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Gastroenterology 1985;89:1046–1049. 32 Bernstein and Blanchard Chapter 3 / Pathogenesis of IBD 33 Chapter 3 / Pathogenesis of IBD 33 33 From: Clinical Gastroenterology: Inflammatory Bowel Disease: Diagnosis and Therapeutics Edited by: R. D. Cohen © Humana Press Inc., Totowa, NJ 3 Etiology and Pathogenesis of Inflammatory Bowel Disease James J. Farrell, MB and Bruce E. Sands, MD CONTENTS INTRODUCTION GENETIC FACTORS MICROBIAL FACTORS IMMUNOLOGY OF IBD I MMUNE CELLS AND PATHOGENESIS NONIMMUNE CELLS IN THE PATHOGENESIS OF IBD C YTOKINES SOLUBLE MEDIATORS AND CELL ADHESION MOLECULES ANIMAL MODELS REFERENCES INTRODUCTION Despite improved understanding of the mechanisms of intestinal inflammation, the etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. Hence, the approaches to the diagnosis and management of both Crohn’s disease (CD) and ulcerative colitis (UC) have been largely empiric. However, progress in IBD research has fostered development of new agents that target pivotal processes in disease pathogenesis (1). This chapter addresses the etiology and patho- genesis of IBD, including the latest developments in animal models. It will serve as a basis for understanding current and future therapeutic development. There is increasing evidence that CD and UC represent a heteroge- neous group of diseases that have a common final pathway (Table 1). No 34 Farrell and Sands 34 Table 1 Distinguishing Features of UC and CD Pathogenesis Component Ulcerative Colitis Crohn’s Disease Environmental factors Beneficial effect of smoking Detrimental effect of smoking No beneficial effect of diet Symptoms improved by selected diets Familial factors High concordance among monzygotic twins Very high concordance among monzygotic twins Normal intestinal permeability in healthy relatives Increased intestinal permeability in healthy relatives Genetic factors Large contribution of the HLA class II region Small contribution of the HLA class II region Linkage with chromosomes 3,7, and 12 Linkage with chromosomes 3,7, and 12 Linkage with chromosome 6 No linkage with chromosome 6 No linkage with chromosome 16 Linkage with chromosome 16 No association with TNFa2b1c2d4e1 Increased association with TNFa2b1c2d4e1 Decreased TNFα-308 allele 2 No linkage TNFα-308 allele 2 Increased IL-1Ra allele 2 in extensive disease Microbial factors Limited role of bacterial flora Important role of bacterial flora No association with M. paratuberculosis Association with M. paratuberculosis No association with measles virus Some association with measles virus Humoral immunity Prominent antibody secretion Moderate antibody secretion Increased IgG1 secretion Increased IgG2 secretion Evidence for autoimmunity Limited evidence for autoimmunity Strong association with pANCA Weak association with pANCA Weak association with ASCA Strong association with ASCA Cell-mediated immunity Prominent mucosal neutrophil infiltration Prominent mucosal T-cell infiltration Normal/hyporeactive T cells Hyperreactive T cells Normal T-cell apoptosis (?) Resistance of T cells to apoptosis (?) Fas-FasL-mediated T cell apoptosis important Fas-FasL-mediated T-cell apoptosis less important Cytokines and mediators Th2-like profile Th1-like profile Cytokine increase limited to involved mucosa Cytokine increase in involved and uninvolved mucosa Prominent production of eicosanoids Moderate production of eicosanoids High substance P/receptor expression limited ?High substance P/receptor expression in to involved mucose but not to enteric neurons. involved and uninvolved mucosa as well as enteric neurons. HLA, human leukocyte antigen; ANCA, antineutrophil cytoplasmic antibodies; ASCA, anti-Saccharomyces cerevisiae antibodies. Adapted from: Fiocchi C. Inflammatory Bowel Disease: Etiology and Pathogenesis. Gastroenterology 1988;115:182–205. Chapter 3 / Pathogenesis of IBD 35 Chapter 3 / Pathogenesis of IBD 35 Fig. 1. Pathogenetic pathways involved in IBD. one agent or single mechanism can account for all aspects of IBD, and several distinct factors are likely to result in either CD or UC. The pathogenesis of CD and UC involves an interplay of environmental, genetic, microbial, immune, and nonimmune factors, which, in combi- nation, result in chronic intestinal inflammation (Fig. 1). These factors are discussed later. Environmental Risk Factors The incidence and prevalence of IBD continues to rise, suggesting an important role played by the environment in its pathogenesis. However, the relative importance of environmental compared to genetic factors in the initiation or progression of UC and CD remains unclear and contro- versial. Smoking, childhood infections, oral contraceptives, diet, prenatal events, breastfeeding, hygiene, microbial agents, occupation, pollution, and stress have all been suggested as possible environmental factors. 36 Farrell and Sands Cigarette smoking appears beneficial in UC, whereas it is detrimental in CD (2). Harries initial study found that smoking protected against UC, with the risk of developing UC among current smokers only 40% that of nonsmokers (3). No gender difference with this protective effect was seen in UC. In contrast, several studies have demonstrated a twofold increase in the risk of CD in smokers (4,5). However, unlike UC, women smokers were four times more likely to develop CD recurrence than non- smokers, whereas male smokers were at less of an increased risk (6). Smoking also appears to be an independent risk factor for recurrence in CD, especially following medically-induced remission (7). Several explanations exist to explain this relationship, including dif- ferences in colonic mucus and proinflammatory cytokine levels. Initial studies revealed that colonic mucus in UC was both quantitatively and qualitatively abnormal, and that mucus production in UC patients who smoked was similar to that of healthy controls (8,9). This suggests that smoking restores a normal pattern of mucus production in UC. How- ever, more recent studies have found similarities in the composition of colonic mucus in nonsmoking UC patients and controls (10). Likewise, reductions in the colonic mucosal concentrations of proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 8 (IL-8) have been observed in smokers with UC compared to nonsmokers with UC. The opposite effect is seen in healthy controls. It is of interest that IL-8 levels alone are reduced in smokers with CD compared with nonsmokers with CD, with no significant reduction in IL-1β levels (11). In addition, nicotine has been shown to have an inhibitory effect in vivo on T-helper 2 cell (Th2) function (the predominant cytokine pattern of UC ) cell function as measured by inhibition of IL-10 production. Nicotine does not appear to have any effect on T-helper 1 cell function (the predomi- nant cytokine pattern of CD) as indicated by IL-2 and tumor necrosis factor-alpha (TNFα) production (12). Finally, the thrombogenic prop- erties of cigarette smoking may contribute to vascular changes reported to be present in CD. To date, no specific dietary factors has been clearly linked to IBD. The association between the consumption of cola drinks, chewing gum, and chocolate with CD, and cola drinks and chocolate with UC, may simply be the expression of a “modern lifestyle” representing unknown risk factors, as opposed to playing a causal role. Zinc and selenium deficiencies are common in CD; and it is possible that these deficiencies contribute to immunological dysfunction seen in IBD (13). Although there have been a number of uncontrolled studies assessing the efficacy of elemental diets in CD, which suggest some degree of clinical im- provement, most controlled studies have found that enteral nutrition is Chapter 3 / Pathogenesis of IBD 37 Chapter 3 / Pathogenesis of IBD 37 less effective than steroids and aminosalicylates (14,15). Meta-analyses reveals that the overall remission rates for diet- and steroid-treated patients were 58% and 80%, respectively (16,17). Some data suggest that elemental diet may improve CD by reducing intestinal permeabil- ity. It has also been suggested that elemental diet may result in beneficial alterations in bowel flora (18). In contrast to Crohn’s disease, elemental diet does not appear to be beneficial in ulcerative colitis. The reason for this discrepancy in response is not known. Certain medications, including oral contraceptives and NSAIDs, have also been implicated in the pathogenesis of IBD. There are several reports linking the use of oral contraceptives and the development of IBD. In a case control study, the relative risk for CD among oral contra- ceptive users was 1.9 (95% confidence intervals (CI), 1.0 to 3.5) when compared to persons who had never used these drugs (19). Moreover, the magnitude of the risk was proportional to the duration of use of oral contraceptives. The data for UC is less clear. Vessey et al. found the relative risk for UC to be 2.5 (95% CI, 1.1 to 5.6) in women using oral contraceptives, but Lashner et al. found no increased risk (20,21). In addition to causing exacerbations of preexisting IBD, NSAID use can occasionally induce a colitis de novo (22). Recent studies indicate that fecal pH is more acidic in patients with IBD than in healthy controls. Fecal pH is reduced in the indomethacin model of chronic ileitis in rats, which is similar in some respects to human IBD (23). In this model, indomethacin significantly changed microcirculation parameters causing a twofold increase in leucocyte adherence and a threefold increase in leucocyte migration, thus providing a possible pathophysiological mechanism for the observations mentioned above. Finally, the increas- ing use of antibiotics in human and veterinary medicine over the last 50 yr has paralleled the increase in CD. Hence, it has been exposure of intestinal flora to sublethal antibiotics that may induce a capacity for toxin production in bacteria, or can make them invasive. It is conceiv- able that CD is caused in genetically susceptible persons by intestinal bacteria whose biological (but not morphological) properties have been altered by antibiotics (24). There is epidemiological evidence showing an increased frequency of childhood infections and tonsillectomies in patients with IBD. Patients with CD are more likely to report an increased frequency of childhood infections in general (odds ratio 4.67) and pharyngitis specifically (odds ratio 2.14), whereas patients with UC reported an excess of infections generally (odds ratio 2.37) (25). Curiously, the ileum is the most preva- lent location of disease in CD patients with previous tonsillectomy. Furthermore, it has been found that appendectomy is protective for the [...]... Podolsky DK Inflammatory bowel disease: is it in the genes? Gastroenterology 1998;115(5): 128 6– 128 9 60 Farrell and Sands 41 Satsangi J, Welsh KI, Bunce M, et al Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease Lancet 1996;347(9010): 121 2– 121 7 42 Asakura H, Tsuchiya M, Aiso S, et al Association of the human lymphocyte-DR2 antigen... proinflammatory and antiinflammatory cytokines, Th1 and Th2 cytokines and chemokines Proinflammatory cytokines include IL-1, IL-6, IL-8, and TNF and contribute to many of the characteristic attributes of IBD: neutrophil infiltration (IL-8), T-cell activation (IL-1), expression of adhesion molecules (IL-1 and TNF), enhanced epithelial permeability (IFN-γ), and epithelial injury (TNF and IFN-γ) IL-1... childbearing age Br Med J (Clin Res Ed) 1986 ;29 2(6 528 ):1101–1103 21 Lashner BA, Kane SV, Hanauer SB Lack of association between oral contraceptive use and ulcerative colitis Gastroenterology 1990;99(4):10 32 1036 22 Kaufmann HJ, Taubin HL Nonsteroidal anti -inflammatory drugs activate quiescent inflammatory bowel disease Ann Intern Med 1987;107(4):513–516 23 Arndt H, Palitzsch KD, Scholmerich J Leucocyte... immune complex 54 Indomethacin Carageenan 2, 4,6-Trinitro- benzene sulfonic acid Dextran sodium sulfate Cyclosporin Peptidoglycan-polysaccharide Transgenic/gene targeted IL -2 /– –/– IL -2 Rα –/– IL-10 –/– TGFβ –/– Gαi2 –/– TCRα Farrell and Sands Site of disease Models 55 Immunologic + hi CD4 CD45RB /mice –/– SCID or Rag Bone marrow Tge26 mice Spontaneous Cotton-top tamarin C3HeJBir mouse SAMP1/Yit mouse... J, Parkes M, Louis E, et al Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12 Nat Genet 1996;14 (2) :199 20 2 55 Rioux JD, Daly MJ, Green T, et al Absence of linkage between inflammatory bowel disease and selected loci on chromosomes 3, 7, 12, and 16 Gastroenterology 1998;115(5):10 62 1065 56 Levine J, Ellis CJ, Furne JK, Springfield... Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis Scand J Gastroenterol 1987 ;22 (2) :21 4 21 8 34 Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins A study of heritability and the influence of smoking Gut 1988 ;29 (7):990–996 35 Bayless TM, Tokayer AZ, Polito JM, 2nd, Quaskey... proinflammatory, and immunosuppressive cytokines can be manipulated in humans as effectively as in animal models 58 Farrell and Sands REFERENCES 1 Fiocchi C Inflammatory bowel disease: etiology and pathogenesis Gastroenterology 1998;115(1):1 82 20 5 2 Thomas GA, Rhodes J, Green JT Inflammatory bowel disease and smoking— a review Am J Gastroenterol 1998;93 (2) :144–149 3 Harries AD, Baird A, Rhodes J Non-smoking:... extraintestinal manifestations in a rat model HLA-B27 transgenic rats develop inflammation in multiple organs, but small and large bowel are spared when these rats are kept in a germ-free environment Similar results are observed in IL -2 and IL-10 and T-cell receptor-(TCR1)-knockout mice The reverse is also true, e.g., reconstitution of germ-free HLAB27 transgenic rats with normal luminal bacteria,... biosynthesis inhibitor, MK-591 Gastroenterology 1997;1 12( 3): 725 –7 32 101 McKenzie SJ, Baker MS, Buffinton GD, Doe WF Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease J Clin Invest 1996;98(1):136–11 1 02 Boughton-Smith NK, Evans SM, Hawkey CJ, et al Nitric oxide synthase activity in ulcerative colitis and Crohn’s disease Lancet 1993;3 42( 8867):338–340 103 Middleton... 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More recently, Th3 and Tr1 cells, distinguished by TGF-b and