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• W2319384827 abstract "Enteropathy is broadly defined as pathologic changes to the intestine, usually associated with inflammation. Traditionally, enteropathy was associated with disease, but this relationship has become clouded in recent years. Patients with silent celiac disease have an enteropathy, but are often outwardly healthy. In children referred for endoscopy, mild pathologic changes without any of the stigmata of inflammatory bowel disease (IBD) are frequently seen in mucosal biopsy specimens, but by and large, these changes are benign. Nonetheless, enteropathy implies injury to the gut that manifests as clinical disease. From a pathologist's point of view, characteristic features allow one to classify, but not necessarily understand, enteropathy. Therefore, a child who is failing to thrive and whose biopsy specimen shows short villi, long crypts, and increased intraepithelial lymphocytes, may have celiac disease. The presence of continuous colonic inflammation with crypt abscesses suggests ulcerative colitis; granulomata and a mononuclear infiltrate with linear ulcers suggest Crohn's disease; and excess collagen suggests collagenous colitis. The pathologic changes help explain the disease in most cases. Therefore, the loss of surface absorptive area when the mucosa becomes flat explains the symptoms of celiac disease. Diarrhea and bleeding in IBD occurs because the disease process causes ulcers through which blood and plasma proteins can leak into the gut lumen. Excess immune activation causes these changes, and consequently, the most commonly used treatment for idiopathic gut inflammation is corticosteroids. However, until recently it has not been possible to mechanistically link inflammation with pathology, and so important questions remain unanswered: In celiac disease, do raised intraepithelial lymphocytes (IEL) or γδ T cells drive the flat mucosa? Or do gluten-reactive lamina propria T cells cause it? What causes the colonic mucosal thickening seen in Crohn's disease and ulcerative colitis? What triggers the development of an ulcer? These questions essentially hinge on a single point: the nature of the cross talk between inflammatory cells and the cells of the gut epithelium, lamina propria, muscularis mucosae, and deeper muscle layers. In this presentation, I will cover some areas in which inflammatory cells have been mechanistically linked with tissue injury in the gut wall. To do this, I will use examples of common diseases. CELIAC DIEASE AND OTHER DISEASES CHARACTERIZED BY VILLOUS SHORTENING AND CRYPT HYPERPLASIA Villous atrophy and crypt hyperplasia are seen in a wide variety of diseases of the small intestine. Celiac disease is the classic situation, but similar changes are seen in cow milk–sensitive enteropathy and other food intolerances, giardiasis, mild small bowel Crohn's disease, worm infections, and autoimmune enteropathy (1). This strongly suggests that the flat mucosa represents a stereotypic response to immunologic insult. Moreover, many studies have shown that the flat mucosa is a feature of cell-mediated immunity in the mucosa rather than an immune complex reaction or an immediate hypersensitivity (2). Because IELs are readily quantified and often increased in diseases of the flat mucosa, it has been thought that they play a major role in the development of the lesion. Thus IEL killing of surface enterocytes in celiac disease would lead to compensatory crypt-cell hyperplasia. Despite the popularity of this notion, not a single experiment has ever substantiated this idea. In celiac disease, the T cells that respond to gluten are not IELs, but are T-helper-cell–type 1 CD4 cells in the lamina propria, producing interferon γ and tumor necrosis factor α (TNF-α)(3). Indeed the changes in the mucosa in untreated celiac disease are an example of tissue remodeling, with the largest changes in the volume of the lamina propria, which increases twofold to threefold (4). Therefore, expansion of the lamina propria compartment swallows the villi. In fact, the flat celiac mucosa is an example of tissue growth, not injury. However, this does not answer the question of the mechanism by which activated gluten-reactive T cells in the lamina propria drive this remodeling, although there are candidate molecules. Cytokine-activated stromal cells produce connective tissue growth factor, and it may be involved in the lamina propria myofibroblast proliferation that must accompany mucosal growth (5). A net increase in matrix deposition must also occur, at least while remodeling is occurring. Finally there must be cross talk between T cells, myofibroblasts, and epithelial cells to drive crypt hyperplasia. Recently, we have been interested in the role of keratinocyte growth factor (KGF) in controlling epithelial proliferation in the intestine. Keratinocyte growth factor is a good candidate for a molecule that can link immune reactions in the lamina propria with epithelial proliferation because its receptor, a splice variant of FGFRII, is expressed only on epithelial cells (6). Keratinocyte growth factor is overexpressed in stromal cells in active IBD (7–9) and is associated with increased epithelial renewal. Functional studies indicate that it is also up-regulated in explants of human fetal small intestine after T-cell activation with bacterial superantigens, coincident with crypt hyperplasia (10). Inhibition of KGF in this model decreases T-cell–mediated crypt hyperplasia (10). Crypt hyperplasia may have evolved as a mechanism to eliminate pathogens that live inside epithelial cells or colonize the epithelial surface (Fig. 1). It is likely that KGF is only one of a number of molecules such as transforming growth factor α, hyperglycemic-glycogenolytic factor, and the other FGFs that may play a role in regulating epithelial proliferation during inflammation.FIG. 1.: Diagrammatic illustration of epithelial growth factors such as keratinocyte growth factor (KGF), made by cytokine-activated myofibroblasts, increasing crypt-cell proliferation.We have recently studied KGF in celiac disease (11). Transcripts are clearly up-regulated compared with normal intestine. However, in situ hybridization shows that the increased transcripts are not found around the crypts as they are in IBD (9), but are present in fibroblasts immediately under the surface epithelium (11). Others have shown that the enzymes that remodel tissues, the matrix metalloproteinases (MMPs), are also overexpressed only in this locality (12). As yet, there is no explanation for these results. However, studies that compare flat and normal mucosa may not be the most informative about the genesis of the lesion. Maximal MMP activity and epithelial growth factors may occur during the transition from normal to flat mucosa. When the tissue has remodeled, it again reaches a steady state, albeit turning over at an increased tempo. The enhanced crypt unit is now a structural feature, and the remodeling and epithelial growth occurs at the surface, where the mucosa is trying to become thicker (13). Overall mucosal thickness is identical between healthy subjects and patients with celiac disease, which strongly suggests a hardwired limit to the thickness of the small bowel mucosa. ULCERS IN CROHN DISEASE, ULCERATIVE COLITIS AND HELICOBACTER PYLORI INFECTION If the flat mucosa is a stereotypic manifestation of T-cell reactions in the gut, then ulcer development is a feature of many types of idiopathic conditions and infections. Ulcers represent a more serious problem to the host because continued protein-losing enteropathy and gut bleeding can lead to death if unchecked. The MMPs play a major role in the development of GI ulcers (14). A crucial step in ulceration of the gut wall in IBD is the activation of a protease cascade, in particular the rapid up-regulation of transcripts for the MMPs by proinflammatory cytokines (15). The MMPs are a group of proteases that have a putative Zn2+-binding site HEXXH, and all require Ca2+ for stability; they also exhibit a preferred cleavage specificity for the N-terminal side of hydrophobic residues (16,17). The MMPs can be subdivided into four different groups according to their substrate specificity: collagenases, stromelysins, gelatinases, and membrane-type metalloproteinases (MT-MMPs). Except for MT-MMP, they are secreted in proenzyme forms requiring extracellular activation. Various agents, such as plasmin or free radicals, can activate MMPs extracellularly, but they can also interact to activate one another (18,19). The MMP activity is tightly regulated by their natural inhibitors, the tissue inhibitors of metalloproteinase (TIMPs) (20). Four TIMPs have been identified so far. As a result of their extensive substrate specificity, activated MMPs can degrade all classes of extracellular matrix. Cytokines generally up-regulate MMP production in gut myofibroblasts, and increased cytokines are present in all mucosal inflammation, for example, ulcerative colitis and Crohn's disease (21). Saarialho-Kere et al. (22) and Vaalamo et al. (23) provided the most important and convincing evidence of MMPs in IBD. They performed in situ hybridization that showed high degrees of expression of MMP and TIMP mRNA around ulcer beds, regardless of the ulcer's cause. They also observed that the cellular source of MMPs in IBD was fibroblastlike stromal cells. We have also observed an up-regulation of active stromelysin-1 protein in IBD compared with normal intestine, whereas TIMP expression remains consistently increased in both groups of individuals (24). We have demonstrated an important role for MMPs in degradation of the gut mucosa during immune reactions. Activation of lamina propria T cells in explant cultures of fetal human small intestine by the lectin pokeweed mitogen or with anti-CD3 antibodies and interleukin (IL)–12 for 72 hours results in a strong Th1-biased response and severe mucosal destruction (25). This response is T-cell dependent because it can be inhibited by cyclosporine and FK506 (26). The first clue that proteases may be important in this model came from the fact that pokeweed mitogen–stimulated explants showed evidence of sulphated glycosaminoglycan degradation in the lamina propria. α2-macroglobulin may have inhibited this phenomenon, suggesting that proteases were important (27). Further observations showed that this T-cell–mediated tissue injury was also associated with markedly increased activated interstitial collagenase and stromelysin-1 after pokeweed mitogen stimulation and that a synthetic MMP inhibitor, CT1399, inhibited the tissue injury. Most important, nanomolar concentrations of recombinant stromelysin-1 (but not interstitial collagenase or gelatinases) caused severe tissue injury in 24 hours (28). Stromal cells are the major cellular sources of stromelysin-1, and stromal cell lines rapidly up-regulate MMP-1 and MMP-3 when cultured with TNF-α or IL-1β (29,30). Consistent with this, pokeweed mitogen–induced tissue injury can be inhibited by a soluble p55 TNF-α receptor human immunoglobulin G1 fusion protein. This p55 TNFR-IgG fusion protein inhibited not only tissue injury but also 95% of stromelysin-1 production (but not collagenase or gelatinases) (30). Stromelysin-1 clearly plays a major role in gut ulceration (Fig. 2) because it can degrade type IV collagen in the basement membrane and lamina propria and epithelial proteoglycans, and E-cadherin on epithelial cells (31). However many other MMPs are also up-regulated in inflamed gut, and their relative roles are not known.FIG. 2.: Matrix metalloproteinase 3 (MMP-3, stromelysin-1) made by cytokine-activated myofibroblasts has a broad specificity and can degrade type IV collagens in basement membranes (BM) of epithelium and endothelium (illustrated) and proteoglycans in the intercellular matrix.LAMINA PROPRIA GUT MYOFIBROBLAST, THE KEY CELL IN MEDIATING IMMUNE ENTEROPATHY Although a number of studies have suggested that cytokines have a direct effect on gut cells, many of these have used epithelial cell lines in vitro. However, evidence suggests that direct injection of cytokines has a damaging effect on the gut (32,33). It also is self-evident that free-radical production by inflammatory cells, especially neutrophils, must play a major role in injury in acute inflammation of the mucosa. In addition, cytokine-induced overexpression of vascular adhesion molecules will draw inflammatory cells into the gut and perpetuate inflammation. Although these effects contribute to injury, I would argue that they are not primary endpoint mediators of gut injury. All of the data cited above can be unified into a general theory of gut injury, in which the main cell involved is the lamina propria myofibroblast. These cells secrete the extracellular matrix required to maintain villus shape, to retain water, and to bind growth factors. Cross talk between epithelial cells and myofibroblasts absolutely is necessary for mucosal development and epithelial cell maturation (34). Myofibroblasts normally turn over lamina propria extracellular matrix at a relatively slow rate. However, when activated by cytokines, MMP production is dramatically enhanced. In the extracellular milieu, MMP activated by free radicals, neutrophil proteases, or plasmin to produce active enzyme may then degrade the mucosa and produce an ulcer. Therefore, mucosal ulceration is self-degradation. However at the same time, the myofibroblast is secreting TIMPs and growth factors, so that the epithelium can recover the areas denuded by the action of MMPs and heal the gut. The balance among all of these factors will determine whether the colonic mucosa thickens, as in colonic IBD, becomes flat as in celiac disease, or ulcerates as in many conditions (Fig. 3). At the moment, we have very little understanding of the factors that control these activities in the human gut. Within the mucosal microenvironment in inflammation, an abundance of soluble molecules and ligands are capable of regulating MMP, TIMP, and growth factor production in myofibroblasts. Heterogeneity may also exist, in that the cells of the pericryptal myofibroblast sheath may be different from the cells deeper in the lamina propria. The desmin-containing contractile myofibroblasts may be functionally different from the non–desmin-positive, α smooth muscle cell actin–positive cells elsewhere. This is clearly a very exciting area of research because it means that gut structure and function in inflammation may be understood at the cellular and molecular level.FIG. 3.: Lamina propria myofibroblasts secrete a number of molecules that can alter mucosal shape and integrity. Proinflammatory cytokines control the transcriptional activity of these various molecules." @default.
• W2319384827 created "2016-06-24" @default.
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• W2319384827 date "2002-05-01" @default.
• W2319384827 modified "2023-10-16" @default.
• W2319384827 title "The Biochemical Basis of Immune Enteropathy" @default.
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• W2319384827 cites W1894541755 @default.
• W2319384827 cites W1919303367 @default.
• W2319384827 cites W1965396386 @default.
• W2319384827 cites W1966159255 @default.
• W2319384827 cites W2006699412 @default.
• W2319384827 cites W2020208782 @default.
• W2319384827 cites W2025758337 @default.
• W2319384827 cites W2028870025 @default.
• W2319384827 cites W2042202567 @default.
• W2319384827 cites W2044135264 @default.
• W2319384827 cites W2061017342 @default.
• W2319384827 cites W2071463971 @default.
• W2319384827 cites W2106740227 @default.
• W2319384827 cites W2109658199 @default.
• W2319384827 cites W2118702749 @default.
• W2319384827 cites W2127820456 @default.
• W2319384827 cites W2128171706 @default.
• W2319384827 cites W2130918485 @default.
• W2319384827 cites W2131132948 @default.
• W2319384827 cites W2143500139 @default.
• W2319384827 cites W2145179279 @default.
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