC class I and associate with a range of human diseases. Because KIR have considerable species-specificity and are lacking from common animal models, we performed extensive comparison of the systems of KIR and MHC class I interaction in humans and chimpanzees. Although of similar complexity, they differ in genomic organization, gene content, and diversification mechanisms, mainly because of human-specific specialization in the KIR that recognizes the C1 and C2 epitopes of MHC-B and -C. Humans uniquely focused KIR recognition on MHC-C, while losing C1-bearing MHC-B. Reversing this trend, C1-bearing HLA-B46 was recently driven to unprecedented high frequency in Southeast Asia. Chimpanzees have a variety of ancient, avid, and predominantly inhibitory receptors, whereas human receptors are fewer, recently evolved, and combine avid inhibitory receptors with attenuated activating receptors. These differences accompany human-specific evolution of the A and B haplotypes that are under balancing selection and differentially function in defense and reproduction. Our study shows how the qualitative differences that distinguish the human and chimpanzee systems of KIR and MHC class I predominantly derive from adaptations on the human line in response to selective pressures placed on human NK cells by the competing needs of defense and reproduction.
Author Summary
Natural killer (NK) cells are versatile lymphocytes that make essential contributions to immune defense and placental reproduction. Essential to NK cell development, diversification and function are variable families of surface receptors that recognize equally variable determinants of polymorphic major histocompatibility complex (MHC) class I molecules, better known as the tissue types matched in clinical organ transplantation. These ligand-receptor interactions evolve rapidly, exhibiting much species specificity and convergent evolution. Consequently, mice represent a poor model, because their receptors are so disparate from the independently evolved human counterparts that are restricted to simian primates. To identify unique and shared aspects of human NK cell biology, we have defined the genomics, population biology, and immunology of variable chimpanzee NK cell receptors and ligands to a level permitting accurate, informed comparison with the well-characterized human system. In both receptors and ligands there are dramatic, qualitative differences between humans and chimpanzees. We show these differences arose during human evolution from the last common human–chimpanzee ancestor, while the chimpanzee system remained relatively stable. That two so closely related species exhibit major differences in NK cell receptors and ligands testifies to the strong and varying selection imposed by the different demands and competing needs of defense and reproduction.
PMCID: PMC2973822  PMID: 21079681
18.  KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C 
The Journal of Experimental Medicine  2009;206(11):2557-2572.
Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between “full-length” and “deleted” forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1+ and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional. Activation of 2DS4+ NKL cells was achieved with A*1102 as ligand, which differs from A*1101 by unique substitution of lysine 19 for glutamate, but not with A*1101 or HLA-C. Distinguishing KIR2DS4 from other KIR2DS is the proline–valine motif at positions 71–72, which is shared with KIR3DL2 and was introduced by gene conversion before separation of the human and chimpanzee lineages. Site-directed swap mutagenesis shows that these two residues are largely responsible for the unique HLA class I specificity of KIR2DS4. Determination of the crystallographic structure of KIR2DS4 shows two major differences from KIR2DL: displacement of contact loop L2 and altered bonding potential because of the substitutions at positions 71 and 72. Correlation between the worldwide distributions of functional KIR2DS4 and HLA-A*11 points to the physiological importance of their mutual interaction.
PMCID: PMC2768862  PMID: 19858347
19.  Chimpanzees use More Varied Receptors and Ligands than Humans for Inhibitory KIR Recognition of the MHC-C1 and MHC-C2 Epitopes 
Humans and chimpanzees have orthologous MHC class I, but few orthologous KIR. Most divergent are lineage III KIR, which in humans include the inhibitory KIR2DL1 and 2DL2/3 specific for HLA-C. Six lineage III chimpanzee KIR were identified as candidate inhibitory MHC-C receptors and studied using cytolytic assays, to assess the capacity of a defined KIR to function with a defined MHC class I allotype, and direct binding assays with KIR-Fc fusion proteins. Pt-KIR2DL6 and 2DL8 were demonstrated to be inhibitory C1 receptors with a specificity and specificity-determining residue (lysine 44) like KIR2DL3. Analogously, Pt-KIR2DL7 is like KIR2DL1, an inhibitory C2 receptor having methionine 44. Pt-KIR3DL4 and 3DL5 are unusual lineage III KIR with D0 domains, which are also inhibitory C2 receptors with methionine 44. Removal of D0 from KIR3DL, or its addition to KIR2DL, had no effect on KIR function. Pt-KIR2DL9, a fourth inhibitory C2 receptor, has glutamate 44, a previously uncharacterized specificity-determining residue that is absent from human KIR. Reconstruction of the ancestral hominoid KIR sequence shows it encoded lysine 44, indicating that KIR having methionine 44 and glutamate 44 subsequently evolved by independent point substitutions. Thus MHC-C2 specific KIR have evolved independently on at least two occasions. None of the six chimpanzee KIR studied resembles KIR2DL2, which interacts strongly with C1 and crossreacts with C2. Whereas human HLA-B allotypes that have functional C1 epitopes are either rare (HLA-B*73) or geographically localized (HLA-B*46), some 25% of Patr-B allotypes have the C1 epitope and are functional KIR ligands.
PMCID: PMC2854666  PMID: 19265141
Natural Killer Cells; Cell Surface Molecules; Comparative Immunology/Evolution; MHC
20.  Evolution and survival of marine carnivores did not require a diversity of KIR or Ly49 NK cell receptors1 
Ly49 lectin-like receptors and killer cell immunoglobulin-like receptors (KIR) are structurally unrelated cell-surface glycoproteins that evolved independently to function as diverse NK cell receptors for MHC class I molecules. Comparison of primates and various domesticated animals has shown that species have either a diverse Ly49 or KIR gene family, but not both. In four pinniped species of wild marine carnivore, three seals and one sea lion, we find that Ly49 and KIR are each represented by single, orthologous genes that exhibit little polymorphism and are transcribed to express cell-surface protein. Pinnipeds are therefore species in which neither Ly49 nor KIR are polygenic but retain the ancestral single-copy state. Whereas pinniped Ly49 has been subject to purifying selection, we find evidence for positive selection on KIR3DL during pinniped evolution. This selection, which focused on the D0 domain and the stem, points to the functionality of the KIR and likely led to the sea lion’s loss of D0. In contrast to the dynamic and rapid evolution of the KIR and Ly49 genes in other species, the pinniped KIR and Ly49 have been remarkably stable during the > 33 million years since the last common ancestor of seals and sea lions. These results demonstrate that long-term survival of placental mammal species need not require a diverse system of either Ly49 or KIR NK-cell receptors.
PMCID: PMC2754575  PMID: 19265140
Comparative Immunology; Comparative Evolution; Natural Killer Cells; Other Animals
21.  A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates 
PLoS Genetics  2009;5(10):e1000688.
There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.
Author Summary
Most receptors of natural killer (NK) cells interact with highly polymorphic major histocompatibility complex (MHC) class I molecules and thereby regulate the activity of NK cells against infected or malignant target cells. Whereas humans, apes, and Old and New World monkeys use the family of killer cell immunoglobulin-like receptors (KIR) as highly diverse NK cell receptors, this function is performed in rodents by the diverse family of lectin-like receptors Ly49. When did this functional separation occur in evolution? We followed this by investigating lemurs, primates that are distantly related to humans. We show here that lemurs employ the CD94/NKG2 family as their highly diversified NK cell receptors. The CD94/NKG2 receptors also belong to the lectin-like receptor family, but are rather conserved in “higher” primates and rodents. We could further demonstrate that lemurs have a single Ly49 gene like other primates but lack functional KIR genes of the KIR3DL lineage and show major deviations in their MHC class I genomic organisation. Thus, lemurs have evolved a “third way” of polymorphic and diverse NK cell receptors. In addition, the multiplied lemur CD94/NKG2 receptors can be freely combined, thereby forming diverse receptors. This is, therefore, the first description of some combinatorial diversity of NK cell receptors.
PMCID: PMC2757895  PMID: 19834558
22.  Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues 
The Journal of Experimental Medicine  2005;201(8):1319-1332.
Expression of killer cell Ig-like receptors (KIRs) diversifies human natural killer cell populations and T cell subpopulations. Whereas the major histocompatibility complex class I binding functions of inhibitory KIR are known, specificities for the activating receptors have resisted analysis. To understand better activating KIR and their relationship to inhibitory KIR, we took the approach of reconstructing their natural history and that of Ly49, the analogous system in rodents. A general principle is that inhibitory receptors are ancestral, the activating receptors having evolved from them by mutation. This evolutionary process of functional switch occurs independently in different species to yield activating KIR and Ly49 genes with similar signaling domains. Selecting such convergent evolution were the signaling adaptors, which are older and more conserved than any KIR or Ly49. After functional shift, further activating receptors form through recombination and gene duplication. Activating receptors are short lived and evolved recurrently, showing they are subject to conflicting selections, consistent with activating KIR's association with resistance to infection, reproductive success, and susceptibility to autoimmunity. Our analysis suggests a two-stage model in which activating KIR or Ly49 are initially subject to positive selection that rapidly increases their frequency, followed by negative selection that decreases their frequency and leads eventually to loss.
PMCID: PMC2213150  PMID: 15837816

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