Major histocompatibility complex susceptibility genes for dermatitis herpetiformis compared with those for gluten-sensitive enteropathy.
01 Dec 1993-Journal of Experimental Medicine (Rockefeller University Press)-Vol. 178, Iss: 6, pp 2067-2075
TL;DR: The findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class II region.
Abstract: Dermatitis herpetiformis (DH) shares some clinical features and major histocompatibility complex (MHC) markers with gluten-sensitive enteropathy (GSE). We compared MHC haplotypes in 27 patients with DH, 35 patients with GSE, and normal controls. As in GSE, the frequencies of two extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were increased in patients with DH. Distributions of fragments of extended haplotypes, consisting of some but not all of the elements of complete extended haplotypes, were analyzed to attempt to localize a susceptibility gene. Besides complete extended susceptibility haplotypes, (DR3, DQ2) and (DR7, DQ2) fragments were most common in GSE. In contrast, DH showed only a few such fragments but many instances of the fragment (SC01). The differences in distribution of these fragments in the two diseases were highly significant (P < 0.002). HLA-DQ2 and DR3 had the highest odds ratios for GSE, but the highest odds ratio for DH was for the complotype SC01. These findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class II region.
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TL;DR: 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.
Abstract: An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest 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 mellitus (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 to 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.
526 citations
TL;DR: The finding that host modifying factors are associated with severe periodontitis suggest a biological mechanism by which some individuals, if challenged by bacterial accumulations, may have a more vigorous immunoinflammatory response, leading to more severe clinical disease.
Abstract: Periodontitis is a collection of chronic inflammatory diseases that are caused by specific bacteria. The bacteria activate inflammatory mechanisms in the periodontal tissues that destroy collagen and bone that support the teeth. Although bacteria are essential for the initiation of periodontitis, the quantity and types of bacteria have not been sufficient to explain the differences in disease severity. In recent years, it has become evident that for many common chronic diseases, there are modifying factors that do not cause the disease but rather amplify some disease mechanisms to make the clinical condition more severe. There are now data to suggest that a few factors which amplify the inflammatory process make people susceptible to an increased severity of periodontitis. Studies of untreated disease in Sri Lanka identified 3 patterns of disease progression. Studies in twins suggested that part of the clinical characteristics of periodontitis may be explained by genetic factors, but previous attempts to identify genetic markers for periodontitis have been unsuccessful Some genetic variations (polymorphisms) are commonly found in our population and represent a mechanism by which individuals may exhibit variations within the range of what is considered biologically normal. Since certain cytokines are key regulators of the inflammatory response and are important in periodontitis, we investigated the relationship between genetic variations associated with cytokine production and periodontitis severity. There are several polymorphisms in the cluster of genes that influence IL-1 biological activity. In recent clinical trials, two of these polymorphisms, when found together, have been associated with a significant increase in the risk for severe generalized periodontitis. Genetic association with periodontitis was evident only when smokers were excluded from the analysis, confirming the importance of smoking, and suggesting that both smoking and the IL- I genotype are independent factors in severe periodontitis. It is notable that 1 polymorphism associated with severe periodontitis in our study is also known to correlate with a 2- to 4-fold increase in IL-1 beta production. These findings are consistent with the current model of how genetic factors influence common chronic diseases. If we apply this model to periodontitis, it would involve the following: 1) a disease-initiating factor that would undoubtedly be specific bacteria such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans. and Bacteroides forsythus: and 2) modifiers of disease mechanisms that account for the clinical severity, including smoking, the IL-I genotype, certain systemic diseases, and psychosocial stress. The association of the IL-I genotype with severe periodontitis is consistent with several lines of periodontal research. Several studies have suggested there is a substantial genetic influence in periodontal disease. Although specific genetic markers have been identified in the uncommon juvenile forms of periodontitis, previous studies of specific genetic markers in adults with periodontitis have not been encouraging. Many investigators have, however, demonstrated a role for IL-1 in the initiation and progression of periodontitis. For example, IL-1 activates the degradation of the extracellular matrix and bone of the periodontal tissues, and elevated tissue or gingival fluid levels of IL-1 beta have been repeatedly associated with periodontitis. In addition, IL-1 is a strong enhancer of tissue levels of PGE2 and TNF-alpha. The association of severe periodontitis with smoking and the IL-1 genotype suggest a role for these factors in the pathogenesis of periodontitis. The finding that host modifying factors are associated with severe periodontitis suggest a biological mechanism by which some individuals, if challenged by bacterial accumulations, may have a more vigorous immunoinflammatory response, leading to more severe clinical disease. (ABSTRACT
193 citations
TL;DR: The concept of the conserved extended haplotype (CEH) is updated using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units with a total haplotype frequency in the Caucasian population of 0.30.
Abstract: The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small ( /= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.
168 citations
Cites background from "Major histocompatibility complex su..."
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TL;DR: It is concluded that dermatitis herpetiformis and celiac disease are associated to the very same HLA-DQ alpha beta heterodimers.
Abstract: HLA-DRB1,-DQA1, and -DQB1 genomic typing of 50 patients with dermatitis herpetiformis and of 290 healthy blood donors was performed. Genes encoding the DQ (alpha 1*0501, beta 1*02) heterodimer were carried by 43 (86%) of the patients and 72 (25%) of the controls. Of the remaining seven patients six (12% of all the patients) carried genes encoding the DQ (alpha 1*03, beta 1*0302) heterodimer. These HLA associations are very similar to those observed in patients with celiac disease. We thus conclude that dermatitis herpetiformis and celiac disease are associated to the very same HLA-DQ alpha beta heterodimers.
124 citations
TL;DR: The results suggest that the human genome, including the major histocompatibility complex (MHC), consists largely of 5- to 200-kb blocks of sequence fixity between which random recombination occurs, and the use of statistical analysis rather than direct haplotype determination and counting fails to reveal the details of haplotype structure essential for gene localization.
Abstract: There is great interest in the use of single-nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) analysis to localize human disease genes. The results suggest that the human genome, including the major histocompatibility complex (MHC), consists largely of 5- to 200-kb blocks of sequence fixity between which random recombination occurs. Direct determination of MHC haplotypes from family studies also demonstrates similar-sized blocks, but otherwise gives a very different picture, with a third to a half of Caucasian haplotypes fixed from HLA-B to HLA-DR/DQ (at least 1 Mb) as conserved extended haplotypes (CEHs), some of which encompass more than 3 Mb. These fixed haplotypes differ in frequency both in different Caucasian subpopulations and in Caucasian patients with HLA-associated diseases, complicating disease susceptibility gene localization. The inherent inability of LD analysis to "see" DNA fixity beyond three markers contributes to the failure of SNP/LD analysis to define in detail or even detect CEHs in the MHC and probably elsewhere in the genome. More importantly, the use of statistical analysis, rather than direct haplotype determination and counting, fails to reveal the details of haplotype structure essential for gene localization. Given the oversimplified picture of the MHC (and probably the rest of the genome) provided only by SNP/LD-defined blocks, it is questionable whether this approach will be of great help in disease susceptibility gene localization or identification.
105 citations
References
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TL;DR: Electrophoretic studies of fragments from defined types of GBG suggested that GBG cleavage induced by complement or properdin activation in serum occurred through this C moiety, since two variants were detectable in one fragment and two were found in the other fragment.
Abstract: Extensive polymorphism of glycine-rich beta-glycoprotein (GBG) was found in human sera. In all instances, GBG consisted of at least five components on electrophoresis. Patterns were such that they provided evidence for four alleles (at a locus designated Gb) which were expressed as autosomal codominant traits. Gb(S) and Gb(F) were found in all populations but with different frequencies, Gb(F1) was found in Negroes, and Gb(S1) was found in Caucasians. From electrophoretic studies of GBG, evidence was obtained that suggested that the GBG molecule was a tetramer consisting of A and B subunits in a proportion of about 1.6:1. The genetically controlled differences in GBG embodied in the Gb system indicated the presence of a third moiety of the molecule (C), possibly a polypeptide subunit. Electrophoretic studies of fragments from defined types of GBG suggested that GBG cleavage induced by complement or properdin activation in serum occurred through this C moiety, since two variants were detectable in one fragment and two were found in the other fragment. On comparison of fetal-maternal Gb types, approximately one-half the pairs showed differences. This indicated that GBG did not cross the placental barrier.
489 citations
TL;DR: Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex.
Abstract: Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the C4A locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.
457 citations
TL;DR: Structural variation in the second component of human complement was identified in about 4% of serum samples from random unrelated individuals of all the major races and suggestive evidence for close linkage between C2 and Bf was obtained.
Abstract: Structural variation in the second component of human complement was identified in about 4% of serum samples from random unrelated individuals of all the major races. Three forms of C2 have been identified by isoelectric focusing in polyacrylamide gel and development of patterns in agarose gel containing antibody-sensitized sheep red cells and C2-deficient serum: C2 C (common), C2 A (acidic), and C2 B (basic). The C2 variants were shown to be inherited as autosomal codominant traits, and suggestive evidence for close linkage between C2 and Bf was obtained.
216 citations
TL;DR: A new DNA-based method of HLA-DP typing is used to analyse the distribution of DPβ alleles in a group of coeliac disease patients and healthy controls and suggests that the polymorphic residues at position 69 and at 56 and 57 may be critical in conferring susceptibility.
Abstract: COELIAC disease is an autoimmune disease of the intestinal mucosa, elicited by ingestion of wheat gluten in genetically susceptible individuals1. Susceptibility to coeliac disease has been associated with the serologically defined variants DR3 and DR7 of the class II antigens encoded by the HLA-D region2,3. Three related class II antigens, each consisting of an alpha and a beta glycoprotein chain, have been identified and are designated HLA-DR, HLA-DQ, and HLA-DP. These highly polymorphic transmembrane proteins bind peptides derived from the processing of foreign antigens4–8 and present them to T lymphocytes; they also influence the specificity of the mature T-cell repertoire9–12. The role of HLA-DP polymorphism in susceptibility has not been as fully explored as that of the other class II antigens because of the complexity of the primed lymphocyte typing (PLT) method for determining DPw specificities13–15. Here we use a new DNA-based method of HLA-DP typing16 to analyse the distribution of DPβ alleles in a group of coeliac disease patients and healthy controls. Two specific DPβ alleles (DPB4.2 and DPB3) are increased in the patient population. Comparison of the DPβ sequences suggests 470 that the polymorphic residues at position 69 and at 56 and 57 may be critical in conferring susceptibility. Further, the contribution of the susceptible DPβ alleles appears to be independent of linkage to the previously reported DR3 and DR7 markers for coeliac disease. The distribution of DQα and β alleles in patients suggests that a specific DQ heterodimer may be responsible for the observed DR associations. Individuals with both this DQ antigen and a specific DPβ allele are at increased risk for coeliac disease.
201 citations
TL;DR: Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on HLA-B38, SC21, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.
Abstract: Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which all were of the subtype DR4, DQw8. From studies of the patients and their families, haplotypes were defined. It was found that, of the patients who carried HLA-DR4, DQw8, 75% carried one or the other (and in one case, both) of two haplotypes [HLA-B38, SC21, DR4] or HLA-B35, SC31, DR4. The former is a known extended haplotype among normal Jews, with a frequency of 0.102, and the latter may also be an extended haplotype in this ethnic group, with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients, all but one had a presumed D-region segment (defined as SC21, DR4, DQw8 or SC31, DR4, DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4, DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4, DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on [HLA-B38, SC21, DR4, DQw8], HLA-B35, SC31, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.
200 citations