B.
DIGESTIVE, ENDOCRINE, IMMUNE, AND NEURAL MECHANISMS
Nutrition and the Immune System1
45 CHARL ES B. STE P H E N S E N A N D S U S A N J . Z U N I N O
OVERVIEW OF THE IMMUNE SYSTEM . . . . . . . . . . . . . . 601
Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Innate and Adaptive Immunity . . . . . . . . . . . . . . . . 601
Passive Protection of Infants . . . . . . . . . . . . . . . . . 602
Organization of the Immune System . . . . . . . . . . . 602
INNATE IMMUNITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Epithelial Surfaces and Barrier Defenses . . . . . . . . 602
Recognition of Pathogens by Innate
Immune Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
Systemic Inflammation and the
Acute Phase Response . . . . . . . . . . . . . . . . . . . . . . 605
Antigen-Presenting Cell Functions:
Linking Innate to Adaptive Immunity . . . . . . . . . . . 605
ADAPTIVE IMMUNITY . . . . . . . . . . . . . . . . . . . . . . . . . . 605
T-Helper Lymphocytes. . . . . . . . . . . . . . . . . . . . . . . 606
Cytotoxic T Lymphocytes . . . . . . . . . . . . . . . . . . . . 606
Regulatory T Lymphocytes . . . . . . . . . . . . . . . . . . . 606
B Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Diversity of T- and B-Lymphocyte
Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
IMPACT OF NUTRITION ON IMMUNITY . . . . . . . . . . . . . 607
Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Vitamin B6, Vitamin B12, and Folate . . . . . . . . . . . . 608
Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Selenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Zinc. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
Copper and Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
Omega-3 and Omega-6 Fatty Acids . . . . . . . . . . . . 609
1
Abbreviations: 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-␬B, nuclear factor-␬B; 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.
MNHD11e_CH045.indd 601
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 para-
sites 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 nem-
atodes (Necator americanus and Ancylostoma duodenale),
and the liver fluke (Schistosoma mansoni). Most patho-
gens 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 com-
promised 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 sys-
tem 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 inte-
grated whole. The innate system is evolutionarily older,
601
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 602 PART I I ■ NUT RI T I ONAL ROL E S IN I N T E G R A T E D B I O LO G I C S Y S T E M S
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 spe-
cies. 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 adap-
tive 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 attenu-
ated 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 micro-
organisms (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 lympho-
cytes (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
MNHD11e_CH045.indd 602
are connected by the blood and lymphatic systems to allow
transmission of information from the innate to the adap-
tive 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 antigen-
presenting 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 lym-
phatic 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), macro-
phages, 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 eryth-
rocytes (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 lym-
phoid tissues and at sites of inflammation. These cells
communicate with one another through cell-to-cell con-
tact and soluble mediators to trigger changes in activity
(e.g., chemotaxis) and gene expression. Cytokines, includ-
ing 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 media-
tors 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 throm-
boxanes 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.
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 C H A P T E R 45 ■ N U T R I T I O N A N D T H E I M M UNE S YS TEM 603

TABLE 45.1 CELLS OF THE IMMUNE SYSTEM

MYELOID CELLS
Common myeloid progenitor: Found in bone marrow; progenitor of all myeloid cells including monocyte lineage and
granulocyte lineage cells
Monocyte lineage
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
Granulocyte lineage
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 immuno-
globulin E molecules on mast cell surface; this activation causes a release of mediators that triggers local and systemic
inflammation, including anaphylaxis

LYMPHOID CELLS
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

OTHER CELLS
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 kera-
tinocytes 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 microor-
ganisms. 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 par-
ticulate antigen from the lumen for delivery to mucosa-
associated APC in underlying lymphoid aggregates,
(c) interdigitating DCs (a type of APC) that send cyto-
plasmic arms between epithelial cells to sample antigen
from the gut lumen directly (2), and (d) Paneth cells in
intestinal crypts that secrete antifungal ␣-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 lympho-
cytes 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 epi-
thelial 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 pro-
pria, help the body differentiate commensal organisms
from pathogens (16).

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 604 PART I I ■ NUT RI T I ONAL ROL E S IN I N T E G R A T E D B I O LO G I C S Y S T E M S
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 dif-
fusion, 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 microor-
ganisms occurs by pattern recognition receptors that rec-
ognize 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 lipopolysaccha-
ride (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 recep-
tors are part of a multiprotein complex in the cytoplasm
termed an inflammasome that results in cleavage of proin-
terleukin (pro-IL)-1␤ and pro-IL-18 to produce the active
cytokines. This pathway can also be activated by nonmicro-
bial tissue irritants such as uric acid crystals, which accu-
mulate 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-␬B
(NF-␬B) (19). Genes induced by NF-␬B include tumor
necrosis factor (TNF)-␣, 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 cathelici-
din and ␤-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-␣, (IFN-␣) and IFN-␥ fol-
lowing recognition of double-stranded RNA by TLR3
MNHD11e_CH045.indd 604
or other sensors such as retinoic acid–inducible gene
(RIG)-1 (21). These interferons bind to cell surface recep-
tors on the same and adjacent cells and induce protective
factors that degrade viral RNA or otherwise interfere with
viral replication. IFN-␣ and IFN-␥ also activate natural
killer (NK) cells to kill target cells.
These initial responses to infection trigger a local inflam-
matory 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-1␤, TNF-␣, 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 pathogen-
specific 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 vascu-
lar endothelium in adjacent capillaries that slows the prog-
ress of leukocytes; (c) loosening of tight junctions between
epithelial cells to allow egress of leukocytes along a chemo-
kine 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 phos-
phate (NADPH) oxidase acidifies the phagolysosome and
injects reactive oxygen species, which kill ingested micro-
organisms. 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 infec-
tions. 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 phago-
somes. Macrophages play a prominent role in responses to
intracellular pathogens such as viruses and M. tuberculosis.
Opsonization and Complement-Mediated Killing
Some serum proteins (e.g., mannose-binding lectin
[MBL]) and C-reactive protein (CRP), and secretory
proteins such as surfactant proteins A and D produced
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