Cellular Immune Response

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Cellular Immune Response Hypersensitivity
Reactions

• Terry Kotrla, MS, MT(ASCP)BB
• Fall 2006

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The Cellular Immune Response

• Important defense mechanism against
• viral infections,
• some fungal infections,
• parasitic disease and
• against some bacteria, particularly those inside
  cells.

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The Cellular Immune Response

• Responsible for
• delayed hypersensitivity,
• transplant rejection and
• possibly tumor surveillance.

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Scanning Electron Micrograph (SEM) of T cell
Lymphocytes attacking a cancer cell.
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The Cellular Immune Response

• This branch of the immune system depends on the
  presence of thymus-derived lymphocytes (T
  lymphocytes).
• Initiated by the binding of the antigen with an
  antigen receptor on the surface of the sensitized
  T lymphocyte.
• Causes stimulation of the T lymphocyte into
  differentiation into two main groups of cells.

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T Lymphocytes

• Helper and suppressor T cells that regulate the
  intensity of the body's immune response.
• T cells capable of direct interaction with the
  antigen. This group can be divided further.
• T cells which, on contact with the specific
  antigen, liberate substances called lymphokines.
• Cytotoxic T cells which directly attack antigen
  on the surface of foreign cells.

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Lymphokines

• A mixed group of proteins.
• Macrophages are probably the primary target
  cells.
• Some lymphokines will aggregate macrophages at
  the site of the infection,
• others activate macrophages, inducing them to
  phagocytose and destroy foreign antigens more
  vigorously.

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Lymphokines

• Attract neutrophils and monocytes to the site of
  infection.
• The end result of their combined action is an
  amplification of the local inflammatory reaction
  with recruitment of circulating cells of the
  immune system

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Lymphokines

• Contact between antigen and specific sensitized T
  lymphocytes is necessary to cause release of
  lymphokines.
• Once released the lymphokine action is not
  antigen specific for example, an immune reaction
  to the tubercle bacillus may protect an animal
  against simultaneous challenge by brucella
  organisms.

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Cytotoxic T cells

• Attach directly to the target cell via specific
  receptors.
• The target cell is lysed
• The cytotoxic cell is not destroyed and may move
  on and kill additional targets.

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Natural Killer Cell

• At least two types of lymphocytes are killer
  cells -- cytotoxic T cells and natural killer
  cells.
• To attack, cytotoxic T cells need to recognize a
  specific antigen, whereas natural killer or NK
  cells do not.
• Both types contain granules filled with potent
  chemicals, and both types kill on contact.
• The killer binds to its target, aims its weapons,
  and delivers a burst of lethal chemicals.

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Control of the Immune Response

• Genetic control
• Rabbits usually produce high levels of antibodies
  to soluble proteins, while mice respond poorly to
  such antigens.
• Within a species it has been found that some
  genetic types are good antibody producers, while
  others are poor
• Termed responders and non-responders.

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Cellular control

• Specific immune response is classically divided
  into two branches, antibody medicated immunity
  of B lymphocytes and cell mediated immunity of T
  lymphocytes.
• T cells play an important role in regulating the
  production of antibodies by B cells.
• Helper T cell - upon interaction with an
  antigenic molecule they release substances which
  help B lymphocytes to produce antibodies against
  this antigen.
• Suppressor T cell are thought to "turn off" B
  cells so that they can no longer cooperate with
  normal T cells to induce an immune response.
• Normal immune response probably represents a very
  fine balance between the action of helper and
  suppressor T cells.

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Hypersensitivity Reactions

• When the immune system "goes wrong"
• Hypersensitivity denotes a state of increased
  reactivity of the host to an antigen and implies
  that the reaction is damaging to the host.
• The individual must first have become sensitized
  by previous exposure to the antigen.
• On second and subsequent exposures, symptoms and
  signs of a hypersensitivity state can occur
  immediately or be delayed until several days
  later.
• Immediate hypersensitivity refers to antibody
  mediated reactions, while delayed
  hypersensitivity refers to cell mediated immunity.

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Four Classifications

• Type I (Immediate) Hypersensitivity
• Type II (cytotoxic) hypersensitivity
• Type III (immune complex mediated)
  hypersensitivity
• Type IV (delayed) hypersensitivity

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Type I (Immediate) Hypersensitivity

• Reactions range from mild manifestations
  associated with food allergies to
  life-threatening anaphylactic shock.
• Atopic allergies include hay fever, asthma, food
  allergies and eczema.
• Exposure to allergens can be through inhalation,
  absorption from the digestive tract or direct
  skin contact.
• Extent of allergic response related to port of
  entry, IE, bee sting introduces allergen directly
  into the circulation.
• Caused by inappropriate IgE production
• This antibody has an affinity for mast cells or
  basophils.

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Type I (Immediate) Hypersensitivity

• When IgE meets its specific allergen it causes
  the mast cell to discharge its contents of
  vasoactive substances into the circulation.
• This release leads to symptoms of
• sneezing,
• runny noses,
• red watery eyes and
• wheezing.
• Symptoms subside when allergen is gone.
• The most common immunological abnormality seen in
  medical practice.

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Doctors sometimes use skin tests to diagnose
allergies.
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The reactions shown here demonstrate allergic
response.
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Type I (Immediate) Hypersensitivity

• Anaphylactic shock is the most serious and
  fortunately the rarest form of this Type I
  hypersensitivity.
• Symptoms are directly related to the massive
  release of vasoactive substances leading to fall
  in blood pressure, shock, difficulty in breathing
  and even death.
• It can be due to the following
• Horse gamma globulin given to patients who are
  sensitized to horse protein.
• Injection of a drug that is capable of acting as
  a hapten into a patient who is sensitive, ie,
  penicillin.
• Following a wasp or bee sting in highly sensitive
  individuals.
• Foods peanuts, shellfish, etc.

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Type I (Immediate) Hypersensitivity
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Anaphylaxis
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Anaphylaxis
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Anaphylaxis
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Epipen
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Type II (cytotoxic) Hypersensitivity

• Manifested by the production of IgG or IgM
  antibodies which are capable of destroying cells
  surface molecules or tissue components.
• Binding of antigen and antibody result in the
  activation of complement and destruction of cell
  to which the antigen is bound.
• Well known common example of this type of
  hypersensitivity is the transfusion reaction due
  to ABO incompatibility.

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Type II (cytotoxic) Hypersensitivity

• In addition to hemolytic reaction to blood the
  following types of reactions are included in this
  category
• Non-hemolytic reaction to platelets and plasma
  constituents.
• Immune hemolytic anemias
• Hemolytic disease of the newborn
• Anaphylactic reactions

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Peripheral Smear
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Type II (cytotoxic) Hypersensitivity
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Type II (cytotoxic) Hypersensitivity

• Some individuals make antibody which cross reacts
  with self antigens found in both the lung and
  kidney.
• Goodpasture syndrome associated with symptoms of
  both hemoptysis and hematuria.
• Some drugs may act as haptens, attach to the RBC
  membrane causing antibodies to be formed that
  react with the penicillin and lead to red cell
  damage and even hemolysis of the coated cells.

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Type III (immune complex mediated)
Hypersensitivity

• Antibody produced in response to exposure to
  antigen, forms immune complexes of antigen and
  antibody which may circulate.
• Complexes cause no symptoms, quickly disappear
  from the circulation.
• In some individuals the immune complexes persist
  in circulation causing clinical symptoms, some of
  them serious.
• Size of complexes produced seems important in
  determining whether they will be eliminated
  quickly from the body or retained long enough to
  cause damage.
• Classical clinical symptoms of immune complex
  disease are due to blood vessel involvement,
  i.e., vasculitis.
• Blood vessels of joints and the kidney are most
  frequently affected, giving rise to symptoms of
  arthritis and glomerulonephritis.

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Type III (immune complex mediated)
Hypersensitivity

• Mechanisms are as follows
• Soluble immune complexes which contain a greater
  proportion of antigen than antibody penetrate
  blood vessels and lodge on the basement membrane
• At the basement membrane site, these complexes
  activate the complement cascade.
• During complement activation, certain products of
  the cascade are produced,attract neutrophils to
  the area. Such substances are known as
  chemotactic substances.
• Once the polymorphs reach the basement membrane
  they release their granules, which contain
  lysosomal enzymes which are damaging to the blood
  vessel.
• This total process leads to the condition
  recognized histologically as vasculitis.
• When it occurs locally (in the skin) it is known
  as an Arthus Reaction, when it occurs
  systemically as a result of circulating immune
  complexes it is know as serum sickness.

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Type III (immune complex mediated)
Hypersensitivity
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Type III (immune complex mediated)
Hypersensitivity

• Chronic immune complex diseases are naturally
  occurring diseases caused by deposits of immune
  complex and complement in the tissues.
• Systemic Lupus Erythematosus (SLE)
• Acute glomerulonephritis
• Rheumatic fever
• Rheumatoid arthritis

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Type IV (delayed) Hypersensitivity

• Used to describe the signs and symptoms
  associated with a cell mediated immune response.
• Results from reactions involving T lymphocytes.
• Koch Phenomenon caused by injection of
  tuberculoprotein (PPD test) intradermally
  resulting in an area of induration of 5 mm or
  more in diameter and surrounded by erythema
  within 48 hours is a positive.

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Positive TB Test
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Type IV (delayed) Hypersensitivity

• Characteristics of this phenomenon are
• Delayed, taking 12 hours to develop.
• Causes accumulation of lymphs and macrophages.
• Reaction is not mediated by histamine.
• Antibodies are not involved in the reaction.
• Cell mediated reactions in certain circumstances
  are wholly damaging and may be seen in the
  following conditions
• Drug allergy and allergic response to insect
  bites and stings.
• Contact dermatitis.
• Rejection of grafts.
• Autoimmune disease.

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Type IV (delayed) Hypersensitivity
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Type IV (delayed) Hypersensitivity
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Summary
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Immunoglobulin Deficiency Diseases

• Primary immunodeficiency syndrome
• Secondary immunodeficiency syndrome
• Acquired Immunodeficiency Syndrome (AIDS)

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Primary immunodeficiency syndrome

• Due to a primary hereditary condition the
  cellular, humoral or both immune mechanisms are
  deficient.
• At one extreme there may be agammaglobulinemia or
  dysgammaglobulinemia in which one or several
  immunoglobulins are absent because of B cell
  deficiency.
• Thymic dysplasia will result in a T cell
  deficiency.
• Wiskott-Aldrich syndrome involves combined
  deficiencies.

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Wiskott-Aldrich syndrome

• Condition with variable expression, but commonly
  includes immunoglobulin M (IgM) deficiency.
• Always causes persistent thrombocytopenia and, in
  its complete form, also causes small platelets,
  atopy, cellular and humoral immunodeficiency, and
  an increased risk of autoimmune disease and
  hematologic malignancy.
• In one study of 154 patients with WAS, only 30
  had a classic presentation with thrombocytopenia,
  small platelets, eczema, and immunodeficiency
  although 84 had clinical signs and symptoms of
  thrombocytopenia, 20 had only hematologic
  abnormalities, 5 had only infectious
  manifestations, and none had eczema exclusively.
• WAS is an X-linked recessive genetic condition
  therefore, this disorder is found almost
  exclusively in boys.
• WAS has been the focus of intense molecular
  biology research, which recently led to the
  isolation of the affected gene product.

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Secondary Immunodeficiency Syndrome

• Results from involvement of the immunogenetic
  system in the course of another disease.
• Tumors of the lymphoid system.
• Hematologic disorders involving phagocytes.
• Protein losing conditions like the nephrotic
  syndrome.
• Other mechanisms occur which are not well
  understood which affect patients with diabetes
  mellitus and renal failure.
• Drugs and irradiation for cancer therapy may
  affect immunologic functions.
• Many drugs used therapeutically as
  immunosuppressive particularly after transplant
  surgery.

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Acquired Immunodeficiency Syndrome (AIDS)

• A condition in which T cell dysfunction results
  from a viral agent.
• Loss of T cell activity renders the patient
  susceptible to a wide variety of rare or unusual
  infections.

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The Immune Response, Functional Aspects

• Recognition
• Processing
• Production

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Recognition

• An individual does not generally produce
  antibodies to antigens regarded as "self".
• The system must have a memory so that the same
  antigen can be recognized after re-exposure.
• Lymphocytes are the recognition cells which
  initiate the immune response.

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Processing

• Subsequent to recognition as foreign, an
  antigen's determinants must be processed in such
  a way that a specific antibody can be produced.
• Macrophages are believed to perform this function
  because they ingest the antigen.

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Production

• The final phase of the immune response is the
  production of antibody.
• This manufacturing system must be regulated in
  some way so that the immune response can be
  discontinued when the antigen stimulation is
  withdrawn

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Terms Used to Describe Immunity

• Active immunity - two types
• Naturally from disease
• Artificially such as from injection or purposeful
  exposure to antigen, i.e., measles.
• Passive immunity involves receiving antibody or
  antibody protection produced by another.
• Naturally such as the transfer of maternal
  antibody across the placenta to the fetus or by
  colostrum.
• Artificially such as Hepatitis B Immune Globulin
  (also known as gamma globulin) given after
  exposure to Hepatitis B.

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References

• http//www.thebody.com/nih/immune_system.html
• http//pathmicro.med.sc.edu/ghaffar/hyper00.htm
• http//home.kku.ac.th/acamed/kanchana/bsi.html