Microscopic Colitis -- Clinical and Pathologic Perspectives
Microscopic Colitis -- Clinical and Pathologic Perspectives
The etiology and pathophysiology of MC is not well understood but is likely to be multifactorial, involving mucosal immune responses to luminal factors in a genetically predisposed individual. This theory is best supported by observations made in patients undergoing surgery with ileostomy. In these patients, fecal stream diversion leads to regression of intestinal inflammation and mucosal barrier dysfunction and, in turn, reconstruction of bowel continuity leads to reappearance of the classic histologic features of MC. The following section is a selection of relevant results of mainly small observational studies describing different factors and mediators that might be involved in the pathogenesis of MC. However, it still largely is unclear which of these findings have true pathogenic relevance.
Familial occurrence of MC has been reported, but the exact role of genetic factors remains to be defined. HLA studies have shown an association of MC with HLA-DQ2 or DQ1/3 and a higher frequency of HLA-DR3DQ2 haplotype and TNF2 allele carriage compared with controls. Furthermore, allelic variation of the matrix metalloproteinase-9 gene does appear to be associated with CC. In contrast to Crohn's disease, functional polymorphism in the nucleotide-binding oligomerization domain-containing protein 2 and caspase recruitment domain-containing protein 15 (NOD2/CARD15) gene has not been detected.
Another factor may be a defect in mucosal barrier function, leading to increased transmucosal permeability of antigens and bacteria, thereby promoting intestinal inflammation. In vitro experiments on colonic biopsy specimens showed significant mucosal barrier dysfunction in CC patients in clinical remission, which was aggravated in active disease presenting with increased transmucosal uptake of nonpathogenic bacteria. Mucosal barrier dysfunction persisted despite short-term, clinically effective treatment with budesonide. Tagkalidis et al observed reduced E-cadherin and zonula occludens 1 expression (induced by interferon [IFN]γ) in CC, which is indicative of altered epithelial barrier function. Burgel et al noted reduced expression of the tight junction proteins occludin and claudin 4. Their findings correlated with reduced epithelial resistance, indicating increased paracellular permeability.
Because MC can present with abdominal pain, urgency, and fecal incontinence, the question arises whether MC patients have normal anal-rectal function. In a small study, patients with active CC had normal anal function and rectal compliance. Furthermore, there were no signs of visceral hypersensitivity.
CD8+ T lymphocytes predominate in both the epithelium and the lamina propria with increased proportions of Ki67+ and CD45RO+ CD8+ mucosal T cells. CD4+ T lymphocytes are comparably rare in the lamina propria.
MC shows a Th1 mucosal cytokine profile with IFNγ as the predominantly increased cytokine in CC, tumor necrosis factor α (TNF-α) in LC, and increased mucosal messenger RNA levels of interleukin (IL)8 and IL15. More recent immunologic studies showed a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile. Mucosal messenger RNA levels of IFNγ, IL12, IL17A, IL21, and IL22 were up-regulated significantly compared with controls, and these correlated with higher clinical activity. Significantly enhanced IL21 and TNF-α protein levels were noted in both CC and LC.
Pathophysiology
The etiology and pathophysiology of MC is not well understood but is likely to be multifactorial, involving mucosal immune responses to luminal factors in a genetically predisposed individual. This theory is best supported by observations made in patients undergoing surgery with ileostomy. In these patients, fecal stream diversion leads to regression of intestinal inflammation and mucosal barrier dysfunction and, in turn, reconstruction of bowel continuity leads to reappearance of the classic histologic features of MC. The following section is a selection of relevant results of mainly small observational studies describing different factors and mediators that might be involved in the pathogenesis of MC. However, it still largely is unclear which of these findings have true pathogenic relevance.
Genetics
Familial occurrence of MC has been reported, but the exact role of genetic factors remains to be defined. HLA studies have shown an association of MC with HLA-DQ2 or DQ1/3 and a higher frequency of HLA-DR3DQ2 haplotype and TNF2 allele carriage compared with controls. Furthermore, allelic variation of the matrix metalloproteinase-9 gene does appear to be associated with CC. In contrast to Crohn's disease, functional polymorphism in the nucleotide-binding oligomerization domain-containing protein 2 and caspase recruitment domain-containing protein 15 (NOD2/CARD15) gene has not been detected.
Epithelial Barrier Function
Another factor may be a defect in mucosal barrier function, leading to increased transmucosal permeability of antigens and bacteria, thereby promoting intestinal inflammation. In vitro experiments on colonic biopsy specimens showed significant mucosal barrier dysfunction in CC patients in clinical remission, which was aggravated in active disease presenting with increased transmucosal uptake of nonpathogenic bacteria. Mucosal barrier dysfunction persisted despite short-term, clinically effective treatment with budesonide. Tagkalidis et al observed reduced E-cadherin and zonula occludens 1 expression (induced by interferon [IFN]γ) in CC, which is indicative of altered epithelial barrier function. Burgel et al noted reduced expression of the tight junction proteins occludin and claudin 4. Their findings correlated with reduced epithelial resistance, indicating increased paracellular permeability.
Mechanism of Diarrhea
Because MC can present with abdominal pain, urgency, and fecal incontinence, the question arises whether MC patients have normal anal-rectal function. In a small study, patients with active CC had normal anal function and rectal compliance. Furthermore, there were no signs of visceral hypersensitivity.
Immunology
CD8+ T lymphocytes predominate in both the epithelium and the lamina propria with increased proportions of Ki67+ and CD45RO+ CD8+ mucosal T cells. CD4+ T lymphocytes are comparably rare in the lamina propria.
MC shows a Th1 mucosal cytokine profile with IFNγ as the predominantly increased cytokine in CC, tumor necrosis factor α (TNF-α) in LC, and increased mucosal messenger RNA levels of interleukin (IL)8 and IL15. More recent immunologic studies showed a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile. Mucosal messenger RNA levels of IFNγ, IL12, IL17A, IL21, and IL22 were up-regulated significantly compared with controls, and these correlated with higher clinical activity. Significantly enhanced IL21 and TNF-α protein levels were noted in both CC and LC.
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