Cellular Immune Response
& Hypersensitivity
Terry Kotrla, MS, MT(ASCP)BB
Fall 2007
The Cellular Immune Response
► Important




defense mechanism against:
viral infections,
some fungal infections,
parasitic disease and
against some bacteria, particularly those inside
cells.
The Cellular Immune Response
► Responsible
for :
 delayed hypersensitivity,
 transplant rejection and
 possibly tumor surveillance.
Scanning Electron Micrograph (SEM) of T cell
Lymphocytes attacking a cancer cell.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
Four Classifications
I (Immediate) Hypersensitivity
► Type II (cytotoxic) hypersensitivity
► Type III (immune complex mediated)
hypersensitivity
► Type IV (delayed) hypersensitivity
► Type
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.
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
► The most
subside when allergen is gone.
common immunological
abnormality seen in medical practice.
Doctors sometimes use skin tests to diagnose allergies. The
reactions shown here demonstrate allergic response.
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.
Type I (Immediate) Hypersensitivity
Anaphylaxis
Anaphylaxis
Anaphylaxis
Epipen
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.
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
Peripheral Smear
Type II (cytotoxic) Hypersensitivity
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.
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.
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.
Type III (immune complex mediated)
Hypersensitivity
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
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.
Positive TB Test
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.
Type IV (delayed) Hypersensitivity
Type IV (delayed) Hypersensitivity
Summary
Immunoglobulin Deficiency Diseases
► Primary
immunodeficiency syndrome
► Secondary immunodeficiency syndrome
► Acquired
Immunodeficiency Syndrome (AIDS)
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.
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.
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.
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.
The Immune Response, Functional
Aspects
► Recognition
► Processing
► Production
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.
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.
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
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.
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