Nutrition and the Immune System1
Charles B. Stephensen
Susan J. Zunino
1Abbreviations: AA, arachidonic acid; APC, antigen-presenting cell; BCR, B-cell receptor; CRP, C-reactive protein; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DHA, docosahexaenoic acid; DTH, delayed-type hypersensitivity; EPA, eicosapentaenoic acid; HIV, human immunodeficiency virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LPS, lipopolysaccharide; LTB, leukotriene B; MBL, mannose-binding lectin; NF-κB, nuclear factor-κB; NK, natural killer; PAMP, pathogen-associated molecular pattern; PGE2, prostaglandin E2; PUFA, polyunsaturated fatty acid; TCR, T-cell receptor; TGF, transforming growth factor; Th cell, T-helper cell; TLR, Toll-like receptor, Treg cell, regulatory T cell; VDR, vitamin D receptor.
OVERVIEW OF THE IMMUNE SYSTEM
Functions
The principal function of the immune system is to protect the host from death and disability caused by infectious diseases (1). “Host,” in this context, refers to a human or other animal infected by a potentially disease-causing (i.e., pathogenic) organism. Pathogens may be viruses, bacteria, fungi (or yeast), protozoa, or multicellular parasites including nematodes and flukes. Disease usually occurs when such organisms are specifically adapted to infect humans—the so-called professional pathogens. The names of many of these pathogens are well known: the measles virus, the cholera bacterium (Vibrio cholerae), the yeast Candida albicans, the malaria protozoa (Plasmodium falciparum and others of this genus), the hookworm nematodes (Necator americanus and Ancylostoma duodenale), and the liver fluke (Schistosoma mansoni). Most pathogens have evolved methods of evading the innate immune response and must be cleared by adaptive immunity. Some pathogens evade adaptive immunity as well (e.g., malaria protozoa or the human immunodeficiency virus [HIV]). The world is also full of opportunistic pathogens that may cause disease when the immune system is compromised by malnutrition, other infections (e.g., HIV), or advancing age. In addition, commensal organisms colonize the skin, intestine, and urogenital tracts and are benign or beneficial to the host. However, these organisms may also be harmful under certain circumstances and thus are also subject to control, but not elimination, by the immune system (2).
The immune system can also be activated by sterile injury that causes tissue damage but does not involve microorganisms (3). In this case, the innate immune system may be activated to stop bleeding and resolve tissue damage. Such sterile inflammation is an important factor in the development of many chronic inflammatory diseases (e.g., coronary artery disease) (4), discussed elsewhere in this book.
Innate and Adaptive Immunity
The immune system has two components: innate and adaptive (5), although the two work together as an integrated whole. The innate system is evolutionarily older,
and it is fully functional at birth. Innate immune cells use a diverse group of receptors to recognize and respond to signature molecules from classes of microorganisms (e.g., flagella from some bacteria, cell wall carbohydrate from yeast, RNA from viral genomes). These responses are essentially the same for all individuals within a species. The adaptive system is different in that the host’s response adapts to a specific pathogen (e.g., measles virus specifically and not RNA viruses in general) to develop immunologic memory that will respond more quickly and more efficiently the next time the same pathogen is encountered. Thus, individuals have different levels of adaptive immunity depending on their exposure history. The adaptive nature of this response explains why the first encounter with a childhood pathogen (e.g., measles) can make a child quite ill, but subsequent infections will likely go unnoticed.
and it is fully functional at birth. Innate immune cells use a diverse group of receptors to recognize and respond to signature molecules from classes of microorganisms (e.g., flagella from some bacteria, cell wall carbohydrate from yeast, RNA from viral genomes). These responses are essentially the same for all individuals within a species. The adaptive system is different in that the host’s response adapts to a specific pathogen (e.g., measles virus specifically and not RNA viruses in general) to develop immunologic memory that will respond more quickly and more efficiently the next time the same pathogen is encountered. Thus, individuals have different levels of adaptive immunity depending on their exposure history. The adaptive nature of this response explains why the first encounter with a childhood pathogen (e.g., measles) can make a child quite ill, but subsequent infections will likely go unnoticed.
Passive Protection of Infants
Infants have a full complement of innate immune cells at birth, although these cells respond less vigorously to microorganisms than do the same cell types from adults (6). In contrast, infants have not yet developed adaptive immunologic memory. However, infants transiently acquire some components of adaptive immunity from their mothers. For example, serum immunoglobulin G (IgG) antibody is transferred across the placenta to give infants protection against infections such as measles for up to 9 months (7). In addition, breast-fed infants receive secretory IgA antibody and many antimicrobial factors from colostrum and breast milk (8). This maternally derived protection for infants is important because the infant’s adaptive immune system responds less robustly to pathogens than does the adult system (9, 10). This attenuated response may be beneficial because colonization of the gut and other epithelial surfaces with commensal microflora presents a major challenge to the developing immune system. Overresponding could be detrimental by causing tissue damage that could impede normal growth and development.
Organization of the Immune System
The immune system in humans and other mammals is made up of organs and tissues located strategically throughout the body to protect against invasion by microorganisms (1, 5). Primary organs, in which immune cells develop, include the bone marrow and thymus. All white blood cells (leukocytes) originate in the bone marrow (Table 45.1). One subset of lymphocytes, T lymphocytes, (also known as T cells) needs an additional maturation step in the thymus, however. In mammals, B lymphocytes (B cells) mature in the bone marrow, but in avian species, this step occurs in the bursa of Fabricius. The lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT) are secondary organs and tissues. These secondary sites are meeting places for immune cells that are connected by the blood and lymphatic systems to allow transmission of information from the innate to the adaptive immune system.
The lymph nodes are located regionally (e.g., along lymphatic vessels draining specific regions of the body), and this information transfer occurs when an antigenpresenting cell (APC), after an encounter with invading microorganisms, travels through lymphatic vessels from peripheral tissues (e.g., skin, respiratory mucosa, gut) to enter the closest draining lymph node (1, 5). Because lymphatic vessels drain all tissues of the body, this APC-based surveillance system can deliver information from any site of infection to a regional lymph node. APC is a functional definition, and antigen presentation can be made by several cell types, including dendritic cells (DCs), macrophages, and B cells.
The spleen, like the lymph nodes, provides a site for APCs to transfer information to lymphocytes. The spleen also filters the blood. In the case of a breach of peripheral defenses, bloodborne microorganisms or infected erythrocytes (e.g., in the case of malaria) are removed from the blood by the spleen.
Intercellular Communication in the Immune System
Cells of the immune system aggregate in secondary lymphoid tissues and at sites of inflammation. These cells communicate with one another through cell-to-cell contact and soluble mediators to trigger changes in activity (e.g., chemotaxis) and gene expression. Cytokines, including interleukins, and chemokines are protein mediators produced by immune and other cells that trigger various responses in cells bearing the appropriate receptors. One large family of chemokines has a standard Cys-Cys or C-C motif, whereas a second family has a C-X-C motif. These chemokines are known as CC and CXC chemokines, respectively. The eicosanoid family of lipid-based mediators is synthesized primarily from arachidonic acid and also from eicosapentaenoic acid (EPA). The eicosanoids include leukotrienes produced from the 5-lipoxygenase enzymatic pathway as well as prostaglandins and thromboxanes from the cyclooxygenase pathway (5).
INNATE IMMUNITY
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 | |||||||||||||||||||
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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, 13). 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, 15). 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.
Local Inflammation
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, 5). 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 and LTE4), prostaglandins (including prostaglandin E2 [PGE2]), 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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