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  • 1
    Electronic Resource
    Electronic Resource
    Differential behavior of cytotoxic effector cells against HLA antigens in strong genetic linkage disequilibrium (1981)
    Springer
    Immunogenetics 13 (1981), S. 297-309 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Five sets of cytotoxic effector cells were generated, using haploidentical, first degree relatives in five different families, against the HLA-A3; B7 serological determinants combined with different DR antigens. When tested against a panel of cells bearing combinations of the HLA-A, -B and -DR antigens it was shown that the HLA-B7 antigen was as strong a CML target determinant alone as it was in the presence of HLA-A3. The strength of the HLA-A3 antigen as target determinant varied. With effector cells primed to the HLA-A3; B7; DR2 haplotype, the A3 antigen alone behaved as a weak target determinant. When the same target cells were tested with the effector cells generated against HLA-A3; B7 without DR2, the A3 antigen behaved as a strong target determinant. A number of target cells lacking the serologically detectable HLA determinants present on the sensitizing HLA haplotype were identified as being killed by specific effector cells. These data suggest either a number of new CML target determinants controlled by different loci or the presence of a single, new locus with multiple alleles controlling CML targets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00364495
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  • 2
    Electronic Resource
    Electronic Resource
    The genomic structure of two ancestral haplotypes carrying C4A duplications (1991)
    Springer
    Immunogenetics 34 (1991), S. 247-251 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Two major histocompatibility complex (MHC) ancestral haplotypes (AH) HLA A24, Bw52, C2C, BfS, C4A3 + 2, C4BQO, DRw15, DQw6 (52.1) and HLA A24, Cw7, B7, C2C, BfS, C4A3 + 3, C4B1, DR1, DQw5 (7.2), which occur with the haplotype frequencies of approximately 10% and 4% respectively in the Japanese population, carry duplicated C4A alleles by C4 allotyping. Southern blot analysis with Taq I indicated that the 52.1 AH has two C4 genes defined by 7.0 kilobase (kb) and 6.0 kb C4 hybridizing fragments but both encode C4A allotypes, being C4A3 and C4A2 respectively. The 7.2 AH carries two C4A3 and one C4B1 alleles and restriction lenght polymorphism (RFLP) analysis with Taq I showed that 6.0 kb and 7.0 kb fragments are in the proportion of 2:1. By pulsed field gel electrophoresis (PFGE) analysis, the lengths of the Pvul fragments carrying C4 and Cyp21 genes were approximately 390 kb for 52.1 and 440 kb to 7.2. The results indicate that the RFLP markers do not correlate with C4 isotype (A or B) or allotype and that the C4 gene copy number is a function of the number of genomic blocks containing C4 and Cyp21.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00215260
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  • 3
    Electronic Resource
    Electronic Resource
    An approach to the localization of the susceptibility genes for generalized myasthenia gravis by mapping recombinant ancestral haplotypes (1992)
    Springer
    Immunogenetics 35 (1992), S. 355-364 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The association of HLA A1, B8, and DR3 with generalized myasthenia gravis (GMG) ini Caucasoids is well established, but no particular gene has been implicated and there is still no adequate explanation in functional terms. In study we have taken advantage of sequential genomic markers between B8 and DR3 so as to map the location of susceptibility gene(s) on the A1, B8, DR3 (8.1) ancestral haplotype. By studying 51 patients, we have delineated a region between HLA B and TNF which is shared by 29/29 patients with B8 and DR3, 19/19 patients with B8 but not DR3 and 2/3 patients with DR3 but not B8. The potential importance of this region was confirmed by examining a similar disease induced by D-Penicillamine (D-PenMG) and associated with different HLA class II alleles (DR1 and/or DR7). Among these patients, 7/16 (44%) have B8, often with other markers of 8.1. These results implicate at least two categories of genes in determining susceptibility to MG; one located in the region between HLA B and TNF may be immunoregulatory, whereas the second, located in the class II region, may relate to the inducing factor (e. g., DR1 or DR7 in D-PenMG).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00179791
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  • 4
    Electronic Resource
    Electronic Resource
    Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM (1992)
    Springer
    Immunogenetics 36 (1992), S. 345-356 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The major histocompatibility complex (MHC) contains multiple and diverse genes which may be relevant to the induction adn regulation of autoimmune responses in insulin dependent diabetes mellitus (IDDM). In addition to HLA class I and II, the possible candidates include TNF, C4, and several other poorly defined polymorphic genes in the central MHC region. This study describes two approaches which take advantage of the fact that the relevant genes are carried by highly conserved ancestral haplotypes such as 8.1 (HLA-B8, TNFS, C4AQO, C4B1, DR3, DQ2). First, three “diabetogenic” haplotypes (two Caucasoid and one Mongoloid) have been compared and it has been shown that all three share a rare allele of BAT3 as well as sharing DR3, DQ2. In 43 sequential patients with IDDM the cross product ration for BAT3S was 4.8 (p〈0.01) and 6.9 for HLA-B8 plus BAT3S (p〈0.001). Second, partial or recombinant ancestral haplotypes with either HLA class I (HLA-B8) or II (HLA-DR3, DQ2) alleles were identified. Third, using haplotypic polymorphisms such as the one in BAT3, we have shown that all the patients carrying recombinants of the 8.1 ancestral haplotype share the central region adjacent to HLA-B. These findings suggest that both HLA and non-HLA genes are involved in conferring susceptibility to IDDM, and that the region between HLA-B and BAT3 contains some of the relevant genes. By contrast, similar approaches suggest that protective genes map to the HLA class II region.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00218041
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  • 5
    Electronic Resource
    Electronic Resource
    Complete sequence of the complement C4 gene from the HLA-A1, B8, C4AQ0, C4B1, DR3 haplotype (1996)
    Springer
    Immunogenetics 43 (1996), S. 250-252 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00587313
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  • 6
    Electronic Resource
    Electronic Resource
    Organization and evolution of C4 and CYP21 genes in primates: importance of genomic segments (1993)
    Springer
    Immunogenetics 37 (1993), S. 170-176 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The evolutionary relationship between two central major histocompatibility complex (MHC) genes, C4 and CYP21, was investigated by employing pulsed field gel electrophoresis (PFGE) and conventional restriction fragment length polymorphism (RFLP) analyses in human and nonhuman primates. Using Taq I in conjunction with C4 and CYP21 probes, it has been found that there are four major types of C4 genes [defined by 7.0, 6.4, 6.0, and 5.4 kilobases (kb) Taq I fragments] and two major types of CYP21 genes (3.7 and 3.2 kb fragments) in human and nonhuman primates including chimpanzee, gorilla, and orangutan. All of the eight possible combinations of C4 and CYP21 genes can be identified on one or more human ancestral haplotypes (AH). It is concluded that each of the major types of C4 and CYP21 (and each of the combinations between these) predated human speciation. PFGE analysis with Mlu I and Pvu I suggested that each C4 + CYP21 segment has a specific length of 30–50 kb and that each AH carries one, two, three, or even more segments. In the case of C4, it is important to note that there is no simple relationship between the RFLP and the protein classifications. Thus, at least some of the expressed polymorphisms could be relatively recent in that they are carried by the same or different gene types. These findings are consistent with the hypothesis that M MHC AHs have been formed from a large pool of specific genomic segments and that further haplospecific polymorphism has developed subsequently.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191881
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  • 7
    Electronic Resource
    Electronic Resource
    Genomic organization of a polymorphic duplicated region centromeric of HLA-B (1992)
    Springer
    Immunogenetics 36 (1992), S. 208-212 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The region between tumor necrosis factor (TNF) and HLA-B in the central major histocompatibility complex (MHC) is polymorphic and associated with several autoimmune diseases. The polymorphisms are haplospecific or haplotypic and retained within the same MHC ancestral haplotype (AH). We have cloned this region from four AHs into λ bacteriophage and found that a highly polymorphic region in the TNF-HLA-B interval is duplicated. Clones from this region isolated from three MHC AHs show two populations. The regions, designated CL1 and CL2, have different sizes of Bam HI fragments carrying the duplicated sequences. These fragments correspond to those seen after Bam HI restriction fragment length polymorphism (RFLP) analysis of genomic DNA from the same cell lines. Pulsed field gel electrophoresis analysis shows that both CL1 and CL2 are in the central MHC and are about 16 kilobases apart. DNA cloning and RFLP analysis demostrate that the Cl region is highly polymorphic but retained within an MHC AH. Polymorphism and duplication are common characteristics of the genes found in the MHC and therefore the CL sequences have the potential to be interesting in this respect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00215049
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  • 8
    Electronic Resource
    Electronic Resource
    Complete sequence of the complementC4 gene from theHLA-A1, B8, C4AQ0, C4B1, DR3 haplotype (1996)
    Springer
    Immunogenetics 43 (1996), S. 250-252 
    Details
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00587313
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  • 9
    Electronic Resource
    Electronic Resource
    The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15 (1999)
    Springer
    Immunogenetics 49 (1999), S. 660-665 
    Details
    ISSN: 1432-1211
    Keywords: Key words IKBL ; MHC ; TNF
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Susceptibility to several disorders, including insulin-dependent diabetes mellitus and multiple sclerosis, has been associated with alleles of HLA class II genes and loci in the TNF cluster in the central major histocompatibility complex (MHC) region. As recombination within this region is rare, it is difficult to determine which genes are important. This will be facilitated by the identification of functional polymorphisms. Hence we are sequencing reverse transcription-polymerase chain reaction products derived from central MHC genes in well characterized and conserved ancestral haplotypes. Here we address the IKBL gene, which lies near the TNF cluster at the telomeric end of the central MHC. Although the IKBL cDNA sequence was conserved between most ancestral haplotypes, a synonymous nucleotide substitution, a 3' untranslated region substitution, and a single nonsynonymous substitution were identified. The latter (IKBL+738) was present in multiple examples of the 7.1 haplotype [HLA-A3, B7, DR2 (DR15)] and resulted in a cysteine to arginine substitution in a predicted protein kinase C phosphorylation site. This polymorphism did not occur in 18 other common haplotypes from the 10th International Histocompatibility Workshop and thus appears haplospecific. A role for IKBL+738 in the association between HLA-A3,B7,DR2(DR15) and susceptibility to multiple sclerosis is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002510050662
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  • 10
    Electronic Resource
    Electronic Resource
    The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases (1999)
    Oxford, UK : Blackwell Publishing Ltd
    Immunological reviews 167 (1999), S. 0 
    Details
    ISSN: 1600-065X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the dearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150–200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitns (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis co the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1600-065X.1999.tb01398.x
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