Cytokines and HYPERSENSITIVITY and Disorder of Human Immunity, Nutrition for Surveillance and for the Response

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◘ Cytokines
 The word cytokines (Greek ''cyto-'', cell;
and ''-kinos'', movement, it means cell
movement).
 They are low molecular weight
glycosylated peptides (~10-30 KDa).
 Cytokines are a group of non-antibody
intracellular messengers proteins, peptides, or glycoproteins produced
by different cells, especially cells of the immune system (lymphocytes
and monocytes).
• Cytokines are a group of proteins made by the immune system that act as
chemical messengers.
• Their major functions are to mediate and regulate immune response and
inflammatory reactions.
• Different cytokines, including:
 chemokines,
 interferons,
 interleukins,
 lymphokines and
 tumor necrosis factor
♣ They act either as:
a) A response to an immune stimulus.
b) An intercellular signal after certain stimulation.
♣ They have different names depending either on:
a) Their origin, such as lymphokines (produced by lymphocytes),
monokines (monocytes).
b) Their activity: chemokines, interleukins (IL), interferons (IFN α, β, γ).
♣ They are often secreted by immune cells for activating and recruiting
further immune cells to increase the system's response to the pathogen.
- Each cytokine has a cell-surface receptor.
- Subsequent cascades of intracellular signaling then alter cell
functions.

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♣ This may include
1-Up-regulation: Production of other cytokines, an increase in the number
of surface receptors for other molecules.
2-Down-regulation: Suppression of their own effect by feedback inhibition.
- Cytokines are characterized by considerable "redundancy", in that
many cytokines appear to share similar functions.
- Adverse reactions to cytokines are characterized by local inflammation
and/or ulceration at the injection sites.
♣ Nomenclature:
- Cytokines are named after their presumed function, or cell secreting it
or their target of action.
- They are secreted by many cell populations, but the predominant
producers are T-helper cells and Mϕ.
a- Interleukins (IL) are cytokines produced by one leukocyte and acting on
another leukocyte such as interleukin-1 (IL-1), IL-6, IL-8, IL-12 and tumor
necrosis factor-α (TNF-α)
b- Lymphokines released by activated T cells, primarily T-helper cells.
C- Chemokines refers to a specific class of cytokines that mediates chemo-
attraction (chemotaxis) between cells.
♣ Cytokines are classified according to its structure to:
 The four-α-helix bundle family: Member cytokines have three-
dimensional structures with four bundles of α-helices.
 This family is divided into three sub-families:
1. The IL-2 subfamily, is the largest
2. The interferon (IFN) subfamily,
3. The IL-10 subfamily.

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♣ Cytokines are classified According to Function:
a- Enhancing cellular immune responses type-1 (IFN-γ, TGF-β, etc.),
b- Affect antibody responses type 2 (IL-4, IL-10, IL-13, etc.).
♦ Cytokines actions:
• Binds to receptors, alter gene expression.
• Can bind to the secreting cell (autocrine).
• Can bind to another cell close by
(paracrine).
• Few cases bind to another cell far away
(endocrine).
♦ Cytokines regulate immune responses by:
1- They activate vascular endothelium.
2- They activate lymphocytes.
3- Activate natural killer (NK) cells.
4- Induce fever and shock.
5-Induce the differentiation of T cells into Th-1.
♦ Diseases
 Adverse effects of cytokines have been linked to many disease states
and conditions ranging from major depression and Alzheimer's
disease to cancer with levels either being elevated or changed.
 Over-secretion of cytokines can trigger a dangerous syndrome known as
a cytokine storm.
 Cytokine storms were the main cause of death in the 1918 "Spanish
Flu" pandemic.
 Deaths were weighted more
heavily towards people with
healthy immune systems, due to its
ability to produce stronger
immune responses, like increasing
cytokine levels.

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Function of Cytokines
♦ Major Histocompatibility Complex (MHC)

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 Major Histocompatibility Complex (MHC) is a cell surface molecule
encoded by a large gene family in all vertebrates.
 MHC molecules mediate interactions of leukocytes (WBCs) with other
leukocytes or body cells.
 MHC molecules enable T-lymphocytes to recognize epitopes of
antigens and discriminate self from non-self.
 MHC determines compatibility of donors for organ transplant as well as
one's susceptibility to an autoimmune disease.
 In humans, MHC is also called human leukocyte antigen (HLA).
 MHC occurs on the cell surface, each MHC molecule displays a
molecular fraction, called epitope, of a protein.
 The presented antigen can be either self or non-self.
 On the cell membrane, the MHC population in its entirety is like a
meter indicating the balance of proteins within the cell.
 The MHC gene family is divided into three subgroups: class I, class
II, and class III.
 Diversity of antigen presentation, mediated by MHC classes I and II,
of the three MHC classes identified, human focus commonly goes to
MHC class I and MHC class II.

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1-MHC I
 Molecules are found on nearly every nucleated cell of the body (they
are rare on red blood cells and platelets).
 Their function is to display fragments of proteins from within the cell
to CD8+ T cells; healthy cells will be ignored, while cells containing
foreign proteins will be attacked by the immune system.
 Because MHC I molecules present peptides derived from cytosolic
proteins, the pathway of MHC I presentation is often called the
cytosolic or endogenous pathway.
2 -MHC II
 Normally occurs only on professional Mϕ, B cells, and especially
dendritic cells but can be conditionally expressed by all cell types.
 An antigen presenting cells (APC) uptakes an antigen, performs antigen
processing, and returns a molecular fraction -the epitope- to the APC's
surface within an MHC II molecule for antigen presentation to CD4+
T cells.

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 The antigens presented by MHC II peptides are derived from
extracellular proteins (not cytosolic as in class I); hence, the MHC II-
dependent pathway of antigen presentation is called the endocytic or
exogenous pathway.
 Loading of MHC II occurs by phagocytosis; extracellular proteins are
endocytosed, ingested in lysosomes, and created by the MHC II
molecule prior to the molecule's migration to the cellular membrane.
◘ HYPERSENSITIVITY
 Hypersensitivity refers to excessive, undesirable (damaging,
discomfort-producing and sometimes fatal) reactions produced by the
normal immune system.
 Hypersensitivity reactions require a pre-sensitized (immune) state of the
host.
 Hypersensitivity reactions can be divided into four types: type I, type
II, type III and type IV, based on the mechanisms involved and time
taken for the reaction.
1-Type I hypersensitivity:
• It is also known as immediate or anaphylactic hypersensitivity.
♣ The reaction may involve:
- Skin (urticaria and eczema),
- Eyes (conjunctivitis),
- Nasopharynx (rhinorrhea, rhinitis),
- Bronchopulmonary tissues (asthma) and
- Gastrointestinal tract (gastroenteritis).
 The reaction may local or systemic.
 The reaction usually takes 15 - 30 minutes from the time of exposure to
the antigen, although sometimes it may have a delayed onset (10 - 12
hours).
 Immediate hypersensitivity is mediated by IgE.

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♦ Pharmacological Mediators of Type I Hypersensitivity.
1-Histamine
- which causes smooth muscle contraction, mucus secretion,
vasodilatation and vascular permeability.
- The target area for its action are respiratory tract, uterus etc.
2-Kininogenase
- causes vasodilatation, vascular permeability and edema.
3-Eosinophil chemotactic factorA (ECF-A)
- which attracts eosinophils and neutrophils to the site of mast cell
degranulation, prevent their movement.
4-Serotonin (5-OH-tryptamine):
- increases respiratory rate, vasoconstriction, stimulate further release of
histamine.
5-Other biologically active factors: leucotrines, prostaglandins, Tryptase,
kenin and heparin.

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♦ Treatment:
a- Drugs;
- Non-steroidal anti-inflammatoy, antihistamines that block histamine
receptors and Steroids.
- Theophylline OR epinephrine: prolongs or increases cAMP levels in
mast cells which inhibits degranulation.
b- Immunotherapy;
- Desensitization (hyposensitization) also known as allergy shots.
- Repeated injections of allergen to reduce the IgE on Mast cells and
produce IgG.
♣ Mast cells
- may be triggered by other stimuli such as exercise, emotional stress,
chemicals (e.g., photographic developing medium, calcium ionophores,
codeine, etc.), anaphylotoxins (e.g., C4a, C3a, C5a….).
- These reactions, mediated by agents without IgE-allergen interaction,
are not hypersensitivity reactions, although they produce the same
symptoms.
2-Type II hypersensitivity (Antibody-dependent cytotoxic reaction):
 Cytotoxic hypersensitivity and may affect a variety of organs and
tissues.
 Results when IgG or IgM bind to cell surface Ag’s:
– Activating Complement.
– Binding Fc receptors on Tc cells leading to an antibody-dependent
cell-mediated cytotoxicity (ADCC)
– Both processes result in lysis of the Ab-coated cell.
 The antigens are normally endogenous (patient's own cell surfaces),
although exogenous chemicals (haptens) which can attach to cell
membranes can also lead to type II hypersensitivity.
 These cells are recognized by Mϕ or dendritic cells, which act as
antigen-presenting cells (APC).
 This causes a B cell response, the antibodies are produced against the
foreign antigen.
 The reaction time is minutes to hours.

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♣ According to the type of antigen, type II can be subdivided to:
1- Isoimmune hypersensitivity reactions which include blood
transfusion, Rh incompatability and graft rejection
2- Autoimmune hypersensitivity reactions.
- Certain autoimmune diseases where Ab’s produced vs membrane Ag’s.
- Grave’s Disease: Ab’s produced vs thyroid hormone receptor.
- Myasthenia Gravis: Ab’s produced vs acetylcholine receptors.
- Autoimmune hemolytic anemia: Ab’s produced vs RBC membrane
Ag’s
3-Type III hypersensitivity:
- Type III hypersensitivity is also known as immune complex
hypersensitivity, when Ag-Ab complexes are not removed properly
from the system, they get deposited on the surrounding tissues,
triggering a variety of inflammation processes.
◘ The reaction may be:
• General (e.g., serum sickness) OR may Involve individual organs such as;
- Skin (e.g., systemic lupus erythematosus, Arthus reaction),
- kidneys (e.g., lupus nephritis),
- Lungs (e.g., aspergillosis),
- Blood vessels (e.g., polyarteritis),
- Joints (e.g., rheumatoid arthritis) or other organs.
 This reaction may be the pathogenic mechanism of diseases caused by
many microorganisms.
 The reaction may take 3 - 10 hours after exposure to the antigen (as in
Arthus reaction). It is mediated by soluble immune complexes.
♦ Insect bites: if an individual has been previously sensitized and has
circulating antibodies, the initial reaction will be type I at the site of the bite
and 4-8 hours later a type III reaction might develop.

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♦ Arthus reaction: deposits of immune complexes draw neutrophils, leading
to an accumulation of fluid (edema) and RBC’s (erythema).
- Severity of the reaction varies from mild swelling and redness to tissue
necrosis.
- Type III reactions can also be generalized (as opposed to localized to a
specific tissue).
- Large amounts of circulating antigen can form immune complexes
which are not easily cleared by phagocytic cells.
♣ Example:
- Serum sickness following the injection of an anti-toxin.
- Serum sickness occurs when immune complexes deposit in various
body sites, resulting in a more generalized systemic inflammatory
response.
- These immune complexes involve non-self proteins such as antibodies
produced in animals for artificial passive immunity (see Vaccines),
certain drugs, or microbial antigens that are continuously released over
time during chronic infections (e.g., subacute bacterial endocarditis,
chronic viral hepatitis).

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◘ Disorder of Human Immunity
♦ Immunodeficiency
 The term immunodeficiency (immune deficiency) generally refers to
the adverse effect of increased risk for infection.
 Immunodeficiency may be primary (PID) or secondary.
- Some people are born with defects in their immune system, primary
(PID) or congenital) immunodeficiency, and it is autosomal recessive
or X-linked.
- A person who has an immunodeficiency of any kind is said to be
immunocompromised.
- An immunocompromised person may be particularly susceptible to
opportunistic infections, in addition to normal infections that could
affect everyone.
- The treatment of primary immunodeficiency depends on the nature of
the defect, and may involve antibody infusions, long-term antibiotics
and (in some cases) stem cell transplantation

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- Most cases of immunodeficiency are acquired (secondary) result from
various immuno-suppressive agents, for example, malnutrition, aging
and particular medications (e.g. chemotherapy, disease-modifying
antirheumatic drugs, immunosuppressive drugs after organ transplants,
glucocorticoids).
- For medications, the term immunosuppression generally refers to both
beneficial and potential adverse effects of decreasing the function of the
immune system.
- Immunodeficiency is also the hallmark of acquired immunodeficiency
syndrome (AIDS) caused by the human immunodeficiency virus (HIV).
- HIV directly infects a small number of T helper cells, and also impairs
other immune system responses indirectly.
◘ Types of Immunodeficiency
1-Humoral immune deficiency, with signs or symptoms depending on the
cause, but generally include signs of;
i-Hypogammaglobulinemia (decrease of one or more types of antibodies)
with presentations including repeated mild respiratory infections,
ii-Agammaglobulinemia (lack of all or most antibody production) which
results in frequent severe infections and is often fatal.
2-T cell deficiency, often causes secondary disorders such as Acquired
Immune Deficiency Syndrome (AIDS).
3-Granulocyte deficiency
- including decreased numbers of granulocytes (granulocytopenia) or, if
absent, (agranulocytosis) such as of neutrophil granulocytes (termed
neutropenia).
- Granulocyte deficiencies also include decreased function of individual
granulocytes, such as in chronic granulomatous disease.
4-Asplenia, where there is no function of the spleen.

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5-Complement deficiency
- Is where the function of the complement system (C) is deficient.
- Immunodeficiency often affects multiple components, with notable
examples including severe combined immunodeficiency (SCI, which
is primary) and acquired immune deficiency syndrome (AIDS caused
by HIV virus, which is secondary).
◘ Autoimmune Diseases
 Autoimmune disorders: Disturbance of self-tolerance results in
autoimmune disease.
 Autoimmune diseases occur due to breakdown of the mechanisms
that maintain auto tolerance
 Auto-antibodies and self reactive T-cells are produced, resulting in
tissue damage by several mechanisms
♣ Etiology Of Autoimmune Diseases
1) Genetic predisposition:
- Familial incidence of autoimmune diseases,
- Most of autoimmune diseases appear to be associated with certain MHC
genes, specially MHC II genes e.g. Rheumatoid arthritis, Thyroditis,
Type I diabetes.
2) Exposure to infectious antigens that cross-react with self antigens
- An immune response to these antigens will result in immune attack
against self antigens e.g. Antibodies against M protein of Strept.
- pyogens may react with heart valves and cause Rheumatic fever
3) Alteration of self antigens or the appearance of new antigens under the
effect of drugs, chemicals, or viral infections.
4) Hormonal influences play a role e.g. systemic lupus erythmatosis (SLE)
affects women 10 times more than men.

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♦ Mechanisms of Disease Production
 The disease may be organ specific e.g. Hashimoto thyroditis.
 The disease may be systemic e.g. SLE or rheumatoid arthritis.
1) Binding of an autoantibody to host cells result in complement fixation
and tissue destruction.
- e.g. Haemolytic anemia (Type II hypersensitivity)
2) Formation of immune complexes and their deposition in tissues, joints,
kidney and skin.
- The immune complexes fix complement resulting in tissue damage e.g.
SLE and rheumatoid arthritis (Type III hyper.).
3) DTH reactions (Type IV)) due to auto reactive T-cells e.g. Ulcerative
colitis and type I diabetes.
♦ Laboratory Diagnosis
1- There is elevated serum immunoglobulins.
2- Complement levels may be decreased.
3- Immune complex detected in serum or organ biopsy.
4- Auto antibodies can be detected in serum e.g. anti-nuclear, anti-smooth
muscles, Rh factor and anti-mitochondrial Ab.
6- Testing for antibodies specific to particular Ag, involved in organ specific
diseases (anti-thyroid Ab) responses to a particular antigen in a fully
immunocomptent person.
- The treatment of autoimmune disease is typically with
immunosuppression- medication that decreases the immune response.
♣ Monoclonal Antibodies (mAbs) Treatment for Cancer Cells
- Monoclonal antibodies (mAb) are antibodies that are identical because
they were produced by one type of immune cell, all clones of a single
parent cell.

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- Cancer cells express a variety of antigens that are attractive targets for
monoclonal antibody-based therapy.
ADCC (Antibody-Dependent Cell-mediated Cytotoxicity)
CDC (Complement-Dependent Cytotoxicity)
ADEPT (antibody directed enzyme prodrug therapy)
MAb, (monoclonal antibody)
◘ Three mechanisms that could be responsible for the cancer treatment.
A. mAbs act directly when binding to a cancer specific antigens and induce
immunological response to cancer cells.
- Such as inducing cancer cell apoptosis, inhibiting growth, or interfering
with a key function.
B. mAbs was modified for delivery of a toxin, radioisotope, cytokine or
other active conjugates.
C. It is also possible to design bi-specific antibodies that can bind with their
Fab regions both to target antigen and to a conjugate or effector cell.
- However, the precise clinical mechanisms often remain uncertain.

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♦ Nutritional Aspects
 Nutrients are important for synthesis and secretion of signaling
molecules, cell proliferation, free radical generation, and the active
process of immune suppression at the end of the response.
 Lacking any nutrient would impair the response.
♦ Nutrition for Surveillance and for the Response.
 A healthy, balanced diet provides all nutrients necessary for adequate
operation of the surveillance mode because that is the normal condition
under which nutrient requirements were determined.
1-Vitamins
A-Vitamin C.
 It enhances immune function indirectly by maintaining optimal levels of
vitamin E.
 Leukocytes have high concentrations of vitamin C that is used rapidly
during infection and phagocytosis.
a) Vitamin C facilitates neutrophil chemotaxis and migration,
b) It induces interferon synthesis,
c) It increase T and B lymphocyte proliferation,
d) It maintains mucous membrane integrity, and
e) It has a role in the expression of delay type hypersensitivity.
f) It diminishes nonspecific extracellular free radical injury and
autotoxicity after the oxidative burst activity of stimulated neutrophils.
B- Vitamin B complex.
1- Folic acid and other B vitamins that are involved in 1-carbon metabolism
Because of the rapid proliferation of many immune cell types, the need to
synthesize DNA, transcribe message, and translate proteins may require
more of these vitamins.
2-Vitamin B6 deficiency induces marked changes in immune function and
thymic hormone activity is diminished.

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3-Folate and vitamin B12 deficiencies are linked to diminished host
resistance and impaired lymphocyte function.
4-Pantothenic acid deficiency suppresses humoral antibody responses to
antigens.
5-Thiamin, biotin, and riboflavin deficiencies have a moderate interfering
action on immune function.
C-Vitamin A
 Vitamin A deficiency compromises acquired adaptive, antigen-specific
immunity, atrophy of thymus, spleen, lymph nodes, and Peyer’s
patches.
 Vitamin A may serve as an adjuvant to elevate antibody responses to
soluble protein antigens in mice.
 Neutrophil phagocytosis is diminished by Vitamin A deficiency and
diminished cytolytic activity by NK cells.
 Vitamins A and D, because of their role in cellular differentiation and
transcription, are theoretically required in greater amount when
mounting an immune response.
D-Vitamin D, (Calcitriol),
 It has a significant regulatory role in cell differentiation and
proliferation of the immune system cells.
E-Vitamin E
 Vitamin E has a major antioxidant action that protects cell membranes
from free radical attack.
 Vitamin E stimulation of immunity is important in the elderly in whom
infectious disease and tumor incidence increase with age.
 Vitamin E facilitates host defense by inhibiting increases in tissue
prostaglandin synthesis from arachidonic acid during infection.

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2-Minerals:
 Zinc role in the reproduction of cells is of critical significance for
immunological reactions since nucleic acid synthesis depends, in part,
on zinc metalloenzymes.
 Zinc deficiency is associated with reversible dysfunction of T
lymphocytes in man.
 It causes atrophy of the thymus and other lymphoid organs .
 Iron deficiency produces anemia and decreases immunocompetence.
 Both iron deficiency and iron excess compromise the immune system.