Module 5 Reading Materials (Supplementary)

Immune System and Immunomodulation

Health is a reflection of the functional or metabolic status of a living organism. In

humans, this involves the ability to adapt and self-manage when faced with physical,
mental or social challenges. A strong, efficiently-functioning immune system is a
cornerstone of good health. An optimally functioning immune system necessitates a
balance between adequate biological defenses to fight infection, disease, or other
unwanted biological invasion versus an appropriate tolerance to avoid allergy and
autoimmune diseases.

Immune System

The immune system provides a sophisticated means of protecting the host against
invading microorganisms or other “foreign” molecules and against malignant cells. Its
function involves the cooperation and interaction of various cell types, cell products,
tissues, and organs. In this connection, the immune system encompasses primary and
secondary lymphoid organs, and it is prominent at sites that are exposed to the exterior,
such as the mucosa of lungs, intestine, and skin. Immune cells are derived from
pluripotent hematopoietic stem cells in the bone marrow. Myeloid and lymphoid stem
cells emerge during the first step of differentiation, which is followed by the
differentiation of lymphocytes of T and B lineage within the thymus and bone marrow,
respectively. Immune responses can be regulated by nervous and endocrine systems.

Innate Immune System

Immune responses are the result of an effective interaction between innate (natural and
non-specific) and acquired (adaptive and specific) components of the immune system.
The innate immune responses are the first line of defense against invading pathogens
which rely on the body’s ability to recognize signature features of pathogens that are not

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present in the uninfected host. These pathogen-specific molecules are recognized by
toll-like receptor proteins. In humans, microbial surface molecules also activate
complement, a group of blood proteins that act together to disrupt the membranes of
microorganisms, thereby targeting them for phagocytosis by macrophages and
neutrophils, and to produce an inflammatory response. Phagocytic cells use a
combination of degrading enzymes, anti-microbial peptides, and reactive oxygen
species (ROS) to destroy the “foreign” invaders. In addition, phagocytic cells release
signaling molecules that trigger an inflammatory response and begin to marshal the
forces of the adaptive immune system. Cells infected with viruses produce interferons
(IFN), which induce a series of cellular responses to inhibit viral replication and activate
natural killer (NK) cells and cytotoxic T-lymphocytes.

Adaptive Immune System

The adaptive immune system exhibits a stronger immune response that the innate one.
as well as immunological memory, wherein each pathogen is “remembered” by a
specific signature antigen. The cells of the adaptive immune system are specialized
leukocytes, called B- and T-lymphocytes. B-cells are involved in humoral immune
responses, whereas T-cells are involved in cell-mediated immune responses. Both B-
cells and T-cells contain receptor molecules that recognize specific chemical targets. T-
cells recognize a “non-self” pattern, such as would be present in a pathogen, but only
after antigens (small “signature” fragments of the pathogen) have been processed and
presented in combination with a “self” receptor called the major histocompatibility
complex (MHC) molecule. Killer T-cells recognize antigens coupled to Class I MHC
molecules whereas helper T-cells recognize antigens coupled to Class II MHC
molecules. A third, minor subtype is the gamma-delta T-cell that recognizes intact
antigens that are not bound to MHC receptors. In contrast, the B-cell antigen-specific
receptor is an antibody molecule on the B-cell surface and recognizes intact pathogens
without any need for antigen processing. Each type of B-cell expresses a different
antibody and so the complete set of B-cell antigen receptors encompass all the
antibodies manufactured by the body. When B- and T-cells are activated and begin to
replicate, some of their progeny become long-lived memory cells. Throughout the
lifetime of a human, these memory cells remember each specific pathogen encountered
and can mount a strong immune response to future challenges.

Disorders related to Immunity

Over the last three decades, there has been a great deal of interest in the immune
system as a potential target of toxicity following exposure to drugs, chemicals or

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environmental pollutants, collectively referred to as “xenobiotics”. Since cells of the
immune system undergo continual proliferation and differentiation for self-renewal to
maintain immune-competence, they can be affected by xenobiotics, resulting in a
cellular imbalance. The interaction of xenobiotics with the immune system can result in
alterations in immune function, such that immuno-suppression leads to changes in host
defense mechanisms against pathogens or neoplasm , or dysregulation of the immune
response that causes allergy, hypersensitivity, and autoimmune reactions.

Immunodeficiency

Immunodeficiency occurs when one or more of the components of the immune system
is/are inactive or deficient. Immunodeficiency can be inherited or “acquired.” Chronic
granulomatous disease, a condition in which phagocytes have a reduced ability to
destroy pathogens, is an example of an inherited, or congenital, immunodeficiency.
Infectious diseases, acquired immune deficiency syndrome (AIDS), and some types of
cancer result from acquired immunodeficiency.

Autoimmunity

Overactive immune responses, such as occurs in autoimmune disorders, also are a

type of immune dysfunction. Here, the immune system fails to properly distinguish
between self and non-self, and attacks components of the body. Under normal
circumstances, many T-cells and antibodies react with “self” peptides. One of the
functions of specialized cells (located in the thymus and bone marrow) is to present
young lymphocytes with self-antigens produced throughout the body and to eliminate
those cells that recognize self-antigens, preventing autoimmunity.

Factors Affecting Immune Function

Age

The aging process weakens the immune system and predisposes geriatric individuals to
a higher risk of immune insults, which are often more severe than in individuals of
younger age groups. Due to such “immune-senescence”, both innate and adaptive
responses are compromised.

Sex

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Sex-dependent factors can influence the susceptibility and progression of disease.
When compared to females, males experience a greater severity and prevalence of
many infectious diseases. Although females typically mount greater immune responses
and more rapid infection clearance (i.e., acute response), they more frequently develop
immune-mediated pathologies, presumably as a result of chronic inflammation. The risk
of death from all malignant cancers is 1.6 times higher for men.

Genetic Variability

Genetic variability among individuals plays an important role in determining variations in

inter-individual immune response.

Stress

Chronic psychological factors can produce low to moderate degrees of immune

suppression resulting in an increased risk of infectious disease. Immune testing in
chronically stressed individuals has provided insights into the relationship between mild
to moderate immune suppression and disease. Individuals experiencing chronic stress
show an increased susceptibility to infection, and their total circulating T-cell counts can
be reduced to as much as 20% below mean control values. CD4/CD8 ratios can be
reduced as much as 40% and NK cell activity by 10-25% below mean control values
under conditions of chronic stress.

Drug/Alcohol Abuse

Extensive alcohol/drug abuse can directly suppress a wide range of immune responses
by impairing the functioning of T-/B-lymphocytes, NK cells, monocytes and
macrophages as well as decreasing inflammatory response, altering cytokine
production and causing free radical damage.

Malnutrition

Nutrition plays a crucial role in the establishment and maintenance of a healthy immune
system. Protein-calorie malnutrition, deficiency of micronutrients, stringent self-imposed
dieting (e.g., anorexia) impair the body’s defense capabilities, depleting white blood
cells as well as crucial protein components of the immune system. A lack of
micronutrients, particularly iodine, iron, vitamin A, and zinc – depending on the severity
– can produce adverse effects on the immune system.

Environmental Pollution

Environmental pollution has become an important risk factor in causing detrimental

effects on immune function. Even short-term exposure to air pollutants can affect
respiratory health, resulting in upper respiratory tract infections and asthma. Many

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environmentally prevalent xenobiotics such as insecticides, herbicides, fungicides as
well as several industrial chemicals (polybrominated biphenyl, styrenes, lead, mercury),
can mimic or antagonize endogenous hormones and adversely affect not only the
endocrine and reproductive systems but also the immune system.

Unhealthy Life Style

Consumption of processed foods, a sedentary lifestyle and many other related factors
impose a greater risk on the immune function.

Immunomodulation

The concept of immunomodulation has been gaining much prominence worldwide with
the realization of the indispensable role of the immune system in maintaining a disease-
free state. In the recent past, the frequency of life-threatening infections has increased
dramatically among cancer patients, transplant recipients, AIDS patients and in
individuals receiving broad-spectrum antibiotics, corticosteroids, or cytotoxic drugs. In
the last two decades, to further complicate matters, there has been an upsurge in the
number of resistant strains of infectious organisms that no longer respond effectively to
antibiotics. It is abundantly clear that antibiotics have gradually lost their “magic touch”
following decades of injudicious and excessive antimicrobial use, resulting in the spread
of microbial genes that confer drug resistance. Selective pharmacological actions
targeting at the level of individual components of a complex immune response is seen
as a particularly attractive approach to the therapy of immunologically-mediated
diseases. The control of disease by immunological means has two objectives: The
development of immunity and the prevention of undesired immune reactions.
Modulation of the immune system can be achieved by a variety of specific and non-
specific approaches. Many synthetic and naturally occurring compounds have
stimulatory, suppressive and regulatory activities on immune function.
Immunomodulation is a broad term which refers to any induced change in the immune
response which may involve induction, expression, amplification or inhibition of any
segment or phase of the immune response. It may involve an enhancement or a
suppression of the indicators of cellular and humoral immunity. Stimulation of the
immune response is desirable for certain individuals such as immunocompromised
patients, whereas suppression of the immune response would be indicated for others
such as transplant recipients or patient with autoimmune or inflammatory diseases.