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..."
...An example of such a study is the case of dermatitis herpetiformis (DH) and gluten-sensitive enteropathy (GSE) (10), Total Number of Haplotypes 122 HLA-B57 HLA-DR 7 No....
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...0101(1) 0701 0801(8) (3) (1) 0602 3701(37) (10)...
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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.
105 citations
References
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TL;DR: It is demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes, and the increased frequency or the decreased frequency of individual MHC alleles is largely explainable by these extended haplotype increases.
Abstract: We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes.
163 citations
TL;DR: Although the sulfones or sulfapyridine have been the mainstay of treatment, it is now clear that the skin disease responds to strict adherence to a gluten-free diet.
Abstract: Dermatitis herpetiformis is an intensely itchy, chronic, papulovesicular eruption that is usually symmetrically distributed on extensor surfaces. Histologically, it is characterized by der...
149 citations
TL;DR: It is concluded that patients with linear IgA deposit have a disease which is pathophysiologically different from those with granular IgA deposits.
135 citations
TL;DR: Examination of the DRB1, DQA1, and DQB1 alleles of 13 Spanish CD patients who were serologically typed to be neither DR3 nor DR5/DR7 corroborate that a second (and "weaker") HLA-associated CD susceptibility gene may be present on some DR4-carrying haplotypes.
132 citations
TL;DR: There are 14 complotypes with frequencies in excess of 1% in the study population of normal sixth chromosomes from Caucasians, and they are also intimately associated with HLA‐DR, so they may be of importance in screening programs for transplantation.
Abstract: The loci for the complement proteins C2 and BF, and the two loci for C4 are closely linked to one another. In many hundreds of meioses no crossing over has been detected between these loci. In addition, the alleles of these four loci occur in specific combinations not predicted by their gene frequencies in much the same way as alleles of the Rh and MNS systems. These units are termed complotypes. There are 14 complotypes with frequencies in excess of 1% in our study population of normal sixth chromosomes from Caucasians. Since they are also intimately associated with HLA-DR, comploytypes may also be of importance in screening programs for transplantation.
116 citations