Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis

Forty two white patients of British or Irish descent with coeliac disease and 28 with dermatitis herpetiformis were typed for class I HLA-A, B, and C, and class II DR and DQ antigens. In coeliac disease there was a significant increase in the frequencies of A1, B8, DR3, DR7, and DQw2 compared with controls but no increase of DR2. In dermatitis herpetiformis there were similarly increased frequencies of A1, B8, DR3, and DQw2. In contrast with coeliac disease, however, the frequency of DR7 (18%) was no different from the control group but there was an increased frequency of DR2.     

HLA-DP and coeliac disease: family and population studies.

We investigated polymorphism of HLA-DP genes in three DR3 related diseases, confirming an association of coeliac disease with a Bgl II DP alpha polymorphism (a restriction fragment sized 3.5 kb present in 75% of patients compared to 34% of control subjects, p less than 0.001), and finding a weaker association with dermatitis herpetiformis (57% v 34%, p = 0.01) and no association with insulin dependent diabetes mellitus. The association with coeliac disease was further investigated. Msp I DP beta polymorphism was studied in 52 healthy subjects and 59 patients: a 4.9 kb fragment was present in 51% of patients with coeliac disease compared to 11.5% of control subjects (p less than 0.001). Furthermore, nearly all subjects with the DP alpha 3.5 kb fragment also had the DP beta 4.9 kb fragment. However, disease frequency was still increased in the DP alpha 3.5 positive/DP beta 4.9 negative group. In seven families, each with at least two affected members, while the DP alpha 3.5 fragment was frequently present in patients it did not preferentially segregate with any particular HLA haplotype--for example, those associated with DR3 or DR7--and therefore is not part of an extended haplotype associated with coeliac disease. We therefore conclude that a gene(s) in the HLA-DP region predisposes to coeliac disease independently of the HLA-DR/DQ regions.     

Association of human leucocyte-DR and DQ antigens in coeliac disease: a family study

BACKGROUND AND AIMS: No family studies regarding the association of coeliac disease with the human leucocyte antigen (HLA)-DQ locus are available. Moreover, no HLA studies have been carried out in coeliac disease patients from India. The aim of this study was to study the HLA class II (DR and DQ) antigens in children with coeliac disease and in their first-degree relatives. METHODS: Fifteen children with coeliac disease and their first-degree relatives (birth parents of all the coeliac disease patients and fifteen siblings) were studied. A group of 123 healthy unrelated and ethnically matched subjects were used as controls. The HLA-DR and -DQ typing was carried out by a complement-dependent microlymphocytotoxicity assay. The transmission disequilibrium test was used for analysis of results. RESULTS: There was no association of coeliac disease with DR phenotypes. Ninety-three per cent of patients (14/15) carried the DQ2 allele. DQ2 was transmitted in 15 of 19 informative cases (transmission probability of 79%, chi2 6.368 with 1 df, nominal P=0.012 and P value corrected for multiple test=0.035). The haplotype relative risk associated with DQ2 was 5.71 (95% confidence interval 1.71-16.28). CONCLUSION: Coeliac disease in Indian children is predominantly associated with HLA-DQ2.     

Increased prevalence of celiac disease without gastrointestinal symptoms in adults MICA 5.1 homozygous subjects from the Campania area

OBJECTIVES: Polymorphisms in the major histocompatibility complex class I chain-related gene A may influence its binding to the Natural Killer Cell Receptor G2D (NKG2D). We looked for polymorphisms in major histocompatibility complex class I chain-related gene A exon 5 and in Human Leukocyte Antigen (HLA)-DQ/DR in adult coeliac disease patients to determine whether they affected coeliac disease phenotypes. METHODS: Adult coeliac disease patients with (n=98) and without (n=93) gastrointestinal symptoms (gastrointestinal symptoms+/gastrointestinal symptoms-) and 108 control subjects from Campania (Italy) were characterized by Polymerase Chain Reaction (PCR) sequence specific oligonucleotide followed by PCR sequence specific primer assays for HLA DQ/DR, and by PCR followed by capillary electrophoresis for major histocompatibility complex class I chain-related gene A exon 5 polymorphisms. Immunoglobulin A (IgA) anti-transglutaminase antibodies were also evaluated by immunosorbent assay. RESULTS: Five different major histocompatibility complex class I chain-related gene A alleles were detected in both coeliac disease patients and control subjects. The major histocompatibility complex class I chain-related gene A 5.1 allele occurred more frequently in patients than in controls (p<0.05), and the major histocompatibility complex class I chain-related gene A 5.1/5.1 homozygous genotype increased the risk of gastrointestinal symptoms- coeliac disease (OR=2.79, 95% CI 1.15-6.79). Gastrointestinal symptoms- coeliac disease patients bearing major histocompatibility complex class I chain-related gene A 5.1/5.1 alleles showed lower anti-transglutaminase levels (18U/L) than the gastrointestinal symptoms+ coeliac disease patients (35U/L). HLA-DQ2/DQ8 genotypes did not differ between gastrointestinal symptoms+ and gastrointestinal symptoms- coeliac disease, although DQ8 tended to be more frequent in gastrointestinal symptoms- coeliac disease (11.7%) than in gastrointestinal symptoms+ coeliac disease (6%). CONCLUSIONS: Our study shows that a double dose of the major histocompatibility complex class I chain-related gene A 5.1 allele could predispose to the onset of gastrointestinal symptoms- coeliac disease. We can hypothesize that a lower level of immunological involvement in gastrointestinal symptoms- coeliac disease patients is associated with absence of gastrointestinal symptoms. This test could represent a second step in the genetic typing of high-risk subjects such as first-degree relatives of coeliac disease patients positive for the DQ2/DQ8 molecule.     

Prevalence of coeliac disease in patients with sarcoidosis

OBJECTIVE: Susceptibility to sarcoidosis and coeliac disease has been linked to the class II haplotype HLA-DR3, DQ2, and an association between the two disorders has been suggested. As a pilot study, we have sought to determine the prevalence of coeliac disease in a cohort of Irish patients with sarcoidosis. DESIGN: Prospective, case-controlled study. METHODS: One hundred and two sarcoid patients (47 males, 55 females) from the west of Ireland and 105 (52 males, 53 females) healthy, ethnically matched, controls underwent interview and screening for coeliac disease and human leucocyte antigen typing by serology. Those with elevated anti-gliadin IgA (AGA) and/or positive endomysial antibody (EMA) were offered small intestinal biopsy. RESULTS: Three (3%) sarcoid patients had a prior diagnosis of coeliac disease. A further 12 (12%) patients and four (4%) controls had elevated AGA (P = 0.047), of whom three and one, respectively, had positive EMA. Small intestinal biopsy in 11 patients and three controls confirmed coeliac disease in one individual each, giving a prevalence of coeliac disease in patients compared with controls of 4/102 (4%) versus 1/105 (1%) (P = 0.21). Sensitivity and specificity of EMA and elevated AGA in sarcoid patients was 100% and 50%, and 50% and 9%, respectively. Of the four affected sarcoid patients, three carried HLA-DR3, DQ2 and one carried DR5 (12), DR7, DQ2. CONCLUSION: We have demonstrated a moderately increased prevalence of coeliac disease in Irish patients with sarcoidosis, which we feel justifies future screening of our sarcoid population. Estimation of EMA is recommended and should be restricted to those with susceptible haplotypes.     

Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in a Brazilian population

BACKGROUND. The incidence of rheumatic heart disease is great in Brazil. We analyzed the distribution of human leukocyte (HLA) antigens in a Brazilian population sample with rheumatic fever or rheumatic heart disease, with the aim of better understanding the mechanisms involved. METHODS AND RESULTS. HLA class I (A, B, and C) and class II (DR and DQ) antigen distribution was studied in 40 patients with diagnosis of rheumatic fever or rheumatic heart disease and compared with a control group of 617 healthy individuals for class I typing, from which 118 were drawn for class II typing. A strong correlation between rheumatic fever and rheumatic heart disease and HLA-DRw53 (72.9% in the disease group versus 39% in the control group: p = 0.00061, relative risk, 4.2; etiologic fraction, 0.43) was found. We also found an increase in the frequency of HLA-DR7 (57.5% in the disease group versus 26.3% in control group: p = 0.00715; relative risk, 3.8; etiologic fraction, 0.56). HLA class I and HLA-DQ typing did not point to any association with these diseases. CONCLUSIONS. HLA-DR7 and HLA-DRw53 are markers for susceptibility to rheumatic fever and rheumatic heart disease in Brazil. These results could be explained by genetic differences resulting from racial or geographical diversity.     

HLA-DR B1 and DQ B1 polymorphisms in patients with coronary artery ectasia

OBJECTIVES: The purpose of our study was to evaluate the significance of polymorphisms in HLA class II genes in coronary artery ectasia (CAE) patients. METHODS AND RESULTS: Twenty-six patients with CAE without associated cardiac defects were enrolled in the study. CAE was defined as luminal dilation of 1.5- to 2.0-fold of normal limits. Ninety-five healthy subjects who were donors for different organ transplantations, were chosen as control group. Physical examination, electrocardiography and chest X-ray were completely normal in these cases. Both the patients and the control group were screened and compared for their HLA class II genotypes. HLA-DR B1*13, DR16, DQ2 and DQ5 genotypes were significantly more frequent in the patient group.When the known risk factors of coronary heart disease were compared in the patients carrying these genotypes with the non-carrying group, no significant differences were encountered. CONCLUSIONS: HLA-DR B1*13, DR16, DQ2 and DQ5 may be associated with the pathogenesis and increase the risk of CAE.     

CTLA-4 gene polymorphism is associated with predisposition to coeliac disease

BACKGROUND: Susceptibility to coeliac disease is strongly associated with particular HLA class II alleles. However, non-HLA genetic factors are likely to be required for the development of the disease. Among candidate genes is the CTLA-4 (cytotoxic T lymphocyte associated) gene located on chromosome 2q33 in humans, which encodes a cell surface molecule providing a negative signal for T cell activation. AIMS: To investigate CTLA-4 exon 1 polymorphism (position 49 A/G) in patients with coeliac disease. PATIENTS: 101 patients with coeliac disease and 130 healthy controls. METHODS: Allele specific hybridisation and restriction enzyme digestion of polymerase chain reaction amplified genomic DNA. RESULTS: The A allele of the CTLA-4 position 49 polymorphism was found on 82.2% of chromosomes in patients with coeliac disease compared with 65.8% in controls (p < 0.0001), mostly in the homozygous form (68.3% in patients versus 47.7% in controls; odds ratio (OR) 2.36, 95% confidence interval (CI) 1.37 to 4.06, p = 0.002). Four patients only had the G/G genotype compared with 21 controls (OR 0.21, CI 10.07 to 0.64, p = 0.002). These differences were maintained when subjects were stratified according to the HLA class II phenotype, in particular when patients and controls were matched for the presence of the predisposing HLA DQB1*02 (DQ2) allele or HLA-DQA1*0501/DQB1*02 heterodimer. CONCLUSION: The CTLA-4 gene polymorphism is a non-HLA determinant that predisposes to coeliac disease. Whether it directly contributes to disease susceptibility or represents a marker for a locus in linkage disequilibrium with CTLA-4 needs further investigation.     

HLA-DR RFLP distributions in two groups of Aboriginal Australians

HLA-DR and -DQ typing by restriction fragment length polymorphism (RFLP) in Aboriginal Australians from the Kimberleys and from Coen shows a restricted number of HLA-DR types in these populations. The polymorphism is essentially limited to DR2, DR4, DRw14 and DRw8. The most common DR.DQ RFLP haplotype in Aborigines shows a novel arrangement of DR and DQ alleles that has important implications for histocompatibility matching if the RFLP patterns reflect functional variation in HLA class II molecules.     

Candidate gene regions and genetic heterogeneity in gluten sensitivity

BACKGROUND: Gluten sensitivity is a common multifactorial disorder, manifested in the small intestine or on the skin as typical coeliac disease or dermatitis herpetiformis, respectively. The only established genetic risk factor is HLA DQ2. AIMS: We tested genetic linkage of previously reported chromosomal loci 5q and 11q in Finnish families with gluten sensitivity. We also tested if genetic linkage to candidate loci on 5q, 11q, 2q33, and HLA DQ differed with respect to clinical manifestations or sex. SUBJECTS: We studied 102 Finnish families with affected sibpairs. For heterogeneity analysis, families were divided into subgroups according to sex and the presence of dermatitis herpetiformis, the skin manifestation of gluten sensitivity. METHODS: Non-parametric linkage between microsatellite markers and disease was tested. Linkage heterogeneity between subgroups was tested using the M test. The transmission/disequilibrium test and association analysis were performed. RESULTS: Evidence of linkage to 11q (MLS 1.37), but not to 5q, was found in the entire dataset of 102 families. Heterogeneity between subgroups was suggested: families with only the intestinal disease showed linkage mainly to 2q33 whereas families with dermatitis herpetiformis showed linkage to 11q and 5q, but not to 2q33. Linkage in all three non-HLA loci was strongest in families with predominantly male patients. HLA DQ2 conferred much stronger susceptibility to females than males. CONCLUSIONS: Independent evidence for the suggested genetic linkage between 11q and gluten sensitivity was obtained. The possible linkage heterogeneity suggests genetic differences between intestinal and skin manifestations, and the gender dependent effect of HLA DQ2.     

Increase of lymphocytes bearing the gamma/delta T cell receptor in the jejunum of patients with dermatitis herpetiformis.

The densities of T cells and of cells bearing the T cell receptors gamma/delta and alpha/delta and the surface antigens CD4 and CD8 in jejunal specimens from 21 patients with dermatitis herpetiformis were compared with those in specimens from 13 untreated adults with coeliac disease and 13 control subjects. In the lamina propria of the jejunum the median density of gamma/delta+ cells was significantly (p less than 0.001) greater in untreated patients with dermatitis herpetiformis than in control subjects (114 v 36 cells/mm2) and similar to that found in the patients with coeliac disease (115 cells/mm2). The difference in gamma/delta+ cell density between patients with dermatitis herpetiformis and control subjects was much greater in the surface epithelium of the jejunum: the median density for 14 untreated patients with dermatitis herpetiformis was 39 cells/mm, for seven patients with dermatitis herpetiformis on a gluten free diet 34 cells/mm, and for control subjects 2 cells/mm; the coeliac patients had the same density as the patients with dermatitis herpetiformis (45 cells/mm). The higher density of cells bearing the alpha/delta T cell receptor in the epithelium (median 77 cells/mm) of untreated patients with dermatitis herpetiformis was associated with a gluten containing diet; in specimens taken from patients with dermatitis herpetiformis on a gluten free diet the median density was similar to that in the control subjects (44 v 39 cells/mm). The increase in the number of lymphocytes bearing the T cell receptor gamma/delta, particularly in the epithelium of the jejunum, seems to be a constant marker for these closely related diseases, whereas the density of alpha/delta+ T cells is dependent on the diet.     

Amino acid and peptide absorption in patients with coeliac disease and dermatitis herpetiformis

A double-lumen perfusion technique has been used to study amino acid and peptide absorption in eight normal control subjects, 13 patients with untreated adult coeliac disease, and 16 patients with dermatitis herpetiformis who had varying morphological abnormalities of the small bowel. All subjects were perfused with isotonic solutions containing 10 mM glycyl-L-alanine and 10 mM glycine + 10 mM L-alanine.Patients with adult coeliac disease had impaired absorption of glycine (p < 0.01) and L-alanine (p < 0.05) from the amino acid solution compared with the control subjects. Amino acid uptake from the dipeptide solution was not significantly impaired, although four individual patients had impaired uptake of both amino acids. In contrast to these findings, very few patients with dermatitis herpetiformis had impaired amino acid absorption from either solution.Sodium absorption was impaired from both solutions when the groups of patients with adult coeliac disease and dermatitis herpetiformis with subtotal villous atrophy and partial villous atrophy were studied, and there were patients in each group who secreted sodium and water.The results suggest that malabsorption of dietary protein is unlikely to occur in dermatitis herpetiformis but may occur and contribute to protein deficiency seen in some severe cases of adult coeliac disease. The impairment of sodium and water absorption provides evidence that there may be functional impairment of the jejunal mucosa in dermatitis herpetiformis as well as in adult coeliac disease.     

First-degree relatives are frequently affected in coeliac disease and dermatitis herpetiformis

BACKGROUND: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. METHODS: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. RESULTS: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1,000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. CONCLUSIONS: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.     

The role of the HLA system in the genetics of Type I diabetes mellitus]

Major determinants of susceptibility to Type 1 (insulin-dependent) diabetes (IDDM) have been mapped to the HLA complex, near to or identical with genes encoding class II molecules. The association of IDDM with HLA-DR3 and/or DR4 antigens and the highest risk for DR3/4 heterozygotes suggest a synergistic effect of the two haplotypes. The characterization at the molecular level of the class II region has provided evidence that DQ rather than DR determinants may primarily influence the disease. In caucasians the susceptibility strongly correlates with the absence of aspartic acid at position 57 on the DQ beta chain and/or the presence of arginine at position 52 on the DQ alpha chain. The formation of a putative DQ susceptibility molecule (DQ alpha Arg52+, DQ beta Asp57-) accounts best for the disease associations when trans-complementation between alpha and beta chains encoded by different haplotypes is postulated to explain the excess of heterozygotes. Observations in other populations and in animal models indicate, however, that other residues on DQ alpha and beta chains, other class II (DR beta) molecules and non-HLA linked genes also contribute to the susceptibility. The mechanism(s) by which susceptibility determinants influence IDDM is not known. It is probably in relation with the role of class II molecules in the antigen presentation to T lymphocytes.     

First-degree Relatives Are Frequently Affected in Coeliac Disease and Dermatitis Herpetiformis

Background: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. Methods: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. Results: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. Conclusions: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.     

Disease expression and class II HLA antigens in systemic lupus erythematosus.

The aim of this investigation was to examine the relationship between Class II HLA antigens and disease expression in systemic lupus erythematosus (SLE). HLA-DR and DQ antigen frequency was studied serologically in 217 SLE patients followed prospectively and compared to 320 healthy controls. The relationship between HLA antigens and the presence of disease manifestations, as well as death was investigated in 117 SLE patients enrolled within the first year of their disease. A univariate analysis confirmed the association between HLA-DR3 and SLE. HLA antigen DR1, DR6, DR7, DQw1 and DQw3 were decreased in patient group compared to the controls. A logistic regression model showed a significantly negative association with HLA-DR1, DR6 and DR7, and a positive association with HLA-DR3. The reduced frequency of HLA-DQw1 and DQw3 was maintained using a logistic procedure. Cox Proportional Hazards models revealed no association between HLA-Class II antigens and death. Logistic regression models revealed no associations between central nervous system (CNS) disease nor musculoskeletal manifestations with any of the DR antigens. There was a trend towards a lower frequency of HLA-DR6 in patients with renal involvement and lower prevalence of HLA-DR1 and HLA-DR7 in patients with vasculitis.     

Mice lacking endogenous major histocompatibility complex class II develop arthritis resembling psoriatic arthritis at an advanced age

OBJECTIVE: To describe and characterize a novel inflammatory toe disease with severe bone destruction that developed spontaneously in "humanized" (HLA transgenic) mice lacking their own major histocompatibility complex (MHC). METHODS: We studied 5 different HLA transgenic mouse lines (HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), DQ6.Ab(0), and DQ8.Ab(0)) in similar genetic background for an extended period of time (>14 months). Clinical, radiologic, and histologic abnormalities were monitored, and the MHC-related major immunologic parameters in affected and resistant mice were compared. RESULTS: Animals of 4 transgenic lines (HLA-DR2.Ab(0), DR4.Ab(0), DQ6.Ab(0), and DQ8.Ab(0)) developed severe toe inflammation accompanied by progressive bone resorption, hyperkeratosis, alopecia, loss of nails, and shortening and thickening of the distal phalanges. HLA-DR3.Ab(0) transgenic mice were resistant to inflammation. The disease manifested only at advanced ages (6 months or older) and affected 70-100% of the mice, with a female preponderance. The clinical signs and the radiographic and histopathologic features of the affected toes were not similar to those of any disease previously described in mice but did resemble those described for human psoriatic arthritis (PsA). Mice from the 4 susceptible lines expressed lower levels of the HLA transgene and exhibited significantly fewer CD4+ cells in the peripheral blood and reduced natural killer cell activity compared with mice from the resistant HLA-DR3.Ab(0) line. CONCLUSION: This novel, spontaneously developing PsA-like toe disease in MHC-manipulated mice seems to be related to the absence of endogenous MHC class II. Replacement with HLA transgene expression that is insufficient (or no replacement at all) may result in imbalanced MHC class I and class II functions and lead to development of the disease.     

Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease.

BACKGROUND--Dermatitis herpetiformis is a lifelong, gluten sensitive skin disease. Patients with dermatitis herpetiformis, similar to patients with coeliac disease not adhering to a gluten free diet, seem to have increased risk for lymphoma. AIMS--This study looked at the occurrence of malignancy and survival of patients with dermatitis herpetiformis and compared the results with those seen in patients with coeliac disease or in the general population. PATIENTS--A total of 305 adult patients with dermatitis herpetiformis diagnosed at the University Hospital of Tampere in 1970-1992 were studied. Most patients started a gluten free diet and at the end of the study 93% of the patients were adhering to the diet. A control group comprised 383 adult patients with coeliac disease, 81% of them adhered to a gluten free diet, 6% had a normal diet, and in 13% the diet history remained unknown. METHODS--The occurrence of malignant diseases and survival of the patients were assessed up to the end of 1993. Standardised incidence ratios (SIR) with 95% confidence intervals were used for the malignant diseases. The survival of the patients was compared with that of the general population. RESULTS--Thirteen (4.3%) patients with dermatitis herpetiformis developed 14 malignant disorders during the follow up (SIR 1.25; 95% confidence intervals 0.68 to 2.09). A non-Hodgkin's lymphoma occurred in four patients with dermatitis herpetiformis, significantly more than expected (SIR 10.3; 2.8-26.3). Thirteen (4.3%) patients with dermatitis herpetiformis died during the follow up but there was no increased general mortality. In coeliac disease, 13 (3.4%) patients developed malignancy (SIR 1.16; 0.62 to 1.97), 31 (8.1%) patients died but the survival rate did not differ from that in the general population. CONCLUSIONS--The incidence of non-Hodgkin's lymphoma was significantly increased in patients with dermatitis herpetiformis. The results also confirm that the patients with dermatitis herpetiformis treated mainly with a gluten free diet have no increased general mortality.     

HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies.

We previously reported antigen frequency differences for HLA-DR4 and HLA-DRw6 between idiopathic dilated cardiomyopathy (IDC) patients and healthy controls in a pilot study. To confirm these findings, we undertook an independent study with a prospective hypothesis regarding the frequencies of DR4 and DRw6; typing for a second family of class II antigens (HLA-DQ) was included because of the proximity of the DQ loci to the DR loci and the strong linkage disequilibrium between some of the DR and DQ alleles. Comparing a new consecutive series of IDC patients (n = 41) and healthy blood bank controls (n = 53), we confirmed an increase of DR4 antigen frequency in patients (49% versus 21%, p less than 0.005). A trend toward decreased expression of DRw6 among patients was also noted (10% of patients versus 23% of controls). HLA-DQw4 was significantly elevated in patients compared with controls (27% versus 6%, p less than 0.005; relative risk, 6.1; etiologic fraction, 0.22). We identified the combined DR4-DQw4 haplotype in five of 41 Caucasian IDC patients (12%) and none of 53 controls (p less than 0.007). A comparison of specific antigen frequencies between the preliminary and validation studies did not reveal significant differences; therefore, the data from the two studies were examined in combination. For the combined studies, DR4 was elevated (51% versus 27% in controls, p less than 0.001), and DRw6 was decreased (9% versus 24% in controls, p less than 0.01). The relative risk for DR4 was 2.8, and the etiologic fraction was 0.33.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunohistologic studies of differential HLA expression in patients with various intestinal diseases

Histocompatibility antigens (HLA) play an important part in immunoregulation and in cell differentiation. This study analyses the expression of HLA class I and class II antigens (DR, DP, DQ) in intestinal biopsy specimen from patients with Crohn's disease, ulcerative colitis, GvHD, radiation colitis and intestinal adenomas using the indirect immunoperoxidase technique. 92 of 94 inflamed specimen from patients with inflammatory bowel disease showed a neoexpression of HLA II (DR greater than DP greater than DQ) on their epithelial cells. The intensity of HLA-DR neoexpression was significantly dependent on an endoscopic as well as a histological index of inflammation. All 75 non-inflamed specimen except 4 from patients with Crohn's disease did not show any evidence of HLA II display on the epithelium. 4 of 18 intestinal adenomas expressed HLA II on their epithelial cells without any correlation to the type of adenoma or the degree of cell dysplasia. Furthermore all specimen from a patient with intestinal GvHD showed an aberrant epithelial HLA II expression, but not that from radiation colitis. The expression of HLA class I antigens was similar in all biopsies studied. Our results suggest, that the epithelial neoexpression of HLA class II antigens may be an important event in the pathogenesis of various bowel diseases.