Fw: Subject Reference: Fw: immunology--Epithelial Barriers and Defenses against I

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Subject: Subject Reference: Fw: immunology--Epithelial Barriers and Defenses

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From: " Myrl Jeffcoat " <myrlj@...>

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Sent: Wednesday, February 13, 2002 9:55 AM

Subject: immunology--Epithelial Barriers and Defenses against Infection

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Epithelial Barriers and Defenses against Infection

L DeFranco, M Locksley and Miranda on

from Chapter 8 of Immunity: The Immune Response to Infection

© 1999-2002 New Science Press Ltd

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8-3 Epithelia present both a physical and an antimicrobial barrier

Figure 8-1.1

Epithelial barriers

Epithelial cells establish barriers at the cutaneous and mucosal interfaces

between host and environment.

Stratified epithelial cells of the skin and oral cavity secrete

glycolipoproteins that maintain a permeability barrier; keratinization of

the outermost skin cells reinforces the cutaneous barrier. The simple

polarized epithelia of the intestine and airways are sealed by intercellular

tight junctions (Figure 8-1.1).

Epithelial cells of the eye, hair follicles, oral, intestinal, respiratory

and genitourinary surfaces are coated by a fluid matrix that physically

restricts access of organisms to the underlying epithelia. The fluid is

constantly replenished and removed by mechanical or ciliary processes that

impede the ability of bacteria to adhere. In addition to complex

glycosaminoglycans and mucins that bind bacterial outer membrane

constituents, the fluid matrix contains antibacterial peptides and proteins

that are constitutively secreted and further induced in response to

bacterial cell wall components, such as lipopolysaccharide.

Antimicrobial peptides, such as â-defensins in the lung and skin,

á-defensins in Paneth cells of the intestinal tract, and antimicrobial

proteins such as lysozyme and secretory leukocyte protease inhibitor (SLPI),

in fluids bathing the cornea of the eye, are toxic to diverse groups of

microbes. Antimicrobial peptides have optimal activities that reflect the

distinctive physiology of given sites, such as the acid pH of the stomach,

the alkaline pH of the vagina or the salinity of the respiratory tract.

Epithelial antimicrobial peptides are complemented by á-defensins, which

comprise the major constituent of neutrophil specific granules.

Cathelicidins, another group of antimicrobial defensins produced by

activated neutrophils and epithelial cells, reinforce the recruitment of

neutrophils and monocytes to inflammatory sites by cross-utilization of

FPRL1, the seven-transmembrane formyl peptide receptor-like 1

chemoattractant receptor.

Nonpathogenic commensals can cause infections when epithelial barriers are

disrupted, particularly in the setting of a further compromised immune

system, such a neutropenia.

Wounds, burns, intravenous access devices and insect vectors allow commensal

organisms on the skin to gain access to the tissues. Cytoablative cancer

chemotherapy or irradiation can also compromise epithelial integrity through

effects on cycling cells that maintain this dynamic barrier. Cystic fibrosis

compromises the volume and salinity of respiratory tract fluids, attenuating

the activity of antimicrobial peptides and leading to overgrowth of

colonizing bacteria and eventual destruction of lung tissue. Antacids, by

neutralizing stomach pH, can allow a normally noninfective bacterial

inoculum to reach the lower intestines and cause disease. Antibiotics, by

destroying susceptible nonpathogenic commensals, can allow the outgrowth of

organisms, such as Clostridium difficile in bowel, which secrete toxins that

mediate disease.

8-4 Innate mechanisms maintain commensals at epithelial barriers

Figure 8-1.2

Table of representative genetic deficiencies causing abnormal responses to

commensal bacterial flora

Deficiencies in adaptive immunity, such as those consequent on the deletion

of RAG genes, do not affect the ability of animals to restrict commensal

organisms to epithelial barriers. In contrast, failure to maintain barriers

against normal microbial flora can be demonstrated in certain genetic

deficiencies associated with innate immunity (Figure 8-1.2). Animals with

these genetic deficiencies die early in life with multiple intestinal,

hepatic, cutaneous and lung microabscesses filled with commensal flora. The

phenotype of these animals contrasts with the chronic intestinal

inflammation that occurs later in life in mice deficient in various genes

that contribute to regulatory modulation of the adaptive immune response to

proinflammatory molecules induced by bacteria within the bowel.

Mice which develop chronic intestinal inflammation provide instructive

models for human inflammatory bowel diseases such as Crohn's disease and

ulcerative colitis.

8-5 Specialized cell types in epithelia initiate and execute adaptive

immune responses

Antigen sampling from epithelia occurs by the close association of an

interdigitating dendritic

cell network in the stratified epithelia of the skin or within the simple

columnar epithelia of the terminal bronchioles of the lung, or through

specialized lymphoid organs that associate with

distinct tissues, such as the tonsils or intestinal MALT. M cells comprise a

unique population of cells in intestinal and respiratory epithelia that

promote the transport of lumenal antigens to ablumenal dendritic cells and

macrophages (see Figure 8-1.1). In each case, however, dendritic cells

represent the sentinel network that escorts bacterially-derived antigens to

the adaptive immune system in the draining of specialized lymphoid organs.

Epithelial â-defensins promote chemotaxis of immature dendritic cells and

memory T cells by cross-utilization of CCR6, the receptor for CCL20

(MIP-3á/LARC), thus serving to link innate with adaptive immunity.

The mechanisms that maintain the integrity of the epithelial barriers are

not known for certain, but T cells are believed to play a part. Their

localization to epithelial basement membranes in both mouse and man is

suggestive, and some loss of intestinal epithelial integrity can be

demonstrated in T cell-deficient mice. Gene expression profiling of

intraepithelial lymphocytes, or IELs, reveals a constitutively active array

of immune defense genes, including cryptdin and granzymes A and B, as well

as transcripts for inhibitory receptors, including CTLA-4, PD-1 and various

NK inhibitory receptors. In humans, intestinal T cells express NKG2D and are

activated by the stress-induced nonpolymorphic MHC class I molecules, MIC-A

and MIC-B.

IgA is the most prevalent immunoglobulin in mucosal secretions and is

believed to contribute to epithelial defense by binding to antigens,

including bacteria and toxins, thus preventing their uptake. Epithelial

cells in the intestine and hepatocytes of the liver mediate transfer of

dimeric serum IgA to the intestinal lumen via the polymeric Ig receptor.

After engagement at the basolateral surface by IgA, the polymeric Ig-IgA

complex undergoes transcytosis to the apical membrane by a process dependent

on the src kinase p62yes. Proteolytic cleavage of the ectodomain of the

polymeric Ig receptor, termed secretory component, releases the complex into

the lumen. Secretory component is believed to protect lumenal IgA from

degradation by bacterial proteases. Recent studies indicate that at least

some IgA can be produced in mice deficient in IgM or IgD, and can

participate in intestinal responses to commensal flora. IgA deficiency is a

common immunodeficiency in humans. Although some individuals suffer from

recurrent sinus, pulmonary and/or intestinal infections, the majority remain

asymptomatic, probably because IgM, which also binds the polymeric Ig

receptor, can compensate for IgA in certain cases, for reasons incompletely

understood.

After opsonization with IgA or IgM, organisms are endocytosed by FcR

expressed on mature B cells, macrophages and dendritic cells in mice and

humans. The FcR gene is located with other FcRs on mouse chromosome 1 and

the syntenic region on human chromosome 1q.32.3. Expression on APC suggests

a role for the receptor in antigen priming for appropriately opsonized

antigens. A second IgA receptor, FcRI (CD89), is an Ig superfamily member

expressed on human monocytes, neutrophils and eosinophils in association

with the adapter protein, FcRã. FcáRI is a low-affinity receptor for

complexed serum IgA, but cannot bind secretory IgA which has a blocked

receptor binding site. Activation of FcáRI on phagocytic cells triggers

phagocytosis, the respiratory burst and cytokine production. A murine

homolog for CD89 remains undiscovered.

Definitions

*commensals: the normal bacterial flora colonizing healthy skin and mucosal

surfaces.

*defensins: family of cationic antimicrobial peptides with 3-4

intramolecular cysteine disulfide bonds; found in mammals, insects and

plants.

*cathelicidins: family of cationic antimicrobial peptides generated in

pre-pro forms that require processing to generate the active peptide;

contain amino-terminal cathelin-like domain and carboxy-terminal

antimicrobial domain.

*FPRL1: formyl peptide receptor-like 1; chemotactic receptor on neutrophils

and monocytes mediating responses to bacterial formyl peptides.

*intraepithelial lymphocyte (IEL): lymphocytes positioned at the base of

polarized epithelial barriers exposed to the external environment; large

numbers occur in the intestine, iIEL, and are comprised of both

thymus-dependent and independent populations of áâ and ãä T cells.

polymeric Ig receptor: receptor mediating transcytosis of immunoglobulin A

across epithelial cells to mucosal surfaces.

References

AM Fahrer, et al: Attributes of ãä intraepithelial lymphocytes as suggested

by their transcriptional profile.

Proc Natl Acad Sci USA 2001, 98: 10261-10266 [Read the abstract on PubMed]

PS Frenette, et al: Susceptibility to infection and altered hematopoiesis in

mice deficient in both P- and E-selectins.

Cell 1996, 84: 563-574 [Read the abstract on PubMed]

LV Hooper, JI Gordon: Commensal host-bacterial relationships in the gut.

Science 2001, 292: 1115-1118 [Read the abstract on PubMed]

AJ Macpherson, et al: A primitive T cell-independent mechanism of intestinal

mucosal IgA responses to commensal bacteria.

Science 2000, 288: 2222-2226 [Read the abstract on PubMed]

I Mellman, RM Steinman: Dendritic cells: specialized and regulated antigen

processing machines.

Cell 2001, 106: 255-258 [Read the abstract on PubMed]

A Shibuya, et al: Fcá/ì receptor mediates endocytosis of IgM-coated

microbes.

Nature Immunol 2000, 1: 441-446 [Read the abstract on PubMed]

MU Shiloh, et al: Phenotype of mice and macrophages deficient in both

phagocyte oxidase and inducible nitric oxide synthase.

Immunity 1999, 10: 29-38 [Read the abstract on PubMed]

M van Egmond, et al: IgA and the IgA Fc receptor.

Trends Immunol 2001, 22: 205-211 [Read the abstract on PubMed]

CL , et al: Regulation of intestinal á-defensin activation by

metalloproteinase matrilysin in innate host defense.

Science 1999, 286: 113-117 [Read the abstract on PubMed]

D Yang, et al: â-defensins: linking innate and adaptive immunity through

dendritic and T cell CCR6.

Science 1999, 286: 525-528 [Read the abstract on PubMed]

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