Intact epithelial surfaces form physical barriers between microbes in the external environment and host tissue (Fig. 1). 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. Furthermore, infection of the barrier epithelial cells themselves is a frequent initial event in the breakdown of barrier integrity and subsequent disseminated infections as well as other inflammatory disorders. We will summarize the main features of innate defense by epithelial barriers here and discuss epithelial barrier immunity in greater detail in Chapter 14.
Fig1. Epithelial barriers. Epithelia at the portals of entry of microbes provide physical barriers, produce antimicrobial peptides including defensins and cathelicidins, and harbor intraepithelial lymphocytes that are believed to kill microbes and infected cells.
The protective function of barrier epithelia is in large part physical. The epithelial cells form tight junctions with one another, blocking the passage of microbes between the cells. In the skin, the outer layer of keratin, which accumulates as keratinocytes on the surface die, serves to block microbial penetration into deeper layers of the epidermis, and cutaneous infections generally occur when there is a barrier breach. Mucus, a viscous secretion containing glycoproteins called mucins, is produced by respiratory, gastrointestinal, and urogenital epithelial cells and physically impairs microbial invasion. The function of these barriers is enhanced by cell surface ciliary action in the bronchial tree and by peristalsis in the gut, which facilitate elimination of microbes. Although these physical properties alone are very important in host defense, other epithelial defense mechanisms have evolved to complement the mechanical barrier.
Epithelial cells, as well as some leukocytes, produce peptides that have antimicrobial properties. Two structurally distinct families of antimicrobial peptides (sometimes called host defense peptides) are the defensins and the cathelicidins.
• Defensins are peptides, 29 to 34 amino acids long, that contain both cationic and hydrophobic regions and three intra chain disulfide bonds. Two families of human defensins, named α and β, are distinguished by the location of these bonds. Defensins are produced by epithelial cells of mucosal surfaces and by granule-containing leukocytes, including neutrophils, NK cells, and cytotoxic T lymphocytes (CTLs). The set of defensin molecules produced differs among different cell types. Paneth cells within the crypts of the small bowel are a major producer of α-defensins. Paneth cell defensins are sometimes called crypticidins; their function is to limit the amount of luminal microbes near the epithelial barrier. Defensins are also produced in the colon, in respiratory mucosal cells, and in the skin. Some defensins are con stitutively produced by some cell types, but their secretion may be enhanced by cytokines and microbial products. In other cells, defensins are produced only in response to cytokines and microbial products. The protective actions of the defensins include both direct toxicity to microbes, including bacteria, fungi, and enveloped viruses, and the activation of cells involved in the inflammatory response to microbes. Defensins kill microbes by a variety of mechanisms, many of which depend on their ability to insert into and disrupt functions of microbial membranes.
• Cathelicidin, produced by neutrophils and barrier epithelial cells in the skin, gastrointestinal tract, and respiratory tract, is synthesized as an 18-kD precursor protein that is secreted and then 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 bind and neutralize LPS, the toxic component of the outer wall of gram-negative bacteria that is recognized by TLR4. LL-37 also binds other negatively charged macromolecules, including DNA, and in DNA-bound form can activate plasmacytoid dendritic cells to secrete type I IFNs. LL-37 may also be an autoantigen in human autoimmune diseases such as psoriasis.
Barrier epithelia contain certain types of lymphocytes, including intraepithelial T lymphocytes, which 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 antigen receptors they express. Some intraepithelial T lymphocytes express the conventional αβ form of the T-cell receptor (TCR), which is present on most T cells in lymphoid tissues and in the circulation. Other T cells in epithelia express a form of antigen receptor called the γδ TCR that may recognize peptide and nonpeptide antigens. A characteristic of intraepithelial T cells is the limited diversity of their antigen receptors, compared with T cells in blood and lymphoid tissues of the adaptive immune system. These intraepithelial T lymphocytes are thought to recognize a small number of commonly encountered microbial structures, a typical feature of innate pattern recognition receptors we have described. It is also possible that these lymphocytes are activated not by antigen recognition but by cytokines and other molecules produced by epithelial cells in response to stress. Intraepithelial lymphocytes may function in host defense by secreting cytokines, activating phagocytes, and killing infected cells.
