Epithelial Barriers

Intact epithelial surfaces form physical barriers between microbes in the external environment and host tissue, and epithelial cells produce antimicrobial chemicals that further impede the entry of microbes (Fig. 4-5). The main interfaces between the environment and the mammalian host are the skin and the mucosal surfaces of the gastrointestinal, respiratory, and genitourinary tracts. These interfaces are lined by continuous layers of specialized epithelial cells that serve many physiologic functions, including preventing the entry of microbes. Loss of the integrity of these epithelial layers by trauma or other reasons predisposes an individual to infections. The protective barrier function is in large part physical. The epithelial cells form tight junctions with one another, blocking passage of microbes between the cells. The outer layer of keratin, which accumulates as surface skin kera-tinocytes die, serves to block microbial penetration into deeper layers of the epidermis. Mucus, a viscous secretion containing glycoproteins called mucins, is produced by respiratory, gastrointestinal, and urogenital epithelial cells. Mucus physically impairs microbial invasion and

Physical barrier to infection

Killing of microbes by locally produced antibiotics, defensins, calthelicidins

Killing of microbes and infected cells by intraepithelial lymphocytes

FIGURE 4-5 Epithelial barriers. Epithelia at the portals of entry of microbes provide physical barriers, produce antimicrobial substances, and harbor intraepithelial lymphocytes that are believed to kill microbes and infected cells.

facilitates microbe removal by ciliary action in the bronchial tree and peristalsis in the gut. Although these physical barrier properties alone are very important in host defense, other epithelial defense mechanisms have evolved to complement the physical barrier.

Epithelial cells as well as some leukocytes produce pep-tides that have antimicrobial properties. Two structurally distinct families of antimicrobial peptides are the defen-sins and the cathelicidins.

• Defensins are small cationic peptides, 29 to 34 amino acids long, that contain three intrachain disulfide bonds. Two families of human defensins, named a and P, are distinguished by the location of these bonds. Defensins are produced by epithelial cells of mucosal surfaces and by granule-containing leukocytes, including neutrophils, natural killer cells, and cytotoxic T lymphocytes. The set of defensin molecules produced differs between different cell types. Paneth cells within the crypts of the small bowel are a major producer of a defensins. Paneth cell defensins are sometimes called crypticidins; their function is to limit the amount of microbes in the lumen. Defensins are also produced elsewhere in the bowel, in respiratory mucosal cells, and in the skin. Some defensins are constitutively produced by some cell types, but their secretion may be enhanced by cytokines or microbial products. In other cells, defensins are produced only in response to cyto-kines and microbial products. The protective actions of the defensins include both direct toxicity to microbes, including bacteria and fungi, and the activation of cells involved in the inflammatory response to microbes. The mechanisms of direct microbicidal effects are poorly understood.

• Cathelicidins are produced by neutrophils and various barrier epithelia, including skin, gastrointestinal tract, and respiratory tract. Cathelicidin is synthesized as an 18-kD two-domain precursor protein and is proteolytically cleaved into two peptides, each with protective functions. Both precursor synthesis and proteolytic cleavage may be stimulated by inflammatory cytokines and microbial products. The active cathelicidins protect against infections by multiple mechanisms, including direct toxicity to a broad range of microorganisms and the activation of various responses in leukocytes and other cell types that promote eradication of microbes. The C-terminal fragment, called LL-37, can also bind and neutralize LPS, a toxic component of the outer wall of gram-negative bacteria that has been mentioned previously.

Barrier epithelia contain certain types of lymphocytes, including intraepithelial T lymphocytes, that recognize and respond to commonly encountered microbes.

Intraepithelial T lymphocytes are present in the epidermis of the skin and in mucosal epithelia. Various subsets of intraepithelial lymphocytes are present in different proportions, depending on species and tissue location. These subsets are distinguished mainly by the type of T cell antigen receptors (TCRs) they express. Some intraepithelial T lymphocytes express the conventional aP form of TCR, which is present on most T cells in lymphoid tissues. Other T cells in epithelia express a form of antigen receptor called the y8 receptor that may recognize peptide and nonpeptide antigens. A common characteristic of these T cells is the limited diversity of their antigen receptors compared with most T cells in the adaptive immune system. The intraepithelial T lymphocytes are believed to recognize a limited number of commonly encountered microbial structures (e.g., PAMPs). Intraepithelial lymphocytes may function in host defense by secreting cyto-kines, activating phagocytes, and killing infected cells.

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