Elsevier

The Lancet

Volume 369, Issue 9573, 12–18 May 2007, Pages 1627-1640
The Lancet

Series
Inflammatory bowel disease: cause and immunobiology

https://doi.org/10.1016/S0140-6736(07)60750-8Get rights and content

Summary

Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel disorders. In this paper, we discuss how environmental factors (eg, geography, cigarette smoking, sanitation and hygiene), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can result in mucosal inflammation. After describing the symbiotic interaction of the commensal microbiota with the host, oral tolerance, epithelial barrier function, antigen recognition, and immunoregulation by the innate and adaptive immune system, we examine the initiating and perpetuating events of mucosal inflammation. We pay special attention to pattern-recognition receptors, such as toll-like receptors and nucleotide-binding-oligomerisation-domains (NOD), NOD-like receptors and their mutual interaction on epithelial cells and antigen-presenting cells. We also discuss the important role of dendritic cells in directing tolerance and immunity by modulation of subpopulations of effector T cells, regulatory T cells, Th17 cells, natural killer T cells, natural killer cells, and monocyte-macrophages in mucosal inflammation. Implications for novel therapies, which are discussed in detail in the second paper in this Series, are covered briefly.

Introduction

Ulcerative colitis and Crohn's disease represent the two main types of inflammatory bowel disease. In the first paper in this two-article Series, we examine current concepts of the causes and immunobiology of these disorders. The second paper in the Series focuses on clinical aspects, including current and evolving therapies for inflammatory bowel disease.1 Crohn's disease was first seen by German surgeon Wilhelm Fabry (aka Guilhelmus Fabricius Hildanus) in 1623,2 and was later described by and named after the US physician Burril B Crohn.3 Ulcerative colitis was first described by the British physician Sir Samuel Wilks in 1859.4

Section snippets

Epidemiology

The highest incidence rates and prevalence of ulcerative colitis and Crohn's disease have been reported from northern Europe, the UK, and North America, where the rates are beginning to stabilise. Rates continue to rise in low-incidence areas such as southern Europe, Asia, and most developing countries5 (table 16, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). In North America, prevalence rates of Crohn's disease for Hispanic (4·1 per 100 000) and Asian people (5·6 per 100 000) is much lower than those

Familial aggregation

Familial aggregation of inflammatory bowel disease was first reported in the 1930s.25 A positive family history is still the largest independent risk factor for the disease. The greatest risk to relatives is of developing the same disease as the affected relative. People with Crohn's disease have a first-degree relative with Crohn's disease in 2·2–16·2% of cases and with inflammatory bowel disease in 5·2–22·5% of cases. The risk of Crohn's disease in a sibling of a Crohn's disease proband is

Geographic, temporal, and seasonal variability

The highest incidence rates and prevalence for ulcerative colitis and Crohn's disease are reported from North America and northern Europe (table 1). The lowest incidence rates are reported from South America, southeast Asia, Africa (with the exception of South Africa), and Australia.5 Although these data suggest a gradient exists from north to south, they could also indicate variation in access to, and quality of, health care as well as different extents of industrialisation, sanitation, and

Immunhomoeostasis in the healthy gut

How is it then that the mucosal immune system is not in a constant uncontrolled state of inflammation when confronted with such a high antigen load? Mucosal surfaces are physical interfaces of the immune system with the outside world. The gut houses a large part of the mucosa-associated lymphoid tissue in the human body. The intestine also harbours the largest and most diverse microbiota consisting of more than 500 species of bacteria95, 96 (figure 3 [explained in panel 3]).

References (169)

  • RH Duerr et al.

    High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11–12

    Am J Hum Genet

    (2000)
  • JD Rioux et al.

    Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci

    Am J Hum Genet

    (2000)
  • J Hampe et al.

    A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort

    Am J Hum Genet

    (1999)
  • I Tamai et al.

    Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1

    FEBS Lett

    (1997)
  • X Wu et al.

    cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family

    Biochem Biophys Res Commun

    (1998)
  • K Lahjouji et al.

    Carnitine transport by organic cation transporters and systemic carnitine deficiency

    Mol Genet Metab

    (2001)
  • F Martinon et al.

    NLRs join TLRs as innate sensors of pathogens

    Trends Immunol

    (2005)
  • SE Girardin et al.

    Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection

    J Biol Chem

    (2003)
  • N Inohara et al.

    Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease

    J Biol Chem

    (2003)
  • DW Abbott et al.

    The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO

    Curr Biol

    (2004)
  • JD Lewis et al.

    Seasonal variation in flares of inflammatory bowel disease

    Gastroenterology

    (2004)
  • E Klement et al.

    Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis

    Am J Clin Nutr

    (2004)
  • BJ Geerling et al.

    Diet as a risk factor for the development of ulcerative colitis

    Am J Gastroenterol

    (2000)
  • KH Weylandt et al.

    Rethinking lipid mediators

    Lancet

    (2005)
  • AE Gent et al.

    Inflammatory bowel disease and domestic hygiene in infancy

    Lancet

    (1994)
  • J Cosnes

    Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice

    Best Pract Res Clin Gastroenterol

    (2004)
  • JR Ingram et al.

    A randomized trial of nicotine enemas for active ulcerative colitis

    Clin Gastroenterol Hepatol

    (2005)
  • A Ekbom et al.

    Perinatal measles infection and subsequent Crohn's disease

    Lancet

    (1994)
  • A Swidsinski et al.

    Mucosal flora in inflammatory bowel disease

    Gastroenterology

    (2002)
  • A Darfeuille-Michaud et al.

    High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease

    Gastroenterology

    (2004)
  • RE Andersson et al.

    Appendectomy is followed by increased risk of Crohn's disease

    Gastroenterology

    (2003)
  • RD Berg

    The indigenous gastrointestinal microflora

    Trends Microbiol

    (1996)
  • Wilhelm Fabry (1560–1624): the other fabricius

    JAMA

    (1964)
  • BB Crohn et al.

    Landmark article Oct 15, 1932: regional ileitis: a pathological and clinical entity, by Burril B Crohn, Leon Ginzburg, and Gordon D Oppenheimer

    JAMA

    (1984)
  • S Wilks

    Morbid appearances in the intestine of Miss Bankes

    London Medical Times & Gazette

    (1859)
  • RE Sedlack et al.

    Incidence of Crohn's disease in Olmsted County, Minnesota, 1935–75

    Am J Epidemiol

    (1980)
  • CG Loftus et al.

    Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940–2000

    Inflamm Bowel Dis

    (2006)
  • EV Loftus et al.

    Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival

    Gut

    (2000)
  • E Langholz et al.

    Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987

    Scand J Gastroenterol

    (1991)
  • P Munkholm et al.

    Incidence and prevalence of Crohn's disease in the county of Copenhagen, 1962–87: a sixfold increase in incidence

    Scand J Gastroenterol

    (1992)
  • CN Bernstein et al.

    Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian province: a population-based study

    Am J Epidemiol

    (1999)
  • JF Blanchard et al.

    Small-area variations and sociodemographic correlates for the incidence of Crohn's disease and ulcerative colitis

    Am J Epidemiol

    (2001)
  • A Lapidus et al.

    Incidence of Crohn's disease in Stockholm County 1955–89

    Gut

    (1997)
  • A Lapidus

    Crohn's disease in Stockholm County during 1990–2001: an epidemiological update

    World J Gastroenterol

    (2006)
  • GC Nguyen et al.

    Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort

    Am J Gastroenterol

    (2006)
  • J Hampe et al.

    Anticipation in inflammatory bowel disease: a phenomenon caused by an accumulation of confounders

    Am J Med Genet

    (2000)
  • A Grossman et al.

    Epidemiology of ulcerative colitis in the Jewish population of central Israel 1970–1980

    Hepatogastroenterology

    (1989)
  • RW Leong et al.

    The epidemiology and phenotype of Crohn's disease in the Chinese population

    Inflamm Bowel Dis

    (2004)
  • JJ Zheng et al.

    Crohn's disease in mainland China: a systematic analysis of 50 years of research

    Chin J Dig Dis

    (2005)
  • J Satsangi et al.

    Clinical patterns of familial inflammatory bowel disease

    Gut

    (1996)
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