Celiac Disease and Primary Biliary Cirrhosis: An Immune Link
Celiac Disease and Primary Biliary Cirrhosis: An Immune Link
Both CD and PBC share several features. From a pathogenic point of view, both of them have been regarded as autoimmune disorders because of a large predominance in female patients, frequent autoimmune comorbidities and an immune response against well-established autoantigens, that is, TG2 and PDC–E2. Prevalence in the female sex is more pronounced in PBC than in CD, but the female:male ratio also remains high in CD, ranging from 4:1 to 2:1. Both CD and PBC share a very similar prevalence (approximately 30%) of associated autoimmune disorders. About one-third of patients with CD and/or PBC are affected by another immune disease, most frequently autoimmune thyroiditis and less frequently Sjogren syndrome. Type 1 diabetes mellitus is found very frequently in association with CD but not with PBC. CD and PBC are two classical examples of human disorders with highly sensitive (>90%) and specific immune markers (>95%), that is, tTGA and AMA, directed against TG2 and PDC-E2, respectively. Environmental infectious factors are also thought to contribute to the onset of both CD and PBC. Indeed, it has been reported that a molecular mimicry between a peptide of TG2 and a rotavirus protein (VP7) in CD patients, as well as between PDC-E2 and a nonpathogenic Gram–negative bacterium (Novosphingobium aromaticivorans), occurs in PBC. The increased intestinal permeability found in CD can result in a large exposure of gut-derived microbial antigens to the liver (Figure 1). The microbial mediated molecular mimicry is considered one of the most relevant triggers that may break the immunologic tolerance and, consequently, contribute to the onset of PBC. Moreover, it has been hypothesized that several other infectious agents are involved in triggering PBC, including Escherichia coli and Mycoplasma. Bogdanos et al. have demonstrated that microbial mimics comprising Helicobacter pylori are major targets of cross-reactivity with human pyruvate dehydrogenase in PBC, strengthening the fact that microbial exposure may be instrumental to the appearance and/or maintenance of AMA responses by a cross-reactive mechanism. Recently, Abenavoli et al. have supported the pathogenic role of H. pylori to induce PBC in a CD patient. A possible role for bacteria has also been recently proposed for the development of CD, as marked abnormalities of intestinal microbiome have been found in the majority of celiac patients. Observations that approximately 3–17% of first-degree relatives of CD patients and 1–6% of those of PBC are affected by CD and PBC, respectively, with a high concordance rate in monozygotic twins, confirm the relevant genetic susceptibility for these disorders.HLA-DQ2 and/or -DQ8, which have been identified as the main haplotypes conferring predisposition to CD, do not correlate with PBC. Recently, findings of a genome-wide association study, undertaken in two different cohorts of North American and Italian patients and controls, indicated a significant association between PBC and polymorphism of HLA-DQB1, IL12A, IL12RB2 and, to a minor extent, STAT4, which have also been found in other autoimmune disorders, including CD. Another common feature of both the disorders is that CD and PBC diagnosis can be accepted in selected cases without the need of intestinal and liver biopsy ('the gold standards' until a few years ago) according to the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and American Association for the Study of Liver Diseases algorithms. As for the clinical presentation, both CD and PBC share some typical symptoms and signs, including fatigue, anemia and osteopenia/osteoporosis.
(Enlarge Image)
Figure 1.
Gut–liver axis: possible pathogenic link between celiac disease and primary biliary cirrhosis. The increased intestinal permeability and the altered gut microbiome, detected in celiac disease, cause the transfer of immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens from the gut to the liver through the portal circulation. An aberrant T lymphocyte (expressing intestinal integrin α4β7 and chemokine receptor CCR9) homing to the liver may contribute to trigger immune hepatic damage. Moreover, a molecular mimicry between bacterial antigens and the E2 component of the pyruvate dehydrogenase, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis.
Shared Features of CD & PBC
Both CD and PBC share several features. From a pathogenic point of view, both of them have been regarded as autoimmune disorders because of a large predominance in female patients, frequent autoimmune comorbidities and an immune response against well-established autoantigens, that is, TG2 and PDC–E2. Prevalence in the female sex is more pronounced in PBC than in CD, but the female:male ratio also remains high in CD, ranging from 4:1 to 2:1. Both CD and PBC share a very similar prevalence (approximately 30%) of associated autoimmune disorders. About one-third of patients with CD and/or PBC are affected by another immune disease, most frequently autoimmune thyroiditis and less frequently Sjogren syndrome. Type 1 diabetes mellitus is found very frequently in association with CD but not with PBC. CD and PBC are two classical examples of human disorders with highly sensitive (>90%) and specific immune markers (>95%), that is, tTGA and AMA, directed against TG2 and PDC-E2, respectively. Environmental infectious factors are also thought to contribute to the onset of both CD and PBC. Indeed, it has been reported that a molecular mimicry between a peptide of TG2 and a rotavirus protein (VP7) in CD patients, as well as between PDC-E2 and a nonpathogenic Gram–negative bacterium (Novosphingobium aromaticivorans), occurs in PBC. The increased intestinal permeability found in CD can result in a large exposure of gut-derived microbial antigens to the liver (Figure 1). The microbial mediated molecular mimicry is considered one of the most relevant triggers that may break the immunologic tolerance and, consequently, contribute to the onset of PBC. Moreover, it has been hypothesized that several other infectious agents are involved in triggering PBC, including Escherichia coli and Mycoplasma. Bogdanos et al. have demonstrated that microbial mimics comprising Helicobacter pylori are major targets of cross-reactivity with human pyruvate dehydrogenase in PBC, strengthening the fact that microbial exposure may be instrumental to the appearance and/or maintenance of AMA responses by a cross-reactive mechanism. Recently, Abenavoli et al. have supported the pathogenic role of H. pylori to induce PBC in a CD patient. A possible role for bacteria has also been recently proposed for the development of CD, as marked abnormalities of intestinal microbiome have been found in the majority of celiac patients. Observations that approximately 3–17% of first-degree relatives of CD patients and 1–6% of those of PBC are affected by CD and PBC, respectively, with a high concordance rate in monozygotic twins, confirm the relevant genetic susceptibility for these disorders.HLA-DQ2 and/or -DQ8, which have been identified as the main haplotypes conferring predisposition to CD, do not correlate with PBC. Recently, findings of a genome-wide association study, undertaken in two different cohorts of North American and Italian patients and controls, indicated a significant association between PBC and polymorphism of HLA-DQB1, IL12A, IL12RB2 and, to a minor extent, STAT4, which have also been found in other autoimmune disorders, including CD. Another common feature of both the disorders is that CD and PBC diagnosis can be accepted in selected cases without the need of intestinal and liver biopsy ('the gold standards' until a few years ago) according to the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and American Association for the Study of Liver Diseases algorithms. As for the clinical presentation, both CD and PBC share some typical symptoms and signs, including fatigue, anemia and osteopenia/osteoporosis.
(Enlarge Image)
Figure 1.
Gut–liver axis: possible pathogenic link between celiac disease and primary biliary cirrhosis. The increased intestinal permeability and the altered gut microbiome, detected in celiac disease, cause the transfer of immunologically active molecules generated from the cross-linking between tissue transglutaminase and food/bacterial antigens from the gut to the liver through the portal circulation. An aberrant T lymphocyte (expressing intestinal integrin α4β7 and chemokine receptor CCR9) homing to the liver may contribute to trigger immune hepatic damage. Moreover, a molecular mimicry between bacterial antigens and the E2 component of the pyruvate dehydrogenase, recognized by antimitochondrial autoantibodies, may have a role in primary biliary cirrhosis pathogenesis.
Source...