HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis.

BACKGROUND: Susceptibility to inflammatory bowel disease (IBD) is partially genetically determined and the HLA class II genes are candidates for a role in genetic susceptibility to IBD, because their products play a central role in the immune response. Multiple studies have reported associations between HLA-DR or -DQ phenotypes and either ulcerative colitis or Crohn's disease, but much of the data are still controversial. AIMS: To estimate overall associations between HLA class II phenotypes and IBD, and to establish the relative risk conferred by HLA-DR and -DQ phenotypes by meta-analysis. METHODS: Medline was searched for publications reporting on the relation between IBD and HLA class II phenotypes. Raw data were extracted by recalculating the number of phenotypes or the number of alleles of the main antigens. Odds ratios and confidence intervals were calculated according to the Mantel-Haenszel method. RESULTS: DR2, DR9, and DRB1*0103 were positively associated with ulcerative colitis, and a negative association was found for DR4 and ulcerative colitis. For Crohn's disease a positive association was found with DR7, DRB3*0301, and DQ4 and a negative association with DR2 and DR3. CONCLUSIONS: Both ulcerative colitis and Crohn's disease are associated with specific HLA class II phenotypes. Further analysis of these phenotypes and subgroup analysis may elucidate how these alleles contribute to susceptibility to IBD.     

HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.

The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.     

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele.

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.     

Expression of MHC class II antigens (HLA-DR, -DP, and -DQ) on human gastric epithelium.

Class II antigen expression on gastric epithelium was investigated using an immunoperoxidase method in relation to the degree of inflammatory cell infiltration in the lamina propria. Sixty-six biopsy specimens from 43 patients with chronic gastritis were examined. The frequency of HLA-DR expression in specimens with cell infiltration was 94%, while that in specimens without cell infiltration was 24%. There was significant difference in the frequency of HLA-DR expression between the two groups (P less than 0.01). HLA-DR was most intensely expressed in the glandular neck portion. The frequency and extent of class II antigen expression on gastric epithelium with cell infiltration were in the following order: DR greater than DP greater than DQ. The extent of DR and DP, but not DQ expression generally paralleled the degree of cell infiltration. Intestinal metaplasia was found in 13 specimens. In the area of intestinal metaplasia, epithelial class II staining was absent except for one specimen. These results suggest that the respective genes of three class II antigens are regulated by different mechanisms and that an immunological mechanism plays a role in the pathogenesis of gastritis.     

Increased HLA A1 and diminished HLA A3 in lymphocytic colitis compared to controls and patients with collagenous colitis

Lymphocytic colitis is a newly described chronic diarrheal disorder. Although its etiology is unknown, the possibility has been raised that autoimmunity may play a role in both lymphocytic and collagenous colitis, a similar clinicopathologic illness. The frequencies of HLA class I and class II antigens were examined in 24 white patients with lymphocytic colitis and in 47 white patients with collagenous colitis. Frequencies in these two disorders were compared to control white populations and to each other. An increased frequency of HLA-A1 was noted in 16 of 24 lymphocytic colitis patients (66.6%) compared with 1089 of 3942 controls (27.6%) (P<0.005; relative risk 5.2). Furthermore, HLA-A3 was found in decreased frequency in lymphocytic colitis patients: 0 of 24 (0%) compared with 1017 of 3942 controls (25.8%) (P<0.05; relative risk 0.0). Collagenous colitis patients had no significant deviation from control frequencies of HLA antigens. In lymphocytic colitis, there was no significant increase in B8 or DR3 antigens, which are found in linkage disequilibrium with A1 and associated with many autoimmune diseases. Moreover, the frequency of autoimmune-associated class I HLA antigens was not increased in lymphocytic colitis. Statistically significant differences existed between lymphocytic and collagenous colitis in HLA-A1, A3, Bw6, and B7 antigen frequencies. The HLA patterns noted previously in other gastrointestinal disorders, including ulcerative colitis and Crohn's disease, were not apparent in lymphocytic or collagenous colitis. HLA typing provides further evidence that lymphocytic colitis is a distinct form of chronic intestinal inflammatory disease associated with HLA class I phenotypes.Presented in part at the American Gastroenterological Association in May 1988 and published with preliminary data in a previous article (reference 1).Supported in part by The National Foundation for Ileitis and Colitis, by an institutional grant from The Johns Hopkins School of Medicine, and by outpatient GCRC grant RR00722.     

HLA antigens and anti-neutrophil cytoplasmic antibodies (ANCA) in inflammatory bowel disease.

HYPOTHESIS AND OBJECTIVES: the hypothesis of this study is that genes involved in the regulation of the immune system, expressed by HLA antigens and anti-neutrophil cytoplasmic antibodies (ANCA), could be determinants of disease susceptibility and behavior in inflammatory bowel disease (IBD). MATERIAL AND METHOD: seventy patients with a diagnosis of inflammatory bowel disease, 46 with ulcerative colitis and 24 with Crohn"s disease were included. HLA class I (A and B) and II (DR) antigens were studied by serological techniques. Detection of ANCA was carried out in all patients by an indirect immunofluorescence method. The relative frequencies of HLA antigens were compared with a control group made up of 156 blood donors. The control group for the ANCA study was made up of 100 individuals. RESULTS: we found a significant increased frequency of HLA-DR2 in patients with ulcerative colitis. No significant differences were found between patients with Crohn"s disease and controls regarding HLA typing. We detected a significant increase of HLA-DR3 in extensive forms of ulcerative colitis. Detection of ANCA was positive in 46% of the patients with ulcerative colitis and in 12% of the patients with Crohn"s disease (p <0.05). We observed an increased frequency of ANCA in patients with UC and HLA-DR2 (p = 0.15). CONCLUSIONS: the association found between HLA-DR3 and extensive forms of ulcerative colitis provides evidence of genetic heterogeneity. The relationship between ANCA and HLA phenotype (although not significant) supports this concept.     

The importance of peripheral immune cells in inflammatory bowel disease.

Background/aims: Inappropriate down regulation of an activated immune system is considered as the main pathogenetic mechanism in inflammatory bowel disease. Migration of circulating cells to a diseased intestine is considered as an important factor in the pathogenesis of inflammatory bowel disease. We aimed to evaluate some features of circulating immune cells in inflammatory bowel disease. Methods: Twenty-two control, 29 Crohn's disease and 17 ulcerative colitis patients were studied. CD2, CD3, CD4, CD8, CD11b, CD11c, CD25, CD45RA, CD45RO, CD54 and HLA DR on the surface of peripheral blood lymphocytes and CD11b, CD11c, CD45RA and CD45RO on the phagocytes were researched with two-color immunofluorescence flow cytometry. Results: The percentages of CD2+ and CD4+ lymphocytes were found significantly reduced in ulcerative colitis. CD3+ and CD8+ lymphocytes in inflammatory bowel disease were higher than in controls. CD45RA+ lymphocytes were found significantly decreased in ulcerative colitis and active Crohn's disease. CD45RO+ lymphocytes and CD45RO+, CD11b+ and CD11c+ phagocytes were significantly increased in Crohn's disease. Conclusions: We demonstrated that there were significant differences between ulcerative colitis and Crohn's disease in the expression of some important surface markers on the peripheral blood immune cells. It seems that circulating CD11b-CD11c and CD45RA-CD45RO expressing phagocytes are important in inflammatory bowel disease and may be useful in distinguishing Crohn's disease from ulcerative colitis. These findings may give us some clues about the immunopathogenesis of inflammatory bowel disease.     

Increased expression Of HLA—DQ antigens by interstitial cells and endothelium in the synovial membrane of rheumatoid arthritis patients compared with reactive arthritis patients

We investigated cellular phenotypes and expression of class II major histocompatibility complex antigens on endothelium and cellular infiltrates in synovium from patients with rheumatoid arthritis (RA) or reactive arthritis, using an indirect immunoperoxidase technique. The RA specimens showed synovial lining layer hypertrophy and several focal accumulations of lymphocytes, both of which were absent in the reactive arthritis synovium. The percentage of cells expressing monocyte/macrophage markers was significantly higher in RA specimens. The percentages of cells expressing B and T cell markers were similar in both diseases. There was no significant difference in the expression of HLA–DR or DP by endothelium in the 2 diseases, but a marked increase in expression of HLA–DQ by endothelium was observed in the RA synovium versus that from patients with reactive arthritis. This overexpression of HLA–DQ was also seen in the interstitial cells of RA patients compared with reactive arthritis patients. In the reactive arthritis synovium, a significant population of cells (30%) was noted to be HLA–DR positive, and negative for macrophage and lymphocyte markers. Some of these cells had a dendritic morphology. The coexpression of HLA–DQ and HLA–DR may play an important role in antigen presentation and disease chronicity in RA.     

Increased group II phospholipase A2 in colonic mucosa of patients with Crohn's disease and ulcerative colitis.

The immunochemical protein content of group II phospholipase A2 (PLA2) and PLA2 enzymatic activity were measured for colonic mucosal biopsy samples obtained from patients with either Crohn's disease of the colon or ulcerative colitis, and control patients without inflammatory bowel disease. Immunoreactive group II PLA2 (IR-PLA2 II) content and PLA2 activity in actively inflamed colonic mucosa of Crohn's disease patients were significantly higher than those in inactively inflamed mucosa of Crohn's disease patients and the colonic mucosa of controls. IR-PLA2 II content and PLA2 activity in severely inflamed mucosa of ulcerative colitis patients were significantly higher than those in the colonic mucosa of the controls. Mucosal PLA2 enzymatic activity was closely correlated with mucosal IR-PLA2 II content in patients with Crohn's disease and ulcerative colitis. These results suggest that an increase in PLA2 enzymatic activity in inflamed colonic mucosa of Crohn's disease and ulcerative colitis was mainly attributed to increased protein content of group II PLA2, and that an increase in mucosal group II PLA2 may be involved in the pathogenesis of intestinal inflammation of Crohn's disease and ulcerative colitis.     

Stomal adenocarcinoma in Crohn's disease.

Malignant change occurring at the site of a stoma in two patients with proved Crohn's disease is described. Patients with ulcerative colitis have an increased risk of colonic malignancy and Crohn's disease is also associated with both small and large bowel carcinoma. Most previous reports of stomal carcinoma have been associated with ulcerative colitis although Crohn's disease seems to carry a greater risk of associated small bowel carcinomas. This is the first report of stomal carcinoma complicating Crohn's disease. Epithelial dysplasia is associated with gastrointestinal carcinomas in both ulcerative colitis and Crohn's disease and a dysplasia-carcinoma sequence has been suggested as the origin of these tumours. In both our patients with stomal adenocarcinoma, dysplasia was identified in adjacent tissues, which suggests a similar mechanism. Malignant change should be suspected if epithelial dysplasia is discovered in a biopsy specimen from the mucosa of an ileostomy in Crohn's disease, and this risk is increased if the dysplasia is of a high grade.     

Class II MHC antigen expression on epithelial cells of salivary glands from patients with Sj?gren's syndrome

Class II MHC molecules are two-chain glycoproteins normally expressed only on the membrane of cells involved in the immune response. These molecules are restriction elements for helper T cells. Using indirect immunofluorescence on cryostat sections of biopsied salivary glands we have demonstrated epithelial expression of class II antigens in patients with Sj?gren's syndrome. The HLA DR+ epithelial cells were seen in close proximity to lymphocyte infiltrates. The finding that class II molecules are also expressed in salivary glands without focal lymphocytic infiltrates suggests a "modulation" as opposed to "induction" of HLA DR antigens on epithelial cells in Sj?gren's syndrome, the distinction being related to the enhancement of low levels of expressions vs. de novo synthesis.     

Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype

Celiac disease is strongly associated with the HLA class II D-region serologic markers DR3 (DRw17) and DQw2. Moreover, by restriction fragment length polymorphism analysis, greater than 90% of DR3 (DRw17), DQw2 celiac disease patients have a polymorphic 4.0-kilobase Rsa I DP B gene DNA fragment. The present study sought to determine if there is a unique HLA class II D-region A or B gene structural variant on the DR3 (DRw17) haplotype found in celiac disease. The polymorphic second exons of the coding DRB, DQA and DQB, and DPA and DPB genes in celiac disease patients with the DR3 (DRw17) haplotype were sequenced after amplification by the polymerase chain reaction. To define the DP B genes associated with celiac disease, the second exons of the coding DP B genes from 27 celiac disease patients were amplified similarly and probed by using a panel of sequence specific oligonucleotides. The HLA-DR, -DQ, and -DP A and B gene second exon sequences of celiac disease patients were noted to be identical to sequences that can be found also, although at a significantly lower frequency, in unaffected individuals. This is compatible with a disease model wherein the HLA class II genes on the DR3 (DRw17) haplotype are necessary, but not sufficient, for the phenotypic expression of celiac disease. Analysis of the DP B genes revealed a significant increase in the frequency of the alleles DPB1 and DPB3 in celiac disease. Furthermore, the increased frequency of the 4.0-kilobase Rsa I DP B gene restriction fragment length polymorphism in celiac disease can be accounted for by the overrepresentation in disease of the alleles DPB1 and DPB3. The HLA-associated susceptibility to celiac disease appears to be multigenic, with specific, but structurally normal, allelic variants in the DP and DQ/DR subregions contributing to disease susceptibility.     

Rheumatologic syndrome in gastrointestinal diseases. Clinical and pathogenetic aspects

Patients with reactive arthritis, sacroiliitis, spondylitis or Reiter's syndrome following intestinal infection from Yersinia, Salmonella, Shigella or Campylobacter organisms have been reported from endemic areas and after epidemic dysenteries. Possession of the antigen HLA B27 affects severity and prognosis of the arthritis and is more often associated with spondylitis and Reiter's syndrome. Articular manifestations are also quite common systemic complications of chronic inflammatory bowel disease. The clinical picture, pathogenetical aspects and treatment of arthritis associated with Crohn's disease, ulcerative colitis and Whipple's disease are reviewed. In only few cases, coeliac disease can be complicated by arthritis. In patients undergoing intestinal bypass surgery systemically absorption of intestinal bacterial antigens and immune complex formation may contribute to the development of bypass-arthropathy and dermatologic manifestations.     

Evidence of active cytomegalovirus infection and increased production of IL-6 in tissue specimens obtained from patients with inflammatory bowel diseases

Recent reports have focused interest on human cytomegalovirus (HCMV) in inflammatory bowel diseases (IBD). Our aim in this study was to examine the frequency of HCMV-infected intestinal cells in tissue sections obtained from patients with IBD, and to investigate if HCMV-infected intestinal cells produce the proinflammatory cytokine IL-6. We studied intestinal tissue sections from 13 patients with ulcerative colitis, 10 with Crohn's disease, 10 cancer patients without intestinal inflammation, and 10 samples from HCMV-infected AIDS patients. HCMV-DNA was detected by in situ hybridization in sections obtained from 12/13 patients with ulcerative colitis, in 10 with Crohn's disease, in 10/10 samples from HCMV-infected AIDS patients, but not in any of the 10 samples that were obtained from uninflamed tissues. HCMV-specific antigens were detected in samples from all HCMV-infected AIDS patients, in 11/13 sections from patients with ulcerative colitis, in 10/10 samples from patients with Crohn's disease, but not in sections from uninflamed tissues. Cells were double positive for an HCMV early antigen and IL-6 in 10/13 sections from patients with ulcerative colitis, in all patients with Crohn's disease, and in 4/10 samples from AIDS patients. In conclusion, these results suggest that active HCMV infection in the intestine is very frequent in patients with IBD, and may contribute to the inflammatory process through an increased production of IL-6.     

Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patients with inflammatory bowel disease and the relation with Crohn''s disease phenotype

BACKGROUND AND OBJECTIVE: Matrix metalloproteinases are associated with matrix turnover in both physiological and pathological conditions. We postulate an association between aberrant matrix metalloproteinases proteolytic activity and the intestinal tissue destruction, seen in patients with Crohn's disease and/or ulcerative colitis. MATERIALS AND METHODS: Surgically resected inflamed and non-inflamed ileum and colon with/without extensive fibrosis from 122 Crohn's disease, 20 ulcerative colitis and 62 control patients were homogenized. Protein levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured by enzyme-linked immunosorbent assays (ELISA), while matrix metalloproteinases and myeloperoxidase activity were measured by specific activity assays. RESULTS: Expression of total levels of matrix metalloproteinases-1, -2, -3 and -9 relative to tissue inhibitor of metalloproteinases-1 and -2 was increased in inflamed inflammatory bowel disease compared to non-inflamed inflammatory bowel disease and control intestinal mucosa. Also, net matrix metalloproteinases-1, -2, -3 and -9 activity in inflamed inflammatory bowel disease was increased, with similar expression profiles in Crohn's disease and ulcerative colitis. Within inflamed inflammatory bowel disease, a close correlation of matrix metalloproteinases with myeloperoxidase was observed. The expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases was similar in inflamed Crohn's disease tissue with or without extensive fibrosis and not related to fistulizing disease. CONCLUSIONS: We have shown increased net matrix metalloproteinases activity in intestinal inflammatory bowel disease tissue, likely to contribute to the tissue damage and remodelling seen in inflammatory bowel disease.     

Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis

BACKGROUND & AIMS: The peroxisome proliferator-activated receptor gamma (PPAR gamma) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor kappa B (NF-kappa B) activity. In inflammatory bowel disease, activators of NF-kappa B, including the bacterial receptor toll-like receptor (TLR)4, are elevated. We aimed to determine the role of bacteria and their signaling effects on PPAR gamma regulation during inflammatory bowel disease (IBD). METHODS: TLR4-transfected Caco-2 cells, germ-free mice, and mice devoid of functional TLR4 (Lps(d)/Lps(d) mice) were assessed for their expression of PPAR gamma in colonic tissues in the presence or absence of bacteria. This nuclear receptor expression and the polymorphisms of gene also were assessed in patients with Crohn's disease (CD) and ulcerative colitis (UC), 2 inflammatory bowel diseases resulting from an abnormal immune response to bacterial antigens. RESULTS: TLR4-transfected Caco-2 cells showed that the TLR4 signaling pathway elevated PPAR gamma expression and a PPAR gamma-dependent reporter in an I kappa kappa beta dependent fashion. Murine and human intestinal flora induced PPAR gamma expression in colonic epithelial cells of control mice. PPAR gamma expression was significantly higher in the colon of control compared with Lps(d)/Lps(d) mice. Although PPAR gamma levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPAR gamma confined to colonic epithelial cells, without any mutation in the PPAR gamma gene. CONCLUSIONS: These data showed that the commensal intestinal flora affects the expression of PPAR gamma and that PPAR gamma expression is considerably impaired in patients with UC.     

Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease.

To test whether there is a difference in the expression of interleukin 8 (IL8) between Crohn's disease and ulcerative colitis and to determine the main site of its synthesis this study analysed IL8 in mucosal biopsy specimens of patients with Crohn's disease and ulcerative colitis by enzyme linked immunosorbent assay (ELISA) and by in situ hybridisation. IL8 was measured by ELISA in 38 normal control patients, eight inflammatory control patients, 55 Crohn's disease biopsy specimens (26 patients), and 67 ulcerative colitis biopsy specimens (35 patients). IL8 mRNA was determined in samples by in situ hybridisation using a specific IL8 RNA probe. IL8 protein was significantly increased in macroscopically inflamed specimens of Crohn's disease (median 118 pg/specimen, p < 0.0001), ulcerative colitis (median 140 pg/specimen, p < 0.001), and inflammatory controls (median 30 pg/specimen, p = 0.010) compared with normal controls (median 4 pg/specimen). IL8 was also increased in uninflamed specimens of Crohn's disease (median 46 pg/specimen, p < 0.001) but not of ulcerative colitis patients (median 9 pg/specimen, p = 0.3). IL8 protein in the mucosa correlated significantly with macroscopic inflammation in Crohn's disease (r = 0.47, p < 0.001) and in ulcerative colitis (r = 0.60, p < 0.001). IL8 mRNA was detected by in situ hybridisation in 31 of 55 biopsy specimens (56%) of Crohn's disease patients, in 38 of 67 specimens of ulcerative colitis patients (57%), in five of eight inflammatory controls (63%) and in five of 38 normal controls (13%). Mucosal IL8 mRNA expression correlated with mucosal IL8 protein (r = 0.46, p < 0.001). IL8 mRNA was only detected in inflammatory cells of the interstitium but not in mucosal epithelial cells. IL8 is produced mainly in the lamina propria of the colon in inflammatory bowel disease and correlates with mucosal inflammation.     

Association of human leucocyte DR and DQ antigens in Crohn's disease in Asian Indians: a family study.

The pathogenesis of Crohn's disease (CD) involves an abnormal immune response to enteric bacteria in genetically susceptible individuals. There are no family studies regarding the association of CD with human leucocyte antigens (HLA) class II. In the present study, we have studied the association of HLA class II antigens in patients with CD and their first-degree relatives. Nine patients with CD and their first-degree relatives were studied. A group of 110 healthy unrelated and ethnically matched subjects were used as controls. Molecular HLA typing was done using the sequence-specific primer-based method. The transmission disequilibrium test (TDT) was used to analyze the results. A total of 65 individuals were included in the study; 52/56 first-degree relatives (92.8%) of 9 patients with CD consented to the study. The median age of patients was 40 years. When the distribution of the HLA class II antigens in patients was compared to that in controls no significant differences were observed even after applying the Yates correction. As the sample size of the population was small, the association of CD with DR and DQ alleles was further analyzed by using the TDT. Even after applying TDT, no significant association was observed. Familial aggregation of CD is uncommon in India. Crohn disease is not associated with HLA class II antigens in Indian patients. Genes of the major histocompatiblity complex are likely to contribute little to the susceptibility to Crohn disease in Indian patients.     

Spontaneous release of interferon gamma by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon gamma inducers

The spontaneous induced release of interferon gamma (IFN gamma) by cultured intestinal lamina propria lymphocytes was investigated in patients with Crohn's disease. In contrast to normal lymphocytes, intestinal lymphocytes from these patients spontaneously released IFN gamma and seemed to contain IFN gamma in their cytoplasm. Autologous peripheral lymphocytes did not release IFN gamma. When stimulated with interferon inducers lamina propria lymphocytes from Crohn's disease tissue showed an increase in IFN gamma release 24 hours after induction with no appreciable further increase over the next two days of culture, while in control cells, either peripheral or intestinal, IFN gamma release progressively increased, peaking 72 hours after induction. These findings indicate that in Crohn's disease the intestinal lymphocytes are stimulated in vivo to produce IFN gamma and that the spontaneous IFN gamma production is compartmentalised to the gut lymphocytes. These data support the concept that locally released IFN gamma has a crucial role in cell interactions in the lamina propria and contribute to the locally occurring immune phenomena in Crohn's disease, including the increased epithelial expression of major histocompatibility complex class II antigens.