domingo, 19 de febrero de 2012

Inmunidad, inflamación y alergia en el intestino inglés

DOI: 10.1126/science.1106442

307, 1920 (2005);

Thomas T. MacDonald,
et al.

Immunity, Inflammation, and Allergy in the Gut (this information is current as of May 18, 2009 ):

The following resources related to this article are available online at

version of this article at:

Updated information and services,
including high-resolution figures, can be found in the online

found at:

A list of selected additional articles on the Science Web sites
related to this article can be

This article
cites 83 articles, 24 of which can be accessed for free:

This article has been
cited by 176 article(s) on the ISI Web of Science.

This article has been
cited by 42 articles hosted by HighWire Press; see:


This article appears in the following
subject collections:

this article
in whole or in part can be found at:

Information about obtaining
reprints of this article or about obtaining permission to reproduce

registered trademark of AAAS.

2005 by the American Association for the Advancement of Science; all rights reserved. The title
Science is a

American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright

(print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the

Downloaded from on May 18, 2009

27. F. Ba¨ckhed
et al., Proc. Natl. Acad. Sci. U.S.A. 101,

15718 (2004).

28. M. Yamanaka, T. Nomura, M. Kametaka,
J. Nutr. Sci.

Vitaminol. (Tokyo)
23, 221 (1977).

29. H. C. Towle,
Proc. Natl. Acad. Sci. U.S.A. 98, 13476


30. R. H. Rolandelli
et al., J. Nutr. 119, 89 (1989).

31. K. M. Flegal, R. P. Troiano,
Int. J. Obes. Relat. Metab.

24, 807 (2000).

32. N. I. McNeil,
Am. J. Clin. Nutr. 39, 338 (1984).

33. R. K. Thauer, K. Jungermann, K. Decker,

41, 100 (1977).

34. A. J. Stams,
Antonie Van Leeuwenhoek 66, 271


35. T. L. Miller, M. J. Wolin,
Arch. Microbiol. 131, 14


36. O. Chacon, L. E. Bermudez, R. G. Barletta,
Annu. Rev.

58, 329 (2004).

37. More information about these genomes is available


cmpr_microbial/index.php?cmpr _microbial

38. T. Kuwahara
et al., Proc. Natl. Acad. Sci. U.S.A. 101,

14919 (2004).

39. A. M. Cerden˜o-Ta´rraga
et al., Science 307, 1463


40. M. Y. Galperin,
Nucleic Acids Res. 32, D3 (2004).

41. Materials and methods are available as supporting

material on
Science Online.

42. We thank L. Angenent for many helpful discussions.

Work cited from the authors’ lab is supported by the

NIH and NSF. F.B. and J.L.S. are supported by

postdoctoral fellowships from the Wenner-Gren

and W. M. Keck Foundations, respectively.

Supporting Online Material


Materials and Methods

Tables S1 to S3




Immunity, Inflammation, and Allergy in the Gut

Thomas T. MacDonald
1*. and Giovanni Monteleone2

The gut immune system has the challenge of responding to pathogens while remaining

relatively unresponsive to food antigens and the commensal microflora. In

the developed world, this ability appears to be breaking down, with chronic inflammatory

diseases of the gut commonplace in the apparent absence of overt

infections. In both mouse and man, mutations in genes that control innate

immune recognition, adaptive immunity, and epithelial permeability are all

associated with gut inflammation. This suggests that perturbing homeostasis

between gut antigens and host immunity represents a critical determinant in the

development of gut inflammation and allergy.

The gastrointestinal tract is the site where the

divergent needs of nutrient absorption and

host defense collide: The former requires a

large surface area and a thin epithelium that

has the potential to compromise host defense.

Many infectious diseases involve the gut, and

the investment by the gut in protecting itself

is evident in the abundant lymphoid tissue

and immune cells it harbors. In westernized

countries, most infectious diseases of the gut

are largely under control, yet gastrointestinal

food allergies and idiopathic inflammatory

conditions have dramatically increased; in other

words, we now have inflammation without

infection. Although the reason for this remains

unknown, a prevailing notion is that the absence

of overt gut infection has upset the

balance between the normal bacteria that

colonize the healthy gut and the mucosal immune


The Gut Epithelial Barrier

The primary cellular barrier of the gut in preventing

antigens encountering the immune

system is the single layer of gut epithelium,

the surface area of which is expanded to the

order of 400 m
2, largely because it is formed

into millions of fingerlike villi in the small

bowel. Each epithelial cell maintains intimate

association with its neighbors and seals

the surface of the gut with tight junctions. In

the upper bowel, the bulk of the antigen exposure

comes from diet, whereas in the ileum

and colon, the additional antigenic load of an

abundant and highly complex commensal microflora


Nevertheless, the gut epithelial barrier does

not completely prevent lumenal antigens from

entering the tissues. Thus, intact food proteins

can be detected in plasma (
1), and a few gut

bacteria can be detected in the mesenteric

lymph nodes draining the gut of healthy

animals (
2). Antigens can cross the epithelial

surface through breaks in tight junctions, perhaps

at villus tips where epithelial cells are

shed, or through the follicle-associated epithelium

(FAE) that overlies the organized lymphoid

tissues of the intestinal wall (
3). Peyer’s

patches (PP) in the small bowel are aggregates

of lymphoid tissue numbering
È200 in

the average adult, although tens of thousands

of much smaller individual follicles also line

the small bowel and colon. FAE contains specialized

epithelial cells termed M cells whose

function is to transport lumenal antigens into

the dome area of the follicle (
3) (Fig. 1).

Antigen-presenting dendritic cells (DC) also

send processes between gut epithelial cells

without disturbing tight junction integrity

and sample commensal and pathogenic gut

bacteria (
4, 5). The gut epithelial barrier therefore

represents a highly dynamic structure that

limits, but does not exclude, antigens from

entering the tissues, whereas the immune system

constantly samples gut antigens through

the FAE and DC processes.

Commensal Bacteria in

Epithelial/Immune Cell Function

in the Gut

Interaction of commensals with gut epithelium.

The gut epithelium itself can also directly

sense commensal bacteria and pathogens; integral

to this are the mammalian pattern recognition

receptors (PRRs), which recognize

conserved structures of bacteria and viruses

and generally activate pro-inflammatory pathways

alerting the host to infection (
6). Two

different classes of PRRs are involved. The

Toll-like receptors (TLRs) are usually associated

with cell membranes and have an external

leucine-rich repeat (LRR) recognition

domain and an intracellular interleukin-1

receptor (IL-1R)–like signaling domain (

The nucleotide-binding oligomerization domain

(Nod) molecules, Nod1 and Nod2 [also

known as CARD4 and CARD15 (caspase

activation and recruitment domain)], are

present in the cytosol of epithelial cells and

immune cells. These proteins also have LRRs

at the C terminus, a Nod domain, and CARD

domains at the N terminus (
8). There is abundant

evidence that signaling through Nod or

TLR activates transcription factor NF-
kB, leading

to pro-inflammatory gene expression (
7, 8)

TLR1 to TLR9 and Nod1 and Nod2 are

each expressed by gut epithelial cells (
6, 9).

Nod1 and Nod2 recognize slightly different

muropeptide motifs derived from bacterial peptidoglycans

6), which suggests that they sense

intracellular infection or attempted bacterial

subversion of epithelial cells (
10). TLRs recognize

many different components of bacteria

and viruses. For example, TLR4 recognizes

Division of Infection, Inflammation, and Repair, University

of Southampton School of Medicine, Southampton

General Hospital, Southampton, SO16 6YD,

2Dipartimento di Medicina Interna e Centro di

Eccellenza per lo Studio delle Malattie Complesse e

Multifattoriali, Universita` Tor Vergata, Rome, Italy.

*Present address: Barts and the London School of

Medicine and Dentistry, Turner Street, London E1

2AD, UK.

To whom correspondence should be addressed.





Downloaded from on May 18, 2009

lipopolysaccharide from the Gram-negative

bacterial cell wall, and TLR5 recognizes bacterial

flagellin (
6, 7). An unresolved question

is how the gut distinguishes between pathogens

and commensal bacteria. One means by

which inappropriate responses to innate signals

from commensals may be achieved is

through the compartmentalization of TLRs

to the basolateral aspects of epithelial cells

or inside epithelial cells (
11, 12).

Mutualism also appears to exist between

the commensal flora and the gut epithelium

to maintain epithelial integrity. For example,

recognition of TLR2 or TLR9 ligands by

epithelial cells increases gut barrier function

13, 14). The normal flora also induces

cytoprotective proteins hsp25 and hsp72 in

colonic epithelial cells

15). Mice deficient in

MyD88, the adapter molecule

essential for TLR

signaling, fail to express

epithelial hsp25 and

hsp72 (
16) and are highly

susceptible to experimental


bowel disease (IBD) initiated

by dextran sodium

sulfate, which suggests

that through TLR signaling,

the bacterial flora

may help protect the gut

epithelium from nonspecific

damage. Nonpathogenic

microorganisms in

the gut have also been

shown to regulate inflammation


in other ways (
17, 18).

For example, avirulent

Salmonella inhibits activation

of NF-
kB in

epithelial cells by blocking


of phosphorylated I


Overall, there is good

evidence that the normal

commensal flora exerts

an anti-inflammatory influence and protects

epithelial cells fromtoxic insult. Epithelial proinflammatory

responses to the commensal

flora exist in vitro (
19, 20), but most individuals

maintain an abundant intestinal flora

without incurring disease.

Interactions of commensals with the mucosal

immune system.
Healthy individuals possess

an abundant and highly active gut immune

system that is tightly regulated to prevent excessive

immune responses to foods and gut

bacteria (Fig. 1) (
21, 22). A major difference

between the systemic and mucosal immune

system is the anatomical separation of the

inductive sites of mucosal immunity in the

organized lymphoid tissue, such as PP, from

the effector sites in the lamina propria (LP)

and epithelium (Fig. 1) (

When T and B cells are activated in

PP, they express the
a4b7 integrin and migrate

to the blood (
23). Gut-specific homing

is achieved by expression of the ligand for

4b7, MADCAM-1, on gut endothelial cells,

which allows PP-derived cells to migrate

through blood vessels into the LP (
23). Chemokines

produced by either colon or small

bowel epithelial cells fine-tune the localization

of lymphocytes to these tissues (

The LP is filled with antibody-producing

plasma cells that secrete between 3 and 5 g of

the IgA immunoglobulin isotype into the

gut lumen each day (
22). Numerous other

immune cells also reside in the gut LP, including

large numbers of CD4
þ T cells (24),

macrophages, DC, mast cells, and eosinophils

21). The gut epithelium also contains abundant

intraepithelial lymphocytes (IEL) (

an intriguing population made up mostly of

þ T cells. Compared with other tissues,

IEL are enriched in T cells expressing the
gd T

cell receptor and often express the homodimeric

form of the CD8
a coreceptor (26). The exact

function of IEL is not known, although it has

been suggested that they may play a role in

epithelial tumor surveillance, protection against

epithelial pathogens, or promotion of healing of

the gut after injury (
25, 26).

The presence of an extensive and activated

intestinal immune system depends on

the commensal flora. Thus, mice bred under

germ-free conditions possess small, underdeveloped

PP lacking germinal centers, few

IgA plasma cells and CD4 cells in the LP,

and reduced numbers of IEL. Furthermore,

reconstitution of germ-free mice with a microbial

flora is sufficient to restore the mucosal

immune system (
27, 28).

The Commensal Flora as the Antigenic

Stimulus for Gut Inflammation

The relationship between the immune system

and the commensal flora is a precarious one,

and perturbations in immune or epithelial homeostasis

can lead to gut inflammation. In

this situation, the commensal flora appears to

act as a surrogate bacterial pathogen, and it is

thought that lifelong

inflammation ensues

because the host response

is incapable of

eliminating the flora.

Chronic inflammatory

bowel disease in

Two main

types of IBD exist:

Crohn’s disease and

ulcerative colitis (UC)

29) (Table 1). Patients

suffer from chronic

diarrhea and weight

loss, abdominal pain,

fever, and fatigue.

Extra-intestinal manifestations

can also

occur, including skin

ulcers, arthritis, and

bile-duct inflammation,

the last especially

in UC. Both UC and

Crohn’s disease are

characterized by mucosal

ulceration, which

is patchy in Crohn’s

disease but continuous

in UC (Fig. 2).

In Crohn’s disease,

ulcers penetrate into

the gut wall, and fistulous

tracts may develop between loops of

bowel or to the skin. The downstream effector

pathways that drive tissue injury are

similar to those in immune-mediated diseases

in other organs. Thus, excess immune activation

leads to an influx of inflammatory cells

from the blood and to increased concentrations

of cytokines, free radicals, and lipid

mediators (
30). There is also massive overexpression

of matrix-degrading enzymes, the

matrix metalloproteinases, by fibroblasts, which

are ultimately responsible for ulceration and

fistulae (

Crohn’s disease bears the immunological

stigmata of an exaggerated CD4 T helper

cell type I response. Thus, intestinal CD4 T

Fig. 1.
The gut makes a huge investment in maintaining an extensive and highly active immune

system. The epithelium overlying organized gut-associated lymphoid tissue (GALT) contains

specialized M cells that constantly transport gut bacteria and antigens from the gut lumen into

the lymphoid tissue. DC in the LP reach through epithelial cells and also sample gut bacteria. The

epithelium is filled with CD8
þ T cells, and the LP contains many CD4 T cells, macrophages, and

IgA antibody–producing plasma cells. Potentially tissue-damaging T cell responses may be

inhibited by immunosuppressive cytokines and regulatory T cells.


PECIAL S ECTION Downloaded from on May 18, 2009

cells isolated from Crohn’s patients produce

large amounts of the Th1 signature cytokine

g (31) and display marked overexpression

of the Th1 cell–specific transcription

factor, T-bet (
32). Mucosal macrophages from

Crohn’s patients also produce large amounts

of the Th1-inducing cytokines IL-12 (
33) and

IL-18 (
34). Th1 cell resistance to apoptosis

and increased cell cycling in Crohn’s disease

inflammation appear to be sustained by cytokines

35, 36). Blocking the pathways that confer

resistance of Th1 cells to apoptotic stimuli

and the use of drugs that enhance mucosal T

cell death, such as the immunosuppressive

agent azathioprine or the antibody to TNF

Infliximab, are effective in down-modulating

intestinal inflammation (

Identifying the particular antigen(s) that

drive the Th1 inflammatory response in the

face of the myriad of potential antigens in the

gut has proven difficult. Nevertheless, the likelihood

is that bacterial antigens are involved,

because stimulation of mucosal CD4 cells from

Crohn’s disease patients with extracts of their

own commensal flora can induce interferon-

production (
40), and in murine colitis, flagellin

from commensal bacteria also activates mesenteric

lymph node CD4 cells (
41). Clinical

observations also support a role for antigens

derived from the commensal flora. Thus, for

example, the antibiotic metronidazole is of

therapeutic benefit in Crohn’s disease of the

distal colon (

Gut inflammation induced by the commensal

flora: Evidence from animal models.

more than 30 models of IBD in rodents fall into

four major groups: colitis that develops spontaneously,

chemically induced colitis, colitis that

develops from defects in epithelial barrier function,

and colitis in mice in which the immune

system has been genetically manipulated or regulatory

cell function has been disrupted (

In a number of these models, the absence

of commensal bacteria under germ-free conditions

leads to an absence of or reduction in

disease (
44). Consistent with evidence from

human IBD, there is evidence in some models

that CD4 T cell lines reactive to enteric

bacterial antigens can cause colitis (
45), although

no individual component of the flora

has been yet identified as being specifically

important. Nevertheless, in some models,

particular bacteria species have been shown

to cause disease (
45). For example, in human

leukocyte antigen–B27 (HLA-B27) transgenic

rats, monoassociation with

induces colitis, while Escherichia

elicit no lesions. In IL-10–deficient mice,

B. vulgatus does not induce colitis,

E. coli can induce disease (45).

These models have been enormously important

in demonstrating that immune responses

to the flora can cause IBD, as well as the

numerous pathways that can lead to chronic

gut inflammation (

Crohn’s disease susceptibility genes and

their relation to innate immunity and intestinal

Crohn’s disease and UC

represent complex genetic diseases but also

tend to run in families. Genome-wide mapping

has identified Crohn’s disease susceptibility

loci on chromosomes 1, 5, 6, 12, 14, 16, and

19 (
46). In 2001, two groups mapped the locus

on chromosome 16 to Nod2 (
47, 48). Three

major polymorphisms have been specifically

associated with
È15% of Crohn’s disease

cases (Arg702Trp, Gly908Arg, and Leu1007fsinsC),

and all are in, or around, the LRR

region of the protein required for recognition

of bacterial muramyl dipeptide (MDP). Individuals

who carry two copies of the risk alleles

have a 20- to 40-fold increase in their

risk of developing Crohn’s disease. About 8

to 17% of Crohn’s patients carry two copies

of the major risk-associated alleles, compared

with 1% of the general population. Interestingly,

Nod2 has not been found to be associated

with Crohn’s disease in Japan (

again highlighting the complex nature of this


Nod2 is expressed in the cytosol of gut

epithelial cells, macrophages, and DC (
8). After

ligand binding, Nod2 oligomerizes and

recruits RICK/RIP, which leads to phosphorylation

and degradation of I
kB and activation

of NF-
kB (50). A consequence of mutations

in Nod2 may therefore be a decreased ability

to kill gut bacteria (
51). Consistent with this,

monocytes from patients with common Crohn’s

disease mutations show defective activation

of NF-
kB and IL-8 secretion when stimulated

with MDP (

Interestingly, Nod2-deficient mice do not

develop spontaneous gut inflammation (
53, 54),

and their macrophages show normal NF-

activation and pro-inflammatory cytokine

production to ligands for TLR3, 4, and 9.

However, they secrete large amounts of IL-12

in response to TLR2 ligands (
55). Concomitant

activation through Nod2 inhibits TLR2 induction

of IL-12 in cells from wild-type mice but

has no effect in Nod2-deficient mice, suggesting

that enhanced IL-12 production in Crohn’s

disease may be due to a failure of Nod2 to

negatively regulate TLR2 signaling, which

then facilitates a Th1 response through IL-12.

It is not known whether Nod2-mediated negative

regulation of TLR2 signaling occurs in

Crohn’s patients bearing the common mutations.

In other studies, macrophages from mice

engineered to express the
3020insC Nod2 mutation

show increased activation of NF-
kB and

increased IL-1
b and IL-6 production when activated

with MDP, which suggests that Nod2 mutations

may, in some situations, lead to a gain

of function and increased pro-inflammatory

cytokine production (

Nod2-deficient mice are also unusually

susceptible to intestinal infection with the

Listeria monocytogenes (54) and

have been found to be deficient in cryptdin

4 and 10, bacteriacidal defensins produced

by Paneth cells found in small intestinal crypts

57). In the human gut, Nod2 is highly expressed

in Paneth cells (
58), and reduced

defensin expression has been reported in

Crohn’s patients with Nod2 mutations (

Nod2 mutations may thus also predispose to

Crohn’s disease indirectly by reducing defensinmediated

innate antimicrobial immunity.

Two other genes associated with Crohn’s

disease have been identified. The first of these,

located on 5q31, encodes the organic cation

transporter (OCTN) genes, and mutations at

these loci affect the ability of the

transporters to pump xenobotics

and amino acids across cell membranes

60). In the gut, these genes

are expressed in epithelial cells,

macrophages, and T cells, correlating

closely with their potential

function in IBD. The second gene

is located on 10q23 and encodes

the guanylate kinase DLG5 (

The mutation in this gene involves

a single amino acid substitution

that is thought to impair the ability

of DLG5 to maintain epithelial

polarity. Both genes may be important

in epithelial permeability,

and disruption of this function could


Fig. 2.
Histological appearance of (A) normal colon, (B) Crohn’s disease, and (C) ulcerative colitis. The normal

colon contains glands filled with mucus-producing goblet cells. The image contains a small lymphoid follicle

with FAE on the left. In the low-power image of Crohn’s disease, the massive mucosal thickening and

distortion of the glands is evident, there is a massive lymphoid infiltrate, and an ulcer penetrates through the

mucosa from the lumen into the submucosa. In ulcerative colitis, the mucosa is also massively thickened and

filled with inflammatory cells. Numerous neutrophil-filled crypt abscesses are present.




Downloaded from on May 18, 2009

lead to inappropriate exposure of the mucosal

immune system to bacterial products.

Inflammatory Immune Responses to

Food Antigens

The other major antigenic challenge facing

the gut derives from ingested food antigens.

Under normal circumstances, oral administration

of protein antigens induces systemic

unresponsiveness when the same antigen is

given parenterally (a phenomenon known as

oral tolerance). In animal models, oral tolerance

appears to be a specific consequence of

the immune environment in the gut, which

favors the generation of T regulatory cells

62). In recent years, food allergy has become

increasingly common, and although there has

been little progress in understanding host mechanisms

involved at the molecular level, there

has been great progress in clinical management


Celiac disease.
In contrast to the lack of

progress in understanding food allergy, huge

progress has been made in understanding

celiac disease. This condition occurs in some

genetically susceptible individuals after the

ingestion of cereal products, including those

from wheat, barley, or rye, and the disease is

treated by adherence to a gluten-free diet

(Table 1). Many celiacs are undiagnosed (silent

celiacs); the disease may affect as many as

0.5 to 1% of the European and North American

population. Celiac disease shows classical

morphological changes to the mucosa

of the upper bowel, with long crypts and

partial or complete atrophy of villi.

Celiac disease involves four components:

gluten; T cells; the major histocompatability

complex locus HLA-DQ; and the endogenous

enzyme, tissue transglutaminase (tTG). The

past 10 years have seen a huge increase in our

understanding of the immunology of celiac

disease and how the interplay among these

four components produces enteropathy. The

original gluten-specific T cell clones isolated

from intestinal biopsies of celiac patients were

found to respond to a peptic/tryptic digest of

gluten restricted by HLA-DQ2 (
64). The peptide

anchor positions of HLA-DQ2 preferentially

bind negatively charged amino acids

65), yet gluten, which is very proline and

glutamine rich, has very few such residues. A

key observation in helping resolve this was

that tTG, which is expressed ubiquitously in

the gut, can deamidate glutamine to glutamic

acid, producing the negatively charged residues

necessary for efficient binding to DQ2

and for T cell activation (

In theory, the identification of the immunogenic

peptides in gluten would allow the

derivation of genetically modified cultivars

of wheat that would not cause disease. A

polypeptide of
a2 gliadin (residues 57 to 89)

appears to survive digestion in the gut (

Interestingly, this polypeptide contains three

concatemerized epitopes that are recognized

by T cells from celiac patients and can be

deamidated by tTG; removing this polypeptide

could, theoretically, make gluten much less

able to activate T cells. However, the in vivo

situation is complex because T cell clones

have been identified, especially from celiac

children, which recognize epitopes of high

molecular weight glutenins and diverse gliadin

epitopes (
68, 69). It may therefore not be

possible to remove all disease-inducing T cell

epitopes from wheat. An alternative approach

may be to modify gluten epitopes so that they

tolerize T cells (

A polypeptide of A-gliadin (residues 31 to

49) produces rapid villus atrophy when infused

into the gut of celiac patients (
71), but of

the many T cell lines and clones made against

gluten peptides, only a single T cell line clone

has been identified that recognizes peptide

31-49 (
72). However, if a similar peptide,

31-43, is added to ex vivo cultured biopsies

Table 1.
Inflammatory diseases of the intestine.

Crohn’s disease Ulcerative colitis Celiac disease

Presently 10–200/100,000 per year.

Increased 8 to 10-fold since 1960s.

10–20/100,000 per year. Incidence

stable since 1960s.

Around 0.5% of the European and

North American population.

A disease of westernized societies,

with the highest incidence in

northern Europe. Excess of cases

in urban compared with rural


UC is seen world-wide and appears

to show no relation with westernization

or affluence.

Restricted to regions of the world

where wheat, barley, and rye are a

major part of the diet.

Probably an excessive cell-mediated

immune response to antigens of

the normal bacterial flora.

Unknown, but perhaps an organspecific

autoimmune disease.

An excessive cell-mediated immune

response to the storage proteins

of wheat, barley, and rye (gluten)

in individuals with HLA-DQ2 or

HLA-DQ8 haplotypes.

Site of disease
Can affect any part of the gut from

mouth to anus, but most commonly

occurs in the ileum and

colon. The lesions are characteristically

patchy, with areas of

normal mucosa between ulcers

(skip lesions). Some extra-intestinal


UC first occurs in the rectum and, as

disease progresses, lesions become

more proximal. Inflammation

is continuous and is restricted

to colon.

Upper small intestine—the duodenum

and jejunum.

Inflammatory response
Inflammation consistsmainly of T cells

and macrophages. Granulomas are

seen in just over half the cases.

Inflammatory cells are present

throughout the gut wall, and deep

fissuring ulcers can lead to fistulae.

Fibrosis of the external muscle

layers frequently occurs.

Inflammation is restricted to the mucosa.

Neutrophils are the major

infiltrating inflammatory cells.

These form crypt abscesses and

damage the epithelium. There is

loss of mucus-secreting goblet


Inflammation restricted to the

mucosa. There is a marked mononuclear

infiltrate into the lamina

propria and an increase in the density

of intraepithelial lymphocytes,

which results in a transformation of

mucosal structure from a situation

of long villi and short crypts to the

flat mucosa, with short or absent


Other features
Smoking is a risk factor for Crohn’s


Smoking appears to protect against

the development of UC, as does


Celiac patients show an increased

prevalence of autoimmune diseases.

Corticosteroids, azathioprine, antibody

to TNF

Corticosteroids, azathioprine,


Gluten-free diet.


PECIAL S ECTION Downloaded from on May 18, 2009

from celiac patients, within hours there is a

rapid increase in HLA-DR mRNA, an increase

in the number of macrophages making IL-15,

and phosphorylation of p38 MAP kinase (

which suggests T cell–independent innate immune

activation by gluten.

A number of potential pathways exist to

explain the effector mechanisms that cause

the pathology in celiac disease (
74). One of

the primary pathways is thought to involve

the major histocompatibility complex class I

chain–related gene (MICA), which is a dominant

ligand for the NKG2D-activating receptor

on human NK cells and CD8 T cells. The

addition of peptide 31-49 to biopsies of treated

celiac disease patients increases MICA on epithelial

cells, which can be blocked by antibody

to IL-15 and recapitulated by recombinant

IL-15 (
75). NKG2D is expressed on the majority

of IEL, and MICA
þ epithelial cells have

been shown to be killed by NKG2D

75, 76). It is possible therefore that some

peptides of gliadin may activate gut macrophages

to produce IL-15, which then increases

MICA on epithelial cells and arms IEL to kill

þ epithelial cells. Celiac disease is also

marked by a significant increase in the numbers

gd cells, yet their possible role in this

condition is not established.

Control of Inflammation in the Gut

Recent years have seen the identification and

characterization of dedicated regulatory T

cells, in both mice and humans, that have the

ability to profoundly suppress a variety of

immune responses (
77, 78). These regulatory

T cells have been shown to be able to significantly

control gut inflammation in mouse

models of IBD (
79) and appear to mediate

their effects through the cytokines IL-10 and

transforming growth factor–
b1 (TGFb1) (79).

Other work has shown that such cells with

specificity for gut bacteria can also inhibit

colitis (
80). It is still not clear whether there

is active suppression of T cell responses to

the flora in normal mice, because systemic

injection of antigens cloned from commensal

flora results in a vigorous T cell response,

suggesting ignorance rather than specific immune

tolerance (

Compared with their characterization in

the mouse, relatively little is known about

regulatory T cells in the human gut (

However, the potential for regulatory T cells

to suppress IBD in humans through the

production of immunosuppressive TGF
b is

theoretically limited, because inflammatory

cells in IBD lesions express high levels of

Smad7, which prevents TGF
b signaling and

immune down-regulation (
83). Nevertheless,

the possible role of T regulatory cells in

controlling immune responses to bacterial

flora in both mice and humans is a question

that needs further investigation.

An understanding of how the gut remains

disease free in the face of constant immune

challenge may involve the separation of the

inductive sites in the PP from the effector

sites in the rest of the mucosa (Fig. 3) (

Because T cells in the PP may potentially respond

to all gut antigens, the problem of activated

cells accumulating in the PP is solved

by T cells leaving and migrating to the LP.

If the T cell has specificity for a pathogen

invading the mucosal tissues, antigen-driven

cell-mediated immunity in the LP would ensue.

However, if the T cell had responded to

an antigen from a commensal or a food antigen,

in a healthy individual, the epithelial

barrier would help prevent the antigen from

entering the LP. The few commensal organisms

that do cross the barrier will be phagocytosed

and killed by macrophages without

provoking pro-inflammatory cytokine production

84), and in the absence of reactivation

the T cells would die by apoptosis.

If this notion is correct, then situations in

which the normal flora either enters in increased

numbers or persists in the LP should

lead to T cell activation and Crohn’s-like

disease. To support this notion, children with

genetic defects that lead to impaired killing

of commensal bacteria by phagocytes can develop

a condition virtually indistinguishable

from Crohn’s disease (
85, 86). Furthermore,

some healthy relatives of Crohn’s patients

have increased intestinal permeability (

which suggests that genetically determined

epithelial permeability is an important contributing

factor in the development of disease.

Chimeric mice with patchy increases in

small intestinal epithelial permeability also

develop spontaneous transmural Crohn’s-like

inflammation (
88). Considered together, such

data suggest that a major determinant in the

initiation of mucosal inflammation is the ability

of antigen to enter into the LP and trigger

T cell activation.


In the evolutionary battle against infectious

disease, the immune system cannot afford to

err on the side of caution, because failure to

mount effective and vigorous immune responses

will be exploited by pathogens. This

is best exemplified by celiac disease, in which

the high prevalence of HLA-DQ2 in the general

population suggests an evolutionary advantage

of this allele against infection, even in

the face of the negative effects of the coincidental

affinity of gluten peptides for HLA-DQ2

to cause celiac disease.

With this in mind, it is probably unrealistic

to prevent chronic inflammatory diseases,

especially in the gut, so attention has

to be paid to new treatments based on understanding

disease at the molecular level. Great

advances have already been made, with the

best to date being the therapeutic antibody to

a, Infliximab, in Crohn’s disease. At the

same time, in the gut there is a silent partner

Fig. 3.
Increased epithelial permeability may be important in the development of chronic gut T

cell–mediated inflammation. CD4 T cells activated by gut antigens in Peyer’s patches migrate to

the LP. In healthy individuals, these cells die by apoptosis. Increased epithelial permeability may

allow sufficient antigen to enter the LP to trigger T cell activation, breaking tolerance mediated by

immunosuppressive cytokines and perhaps T regulatory cells. Pro-inflammatory cytokines then

further increase epithelial permeability, setting up a vicious cycle of chronic inflammation.




Downloaded from on May 18, 2009

whose influence on the host immune response

is only beginning to be appreciated, namely

the commensal flora. There are clear indications

that the flora is beneficial but also has

the potential to be harmful, and increasing

knowledge of how the flora interacts with the

immune system should allow exploitation of

the former and minimization of the latter.

References and Notes

1. S. Husby, J. C. Jensenius, S. E. Svehag,
Scand. J. Immunol.

, 83 (1985).

2. R. D. Berg,
Trends Microbiol. 3, 149 (1995).

3. M. R. Neutra, N. J. Mantis, J. P. Kraehenbuhl,

2, 1004 (2001).

4. M. Rescigno
et al., Nature Immunol. 2, 361 (2001).

5. J. H. Niess
et al., Science 307, 254 (2005).

6. D. J. Philpott, S. E. Girardin,
Mol. Immunol. 41, 1099


7. K. Takeda, S. Akira,
Semin. Immunol. 16, 3 (2004).

8. N. Inohara, G. Nunez,
Nature Rev. Immunol. 3, 371


9. J. M. Otte, E. Cario, D. K. Podolsky,

, 1054 (2004).

10. J. Viala
et al., Nature Immunol. 5, 1166 (2004).

11. A. T. Gewirtz, T. A. Navas, S. Lyons, P. J. Godowski, J. L.

J. Immunol. 167, 1882 (2001).

12. M. W. Hornef, B. H. Normark, A. Vandewalle, S. Normark,

J. Exp. Med.
198, 1225 (2003).

13. K. Madsen
et al., Gastroenterology 121, 580 (2001).

14. E. Cario, G. Gerken, D. K. Podolsky,

, 224 (2004).

15. K. Kojima
et al., Gastroenterology 124, 1395 (2003).

16. S. Rakoff-Nahoum, J. Paglino, F. Eslami-Varzaneh, S.

Edberg, R. Medzhitov,
Cell 118, 229 (2004).

17. A. S. Neish
et al., Science 289, 1560 (2000).

18. D. Kelly
et al., Nature Immunol. 5, 104 (2004).

19. D. Haller
et al., J. Biol. Chem. 278, 23851 (2003).

20. M. Akhtar, J. L. Watson, A. Nazli, D. M. McKay,

, 1319 (2003).

21. T. T. MacDonald,
Parasite Immunol. 25, 235 (2003).

22. P. Brandtzaeg, R. Pabst,
Trends Immunol. 25, 570 (2004).

23. D. J. Campbell, C. H. Kim, E. C. Butcher,
Immunol. Rev.

, 58 (2003).

24. T. T. MacDonald, G. Monteleone, in
Mucosal Immunology,

J. Mestecky, J. Bienenstock, M. Lamm, W. Strober,

J. McGhee, L. Mayer, Eds. (Elsevier, San Diego, CA, ed. 3,

2005), pp. 407–413.

25. A. Hayday, E. Theodoridis, E. Ramsburg, J. Shires,

2, 997 (2001).

26. H. Cheroutre,
Annu. Rev. Immunol. 22, 217 (2004).

27. H. L. Klaasen
et al., Infect. Immun. 61, 303 (1993).

28. Y. Umesaki, Y. Okada, S. Matsumoto, A. Imaoka, H.

Microbiol. Immunol. 39, 555 (1995).

29. D. Podolsky,
N. Engl. J. Med. 347, 417 (2002).

30. T. T. MacDonald, S. L. Pender, in
Kirsner’s Inflammatory

Bowel Disease
, R. B. Sartor, W. J. Sandborn, Eds. (Saunders,

London, 2004), pp. 163–178.

31. T. T. MacDonald, G. Monteleone,
Trends Immunol. 22,

244 (2001).

32. M. F. Neurath
et al., J. Exp. Med. 195, 1129 (2002).

33. G. Monteleone
et al., Gastroenterology 112, 1169 (1997).

34. G. Monteleone
et al., J. Immunol. 163, 143 (1999).

35. M. Boirivant
et al., Gastroenterology 116, 557 (1999).

36. A. Sturm
et al., Gut 53, 1624 (2004).

37. R. Atreya
et al., Nature Med. 6, 583 (2000).

38. I. Tiede
et al., J. Clin. Invest. 111, 1133 (2003).

39. J. M. Van den Brande
et al., Gastroenterology 124, 1774


40. R. Duchmann
et al., Clin. Exp. Immunol. 102, 448


41. M. J. Lodes
et al., J. Clin. Invest. 113, 1296 (2004).

42. P. Rutgeerts
et al., Gastroenterology 108, 1617 (1995).

43. G. Bouma, W. Strober,
Nature Rev. Immunol. 3, 521


44. R. B. Sartor, in
Kirsner’s Inflammatory Bowel Disease,

R. B. Sartor, W. J. Sandborn, Eds. (Saunders, London,

2004), pp. 138–162.

45. Y. Cong
et al., J. Exp. Med. 187, 855 (1998).

46. G. E.Wild, J. D. Rioux,
Best Pract. Res. Clin. Gastroenterol.

, 541 (2004).

47. Y. Ogura
et al., Nature 411, 603 (2001).

48. J. P. Hugot
et al., Nature 411, 599 (2001).

49. N. Inoue
et al., Gastroenterology 123, 86 (2002).

50. Y. Ogura
et al., J. Biol. Chem. 276, 4812 (2001).

51. T. Hisamatsu
et al., Gastroenterology 124, 993 (2003).

52. J. Li
et al., Hum. Mol. Genet. 13, 1715 (2004).

53. A. L. Pauleau, P. J. Murray,
Mol. Cell. Biol. 23, 7531


54. K. S. Kobayashi
et al., Science 307, 731 (2005).

55. T. Watanabe, A. Kitani, P. J. Murray, W. Strober,

Nature Immunol.
5, 800 (2004).

56. S. Maeda
et al., Science 307, 734 (2005).

57. A. J. Ouellette,
Best Pract. Res. Clin. Gastroenterol.

, 405 (2004).

58. Y. Ogura
et al., Gut 52, 1591 (2003).

59. J. Wehkamp
et al., Gut 53, 1658 (2004).

60. V. D. Peltekova
et al., Nature Genet. 36, 471 (2004).

61. M. Stoll
et al., Nature Genet. 36, 476 (2004).

62. A. M. Mowat,
Nature Rev. Immunol. 3, 331 (2003).

63. H. A. Sampson,
J. Allergy Clin. Immunol. 113, 805 (2004).

64. K. E. Lundin
et al., J. Exp. Med. 178, 187 (1993).

65. Y. van de Wal, Y. M. Kooy, J. W. Drijfhout, R. Amons,

F. Koning,
Immunogenetics 44, 246 (1996).

66. O. Molberg
et al., Nature Med. 4, 713 (1998).

67. L. Shan
et al., Science 297, 2275 (2002).

68. W. Vader
et al., Gastroenterology 122, 1729 (2002).

69. O. Molberg
et al., Gastroenterology 125, 337 (2003).

70. C. Y. Kim, H. Quarsten, E. Bergseng, C. Khosla, L. M.

Proc. Natl. Acad. Sci. U.S.A. 101, 4175 (2004).

71. R. Sturgess
et al., Lancet 343, 758 (1994).

72. H. A. Gjertsen, K. E. Lundin, L. M. Sollid, J. A. Eriksen,

E. Thorsby,
Hum. Immunol. 39, 243 (1994).

73. T. T. MacDonald, M. Bajaj-Elliott, S. L. Pender,

Immunol. Today
20, 505 (1999).

74. L. Maiuri
et al., Lancet 362, 30 (2003).

75. S. Hue
et al., Immunity 21, 367 (2004).

76. B. Meresse
et al., Immunity 21, 357 (2004).

77. C. A. Piccirillo, E. M. Shevach,
Semin. Immunol. 16, 81


78. A. O’Garra, P. Vieira,
Nature Med. 10, 801 (2004).

79. K. J. Maloy, F. Powrie,
Nature Immunol. 2, 816 (2001).

80. Y. Cong, C. T. Weaver, A. Lazenby, C. O. Elson,

169, 6112 (2002).

81. C. O. Elson, personal communication.

82. S. Makita
et al., J. Immunol. 173, 3119 (2004).

83. G. Monteleone, F. Pallone, T. T. MacDonald,

25, 513 (2004).

84. L. E. Smythies
et al., J. Clin. Invest. 115, 66 (2005).

85. J. A. Winkelstein
et al., Medicine (Baltimore) 79, 155


86. D. Melis
et al., Acta Paediatr. 92, 1415 (2003).

87. R. J. Hilsden, J. B. Meddings, L. R. Sutherland,

, 1395 (1996).

88. M. L. Hermiston, J. I. Gordon,
Science 270, 1203 (1995).

89. The authors wish to thank L. Sollid for advice and

A. Bateman for assistance with the illustrations. T.T.M.

receives payment for consultancy to Danone UK Ltd.

and Oxagen Ltd.



S PECIAL S ECTION Downloaded from on May 18, 2009

No hay comentarios:

Publicar un comentario