Locus specificity of polymorphic alleles and evolution by a birth-and-death process in mammalian MHC genes.
(1/978)
We have conducted an extensive phylogenetic analysis of polymorphic alleles from human and mouse major histocompatibility complex (MHC) class I and class II genes. The phylogenetic tree obtained for 212 complete human class I allele sequences (HLA-A, -B, and -C) has shown that all alleles from the same locus form a single cluster, which is highly supported by bootstrap values, except for one HLA-B allele (HLA-B*7301). Mouse MHC class I loci did not show locus-specific clusters of polymorphic alleles. This was considered to be because of either interlocus genetic exchange or the confusing designation of loci in different haplotypes at the present time. The locus specificity of polymorphic alleles was also observed in human and mouse MHC class II loci. It was therefore concluded that interlocus recombination or gene conversion is not very important for generating MHC diversity, with a possible exception of mouse class I loci. According to the phylogenetic trees of complete coding sequences, we classified human MHC class I (HLA-A, -B, and -C) and class II (DRB1) alleles into three to five major allelic lineages (groups), which were monophyletic with high bootstrap values. Most of these allelic groups remained unchanged even in phylogenetic trees based on individual exons, though this does not exclude the possibility of intralocus recombination involving short DNA segments. These results, together with the previous observation that MHC loci are subject to frequent duplication and deletion, as well as to balancing selection, indicate that MHC evolution in mammals is in agreement with the birth-and-death model of evolution, rather than with the model of concerted evolution. (+info)
HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.
(2/978)
A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both. (+info)
HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy.
(3/978)
The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02(+) healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02(-) HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections. (+info)
Engagement of natural cytotoxicity programs regulates AP-1 expression in the NKL human NK cell line.
(4/978)
NK cell cytotoxicity is a fast and efficient mechanism of target cell lysis. Using transcription analysis, such as multiplex messenger assays, we show here that natural cytotoxicity exerted by the human NKL cell line correlates with mRNA accumulation of very early activator protein (AP)-1 transcription factor genes such as JunB, FosB and c-Fos. In addition, DNA-binding activities of Jun-Fos heterodimers were observed by electrophoretic mobility shift assays during the course of natural cytotoxicity. Interaction between immunoglobulin-like transcript-2/leukocyte Ig-like receptor 1 on NKL cells and HLA-B27 on target cells leads to an impairment of NKL natural cytotoxicity, which correlates with an absence of JunB, FosB, and c-Fos transcription, as well as an absence of their DNA-binding activity. Our studies thus indicate that, despite the rapidity of NK cell-mediated lysis, AP-1 transcription factor is activated during the early stage of NK cell cytolytic programs and that engagement of NK cell inhibitory receptors for MHC class I molecules impairs the very early activation of AP-1. (+info)
Differences in gene conversion rates among exons between HLA-A and HLA-B loci.
(5/978)
To examine whether gene conversion occurs between two homologous loci of HLA-A and HLA-B, DNA sequences were compared and the differences or the numbers of substitutions per site at synonymous and nonsynonymous sites were calculated in the coding region and in the non-coding region. (1) Totally differences at synonymous sites in introns and coding regions are small as compared with the differences in the 5' flanking region. This indicates that gene conversion should occur between HLA-A and HLA-B loci. (2) In exon2 and exon3, the differences at synonymous sites are smaller than at nonsynonymous sites. This suggests that these exons are subject to positive natural selection, which is consistent with the reports of Hughes and Nei [1,2], because exon2 and exon3 encode alpha 1 and alpha 2 domains of the HLA molecule respectively which include mainly the antigen recognition sites (ARS). (3) in exon4, the difference at the synonymous site is the same as that in the 5' flanking region, which suggests that gene conversion does not frequently occur. The difference in this exon is extremely small at the nonsynonymous sites. This exon encodes the alpha 3 domain which does not have the antigen recognition sites but have an important function in maintaining the structure of the HLA molecule. From the above results, it can be concluded that gene conversion between HLA-A and HLA-B occurs more frequently in the two exons, exon2 and exon3 which have ARS regions. Furthermore, to examine a possibility that the variability of GC content along sequence influences the difference, the GC content was calculated along the sequence. (+info)
The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis.
(6/978)
OBJECTIVE: To investigate the relative contribution of HLA antigens in the susceptibility to psoriasis and to localize additional genetic factors involved in psoriatic arthritis (PsA). METHODS: DNA from 45 patients with psoriasis, 65 with PsA, and 177 healthy control subjects was examined by polymerase chain reaction (PCR) using sequence-specific oligonucleotide probes to determine HLA-C. To examine whether MICA (class I major histocompatibility complex chain-related gene A) confers additional susceptibility, trinucleotide repeat polymorphism in the transmembrane region of the MICA gene was investigated by radioactive PCR. Further analysis of MICA was made by PCR-single-strand conformational polymorphism to determine the allelic variant corresponding to MICA transmembrane polymorphism. RESULTS: Our results reveal new findings: 1) the frequency of the Cw*0602 allele was significantly increased in both patient groups: psoriasis (corrected P [Pcorr] < 10(-5), relative risk [RR] 6.2), PsA (Pcorr < 10(-6), RR 6.3), 2) the trinucleotide repeat polymorphism MICA-A9 was present at a significantly higher frequency in PsA patients (Pcorr < 0.00035, RR 3.2), whereas a similar distribution was found in both the control and psoriasis population, 3) this polymorphism corresponds to the MICA-002 allele and was found to be overrepresented in patients with the polyarticular form (Pcorr < 0.0008, RR 9.35), 4) the increase in MICA-A9 in PsA patients is independent of linkage disequilibrium with Cw*0602, 5) this allele confers additional relative risk (RR 3.27, etiologic fraction 0.44; etiologic fraction is the proportion of disease cases among the total population that are attributable to 1 allele when the relative risk is > 1) in PsA patients who carry Cw*0602. CONCLUSION: The data obtained in this study are consistent with the polygenic inheritance of psoriasis. Cw*0602 appears to be the stronger genetic susceptibility factor for psoriasis. Independent of the HLA-C association, MICA-A9 polymorphism corresponding to the MICA-002 allele is a possible candidate gene for the development of PsA. (+info)
HLA-B15 peptide ligands are preferentially anchored at their C termini.
(7/978)
Therapies to elicit protective CTL require the selection of pathogen- and tumor-derived peptide ligands for presentation by MHC class I molecules. Edman sequencing of class I peptide pools generates "motifs" that indicate that nonameric ligands bearing conserved position 2 (P2) and P9 anchors provide the optimal search parameters for selecting immunogenic epitopes. To determine how well a motif represents its individual constituents, we used a hollow-fiber peptide production scheme followed by the mapping of endogenously processed class I peptide ligands through reverse-phase HPLC and mass spectrometry. Systematically mapping and characterizing ligands from B*1508, B*1501, B*1503, and B*1510 demonstrate that the peptides bound by these B15 allotypes i) vary in length from 7 to 12 residues, and ii) are more conserved at their C termini than their N-proximal P2 anchors. Comparative peptide mapping of these B15 allotypes further pinpoints endogenously processed ligands that bind to the allotypes B*1508, B*1501, and B*1503, but not B*1510. Overlapping peptide ligands are successful in binding to B*1501, B*1503, and B*1508 because these B15 allotypes share identical C-terminal anchoring pockets whereas B*1510 is divergent in the C-terminal pocket. Therefore, endogenous peptide loading into the B15 allotypes requires that a conserved C terminus be anchored in the appropriate specificity pocket while N-proximal anchors are more flexible in their location and sequence. Queries for overlapping and allele-specific peptide ligands may thus be contingent on a conserved C-terminal anchor. (+info)
Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules.
(8/978)
Recent investigations have shown that malignant transformation may down-regulate the expression of class I HLA molecules, beta2-microglobulin (beta2m) and members of the antigen-processing machinery. In the present study, we HLA-genotyped and identified at a biochemical level the three (HLA-A25, -B8, -Cw7) class I alleles expressed by the previously described [D'Urso CM et al (1992) J Clin Invest 87: 284-292] beta2m-defective human melanoma FO-1 cell line and tested their ability to interact with calnexin, calreticulin and the TAP (transporter associated with antigen processing) complex. All these alleles were found to bind calnexin, but not calreticulin or the poorly expressed TAP complex, both in parental and beta2m-transfected FO-1 cells, demonstrating a complex defect of class I expression in FO-1 cells. In these conditions, Cw7 heavy chains interacted with calnexin more strongly than A25 and B8, and preferentially accumulated in the endoplasmic reticulum, in both a calnexin-associated and a calnexin-free form. In addition, they could be transported to the cell surface at low levels even in the absence of beta2m, without undergoing terminal glycosylation. These results establish a parallel between HLA-C and the murine Db and Ld molecules which have been found to be surface expressed and functional in beta2m-defective cells. They also demonstrate distinctive features of HLA-C molecules. We propose that the accumulation of several assembly intermediates of HLA-C might favour the binding of peptide antigens not readily bound by HLA-A and -B molecules in neoplastic cells with suboptimal class I expression. (+info)