Immunonutrition Interactions of Diet, Genetics, and
Inflammation, 1st Edition
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Contents
Preface.......................................................................................................................vii
Editors........................................................................................................................ix
Contributors...............................................................................................................xi
Chapter 1 Evolution of Innate and Adaptive Immunity.........................................1
David Heber and Bharat B. Aggarwal
Chapter 2 Cellular Mechanisms of Cytokine Activation..................................... 19
David Heber and Bharat B. Aggarwal
Chapter 3 Cellular Lipids and Inflammation....................................................... 39
David Heber and Susanne Henning
Chapter 4 Biomarkers of Inflammation and the Western Diet............................ 53
David Heber and Susanne Henning
Chapter 5 Phytochemicals and Immune Function............................................... 67
David Heber
Chapter 6 Genetic and Environmental Modifiers of Immune Function.............. 85
David Heber
Chapter 7 Cancer and Inflammation.................................................................. 101
David Heber
Chapter 8 Abdominal Obesity: Pathophysiology and Related Metabolic
Complications.................................................................................... 115
Ana F.T.A. Junqueria and Caroline M. Apovian
Chapter 9 Type 2 Diabetes and Inflammation................................................... 141
Zhaoping Li and David Heber
v
vi Contents
Chapter 10 Heart Disease and Inflammation....................................................... 149
Kaveh Daniel Navab
Chapter 11 Chronic Kidney Disease and Inflammation...................................... 167
Karl J. Neff and Carel Le Roux
Chapter 12 Alzheimer’s Disease and Inflammation............................................ 181
Stephen T. Chen and Gary W. Small
Chapter 13 Nutrition in Autoimmunity: A Focus on Systemic Lupus
Erythematosus and Rheumatoid Arthritis........................................ 211
Maureen McMahon
Chapter 14 Asthma and Inflammation................................................................. 229
Andre Nel and David Heber
Chapter 15 Muscle and Immune Function........................................................... 245
Anthony Thomas and David Heber
Chapter 16 Approaches to Reducing Abdominal Obesity................................... 259
Zhaoping Li and David Heber
Chapter 17 Barriers to Fruit and Vegetable Consumption and Practical
Strategies for Increasing Fruit and Vegetable Intake........................ 279
Susan Bowerman
Chapter 18 Healthy Fats and Oils: Balancing Omega-3 and
Omega-6 Acids in Tissues................................................................. 291
Bill Lands
Chapter 19 Spices and Dietary Supplements with
Anti-Inflammatory Activity........................................................... 317
Bharat B. Aggarwal and David Heber
Preface
Immune function and nutrition are closely intertwined in human health. The immune
system is composed of an innate immune system and an adaptive immune system.
The latter is only found in vertebrates while the former is an ancient system that goes
back in evolution to insects and plants.
It is the innate immune system that is overactivated in response to the Western
diet and obesity-associated diseases due to chronic low-grade inflammation. These
diseases range from type 2 diabetes to heart disease, which are closely aligned with
the accumulation of visceral and liver fat resulting in insulin resistance. Individuals
who are about 30 lb overweight or have a body mass index (BMI) of 30 or more
have a 30-fold increased risk of type 2 diabetes mellitus. This 3000% increased risk
is not simply another risk factor but an intrinsic part of the pathogenesis of diabetes
bringing us to call this condition diabesity. However, the etiology of diabetes is not
simply linked to weight but to visceral fat. Individuals in India and China can accu-
mulate visceral fat at normal or even low BMI. Some 70 million Americans have
high blood sugar or prediabetes, and the syndrome, called metabolic syndrome,
affects 50% of individuals between the ages of 50 and 65 in the United States and
many other countries.
The interaction of immune function and nutrition underlies the low-grade chronic
inflammation involved in the etiology of many of the common age-related chronic
disease conditions covered in this textbook. The largest portion of the immune sys-
tem is located adjacent to the gastrointestinal tract. Plants, which also have an innate
immune system, live in soil that is made up of both friendly and potentially toxic
bacteria. Plant roots attract helpful bacteria and repel those bacteria that could attack
them. Humans carry their soil with them in the form of trillions of gut bacteria,
which interact with the immune system. Both dietary intake and obesity influence
the gut microflora, called the microbiome. Plants affect the local bacteria in the soil;
it is thus not surprising that dietary phytochemicals and prebiotics in the human diet
also affect gut microflora.
Diet and exercise are necessary strategies in efforts to reduce visceral fat and
modulate systemic immune function through increased intakes of fruits, vegeta-
bles, plant protein, fish oils, prebiotic fibers, and spices. Nutrition in the broadest
sense determines the health of the immune system. When malnutrition results in
death, it is most commonly caused by infections due to loss of immune function.
Therefore, both in obesity and malnutrition, nutritional factors influence immune
function. This close interaction is the genesis of the term immunonutrition, which
represents a new interdisciplinary field of nutritional and medical research.
It is our hope that this textbook will stimulate increased interest in this new inter-
disciplinary field among students and junior investigators who will carry this field
into the future. There is a need for more human studies to complement the exciting
vii
viii Preface
basic research already developed in cell culture and animal models demonstrating
the mechanisms underlying the interaction of nutrition and immune function. We
hope that this book will achieve these objectives.
David Heber MD, PhD, FACP, FACN
Los Angeles, California
Bharat B. Aggarwal, PhD
Houston, Texas
Editors
David Heber, MD, PhD, FACP, FACN, is the direc-
tor of the UCLA Center for Human Nutrition at the
University of California, Los Angeles. He has been
on the faculty of the UCLA School of Medicine
since 1978 and is currently professor of medicine
and public health. Dr. Heber is board certified in
internal medicine and endocrinology and metabo-
lism by the American Board of Internal Medicine
and is certified as a physician nutrition specialist. He
is a former chair of the Medical Nutrition Council
of the American Society of Nutrition. He directed
both the NCI-funded Clinical Nutrition Research Unit and the NIH Nutrition and
Obesity Training Grants at UCLA. He has written over 230 peer-reviewed scientific
articles and 60 book chapters, as well as three professional texts. He has written four
books for the public, including What Color Is Your Diet? (Harper Collins/Regan
Books, 2001) and the L.A. Shape Diet (Harper Collins/Regan Books, 2004). His
main research interests are obesity prevention and treatment and phytonutrients in
cancer prevention and treatment.
Dr. Bharat B. Aggarwal is a Ransom Horne,
Jr. Distinguished Professor of Cancer Research,
Professor of Cancer Medicine, Professor of
Immunology, Professor of Biochemistry, and
Professor of Experimental Therapeutics, as well
as Chief, Cytokine Research Section, in the
Department of Experimental Therapeutics at the
University of Texas MD Anderson Cancer Center
(MDACC), Houston, Texas. He also serves as a
member of the University of Texas Graduate School
of Biomedical Sciences, Houston; as an adjunct
professor at Albert B. Alkek Institute of Biosciences and Technology, Texas A&M
University, Houston, Texas; and as a member in various institutional committees
of MDACC.
Dr. Aggarwal earned his PhD in biochemistry from the University of California,
Berkeley, and received his postdoctoral training from the Hormone Research
Laboratory at the University of California Medical Center, San Francisco. He
then started his career with Genentech Inc., where he worked for almost 10 years.
His work led to the discovery of TNF-α and TNF-β, essential components of the
immune system, and to the identification of their receptors.
In 1989, Dr. Aggarwal accepted the position of professor and chief of the
Cytokine Research Section at M. D. Anderson Cancer Center, where he currently
ix
x Editors
holds the Ransom Horne, Jr., Endowed Professorship in Cancer Research. Since
then, he has been investigating the role of inflammatory pathways mediated
through TNF, NF-kappaB, and STAT3 for the prevention and therapy of cancer
and other chronic diseases. While searching for novel and safe anti-inflammatory
agents, his group has identified more than 50 novel compounds from dietary
sources and from traditional medicine that interrupt these cell-signaling pathways.
These agents have been tested in various animal models, and some of them are
now in clinical trials. Dr. Aggarwal has published more than 600 papers in peer-
reviewed international journals (including Science, Nature, Cancer Cell, PNAS,
Journal of Experimental Medicine, Blood, JBC, Cancer Research, and Journal of
Immunology), invited reviews, and book chapters.
Dr. Aggarwal is an inventor/coinventor of over 33 patents. He has been included
in ISI Highly Cited among the most popular authors in the immunology category
since 2001. He has also been listed as one of the top 25 researchers worldwide in the
area of apoptosis. His papers exhibit very high citation index (some exceed 1000).
His overall citation is now at 75,900 with an H-index of 106.
Dr. Aggarwal currently serves as a member of the editorial boards of 24 inter-
national journals. He has previously served as a reviewer for more than 160 jour-
nals, various grant proposals, and of several PhD theses. Dr. Aggarwal has edited
12 books and has served as guest editor for special issues of Biotherapy, Cancer
Letters, and Current Opinion in Pharmacology. He has trained over 80 postdoctoral
fellows and visiting professors from around the world. He has co-organized and
served as a member in many national and international conferences and symposia,
started the International Society of Translational Cancer Research, and has delivered
over 350 lectures/seminars/keynote talks in more than 50 countries.
He has recently authored a book entitled Healing Spices (released in January 2011
by Sterling), which is already a bestseller.
Dr. Aggarwal has received numerous awards, including the following:
• ARTOI Award, Association for Research Integrated Oncology Therapies,
Rome, Italy, 2012
• 2011 James A. Duke Award Excellence in Botanical Literature Award,
American Botanical Council, Anaheim, California, 2012
• World Congress Science Prize from Oxygen Club of California, 2010
• Excellence in Research Award of McCormick Research Institute from the
American Association of Nutrition, 2008
• Outstanding Scientist Award from the American Association of Indian
Scientists in Cancer Research, 2006
• Ranbaxy Award for Outstanding Scientist of the Year, 2004
Contributors
Bharat B. Aggarwal Susanne Henning
Department of Experimental Department of Medicine
Therapeutics Center for Human Nutrition
MD Anderson Cancer Center David Geffen School of Medicine
The University of Texas University of California, Los Angeles
Houston, Texas Los Angeles, California
Caroline M. Apovian Ana F.T.A. Junqueria
Section of Endocrinology, Diabetes and Section of Endocrinology, Diabetes and
Nutrition Nutrition
Department of Medicine Department of Medicine
Boston Medical Center Boston Medical Center
School of Medicine Boston, Massachusetts
Boston University
Boston, Massachusetts Bill Lands
American Association for the
Susan Bowerman Advancement of Science
Department of Medicine Washington, DC
Center for Human Nutrition and
David Geffen School of Medicine
American Society for Nutrition
University of California, Los Angeles
Bethesda
Los Angeles, California
and
Stephen T. Chen Society for Free Radical Biology and
Department of Psychiatry and Medicine
Biobehavioral Sciences Indianapolis, Indiana
Division of Geriatric Psychiatry
David Geffen School of Medicine Carel Le Roux
and Diabetes Complications Research Centre
Semel Institute for Neuroscience and Conway Institute of Biomolecular and
Human Behavior Biomedical Research
University of California, Los Angeles University College Dublin
Los Angeles, California Dublin, Ireland
David Heber Zhaoping Li
Department of Medicine Department of Medicine
Center for Human Nutrition Center for Human Nutrition
David Geffen School of Medicine David Geffen School of Medicine
University of California, Los Angeles University of California, Los Angeles
Los Angeles, California Los Angeles, California
xi
xii Contributors
Maureen McMahon Gary W. Small
Division of Rheumatology Department of Psychiatry and
Department of Rheumatology Biobehavioral Sciences
David Geffen School of Medicine Division of Geriatric Psychiatry
University of California, Los Angeles David Geffen School of Medicine
Los Angeles, California and
Semel Institute for Neuroscience and
Kaveh Daniel Navab Human Behavior
Department of Anesthesiology University of California, Los Angeles
David Geffen School of Medicine Los Angeles, California
University of California, Los Angeles
Los Angeles, California Anthony Thomas
Karl J. Neff Larry L. Hillblom Islet Research
Diabetes Complications Research Centre Center
Conway Institute of Biomolecular and David Geffen School of Medicine
Biomedical Research University of California, Los Angeles
University College Dublin Los Angeles, California
Dublin, Ireland
Andre Nel
Department of Medicine, Pediatrics and
Public Health
Division of NanoMedicine
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, California
1 Evolution of Innate and
Adaptive Immunity
David Heber and Bharat B. Aggarwal
CONTENTS
Introduction................................................................................................................. 1
Evolution of Innate Immunity..................................................................................... 5
Innate Immune System in Plants............................................................................ 5
Innate Immune System in Humans........................................................................ 6
Evolution of Cellular Immunity.................................................................................. 6
Immunity and Inflammation................................................................................... 7
Cellular Immunity.................................................................................................. 7
Adaptive Immune System........................................................................................... 9
Malnutrition and Immune Function.......................................................................... 10
Immune Function in Obesity.................................................................................... 11
Macrophage Receptors for Omega-3 Fatty Acids..................................................... 11
Immune Function and Vitamin and Mineral Balance............................................... 12
Practical Considerations for Modulating Immune Function..................................... 14
References................................................................................................................. 15
INTRODUCTION
The human immune system can be divided into two functional entities: the innate
and the adaptive immune systems. The innate immune system appeared early in
evolution prior to the time that plants and animals took separate paths, but the
basic mechanisms of pathogen recognition and activation of the innate immune
response are conserved throughout the evolution of plants and animals includ-
ing humans [1]. Innate immunity is the first line of defense against infectious
microorganisms in humans and relies on germ line–encoded pattern recognition
receptors (PRRs) to recognize pathogen-derived substances [1]. Activation of the
innate immune system through these receptors leads to the expression of a vast
array of antimicrobial effector molecules that attack microorganisms at many
different levels.
The innate immune system has been studied extensively in fruit flies (Drosophila
melanogaster) [2] and even in worms such as Caenorhabditis elegans. These ani-
mals have the same genes as vertebrates, including mice and humans, that encode
intracellular signaling pathways leading to the activation of the transcription fac-
tor nuclear factor-kappa B (NFκB). These gene cassettes encode various proteins
1
2 Immunonutrition: Interactions of Diet, Genetics, and Inflammation
Plants Animals
Adaptive
Angiosperms *Vertebrates* immunity
Gymnosperms Echinoderms
Seed producers Fungi Rotifers
Horsetails Club fungi Anthropods
Club moss Sac fungi Annelids
Ferns Bread mold Mollusks
Bryophytes Worms
Sponges
Protista
Algae
Molds
Amoeba
Innate Flagellates Innate
immunity immunity
Prokaryotes
Cyanobacteria
Eubacteria
Archaeobacteria
Protocells
FIGURE 1.1 Adaptive immune function is a late evolutionary development in vertebrates
while innate immune function can be traced back to the earliest cell types including bacteria.
of signaling pathways modulating NFκB activation and inflammation discussed
elsewhere in this textbook. This evolutionary history combined with other evidence
supports the notion that the activation of NFκB is the central signaling pathway of
activation in innate immunity, leading in turn to the transcription of a set of genes
dependent on NFκB [3]. Moreover, this pathway is a universal pathway that leads to
activation in all host defense systems.
The adaptive immune system evolved much later in higher species (see
Figure 1.1).
In contrast to innate immunity, the adaptive immune system generates
antigen-specific receptors, antibodies, and T-cell receptors by somatic cell DNA
rearrangement [4]. These receptors, found only in higher eukaryotes, recognize
specific pathogen-encoded proteins. Mammals have a complex immune response,
which relies on communication between the innate and adaptive arms of the immune
system.
In the human gut, trillions of bacteria live in symbiosis with the host and affect
both host nutrition and immune function. Studies confirm that gut microbiota carry
on a dynamic interaction with the intestinal innate and adaptive immune systems,
affecting different aspects of its development and function. Communication between
the mucosal immune system and endogenous microflora favors mutual growth, sur-
vival, and inflammatory control of the intestinal microbiome [5].
Since humans evolved in equilibrium with plants, insects, and bacteria, the
innate and adaptive immune systems were clearly influenced by the innate immune
Evolution of Innate and Adaptive Immunity 3
The mammalian The Drosophila
Toll-like receptor Toll signaling
signaling pathway pathway
TLR Toll
MyD88 dMyD88
IRAK TRAF6 Pelle
Cactus
IKK kinase
IκB Cactus
NFκB DIF
FIGURE 1.2 Comparison of the mammalian and fruit fly Toll-like receptor signaling path-
ways. The intracellular domain of the toll-like receptors in flies and mammals interact with
a homologous domain in the adaptor protein MyD88. The terminal parts of the pathway
are also homologous between Drosophila and mammals; phosphorylation of Cactus initiates
its degradation and the release of the Dif/Relish dimer, which is a transcription factor and
homologue of NFκB. (From Janeway, C.A., Jr. et al., Immunobiology: The Immune System in
Health and Disease, 6th edn., pp. 52–53, Garland Science, New York, 2005.)
system of plants. Toll receptors in fruit flies perform the same defensive function
as in mice, and there are analogous signaling pathways in both mice and fruit
flies largely conserved through evolution in the human innate immune system
(see Figure 1.2).
The genes of innate immune function in plants are not arranged in the same
order as in fruit flies, but all the signaling elements can be identified in plants as
separate or fused genes [6]. During pathogen-initiated or environmental stress, plant
hormonal signaling pathways prioritize defense over other cellular functions. This
connection, in turn, provides the necessary background for the immune modula-
tory effects of plant substances under the general rubric of phytochemicals found in
4 Immunonutrition: Interactions of Diet, Genetics, and Inflammation
fruits, vegetables, grains, spices, and herbs. Typically, plants raised under stressful
conditions such as low light and water produce increased concentrations of specific
molecules. In other situations, a specific external stress such as ultraviolet light in
dark-adapted mushrooms can lead to the elaboration of defensive toxins.
The cloning of the obese gene (ob) in mice, leading to the discovery of leptin,
began a decade of intensive cellular and molecular investigation on the regulation of
body weight, food intake, and physical activity [7]. The role of leptin has largely been
misunderstood due to the observation that when this protein is administered to obese
mice lacking only this gene in a homozygous condition (the ob/ob mouse), these mice
become thin. A very small number of humans with this genetic condition have also
been shown to become thin following leptin administration. However, despite the ori-
gin of the name leptin (from the Greek root for thinning), its primary role is in the
recovery from starvation and as a cytokine in the immune response. As levels of leptin
in the circulation and central nervous system fall with malnutrition, food intake is
increased and physical activity is decreased. In fact, low leptin levels are a biomarker
of malnutrition in elderly hospitalized patients, and levels rise as malnourished indi-
viduals are renourished [8]. The circulating levels of leptin are proportional to fat mass
but are lowered rapidly by fasting or increased by inflammatory mediators.
The impaired T-cell immunity of mice now known to be defective in leptin (ob/
ob) or its receptor (db/db) is related to the absence of functional leptin signaling due
to the absence of a functional leptin protein (ob/ob) or the leptin receptor protein
(db/db) [9]. Impaired cell-mediated immunity and reduced levels of leptin are both
features of low body weight in humans. Indeed, malnutrition predisposes to death
from infectious diseases, and the impaired immune function resulting from protein-
energy malnutrition and HIV infection is well documented [10]. On an evolutionary
basis, the ability to fight off infection and the ability to store fat in cells were both
critical to survival. While the adaptation to starvation and associated gradual weight
loss do not impair immune function, rapid weight loss does [11]. Moreover, the close
interrelationship of immune function and nutrition has been confirmed with modern
molecular-nutrition tools.
Over the last century, the intricate interaction between human immunity and
metabolism has been recognized and investigated extensively [12]. Indeed, it has
been demonstrated that adipose tissue is not merely the site of energy storage, but
can be considered as an immune-related organ producing a series of molecules
named adipocytokines. Nutritional depletion, specific deficiencies, and kwashiorkor-
like malnutrition suppress immune function [13].
The immune system in humans is an integral part of the adaptation to starvation.
The observation that depletion of the body cell mass to less than half of its normal
mass is incompatible with life regardless of the etiology of malnutrition hinges on
the decompensation of immune function. On the other hand, staying with the theme
that humans are well adapted to starvation but poorly adapted to overnutrition, there
is chronic low-grade inflammation associated with overweight and obesity, medi-
ated by intra-abdominal fat-resident immune cells that cause a systemic inflamma-
tion [14]. In order to understand these two poles of the interaction of nutrition and
immune function, it is necessary to understand the difference between innate and
adaptive immune mechanisms and their evolution.
Evolution of Innate and Adaptive Immunity 5
EVOLUTION OF INNATE IMMUNITY
Genetic studies of plants and animals have demonstrated that the innate immune
system existed at the time the ancestors of plants and animals separated in evolu-
tion. The Toll pathway of NFκB activation has been demonstrated conclusively in
fruit flies, mice, and humans and is also believed to occur in plants [15]. The DNA
sequences of this pathway are found in invertebrates, vertebrates, and plants.
Insects have a very potent innate immune response that effectively combats a
broad spectrum of pathogens. For example, Drosophila can withstand, and clear,
bacterial burdens that, relative to their size, would be lethal to mammals [16].
Induction of innate immunity in both mammals and insects leads to the activation of
similar effector mechanisms, such as stimulation of cell-based phagocytic activity
and expression of antimicrobial peptides [17]. For example, Drosophila produces
a wide range of potent antimicrobial peptides in response to infection by fungi or
bacteria [18]. Induction of the antimicrobial peptides is regulated at the level of tran-
scription, and they are expressed primarily in the fat body, the insect liver analog.
In fruit flies, immunity to infection by various microorganisms can be affected
by making different Toll-pathway genetic mutations. An immune specificity sys-
tem based on variations in the Toll gene and other PRRs appears to exist in the
fruit fly. Whether this same genetic variation exists in mice and humans is as yet
unknown. However, there are significant similarities in the signaling pathways used
by humans and flies to activate the innate immune response. In both cases, infection
leads to the activation of toll-like receptors (TLRs), which in turn initiate intracel-
lular signaling cascades that culminate in the activation of NF-κB-related transcrip-
tion factors.
Innate Immune System in Plants
Plants must survive complex environments in which they interact with a broad range
of microbial pathogens such as fungi, bacteria, and viruses with different infec-
tion strategies as well as herbivore insects and animals. The evolutionary arms
race between plants and their attackers provided plants with a highly sophisticated
defense system that, like the animal innate immune system, recognizes pathogen
molecules and responds by activating specific defenses that are directed against the
invader [19]. Recent advances in plant immunity research have provided exciting
new insights into the underlying defense-signaling network. Diverse small-molecule
hormones play pivotal roles in the regulation of this network. Their signaling path-
ways cross-communicate in an antagonistic or synergistic manner, providing the
plant with a powerful capacity to finely regulate its immune response.
Phytohormones are small molecules that are essential for the regulation of plant
growth, development, reproduction, and survival. They act as signal molecules and
occur in low concentrations. Classic phytohormones are abscisic acid (ABA), auxins,
cytokinins, ethylene (ET) and gibberellins, brassinosteroids, jasmonates (JAs), and
salicylic acid (SA). Changes in hormone concentration or sensitivity, which can be
triggered under stress conditions, mediate a whole range of adaptive plant responses.
The importance of SA, JAs, and ET as primary signals in the regulation of the plant’s
6 Immunonutrition: Interactions of Diet, Genetics, and Inflammation
immune response is well established [20–24]. More recently, ABA [25,26], auxins
[27,28], gibberellins [29], cytokinins [30,31], and brassinosteroids [32] have also
been demonstrated to play important roles in innate immunity. The involvement of
so many plant-growth regulators in plant immunity suggests that the control of plant
growth, development, and defense is interconnected in a complex network of cross-
communicating hormone-signaling pathways. Therefore, the innate immune system
enables plants to utilize their resources in a cost-efficient manner by regulating the
amounts of substrates committed to cell formation. These defense responses may have
evolved to save energy under enemy-free conditions, as they only involve costs when
defenses are activated upon pathogen or insect attack. Trade-offs between plant-growth
rate and disease resistance are established by numerous studies and are consistent with
the idea that plant growth and defense are interconnected via common signaling path-
ways just as human nutritional status and immune function are interconnected.
Innate Immune System in Humans
The innate immune system consists of the cells and mechanisms that defend the
host from infection by other organisms, in a nonspecific manner. This means that
the cells of the innate system recognize and respond to pathogens in a generic way,
but unlike the adaptive immune system, it does not confer long-lasting or protective
immunity to the host. Innate immune systems provide immediate defense against
infection and are the dominant immune systems found in plants, fungi, insects, and
primitive multicellular organisms. It is thought to be an older evolutionary develop-
ment than the adaptive immune system. The innate immune system is activated by
danger signals and can be likened to firemen playing cards in the fire station until
the alarm goes off, and they all jump down the pole and onto fire trucks to put out
the fire. A fresh perspective is offered by approaching the immune system by the
premises laid down by Polly Matzinger in her danger model [33,34]. Even today,
more than a decade after its emergence, this model offers a fundamentally different
interpretation of classic and newly emerging concepts in immunology.
The innate immune system in humans carries out the following functions:
(a) recruitment of immune cells to sites of infection, through the production of
chemical factors, including specialized chemical mediators called cytokines and
chemokines; (b) activation of the complement cascade to identify bacteria, activate
cells, and promote clearance of dead cells or antibody complexes; (c) identification
and removal of foreign substances present in organs, tissues, blood, and lymph by
specialized white blood cells; and (d) activation of the adaptive immune system
through a process known as antigen presentation.
EVOLUTION OF CELLULAR IMMUNITY
It has been proposed that single-cell protozoa such as the amoeba may be the evo-
lutionary ancestors of the macrophage and other mobile cells of the immune system
[15]. Protozoa such as the amoeba need to discriminate between food and other
amoebas. If amoebas could not make this distinction they would consume them-
selves and the other members of their species, leading to extinction. Specific surface
Evolution of Innate and Adaptive Immunity 7
receptors on amoebas discriminate between food to be engulfed and digested from
another amoeba. The nature of this hypothesized receptor is not yet established, but
it would have to be highly specific in order to discriminate self from nonself, the
most basic functions of immune function.
Macrophages, like protozoa, move at random unless exposed to a chemoattrac-
tant. Then, they all head in the same direction. In this respect also, protozoa behave
like macrophages and may have migrated into the cavities of early multicellular
organisms where they performed some symbiotic role. There are many areas of this
evolutionary hypothesis that remain unknown. For example, did the early macro-
phages lead to the evolution of lymphocytes or dendritic cells? The dendritic cells
are named for their long projections of cytoplasm resembling the dendritic processes
on nerve cells. Their one function is to seek out antigens and present them to the
subpopulation of T-lymphocytes as part of the adaptive immune response.
Immunity and Inflammation
The activation of the innate immune system is accompanied by inflammation (Latin,
inflammatio, a setting on fire), a complex biological response of vascular tissues to
harmful stimuli, such as pathogens, damaged cells, or irritants. The inflammatory
response is characterized by the following symptoms: redness (rubor), heat (calor),
swelling (tumor), and pain (dolor). Inflammation is a protective attempt by the organism
to remove the injuring stimulus as well as initiate the healing process for the tissue.
Inflammation can be classified as either acute or chronic. Acute inflammation is
the initial response of the body to harmful stimuli and is achieved by the increased
movement of plasma and leukocytes from the blood into the injured tissues. A cas-
cade of biochemical events propagates and matures the inflammatory response,
involving the local vascular system, the immune system, and various cells within
the injured tissue [35]. Prolonged inflammation, known as chronic inflammation,
leads to a progressive shift in the type of cells which are present at the site of inflam-
mation and is characterized by simultaneous destruction and healing of the tissue
from the inflammatory process. Chronic inflammation is associated with many
diseases including heart disease, diabetes, and common forms of cancer. So while
acute inflammation and healing is a life-saving adaptation analogous to the ability
to store energy as fat, prolonged inflammation damages critical tissues and organs in
the body. Obesity is associated with increased chronic inflammation while starvation
is associated with impaired immune function.
In the absence of inflammation, wounds and infections would never heal, and
progressive destruction of the tissue would compromise the survival of the organism
[36]. However, chronic inflammation can also lead to a host of diseases, such as hay-
fever, atherosclerosis, and rheumatoid arthritis. It is for that reason that inflammation
is normally closely regulated by the body.
Cellular Immunity
White blood cells (WBCs) are called leukocytes and are able to move freely through
the circulation, lymphatics, and tissues in order to capture cellular breakdown
8 Immunonutrition: Interactions of Diet, Genetics, and Inflammation
products, foreign materials, or invading pathogens. Most leukocytes cannot divide or
reproduce on their own but are the products of stem cells found in the bone marrow
which develop into one or another type of white cell. Leukemia is the unregulated
overproduction of cells from one step of the process such as promyelocytic leukemia
where the promyelocyte crowds out the development of other white cells leading
to infection, other red cells leading to anemia, or platelets leading to bleeding. The
different leukocytes of the innate immune system include natural killer cells or NK
cells, mast cells, eosinophils, basophils, and the phagocytic cells including macro-
phages, neutrophils, and dendritic cells and function within the immune system by
identifying and eliminating pathogens that might cause infection.
When activated, mast cells rapidly release characteristic granules, rich in hista-
mine and heparin, along with various hormonal mediators and chemokines or che-
motactic cytokines into the environment. Histamine dilates blood vessels, causing
the characteristic signs of inflammation, and recruits neutrophils and macrophages.
Macrophages, neutrophils, and dendritic cells are called phagocytic cells because
they engulf and internalize foreign matter, cell debris, or pathogens.
Macrophages, from the Greek, meaning large eating cell, are large phagocytic
white blood cells that move outside the vascular system across the cell membranes
of capillary vessels and enter the areas between cells in response to danger signals
from invading pathogens, foreign materials, or dying cells. In tissues, organ-specific
macrophages are differentiated from phagocytic cells present in the blood called
monocytes. Macrophages are the most efficient phagocytes and can engulf and
digest substantial numbers of bacteria, cellular material, or microbes. The binding
of molecules to receptors on the surface of a macrophage triggers it to engulf and
destroy its meal through the generation of a respiratory burst, causing the release
of reactive oxygen species. The stimulated macrophage also produces chemokines,
proteins that summon other cells to the site of infection or injury.
Neutrophils, along with eosinophils and basophils, are known as granulocytes
due to the presence of granules in their cytoplasm. Polymorphonuclear cells (PMNs)
are white cells with distinctive lobed nuclei. Neutrophil granules contain a variety
of toxic substances that kill or inhibit growth of bacteria and fungi. Similar to mac-
rophages, neutrophils attack pathogens by activating a respiratory burst. The main
products of the neutrophil respiratory burst are strong oxidizing agents including
hydrogen peroxide, free oxygen radicals, and hypochlorite. Neutrophils are the most
abundant type of phagocyte, normally representing 50%–60% of the total circulating
leukocytes, and are usually the first cells to arrive at the site of an infection. The
bone marrow of a normal healthy adult produces more than 100 billion neutrophils
per day and more than 10 times that many per day during acute inflammation.
Basophils and eosinophils are similar to the neutrophil in containing granules.
When activated by a pathogen encounter, basophils release histamine, which is
important in the defense against parasites, and plays a role in allergic reactions (such
as asthma). Upon activation, eosinophils secrete a range of highly toxic proteins and
free radicals that are highly effective in killing bacteria and parasites, but are also
responsible for tissue damage occurring during allergic reactions. Activation and
toxin release by eosinophils are therefore tightly regulated to prevent any inappropri-
ate tissue destruction.
