Page 304 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Host Defenses at Mucosal Surfaces

Prosper N. Boyaka, Kohtaro Fujihashi

Mammals have evolved a sophisticated network of cells and by goblet cells. This layer of glycoproteins interferes with the
molecules that serves to maintain homeostasis on exposed mucosal attachment of microorganisms to the mucosal surface. The
surfaces. This system is anatomically and functionally distinct replacement of damaged or infected enterocytes by crypt epithelial
from its bloodborne counterpart and is strategically located at cells, which differentiate into enterocytes as they migrate toward
the portals through which most pathogenic microorganisms the desquamation zone at the villus tip, ensures the integrity of
enter the body. This specific branch of the immune system may this barrier. Multilayered squamous epithelial cells cover other
have developed in response to the size of the mucosal surfaces, mucosal surfaces, including the oral cavity, pharynx, tonsils,
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which cover an area of ≈70 m in the airways and ≈400 m in urethra, and vagina. These epithelia lack tight junctions. Instead,
the gut of an adult human, and the large numbers of commensal mucus coats the intercellular space between the lower stratified
bacteria and exogenous antigens to which mucosa are exposed. 1,2 epithelial cell layers. Polymeric immunoglobulin A (pIgA) and
commensal microbes support the physical barrier function of
THE INNATE MUCOSAL DEFENSE SYSTEM mucosal tissues. Perturbation of the commensal microbiome,
which is present in the mucus ecosystem, facilitates opportunist
Cells and molecules that contribute to innate defense of the infections by pathogens, such as Clostridium difficile.
mucosa include the physical barrier provided by epithelial cells,
the movement of the epithelial cilia, the production of mucus Defensins and Other Mucosal Antimicrobial Peptides
by goblet cells, the secretion of molecules with innate antimi- Selected epithelial cell subsets contribute to innate responses
crobial activity, and the cytolytic activity of natural killer (NK) through the production of antimicrobial peptides, iron transport-
cells (Fig. 20.1A). Innate lymphoid cells (ILCs; Chapter 3) were ers, and enzymes. Defensins are 30–40 amino acid β-sheet peptides
identified recently as key players in innate mucosal immunity with antiviral activity and antimicrobial effects similar to those
(see Fig. 20.1B). In concert with the commensal microbiota of antibiotics. Defensins are structurally segregated into α and
(Chapter 14), these innate mechanisms provide a first line of β categories. α-Defensins are secreted by tracheal epithelial cells
defense against exogenous antigens and invading pathogens. and by Paneth cells in intestinal crypts. α-Defensins are homolo-
gous to peptide mediators of nonoxidative microbial cell killing
KEY CONCEPTS in neutrophils (termed human neutrophil peptides [HNPs]).
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Innate Defenses of the Mucosal Immune System Human β-defensin 1 (HBD-1) is expressed in the epithelial cells
of the oral mucosa, trachea, bronchi, mammary glands, and
The innate defenses of the mucosal immune system provide a first line salivary glands, whereas HBD-5 is expressed in the gut. Inflam-
of defense against exogenous antigens and invading pathogens. These matory cytokines (Chapter 9), including interleukin-1 (IL-1),
defenses include: IL-17, tumor necrosis factor-α (TNF-α) and bacterial lipopolysac-
• Physical barriers: the epithelium, the epithelial cilia, goblet cell mucus
production charide (LPS), regulate defensin production.
• Mucosal antimicrobial molecules: Paneth cell production of α defensins Other antimicrobial products of the epithelium include
in the small intestine; epithelial cell production of β defensins in the lactoferrin, lysozyme, peroxidases, secretory phospholipase A2
oral mucosa, trachea, bronchi, mammary glands, and salivary glands; (S-PLA2), and cathelin-associated peptides. Lactoferrin, a member
lactoferrin, lysozyme, lactoperoxidase, and secretory leukocyte protease of the transferrin family, is found in exocrine secretions. High
inhibitor (SLPI) concentrations of lysozyme (1209–1325 µg/mL) are found in
• Cellular innate immunity: mucosal natural killer (NK) cells, innate tears, saliva, colostrum, serum, and urine. Human milk contains
lymphoid cells (ILCs), dendritic cells (DCs). and polymorphonuclear
neutrophils (PMNs). lysozyme in concentrations ranging from 20 to 245 µg/mL,
depending on the lactation period. Milk leukocytes produce
Epithelial Cells and Other Effectors of the Mucosal myeloperoxidase (MPO), and mammary gland cells produce
human lactoperoxidase (hLPO). Both peroxidases display proper-
Physical Barrier ties similar to those of human salivary peroxidases (hSPO).
All mucosal surfaces are covered by epithelial cells, which S-PLA2 is released by Paneth cells. Secretory leukocyte protease
contribute to their selective barrier function. In the gastrointestinal inhibitor (SLPI) is found in human saliva, nasal secretions, tears,
(GI) tract, tightly joined enterocytes constitute the cellular cervical mucus, and seminal fluid. It is believed to be responsible
component of the physical barrier and are covered by a blanket for the anti–human immunodeficiency virus (HIV) properties
of mucus. Mucus consists of glycoproteins secreted into the lumen of external secretions.

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