Download Dysregulation of Intestinal Mucosal Immunity

Dysregulation of Intestinal Mucosal Immunity:
Implications in Inflammatory Bowel Disease
F. Stephen Laroux,1 Kevin P. Pavlick,1 Robert E. Wolf,2 and Matthew B. Grisham1
Departments of 1Molecular and Cellular Physiology and 2Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932
T
he intestinal mucosal immune system is an important location where decisions regarding host responses to enteric
antigens are made. For example, the mucosal immune compartment must be able to choose the appropriate effector function (e.g., tolerance vs. clearance) necessary to deal with each
encountered antigen whether it be innocuous or pathogenic
in nature. This decision-making process is a complex interplay
between several cell types present in the mucosa (e.g., T cells,
B cells, dendritic cells, etc.). Specific subsets of CD4+ T
lymphocytes play a major role in mediating and regulating
these effector functions in vivo and are called T helper (Th)
cells. On the basis of their patterns of cytokine production,
murine and human Th cells may be divided into several additional subsets termed Th1, Th2, Th0, Th3, Thp, and Tr1 cells
(16). Activated Th1 cells secrete interleukin (IL)-2, interferon
(IFN)-γ, and lymphotoxin-α, whereas Th2 cells produce IL-4,
IL-5, IL-6, IL-9, IL-10, and IL-13. Th0 cells synthesize and
release both Th1 and Th2 cytokines, whereas Th3 cells produce large amounts of transforming growth factor (TGF)-β.
Evidence is accumulating to suggest that both Th1 and Th2
cells are derived from a common IL-2-secreting precursor T
cell termed Thp. There is also good evidence demonstrating
that macrophage- or antigen-presenting cell (APC)-derived IL12 is crucial for inducing Th1 differentiation, whereas IL-4 is
required to promote the differentiation of Thp cells into Th2
cells (1). A number of different studies have shown that Th1
cells are involved in an immune-mediated inflammatory
response termed delayed-type hypersensitivity (DTH) or type
IV hypersensitivity. This type of cell-mediated immunity is the
primary defense against certain infectious agents such as intracellular bacteria, fungi, and protozoa. This protective immune
response involves not only activation of Th1 cells and the subsequent release of their cytokines but also involves Th1
cytokine-mediated activation of macrophages and other
phagocytic leukocytes to release additional proinflammatory
cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6,
IL-8, IL-12, and IL-18. On the other hand, a Th2-type response
is required for humoral immune responses (i.e., antibody production) and offers effective protection against extracellular
pathogens such as helminths.
A recent study by Groux and co-workers (5) has characterized a new subset of CD4+ T cells that differ substantially from
the classic Th1 and Th2 cells. These cells are generated by
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repetitive antigenic stimulation of mouse or human CD4+ T
cells in the presence of IL-10 and are termed T regulatory-1
(Tr1) cells (5). These Tr cells are immunosuppressive in different models of immune-mediated inflammation. Indeed, Tr1
cells are capable of attenuating established colitis (5). Whether
Tr1 cells act to inhibit the activation, recruitment, and/or effector functions of pathogenic leukocytes remains to be established.
As stated above, DTH is characterized by the production of
several T cell- and macrophage-derived proinflammatory
cytokines. Because many of these mediators may have devastating effects on surrounding tissue, DTH is tightly regulated to
ensure efficient destruction of invading pathogens while minimizing injury to the surrounding tissue. There are, however, situations in which this immune regulation fails and severe
inflammatory tissue injury may develop. This regulatory failure
is thought to precipitate the onset of inflammatory bowel disease (IBD). To fully appreciate the molecular and cellular
events that contribute to chronic gut inflammation, a brief
overview of the mechanisms involved in immune control of
intestinal inflammatory responses is provided.
Mounting an effective immune response against antigens
within the intestinal and/or colonic interstitium involves the
selective migration (i.e., homing) of naïve T cells from the
peripheral circulation into the Peyer’s patches or mesenteric
lymph nodes draining the gut. This selective and very efficient
extravasation process is accomplished by the specific interaction between T cell-associated L-selectin and its ligand (glycosylation-dependent cell adhesion molecule-1) located on specialized endothelial cells in lymphoid tissue called high
endothelial venules. In addition, naïve T cells may home
specifically to the gut mucosa via the interaction of T cell-associated α4β7-integrin and endothelial cell-associated mucosal
addressin cell adhesion molecule-1 (MAdCAM-1) (1). If the
naïve T cell encounters its specific antigen presented on the
surface of APCs in association with the major histocompatability complex class II (MHC II), the T cell will bind the MHC
II-antigen complex via its T cell receptor (TCR) complex and
become activated. Activated T cells proliferate, shed their Lselectin, and increase surface expression of additional adhesion molecules such as LFA-1 (CD11a/CD18), very late antigen
(VLA)-4 (α4β1-integrin), VLA-5, VLA-6, and CD44 (1). The progeny of these activated T cells may then differentiate into effec0886-1714/01 5.00 © 2001 Int. Union Physiol. Sci./Am.Physiol. Soc.
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The mucosal interstitia of the intestine and colon are continuously exposed to large amounts of
dietary and microbial antigens. Fortunately, the mucosal immune system has evolved efficient
mechanisms to distinguish potentially pathogenic from nonpathological antigens. There are,
however, situations in which this immune regulation fails, resulting in chronic gut inflammation.
tor (e.g., Th cells) or memory cells. Unlike effector cells, memory cells may exist for long periods of time (20 yr) in the
absence of antigen stimulation (1). These lymphocytes do not
produce effector molecules, such as cytokines, unless they
again encounter antigen. Following the initial activation of T
cells within the lymphoid tissue, effector or memory cells reenter the circulation via the efferent lymphatics and the thoracic
duct.
On return to the systemic circulation, activated T cells no
longer efficiently home to lymphoid tissue due to loss of surface L-selectin. Instead, these cells preferentially home to sites
of infection/inflammation where the offending antigen originally gained access to the tissue (i.e., the gut). This new pattern
of homing is mediated by the interaction of lymphocyte-associated VLA-4 (α4β1-integrin), LFA-1, and CD44 with venular
vascular cell adhesion molecule (VCAM)-1, intracellular adhesion molecule (ICAM)-1 and -2, and hyaluronate, respectively
(1). Thus effector and memory T cells possess very different
homing patterns from those of naïve cells. Once extravasated,
an effector or memory T cell may reencounter its specific antigen via the specific binding of its TCR to antigen bound by the
MHC II complex expressed on APCs such as dendritic cells,
macrophages, and possibly endothelial cells (Fig. 1). This second antigen-specific interaction activates lymphocytes to synthesize and release IFN-γ and IL-2. IL-2 promotes the clonal
expansion of T cells and enhances the function of Th cells and
B cells, whereas IFN-γ interacts with and activates APCs and
macrophages to produce IL-12 (1). IL-12 then feeds back onto
the T cells to further enhance production of IFN-γ and promote
the differentiation of these T cells to Th1 cells capable of producing even larger amounts of IFN-γ, IL-2, and lymphotoxin-α.
IFN-γ can then activate endothelial cells and enhance
endothelial cell adhesion molecule (ECAM) expression on the
postcapillary venule. In addition, IFN-γ-activated macrophages
produce large amounts of proinflammatory cytokines such as
TNF-α, IL-1, IL-6, IL-8, IL-12, and IL-18 as well as reactive
oxygen and nitrogen metabolites (e.g., superoxide, hydrogen
peroxide, nitric oxide). All of the above-mentioned mediators
are thought to be important in recruiting and activating phagocytic leukocytes such as polymorphonuclear neutrophils
(PMNs) and monocytes/macrophages for the efficient destruction of the invading pathogens. Failure to downregulate production of these proinflammatory cytokines leads to severe
inflammatory tissue injury (Fig. 1).
Regulation of intestinal immune responses
The potential for the mucosal immune system to produce
local tissue injury suggests that healthy individuals possess
mechanisms to limit the immune response and in some cases
completely suppress it. It is thought that this is accomplished
by additional subsets of CD4+ T cells such as Tr1 and possibly
Th3 cells (5). Tr1 cells have been suggested to suppress or limit
intestinal DTH-induced injury by direct antigen-driven suppression of Th1 cells via the synthesis and release of large
amounts of the regulatory cytokines IL-10 and TGF-β (Fig. 2).
IL-10 is a Th2-type cytokine with a spectrum of biological
activities. It is produced by several different cell types includNews Physiol. Sci. • Volume 16 • December 2001
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FIGURE 1. Intestinal immune response to enteric antigens. Effector CD4+ T cells produce T helper-1 (Th1)-type cytokines in response to processed and presented
antigen by antigen-presenting cells (APCs). These cytokines may affect the gut epithelium directly and/or activate a resident macrophage (Mφ) to release large
amounts of proinflammatory mediators: cytokines as well as reactive metabolites of oxygen (ROS) and nitric oxide (NO). The net result is the recruitment of additional leukocytes and subsequent tissue injury. TNF, tumor necrosis factor; IFN, interferon; IL, interleukin.
ing subsets of T cells, macrophages, and CD5+ B cells and
serves to inhibit both the differentiation of Thp to Th1 cells as
well as the synthesis of Th1 and/or macrophage-derived proinflammatory cytokines (12). In addition, IL-10 promotes the
maturation of TGF-β-producing Th3 cells in vitro and attenuates the formation of macrophage-derived reactive oxygen and
nitrogen metabolites (12). Finally, IL-10 has been shown to
inhibit surface expression of MHC II molecules and ICAM-1.
A second subset of CD4+ T cells that is thought to suppress
Th1-type immune responses are the Th3 cells. These cells have
been shown to produce large amounts of TGF-β and varying
amounts of other Th2-type cytokines such as IL-4 and IL-10.
TGF-β is a pleiotropic cytokine that has been shown to be
important in downregulating the excessive inflammation
observed in a variety of experimental mouse and human
immune-based diseases, including IBD (15, 17). Although the
biological activity of TGF-β is complex, in general it appears
to inhibit the generation of Th1 cells, IL-12 production, and
cell-mediated immunity in vivo (1, 17). Recent evidence suggests that both Tr1 and Th3 cells possess TCRs that are specific
for the same antigens recognized by the effector T cells they
regulate. These observations suggest that the presence of regulatory cells within the intestinal and/or colonic interstitium
provides a controlled immune response to luminal antigens,
thereby limiting inflammatory tissue injury and dysfunction
(Fig. 2). Not surprisingly, animals rendered deficient in certain
regulatory cytokines such as IL-10 or TGF-β lack the appropriate regulatory cell responses and subsequently develop
chronic gut inflammation (19).
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IBD: breakdown in the regulation of intestinal immune
responses
The IBDs (Crohn’s disease and ulcerative colitis) are chronic
inflammatory disorders of the intestinal tract characterized by
rectal bleeding, severe diarrhea, exudation, fever, abdominal
pain, and weight loss. Histopathological inspection of tissue
obtained from the involved segment of the small and/or large
bowel reveals vasodilation, venocongestion, edema, infiltration of large numbers of inflammatory cells, erosions, and
ulcerations (10). Despite several decades of extensive investigation, the etiology and specific pathogenetic mechanisms
responsible for IBD remain poorly defined. Recent experimental and clinical studies suggest that the initiation and pathogenesis of these diseases are multifactorial, involving interactions among genetic, environmental, and immune factors (3).
Regardless of how exactly these interactions ultimately promote chronic gut inflammation, it is becoming increasingly
apparent that the immune system plays a crucial role in disease
pathogenesis. Because the inflammation is localized primarily
to the intestinal tract in IBD, investigators have focused on the
intestinal lumen as the site for the antigenic trigger. Indeed, the
chronic relapsing nature of IBD, coupled with the fact that a
large percentage of patients with Crohn’s disease will experience recurrence of the disease following surgical resection of
the involved bowel segment, suggests that the antigen or antigens that initiate and perpetuate this disease are part of the normal gut flora. Although several different etiologic theories have
been proposed to account for this apparent immune activation,
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FIGURE 2. Immune regulation in the intestine. Specific subsets of CD4+ T cells, termed regulatory T cells (Tr1 and/or Th3), serve to limit the activation and inflammatory mediator production of resident APCs interacting with CD4+ effector T cells in response to luminal antigens. Through the secretion of regulatory cytokines
such as IL-10 and transforming growth factor (TGF)-β, Tr1 and/or Th3 cells also inhibit activation of tissue macrophages, thus providing a mechanism for distinguishing between innocuous and potentially pathogenic antigens crossing the intestinal epithelial barrier and determining the appropriate response.
Powrie and co-workers (13) have proposed that a dysregulation
of macrophage activation due to the absence of regulatory T
cells is a key event in the pathogenesis of chronic gut inflammation. Resident macrophages are long-lived phagocytic and
secretory cells found in the interstitium of a variety of different
tissues including the gut, liver, lung, skin, nervous system, and
lymphoid tissue. These tissue-associated leukocytes function as
a first line of defense against a variety of infectious microorganisms and particulate matter. By virtue of their tissue distribution and their ability to produce or respond to local and circulating mediators, tissue macrophages occupy a central position in the inflammatory cascade. For example, activated
macrophages will release a plethora of proinflammatory mediators including cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-12, IL18), metalloproteinases (collagenase, gelatinase), arachidonate
metabolites (prostaglandins, leukotrienes), lipid mediators
(platelet-activating factor), and reactive oxygen and nitrogen
metabolites (superoxide, hydrogen peroxide, nitric oxide) (1)
(Fig. 1). Many of these macrophage-derived mediators activate
the venular endothelium to express ECAMs facilitating the
recruitment of additional inflammatory cells such as neutrophils and monocytes, which in turn contribute to the inflammatory cascade by releasing copious amounts of TNF-α, IL-8,
reactive oxygen and nitrogen species, and metalloproteinases
(Fig. 1). This type of dysregulated DTH would ultimately result
in a dramatic shift or imbalance in the cytokine production
profile within the intestinal interstitium such that a Th1
FIGURE 3. All segments of the microcirculation contribute to the pathophysiology of chronic gut inflammation. A variety of inflammatory mediators (e.g., histamine, bradykinin, NO, prostaglandins) produced by the affected tissue dilates arterioles, leading to increased blood flow (hyperemia) and hydrostatic pressure in
the downstream capillaries. The increased capillary hydrostatic pressure enhances the capillary filtration rate and contributes to the interstitial edema associated
with gut inflammation. Proinflammatory cytokines [TNF, IFN-γ, IL-12] released by activated mast cells, macrophages, and lymphocytes activate venular endothelial cells and increase expression of endothelial cell adhesion molecules that mediate leukocyte-endothelial cell adhesion and eventual emigration (tissue infiltration) of leukocytes. Leukocyte emigration contributes to vascular protein leakage (extravasation). Consequently, inflammation results in a diminished endothelial barrier function in venules that promotes the accumulation of albumin and other plasma proteins in the interstitium. The resultant increase in interstitial oncotic
pressure further promotes fluid filtration across capillaries and accelerates the development of interstitial edema (reproduced with permission from Ref. 11).
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data obtained from several experimental studies suggest that
the chronic gut inflammation may result from a dysregulated
immune response toward components of the normal gut flora.
One of the important conceptual advances in IBD research
has been the proposal that failure to regulate normally protective cell-mediated immune responses in the intestinal and/or
colonic mucosa results in sustained activation of the mucosal
immune system and the uncontrolled overproduction of proinflammatory cytokines and mediators (Fig. 1). This hypothesis
has arisen from data obtained from several different studies
using genetically engineered or immune-manipulated rodent
models of IBD. These different models of chronic gut inflammation appear to stratify into three different groups. The first
group consists of mice with alterations in T cell subsets and T
cell selection, including the TCR-α chain- or TCR-β chain-deficient mice, MHC II-deficient mice, SCID mice reconstituted
with CD4+CD45RBhigh T cells, human CD3ε transgenic mice
reconstituted with T cell-depleted F1 bone marrow cells, and
HLA-B27 transgenic rats. The second group involves mice that
develop spontaneous and chronic colitis as a result of targeted
gene deletion of IL-2, IL-10, or TGF-β. Finally, genetically engineered mice deficient in certain cellular signaling proteins,
such as Gαi2, develop spontaneous and chronic colitis (19). It
has been suggested that most, if not all, of the genetically engineered or immune-manipulated mouse models of IBD develop
chronic colitis due to a lack of appropriate downregulation of
normal DTH responses toward luminal antigens. Furthermore,
response would predominate. Indeed, this is exactly what is
observed in IBD (18).
Intestinal microcirculation: target of the inflammatory
response
One of the major functions of cell-mediated immunity (i.e.,
DTH) is to enhance recruitment, phagocytic function, and
microbicidal activity of phagocytic leukocytes (PMNs, monocytes, macrophages) via the production of Th1 and
macrophage-derived cytokines (Fig. 1) (reviewed in Ref. 11).
A consequence of unregulated proinflammatory cytokine production is the sustained activation of the microvascular
endothelium and the recruitment of large numbers of potentially injurious leukocytes into the intestine and/or colon.
Proinflammatory cytokines and mediators released by activated mast cells, macrophages, PMNs, and lymphocytes activate venular endothelial cells and increase expression of
ECAMs that mediate leukocyte-endothelial cell adhesion and
the consequent emigration (infiltration) of leukocytes, a common feature in active episodes of IBD. Recently, we have
shown large and significant increases in a variety of different
ECAMs in different models of experimental and human IBD.
For example, we have shown (8, 9) that the onset of chronic
colitis is associated with large and significant increases in surface expression of E-selectin, ICAM-1, VCAM-1, and MAdCAM-1. A recent series of experimental and clinical studies
have demonstrated that infusion of an antisense oligonucleotide directed against ICAM-1 message produces clinical
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improvement in a mouse model of colitis as well as in steroidresistant Crohn’s disease patients (2, 20). Similarly, recent
studies using small-molecular-weight antagonists or
immunoneutralizing monoclonal antibodies to either α4β7integrin or MAdCAM-1 demonstrate that the α4β7integrin/MAdCAM-1 interaction plays an important role in the
pathophysiology of different experimental models of colitis (6,
14). These findings underscore the importance of adhesion
molecule expression in the progression of IBD and may represent potentially important therapeutic targets for the treatment of IBD.
Vascular endothelial cells normally serve as a barrier that
minimizes the movement of fluid and proteins from the blood
to the interstitium. However, the uncontrolled inflammatory
response associated with IBD produces dramatic alterations in
gut microvascular function that contribute greatly to the pathophysiology observed in both experimental and human IBD
(Fig. 3). For example, many of the inflammatory mediators
(e.g., prostaglandins, nitric oxide, bradykinin) produced during
this unrestrained inflammatory response will increase blood
flow (hyperemia), thereby producing the characteristic erythema observed in patients with IBD. Indeed, Hulten and coworkers (7) demonstrated that blood flow to the colon of
patients with IBD increases two- to sixfold. A consequence of
this enhanced arteriolar blood flow is increased hydrostatic
pressure in the downstream capillaries, resulting in increased
fluid movement across intestinal capillaries and subsequent
interstitial edema (Fig. 3). Similarly, the fluid filtration that
results from such a large increase in capillary pressure would
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FIGURE 4. Transendothelial and transepithelial leukocyte migration in response to dysregulation of the mucosal immune system. Leukocytes migrate toward the
bacterial gradient present in the gut lumen, leading to the formation of crypt abscesses in both experimental and clinical inflammatory bowel disease (IBD). A key
component of this directed migration is the interaction between endothelial cell adhesion molecules and their respective leukocyte-expressed ligands (see inset).
P-Sel, P-selectin; ICAM, intracellular adhesion molecule; VCAM, vascular cell adhesion molecule; PSGL, P-selectin glycoprotein ligand; LFA, lymphocyte function-associated antigen; VLA, very late antigen.
Conclusion
A major conceptual advancement that has been made in
recent years in our understanding of the etiology of idiopathic
IBD has been that the failure to regulate the normally protective mucosal immune response toward enteric bacteria results
in the uncontrolled overproduction of proinflammatory mediators. Many of these mediators affect gut function by virtue of
their effects on the microcirculation, resulting in a chronic
inflammatory response. Mechanisms to limit proinflammatory
cytokine and mediator expression as well as ways to block
their effects on the microvasculature may prove useful in the
treatment of IBD.
Some of this work was supported by grants from the National Institute of
Diabetes and Digestive and Kidney Diseases (DK-47663), the Crohn’s and
Colitis Foundation of America, the Feist Foundation, and the Arthritis Center
of Excellence of Louisiana State University Health Sciences Center.
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lead to disruption of the mucosal barrier and exudation of
interstitial fluid into the lumen (4). Accumulation of plasma
proteins within the mucosal interstitium results in an increase
in interstitial oncotic pressure, which in turn alters the balance
of forces governing capillary fluid exchange to favor enhanced
filtration. Therefore, the combined effects of increased vascular
pressures, resulting from arteriolar dilation, and an increased
hydraulic conductance, which reflects the endothelial barrier
dysfunction, leads to a profound enhancement of vascular
fluid filtration in the inflamed bowel.
Since leukocyte infiltration is a hallmark histopathological
feature of IBD, these cells may also contribute to the increased
vascular permeability. There is increasing evidence to suggest
that adhesion and emigration of leukocytes from inflamed
postcapillary venules results in an increased plasma protein
extravasation at the sites of leukocyte transendothelial migration (4). The resultant increase in interstitial oncotic pressure
further promotes fluid filtration across capillaries and accelerates the development of interstitial edema (Fig. 3). Whether this
relationship between vascular permeability and leukocyte trafficking represents physical disruption of endothelial junctions
by transmigrating leukocytes or results from the production of
reactive oxygen metabolites and/or proteases from activated,
adherent leukocytes remains to be determined (4).
The formation of crypt abscesses represents the terminal step
in PMN migration out of the circulation (Fig. 4). For PMNs to
be present within the lumen of the bowel, these inflammatory
cells must extravasate from the circulation and move through
the interstitial matrix as well as interact with the basement
membrane and basolateral aspect of the crypt epithelium
before emigration into the lumen. The driving force for this
directed migration out of the tissue into the lumen is provided
by the bacterial gradient present in the distal bowel.
Transendothelial as well as transepithelial migration of PMNs
and other leukocytes may account for some of the fluid accumulation (edema) and enhanced mucosal (i.e., epithelial) permeability observed in patients with active IBD.