Barrett's oesophagus - ulcerative colitis, sarcoidosis, Indian ethnicity and the HLA-7 1 ancestral haplotype: shared immunogenetics?|
In South-East Asia and Britain, a predilection for Indian ethnicity has been reported in several studies relating to Barrett's oesophagus and/or gastro-oesophageal reflux disease (GERD), ulcerative colitis and sarcoidosis.
Moreover, the risk of ulcerative colitis, reflux disease and sarcoidosis is highest in monozygotic twins. Interestingly, a common Human Leucocyte Antigen i.e. HLA-B*07 and/or a common ancestral haplotype, i.e. 7.1 AH (A*03, B*07 and DRB1*15) association has been reported in all three diseases, which are thought to be due to a complex interplay of immunogenetic and environmental factors.
A racial predilection and the HLA-7 . ancestral haplotype as a potential common denominator lead us to speculate that these diseases may have a common aetiology.
Furthermore, familial clustering is well documented in all three diseases, which may reflect a genetic influence and/or a common environment and lifestyle. Studies and case reports documenting the coexistence of at least two of these disorders within the same patients lend further credence to an association between them.
Nevertheless, despite the interesting and intriguing data presented here, much more evidence is required by way of epidemiological, linkage, genetic association, immunogenetic and animal studies to explore the potential link (if any) between these three inflammatory conditions. Understanding the aetiology of any one of these diseases may in turn explain the pathogenesis of the others.
Independent studies on GERD and Barrett's oesophagus [1-4], ulcerative colitis (UC) [5-7] and sarcoidosis [8-9] in multiethnic Asian patient populations in Malaysia and Singapore have revealed a striking common denominator, i.e. an over-representation of Indian (South Asian) ethnicity. This predilection for Indians is even more striking when one considers that they make up less than 8% of the multiracial populations of these South-East Asian nations [10,11] though they account for 45% of patients diagnosed with Barrett's oesophagus  18-35% of those with ulcerative colitis [5-7] and 50-70% of reported cases of sarcoidosis. [8,9]. In Britain, a recent community study revealed that South Asian origin was a risk factor for gastro-oesophageal reflux disease (GERD) . Nevertheless, Indian ethnicity has not been shown to be a risk factor for Barrett's oesophagus (a complication of GERD) in British patients . In the Malaysian patient population, we have demonstrated that Helicobacter pylori infection and gastric corpus atrophy is highest in Indians, which somewhat ameliorates the risk for developing Barrett's oesophagus (Rajendra et al., manuscript submitted).
We speculate that this may also apply to British Asian individuals with GERD. Interestingly, Montgomery et al. reported that South Asians born in Britain had a significantly higher risk of developing inflammatory bowel disease (IBD) than the indigenous European population . The authors postulated that this may reflect a greater genetic predisposition to IBD that is uncovered by exposure to environmental factors. In Britain, sarcoidosis has been found to be more common, more severe and more extensive in both Blacks and Asians when compared with Caucasians .
A comparative study of sarcoidosis in South Africa between 1969 and 1975 revealed that the minimum incidence was 23.2/100,000 in Blacks, 11.6/100,000 in Asians and 3.7/100,000 in Whites . Racial differences in disease frequency suggest a genetic causal factor, though social, cultural and environmental factors could equally account for the observed differences.
The HLA system located on chromosome 6 is the most polymorphic region in the human genome. It contains 224 genes, many of which encode proteins essential for antigen presentation and processing. The HLA complex is also an excellent marker for population genetic analyses and disease association studies. The highly polymorphic genes located in the Major Histocompatibility Complex (MHC) are inherited en bloc in haplotypes. Haplotypes which are alleles found at different loci on a chromosome are maintained by linkage disequilibrium (LD). Some of these DNA segments occur frequently in the population and have been conserved over time as extended  or ancestral haplotypes  which can be traced to a common ancestor. Equally intriguing and strongly suggestive of a genetic basis for Barrett's oesophagus, ulcerative colitis and sarcoidosis is the fact that a common Human Leucocyte Antigen, i.e. HLA-B*07 and/or a common ancestral haplotype (7.1 AH) association has been reported in all three diseases.
Immunogenetics of Barrett's oesophagus
Chronic gastro-oesophageal reflux (GERD) predisposes to Barrett's oesophagus, which is a precursor lesion for oesophageal adenocarcinoma . It has been hypothesized that Barrett's metaplasia develops as an adaptive epithelium in response to chronic damage by gastro-oesophageal refluxate . The immune profiles that characterize the varied phenotypic responses to GERD  in response to a common antigenic stimulus may be important in modulating disease. Tumour cells often express new antigens as a result of the multiple genetic alterations that are associated with cell transformation  and immune recognition of these neo-antigens is a key event in the history of a cancer . Host cytotoxic (CTL) and helper T (TH) cells can potentially recognize these neo-antigens presented by human leucocyte antigen (HLA) Class I or II molecules, respectively .
We recently reported that the inheritance of the HLA B7 gene incurs an increased risk for Barrett's oesophagus in South Asians (predominantly South Indians) but not Orientals (Malays and Chinese) , though it must be stressed that these results are only preliminary given the small number of patients studied.
In addition, the HLA B07 positive patients with Barrett's oesophagus had a significantly greater family history of heartburn, compared to their HLA-B07 negative counterparts, indicating that this genetic component could possibly be associated with particular disease manifestations of GERD. Racial differences in reflux disease, [1-4] familial aggregations of GERD symptoms/Barrett's oesophagus [26-29] and twin studies [30,31] lead us to speculate that there may well be one or more GERD genes. One of these key genes for the development of GERD could be the HLA-B07 allele or other gene(s) tightly linked to this allele.
HLA molecules perform a crucial function in the regulation of the immune response. The observed association with major histocompatibility complex (MHC) class I genes may reflect linkage disequilibrium to other MHC or non-MHC genes or may reflect a role for MHC class I molecules in disease pathogenesis. . Malignant transformation of cells is frequently associated with altered HLA class I expression and/or function. These abnormalities provide tumour cells with escape routes from immune recognition. Class I molecules are also important to fight some viral and bacterial infections, although no infective aetiology has yet been implicated in the pathogenesis of Barrett's oesophagus. Recently, we investigated MHC expression in patients with Barrett's oesophagus and in controls with a healthy oesophagus and no reflux symptoms. . It was found that HLA class I expression was downregulated and class II upregulated in Barrett's oesophagus. As these changes predate malignant transformation, we believe that this altered MHC expression might be an essential step in disease progression, possibly by facilitating evasion from immune surveillance .
Ulcerative colitis and HLA associations
Ulcerative colitis is a chronic inflammatory mucosal disease of the colon, which is thought to be due to a complex interplay of immunogenetic and environmental factors. In this regard, Barrett's metaplasia, which arises in a background of reflux-induced chronic inflammation and ulceration, bears some similarity to that seen in inflammatory bowel disease . Furthermore, both conditions predispose to malignancy at a rate of approximately 0.4% per annum which is reduced by chemoprevention with non-steroidal anti-inflammatory drugs. [34,35]. As with reflux disease, risk of ulcerative colitis is highest in identical twins , suggesting that genetic factors may be involved in pathogenesis. In addition, familial association is well documented, [37-39], though this may indicate a common environment and lifestyle rather than a genetic influence. A number of susceptibility loci for inflammatory bowel disease have been identified on chromosomes 2,3,6, 7,12,14,16, and 19 [40-42]. Linkage and association studies reveal that the HLA complex (on chromosome 6) is important in conferring genetic susceptibility to ulcerative colitis . Many of the described associations are specific to particular ethnic groups implying linkage disequilibrium (LD) with other polymorphisms in the HLA region . The most widely replicated associations are those between HLA-DRB1*0103 [45-49] DRB1*1501 and DRB1*1502 and extensive disease. [45,46,50,51].
Interestingly, HLA-B*07 is in linkage disequilibrium with DRB1*15 as part of the ancestral haplotype (7.1 AH i.e. HLA-A3, B7, DR15). Not surprisingly, a Spanish group has reported that the HLA-B*07 allele was over-represented in distal UC , reinforcing the emerging notion that HLA might have a greater role in modifying IBD phenotype than in overall disease susceptibility. In this study, all patients carrying the B7 allele also had the MICA-A5.1 gene. Both these genes are in linkage disequilibrium with HLA-DR15 in Caucasians as part of the extended haplotype EH7.1 (DR15/MICA5.1/B7) and thus explain the associations previously described [45,53,54]. Moreover, the HLA-DRB1*0103 allele, which is a susceptibility locus for UC, has been reported to be associated with MICA-A5 in the same populations. Relatively recently, a central MHC gene (HLA class III) susceptibility locus has been reported . The inhibitor of KB-like gene (IKBL) + 738 C has been linked to extensive and more severe colitis in Spanish but not British patients [45, 51].
In Caucasians, the IKBL + 738C gene is found predominantly in haplotypes carrying the DRB1*1501 and HLA B7 alleles (7.1 AH).55 A very recent study from Spain has found that the allelic combination DRB1*0103/D6S273-5/BAT_2-8/TNFa11b4c1d3e3/IKBL+738(C)/MICA5.1 that includes the telomeric class III markers of the 7.1 ancestral haplotype is very significantly increased in patients with UC compared to controls .
Mapping studies suggest that the MICA and MICB genes (two of seven members of the MIC gene family whose genomic structure is similar to HLA class I genes) located 53.4 kb and 141.2 kb centromeric from the HLA-B locus may be additional genes implicated in the development of UC. These genes are expressed on the gastrointestinal epithelium , and encode proteins that bind to NKG2D, which is expressed on NK cells, CDa▀ T cells, ?dT cells and macrophages [58, 59]. The MICA gene is in tight linkage disequilibrium with the human leucocyte antigen-B (HLA-B). In fact, MICA*5.1 has been associated with peripheral arthropathy in Caucasian patients with UC , though this was not replicated in a subsequent study by the same group . MICA*6 has been linked with UC in Japanese [61, 62], though a German group were unable to replicate these findings in their UC population . It is unclear how HLA genes exert their influence in IBD.
It has been postulated that HLA molecules bind peptides which may be derived from bacteria, thus stimulating inflammatory responses. In addition, molecular mimicry might exist between a bacterial peptide presented on a specific HLA allele and a gut antigen, thus stimulating T cells and consequent gut inflammation. It has been suggested that this process is facilitated by the increased expression of HLA class II molecules in UC .
Immunopathology of sarcoidosis
Sarcoidosis is a multisystem disease of unknown aetiology that is characterized pathologically by the presence of non-caseating granulomas , not dissimilar to Crohn's disease. It has immunopathological features of being antigen-driven and Th-1 cell-dependent . As in Barrett's oesophagus and ulcerative colitis, hereditary susceptibility to sarcoidosis is suggested by familial clustering [67, 68], ethnic differences , reports of sarcoidosis in monozygotic twins [70-74] and substantial HLA gene contributions [75-77]. Both HLA Class I (HLA-B8 and B7) and II (HLA-DR5,- DR8 and -DR9 in Japanese, -DR5 in Germans and HLA-DRB1*15 in Scandinavians) alleles have been strongly associated with sarcoidosis . Amongst the class I alleles, HLA-B7 and HLA-B8 are the most frequently linked to disease . Grunewald et al. from Sweden recently reported that HLA-B*07 independently increased the risk for persistent sarcoidosis as well as for resolving disease.78 HLA-DRB1*15 was associated with persistent disease, which confirmed their previous findings . The ancestral haplotype of A*03, B*07 and DRB1*15 was very strongly associated with persistent disease, i.e. this combination was found in 25% of patients with sarcoidosis as opposed to 7% of healthy subjects. HLA-B*07 and HLA-B*08 may predispose to early events in inflammation and granuloma formation . Both these alleles may also influence the inflammatory response through presentation of distinct antigen peptides.
Sarcoidosis may also be a disease involving immune reactions against self- structures which are modulated by HLA class I alleles. As in ulcerative colitis, molecular mimicry might exist between viral peptides presented on various class I alleles and self antigens, thus generating T cell clones and consequent tissue inflammation [78, 80]. Another mechanism may involve class I derived peptides that influence both the selection of the T cell repertoire and the capacity to generate specific immune responses . Also, exogenous antigens can be presented by HLA class I molecules , incriminating CD8+ T cells in the pathogenesis of sarcoidosis. Finally, it has also been suggested that the ancestral haplotype A*03, B*07 and DRB1*15 might be linked to other immunomodulatory genes which could influence and modulate inflammation .
Coexistence of at least two disorders
Studies and case reports documenting the coexistence of at least two of these disorders within the same patients lend further credence to an association between the diseases. Thus, it has been reported that patients with active UC had a higher prevalence of reflux compared with controls (60% v 17%, P < 0.001) . In a series of 680 patients with ulcerative colitis, pulmonary or extra-pulmonary sarcoidosis was present in eight . Three of the patients had the HLA B8 DR3 phenotype. The authors concluded that patients with ulcerative colitis who possess this HLA phenotype may possibly be more susceptible to developing sarcoidosis. Several case reports documenting the co-existence of ulcerative colitis and sarcoidosis have also been published [85-88]. Interestingly, sarcoidosis presenting with the macroscopic appearance of Barrett's oesophagus has also been described .
Currently, there is no data on HLA B7 allele association with ulcerative colitis or sarcoidosis in Indians. Nevertheless, we speculate that this allele may be robust across racial boundaries (i.e. Caucasian and South Asian) for the following reasons. HLA-B7 is one of the most frequently found HLA-B specificities in American Caucasians (allele frequency 0.142) and, European Caucasians (0.136) as well as North and South Indians (0.076 and 0.192 respectively) . Furthermore, phylogenetic tree and correspondence analysis on HLA-B and HLA-C allele frequencies indicate that the Indians share a strong European lineage [91, 92]. Not surprisingly, Risch et al. categorize Caucasians and Indians together as a major world (continental) racial grouping; the others being Africans, Pacific Islanders, Asians and Native Americans .
In summary, therefore, we have described three inflammatory conditions with some uncanny similarities in immunogenetics. A strong genetic basis, the predilection for Indians and the HLA-7.1 ancestral haplotype or sub-loci within this allele as a potential common denominator lead us to speculate that these diseases may share a common aetiology and pathogenesis. In view of the limited evidence provided here, higher resolution genetic analyses, linkage and genetic association investigations as well as epidemiological and randomized case-control studies are required to ascertain the potential link (if any) between these three inflammatory conditions. Furthermore, patho-physiology and animal studies might also help. Unravelling the pathogenesis of any one of these diseases may in turn illuminate our understanding of the aetiology of the others.
We declare no conflicts of interest.
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