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Abstracts
S113
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RECEPTOR-LIGAND ANALYSIS DEFINES MINIMAL KILLER CELL Ig-LIKE RECEPTOR (KIR) IN HUMANS Zeying Du, David W. Gjerston, Elaine F. Reed, Raja Rajalingam. UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA Aim: Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and HLA class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR and HLA, and their independent segregation results in a variable number and type of iKIR⫹HLA pairs inherited in individuals. The aim of study is to test if coexistence of a minimum of one iKIR and its specific HLA class I is necessary to maintain self-tolerance and enable NK cell competency. Methods: KIR and HLA genotyping was performed in 759 unrelated individuals. The diversity in the coinheritance of iKIR⫹HLA pairs and activating KIR (aKIR) genes were analyzed in four ethnic populations. Scope: The results showed that every individual studied inherited a minimum of one iKIR⫹HLA pair suggesting that MHC class I-dependent inhibitory signaling is essential for human NK cells. In contrast, 13.4% of the study group lacked all aKIR genes. Twenty percent of the study group carried only one of the four iKIR⫹HLA pairs. Interestingly, 3% of the study group carrying only KIR2DL3⫹HLA-C1 as an iKIR⫹HLA pair lacked aKIR genes. These data suggest that a single iKIR can maintain self-tolerance and constitute the minimal KIR repertoire for human NK cells. Genotypes carrying an equal number of iKIR⫹HLA pairs and aKIR genes were represented in 20% of our study group. The remaining individuals had either a dominant inhibitory KIR genotype (iKIR⫹HLA⬎aKIR) or a dominant activating KIR genotype (iKIR⫹HLA⬍aKIR). Conclusions: Genotypes encoding imbalanced inhibitory and activating interactions may contribute to the susceptibility or resistance to human diseases.
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SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HEAT SHOCK PROTEIN 70 GENE CLUSTER AND THEIR RELATIONSHIPS TO CLASSICAL HUMAN LEUKOCYTE ANTIGEN VARIANTS Elena Lobashevsky,1 Chengbin Wang,1 Sadeep Shrestha,1 Alex Lazaryan,1 Brahim Aissani,1 Kisani Ogwaro,1 Craig M. Wilson,2,3 Jianming Tang,3 Richard A. Kaslow.1,3 1Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 3Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA Aim: Like human leukocyte antigen (HLA), members of the heat shock protein 70 (Hsp70) family play an active role in antigen presentation. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the Hsp70 gene cluster (HSPA1A, HSPA1B and HSPA1L) on chromosome 6 in relation to known HLA class I and class II haplotypes. Methods: Restriction fragment length polymorphism and TaqMan assays were used to define five informative SNPs (3 non-synonymous, 1 synonymous and 1 in 3’ untranslated region) in 385 adolescents of mixed ethnic origin; the cohort includes HIV-1 seropositive and seronegative individuals. HLA class I and class II alleles and haplotypes of these individuals have already been identified by standard molecular techniques and analyzed. Local haplotypes involving the five SNPs (rs2075800, rs2227955, rs2227956, rs1043618, rs2763979, in order from telomere to centromere) were assigned using the expectationmaximization algorithm (SAS Genetics, version 9.1). Linkage disequilibrium (LD) between SNP haplotypes and HLA class I or class II haplotypes were analyzed in a similar way. Scope: The five SNPs were found on four common haplotypes, with individual frequencies ranging from 0.05 to 0.59. These SNP haplotypes were in LD with several HLA class I haplotypes, including B*07-Cw*07, B*15-Cw*02, B*15-Cw*03, B*42-Cw*17, B*44-Cw*04, B*53-Cw*04 and B*58-Cw*06. HLA class II haplotypes in LD with the SNP haplotype were mostly DRB1*03-DQB1*02, DRB1*03-DQB1*04, DRB1*07DQB1*02, DRB1*08-DQB1*03 and DRB1*15-DQB1*06. At least three of these extended haplotypes (underlined) were frequent in African-Americans but rare in other ethnic groups. The B alleles in several of these haplotypes have previously been associated with a favorable or an unfavorable course of human immunodeficiency virus type 1 (HIV-1) infection. Conclusions: The extended haplotypes involving the gene cluster encoding Hsp70-related molecules and classic HLA variants differ by ethnicity in their occurrence and frequency. In view of strong HLA class I associations with HIV-1 infection, LD between haplotypes spanning the Hsp70 gene cluster should be of particular relevance to research on the molecular machinery for antigen presentation in the context of that infection and others.
S113
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RECEPTOR-LIGAND ANALYSIS DEFINES MINIMAL KILLER CELL Ig-LIKE RECEPTOR (KIR) IN HUMANS Zeying Du, David W. Gjerston, Elaine F. Reed, Raja Rajalingam. UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA Aim: Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and HLA class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR and HLA, and their independent segregation results in a variable number and type of iKIR⫹HLA pairs inherited in individuals. The aim of study is to test if coexistence of a minimum of one iKIR and its specific HLA class I is necessary to maintain self-tolerance and enable NK cell competency. Methods: KIR and HLA genotyping was performed in 759 unrelated individuals. The diversity in the coinheritance of iKIR⫹HLA pairs and activating KIR (aKIR) genes were analyzed in four ethnic populations. Scope: The results showed that every individual studied inherited a minimum of one iKIR⫹HLA pair suggesting that MHC class I-dependent inhibitory signaling is essential for human NK cells. In contrast, 13.4% of the study group lacked all aKIR genes. Twenty percent of the study group carried only one of the four iKIR⫹HLA pairs. Interestingly, 3% of the study group carrying only KIR2DL3⫹HLA-C1 as an iKIR⫹HLA pair lacked aKIR genes. These data suggest that a single iKIR can maintain self-tolerance and constitute the minimal KIR repertoire for human NK cells. Genotypes carrying an equal number of iKIR⫹HLA pairs and aKIR genes were represented in 20% of our study group. The remaining individuals had either a dominant inhibitory KIR genotype (iKIR⫹HLA⬎aKIR) or a dominant activating KIR genotype (iKIR⫹HLA⬍aKIR). Conclusions: Genotypes encoding imbalanced inhibitory and activating interactions may contribute to the susceptibility or resistance to human diseases.
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SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HEAT SHOCK PROTEIN 70 GENE CLUSTER AND THEIR RELATIONSHIPS TO CLASSICAL HUMAN LEUKOCYTE ANTIGEN VARIANTS Elena Lobashevsky,1 Chengbin Wang,1 Sadeep Shrestha,1 Alex Lazaryan,1 Brahim Aissani,1 Kisani Ogwaro,1 Craig M. Wilson,2,3 Jianming Tang,3 Richard A. Kaslow.1,3 1Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 3Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA Aim: Like human leukocyte antigen (HLA), members of the heat shock protein 70 (Hsp70) family play an active role in antigen presentation. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the Hsp70 gene cluster (HSPA1A, HSPA1B and HSPA1L) on chromosome 6 in relation to known HLA class I and class II haplotypes. Methods: Restriction fragment length polymorphism and TaqMan assays were used to define five informative SNPs (3 non-synonymous, 1 synonymous and 1 in 3’ untranslated region) in 385 adolescents of mixed ethnic origin; the cohort includes HIV-1 seropositive and seronegative individuals. HLA class I and class II alleles and haplotypes of these individuals have already been identified by standard molecular techniques and analyzed. Local haplotypes involving the five SNPs (rs2075800, rs2227955, rs2227956, rs1043618, rs2763979, in order from telomere to centromere) were assigned using the expectationmaximization algorithm (SAS Genetics, version 9.1). Linkage disequilibrium (LD) between SNP haplotypes and HLA class I or class II haplotypes were analyzed in a similar way. Scope: The five SNPs were found on four common haplotypes, with individual frequencies ranging from 0.05 to 0.59. These SNP haplotypes were in LD with several HLA class I haplotypes, including B*07-Cw*07, B*15-Cw*02, B*15-Cw*03, B*42-Cw*17, B*44-Cw*04, B*53-Cw*04 and B*58-Cw*06. HLA class II haplotypes in LD with the SNP haplotype were mostly DRB1*03-DQB1*02, DRB1*03-DQB1*04, DRB1*07DQB1*02, DRB1*08-DQB1*03 and DRB1*15-DQB1*06. At least three of these extended haplotypes (underlined) were frequent in African-Americans but rare in other ethnic groups. The B alleles in several of these haplotypes have previously been associated with a favorable or an unfavorable course of human immunodeficiency virus type 1 (HIV-1) infection. Conclusions: The extended haplotypes involving the gene cluster encoding Hsp70-related molecules and classic HLA variants differ by ethnicity in their occurrence and frequency. In view of strong HLA class I associations with HIV-1 infection, LD between haplotypes spanning the Hsp70 gene cluster should be of particular relevance to research on the molecular machinery for antigen presentation in the context of that infection and others.