Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

Natural killer (NK) and some T cells express killer cell immunoglobulin-like receptors (KIRs),

Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric ''half'' was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family.

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson's F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright's FST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

The frequency of joint symptoms was determined amongst 2022 affluent and 2210 poor adults in Karachi, Pakistan. Joint pain was significantly (P = 0.025) more common amongst the affluent (6.6%) compared with the poor (5%) and this was due to a significantly greater frequency of knee pain in the richer community (3% vs 1.8%; P = 0.008). The prevalence increased with age and was more common in females. Almost half were associated with varus deformity, suggesting the presence of associated OA in a high proportion. The overall frequency of knee pain seemed no greater than in series reported from the West. Compared with age- and sex-matched controls, body weight was significantly greater amongst those with knee pain, both amongst the affluent (P = 0.005) and the poor (P = 0.02). Control subjects were heavier in the affluent population, suggesting that the greater frequency of knee symptoms in this community was due to their relative obesity. Knee bending at prayer was most common amongst the affluent controls and may indicate that religious observance also contributed to the problem in the richer population. Squatting was a characteristic of the poor who had less knee pain than the affluent. Knee flexing could not therefore be confidently implicated. No relationship could be demonstrated between knee pain and joint laxity.

The association of particular HLA-DR alleles and the shared epitope with rheumatoid arthritis (RA) is now well established. The strength of these links varies between races. Furthermore, the proposition that the presence of the shared epitope is indicative of severe disease has been more difficult to sustain in non-Europeans. This study examines the frequency of HLA-DR and HLA-DRB1 amongst Pakistanis for the first time. Using the polymerase chain reaction (PCR) and sequence-specific oligonucleotide probes (PCR-SSOP) and primers (PCR-SSP), HLA-DR phenotype and genotype frequencies were ascertained in 86 RA hospital out-patients and 79 healthy controls matched for age, gender and ethnicity. HLA-DR1 and HLA-DR4 frequency was similar in patients and controls. HLA-DR10 occurred in 26 instances (15%) in RA and in eight (5%) controls (Pcorr = 0.048). HLA-DR2 was also increased in patients (P = 0.053) and its major subtype DR15 was significantly increased (Pcorr = 0.03). HLA-DR5 frequency was 5% in patients and 19% in controls (Pcorr = 0.002). The HLA-DR4 alleles possessing the shared epitope were more common in RA (Pcorr = 0.03) and this difference was enhanced by inclusion of other alleles possessing the shared epitope (Pcorr = 0.002). Shared epitope alleles were observed in 43 (50%) patients and 17 (22%) controls (Pcorr = 0.003). The shared epitope did not distinguish patients with more severe disease, as reflected by pain, joint deformities, disability, rheumatoid factor or X-ray damage. The distribution of HLA-DR alleles in Pakistanis with RA supports the shared epitope hypothesis. In common with other non-European racial groups, HLA-DR4 was not associated with RA. Unlike other groups, there was a weak link of RA with HLA-DR2. A protective effect of HLA-DR5 was apparent. In accord with some other studies, the shared epitope in this hospital out-patient population was not a marker for more severe disease.

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The impact of environmental factors on the causation of rheumatoid arthritis (RA) is thought to be considerable. We explored this by comparing the prevalence of RA amongst Pakistanis living in England, where it is relatively high amongst ethnic English, and in Pakistan. The frequency of other rheumatic diseases was also compared. Information on 2056 adult Pakistanis in England and 4232 in Pakistan was obtained by house-to-house surveys using identical protocols. Positive respondents were examined by the same two clinicians in both countries. Rheumatic complaints increased with age and were more common in females in both communities. The standardized morbidity ratio (SMR) (95% CI) of RA in England was 2.1 (1.1-3.1) compared with Pakistan, a difference that was entirely attributable to females. The SMR (95% CI) for women was 3.0 (0.4-5.6) and for men 0.86 (-0.84 to 2.56). In Pakistan, there was a trend to more reporting of some but not all rheumatic complaints amongst the affluent segment of the population. This was increasingly apparent amongst those resident in England and the possibility of an impact of easier ascertainment amongst the more educated cannot be discounted. Low back pain was significantly more common in England. Furthermore, the colder climate was frequently invoked as a cause of more symptoms in England. Thus, several factors may have influenced the observation that RA is more common amongst Pakistanis in England compared with Pakistan. An environmental factor cannot be excluded. However, the frequency of non-specific musculoskeletal pain was similar. The regions of Pakistan from which the two populations were derived were also different and immunogenetic heterogeneity might also have contributed to the difference in RA prevalence.