Epithelial Surfaces and Barrier Defenses
The innate immune system protects portal-of-entry sites used by pathogens to cause infections, including the skin, conjunctiva, respiratory tract, gut, and urogenital tract (1
). Tissues at these portals are designed to protect against infection using various common mechanisms. These sites have a surface layer of epithelial cells interspersed with a few lymphoid or myeloid immune cells. The subepithelial tissue provides structure and contains blood vessels to provide entry into the epithelium for immune cells when needed, and lymphatic drainage to allow egress of APCs to the draining lymph node. Two interesting examples to consider are the skin and the intestine.
TABLE 45.1 CELLS OF THE IMMUNE SYSTEM
Common myeloid progenitor: Found in bone marrow; progenitor of all myeloid cells including monocyte lineage and granulocyte lineage cells
Monocyte: Found in blood, differentiates to macrophage on entering tissues
Macrophage: Phagocytic cell found in tissues involved in defense against microorganisms and in “sterile” inflammation initiated by tissue damage (e.g., wound or plaque in coronary artery)
Immature dendritic cell: Found in blood, differentiates to dendritic cell in tissues
Dendritic cell: Functions as an antigen-presenting cell; delivers antigen from the periphery to lymphocytes in draining lymph nodes
Neutrophil: Principal phagocytic cell in blood; enters tissue in response to inflammation to kill invading bacteria by phagocytosis (ingestion), oxidative metabolism, and secretion of antibacterial peptides
Eosinophil: Found in blood; enters tissue to mediate inflammation in response to parasitic infections and allergies, including asthma Basophil: Found in blood; enters tissue in response to parasitic infections
Mast cell: Found in tissues primarily at submucosal sites; responds to some antigens, including allergens, through immunoglobulin E molecules on mast cell surface; this activation causes a release of mediators that triggers local and systemic inflammation, including anaphylaxis
T cell: Normally found in blood and lymph nodes as well as in tissue at sites of inflammation; cell surface TCR recognizes peptide antigens; CD8+ “killer” T cells recognize and kill virus-infected host cells; CD4+ T-helper cells produce cytokines that stimulate development of CD8+ T cells and B cells and stimulate protective responses of some myeloid cells, including macrophages B cell: Normally found in blood and lymph nodes; cell surface BCR is a membrane-anchored immunoglobulin that recognizes foreign antigens: after antigenic stimulation, B cells develop into antibody-secreting plasma cells found in bone marrow and at submucosal surfaces
NK cell: Found in blood and tissues; does not have antigen-specific cell surface receptor; recognizes and kills virus-infected and other “stressed” or damaged cells through change in expression of cell surface receptors
NK T cell: Minor but diverse cell type that responds to nonpeptide “antigens” (typically lipid; presented by CD1 rather than MHC) through TCR of limited diversity; can be cytotoxic or regulatory
Megakaryocyte: Found in bone marrow; precursor to small, nonnucleated platelets that are found in blood and mediate blood clotting
Erythroid progenitor cells: Found in bone marrow; progenitors for red blood cells
BCR, B-cell receptor; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor.
The skin consists of two cellular layers, epidermis and dermis (11
). The epidermis consists of four layers of keratinocytes interspersed with melanocytes and Langerhans cells, a professional APC and the principal immune cell of the uninfected epidermis. Some commensal microorganisms adhere to the epithelial surface and are adapted to persist in this niche (12
). Pathogens, including strains of Staphylococcus aureus
, may penetrate the skin by using special virulence factors (e.g., enzymes to break down extracellular matrix) to cause deeper infections that, if the local immune response is not sufficient, may become systemic (1
). The dermis contains blood capillaries and lymphatic drainage as well as various immune cells, the number and type varying depending on the immunologic challenge. Not all such challenges come from microorganisms. Inflammation in the skin may be triggered by irritants (e.g., chemicals, ultraviolet [UV] light), to which a person may become sensitized (e.g., poison ivy, which elicits an adaptive immune response).
The mucosal epithelium of the intestine consists of a single layer of absorptive epithelial cells interspersed with other cells, including (a) goblet cells that secrete a protective layer of mucus, (b) M cells that collect particulate antigen from the lumen for delivery to mucosaassociated APC in underlying lymphoid aggregates, (c) interdigitating DCs (a type of APC) that send cytoplasmic arms between epithelial cells to sample antigen from the gut lumen directly (2
), and (d) Paneth cells in intestinal crypts that secrete antifungal α-defensins. The lamina propria underlying the gut epithelium contains abundant immune cells, particularly lymphocytes. Unlike in the dermis, many lymph nodes are present in the lamina propria (termed Peyer patches
). These lymphocytes are localized to the lamina propria. Several factors including peristalsis, the mucus barrier, the relatively rapid turnover of epithelial cells, and secreted factors (e.g., IgA, antimicrobial peptides) help protect this epithelial barrier from microorganisms (14
). IgA and IgM are transported across intestinal epithelial cells and into the gut lumen by the polymeric Ig receptor (pIgR). The extensive network of APCs in the lamina propria, in concert with regulatory T (Treg) cells in the lamina propria, help the body differentiate commensal organisms from pathogens (16
Other mucosal sites include the mouth, nasopharynx, trachea, esophagus, stomach, and urogenital tract. These sites have similar organizational features and functions (1
). The lungs present a unique challenge in that alveoli are gas exchange surfaces and, because of the limits of gas diffusion, cannot be organized into multicellular layers. The final line of defense in the lungs is formed by the alveolar macrophages, which engulf and clear tiny particles and microorganisms (e.g., Mycobacterium tuberculosis
Recognition of Pathogens by Innate Immune Cells
Epithelial cells are immune cells in that they can recognize and respond to pathogens (11
) and thus are an integral part of the response to infection. Recognition of microorganisms occurs by pattern recognition receptors that recognize signature pathogen-associated molecular patterns (PAMPs) found in macromolecules common to groups of microorganisms but not typically found in mammals. The Toll-like receptors (TLRs) are the best studied and recognize PAMPs from different classes of bacteria, yeast, and viruses (17
). For example, bacterial lipopolysaccharide (LPS) is recognized by TLR4, bacterial flagellin by TLR5, single-stranded RNA by TLR7, and repeated DNA sequences of the bases C and G (common in bacterial but not mammalian genomes) by TLR9. These same receptors are also used by APCs and macrophages.
Other receptors perform similar functions. For example, nucleotide-binding domain, leucine-rich repeat-containing (NLR) proteins also recognize PAMPs (18
). These receptors are part of a multiprotein complex in the cytoplasm termed an inflammasome
that results in cleavage of prointerleukin (pro-IL)-1β and pro-IL-18 to produce the active cytokines. This pathway can also be activated by nonmicrobial tissue irritants such as uric acid crystals, which accumulate in tissues of patients with gout, and the adjuvant alum, which is used in many human vaccines.
Binding of PAMPs to their cognate receptors activates cytoplasmic signal transduction pathways that initiate gene transcription in the nucleus. For example, the transcription of many proinflammatory cytokine and chemokines genes is regulated by the transcription factor nuclear factor-κB (NF-κB) (19
). Genes induced by NF-κB include tumor necrosis factor (TNF)-α, IL-6, cyclooxygenase-2, and 5-lipoxygenase. Keratinocytes in the skin express TLRs that are activated during infections causing production of chemokines that attract T cells (e.g., CCL20 and CXCL9, 10 and 11) and neutrophils (CXCL1 and 8) (11
) and cationic antimicrobial peptides (AMPs), such as cathelicidin and β-defensin (20
), that mediate killing of invading bacteria and thus protect epithelial surfaces from infection.
The innate immune response can also protect against viral infections. Virus replication in most cells induces transcription of interferon-α, (IFN-α) and IFN-γ following recognition of double-stranded RNA by TLR3 or other sensors such as retinoic acid-inducible gene (RIG)-1 (21
). These interferons bind to cell surface receptors on the same and adjacent cells and induce protective factors that degrade viral RNA or otherwise interfere with viral replication. IFN-α and IFN-γ also activate natural killer (NK) cells to kill target cells.
These initial responses to infection trigger a local inflammatory response involving cells already at the site and cells recruited to the site by soluble mediators (1
). Many tissues contain resident macrophages that also respond to infection by producing chemokines (CXCL8), cytokines (including IL-12, IL-1β, TNF-α, and IL-6), leukotrienes (including LTB4
), prostaglandins (including prostaglandin E2
]), and platelet-activating factor that mediate inflammation. The goal of this inflammation is to eliminate the pathogen or to minimize spread of the pathogen until adaptive immunity can produce a pathogenspecific response. The key events in inflammation include the following: (a) release of preformed mediators and rapid enzymatic production of mediators, followed by transcription and translation of chemokine and cytokine genes; (b) induction of cell adhesion molecules (e.g., intercellular adhesion molecule 1 [ICAM-1]) in the vascular endothelium in adjacent capillaries that slows the progress of leukocytes; (c) loosening of tight junctions between epithelial cells to allow egress of leukocytes along a chemokine gradient; (d) stimulation of blood clotting by activation of platelets to minimize “escape” of pathogens; (e) killing of microorganisms or infected cells by the leukocytes attracted to the site; and, (f) a recovery phase stimulates repair of damage caused by pathogens or the responding leukocytes.
Killing of bacteria by macrophages and neutrophils
Monocytes from the blood differentiate into macrophages following extravasation (22
). Macrophages ingest invading microorganisms into phagocytic vesicles, the phagosome, by using several cell surface receptors. The phagosome fuses with lysosomes containing antibacterial peptides and enzymes (e.g., lysozyme). Following fusion, a respiratory burst involving nicotinamide adenine dinucleotide phosphate (NADPH) oxidase acidifies the phagolysosome and injects reactive oxygen species, which kill ingested microorganisms. Neutrophils are the most common white blood cell but are not found in healthy tissue. Their numbers at sites of inflammation increase rapidly during bacterial infections. Neutrophils kill engulfed bacteria in a manner similar to macrophages. The life span of the neutrophil is short, and these cells typically die after one round of phagocytosis and granule discharge. Macrophages live longer, have more cellular transcription machinery, and can regenerate phagosomes. Macrophages play a prominent role in responses to intracellular pathogens such as viruses and M. tuberculosis
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