Hypersensitivity
Excess
and inappropriate activation of
our immune system to an antigenic stimulus results the tissue damage by
chemical mediators released from tissue is called Hypersensitivity.
Hypersensitivity reactions require a
pre-sensi-tized (immune) state of the host. However based on the mechanisms
involved and time taken for reaction, they are classified in to four groups;
Type I, type II, type III and type IV,
TYPE I HYPERSENSITIVITY
Allergen (antigen )macrophage
(antigen-presenting cell) Antigen presentation
the cell (helper Tcell ) B cell
IgE produced mast cell Allergen binds to
IgE molecules.
Type I
hypersensitivity is also known as immediate or anaphylactic
hypersensitivity.
·
This reaction occurs in
skin (urticaria and eczema),eyes(conjunctivitis), nasopharynx
(rhinorrhea, rhinitis), bronco pulmonary
tissues (asthma) and gastrointestinal tract (gastroenteritis).
·
However it takes 15 –
30 minutes from the time of exposure to the antigen, but some-times it may be
last for 10-12 hours .
·
This is usually
mediated by IgE Antibody.
·
The primary cellular
component of this hypersensitivity reaction is mast cell or basophil.
Sequential events
Anaphylaxis
It includes sensitization
stage and Effector stage
Sensitization stage
It starts with initial exposure of patient to an
allergen, allergen may be sea food, pollen and latex rubber once the
allergen enters inside APC or Dentritic
cell taken up the allergen and broken in into small fragments thereby
display the fragments on the surface along the MHC II molecule, and then
migrant into nearby Iymphnode, where it
initiates the TH cell to be matured into THI cell and TH2 cell,
this TH2 cell is now bind with the APC with the help of CD4.once
it is bound on APC,TH2 cell start to secrete cytokine like IL-4
triggers the B cell to be activated,
once the B cells are getting activated that becomes differentiated
into plasma cells and memory B cells.
These plasma cells are
secreting Abs called IgE . this IgE
antibodies are freely circulating in blood. However, some of the Abs are bound
with allergen and unbound Antibodies will be migrated into mast cell once it makes contact to mast
cell with FC receptor it becomes sensitized .
Effector stage
This stage is
effectively destruct the cells or it seems to be the stage of damage. When the
same allergen enters inside the host for
the second time, allergen gets attached on the surface of IgE on sensitized
mast cell. Which results in
Degranulation in which, physiological indicators such as histamine,
leukoterine prostaglandin are liberated
from mast cell.
Complication
As a result, mediator
trigger smooth muscels contractions in bronchiole, arterioles dilate
reduce blood pressure. This increases capillary permeability and rapid loss of
fluid into tissue
Space . eg. Anti
sera , Insect venom produce systemic anaphylaxis.
Localized Anaphylaxis (
Atopy )
This reaction includes allergic rhinitis
(hayfe-ver), Asthma , food allergy , atopic dermatitis and drug allergy.
Allergic rhinitis
It is caused by
airborne allerge it is the common atopic
disorder. Approximately, 10% of the population is getting affected. It is
resulted when the person exposure to airborne allergen thereby conjunctiva
and nasal mucosa are prone affected. Moreover,
persons develop with symptoms of running nose as well as sneezing and coughing.
Bronchial Asthma
It is the second most
atopic disorder. It develops due to contraction of bronchial smooth muscle and
airway edema. In this, alveoli get filled with fluid and mucous as a consequence whistling sound
forms during exhalation.
Treatment
·
Symptomatic treatment
is achieved with anti-histamines which block histamine receptors.
·
Chromo Lyn sodium
inhabits mast cell degranulation, probably, by inhibiting Ca++ influx.
·
Late onset allergic
symptoms, particularly bronchoconstriction which is mediated by leukotriene,
are treated with leukotriene receptor blockers (singular, Aciculate) or
inhibitors of the cyclooxygenase pathway (Zileutoin).
·
Symptomatic, although
short term, relief from bronchoconstriction is provided by bronchodilators
(inhalants ) such as isoproterenol derivatives (Terbutaline , Albuterol).
·
Theophylline
elevates cAMP by inhibiting cAMP - phosphodiesterase and inhibits intra-cellular Ca release is also
used to relieve bronco pulmonary symptoms.
·
The use of IgE
antibodies against the Fc portions of IgE that binds to mast cells has been
approved for treatment of certain allergies ,as it can block mast cell
sensitization.
·
Hyposensitization
(immuno therapy or desensitization ) is another treatment modality which is
successful in a number of allergies, particularly to insect venoms and, to some
extent, pollens . the mechanism is not clear.
Type II
Hypersensitivity
·
Type II
hypersensitivity is also known as cytotoxic hypersensitivity as it affects cells and tissues.
·
The antigens are
normally endogenous, even exogenous chemicals (haptens) also lead the type II
hypersensitivity, when it is attached on cell membrane.
·
The hypersensitivity
reaction develops due to destruction of self cell. Though, self cell seems to
be healthy there is a wrong signal take place to be destructed, it may be due
to persistant infections and the
reaction is mediated by IgG and IgM antibodies. Some time normal cell may be
coated by these antibodies, which
trigger the cytotoxic cells of our system to be bound over the target cells.
Thus, destruction takes places the normal cell get damaged.
Examples
·
Hemolytic anemia,
·
Granulo cytopenia and
·
Thrombocytopenia
Hemolytic anemia
It is the auto immune
disorder. In this, cytotoxic cells of host system kill the target RBC cells
which results in hemolytic anemia.
Mechanism
It is otherwise known
as anti body mediated hypersensitivity it occurs the following steps of the
mechanism they are complement activation opsonisation or opsonized phagocytosis
and ADCC
Complement Activation
Antigen on the RBC are
recognised by antibody present in the
individual, Abs bind to this antigen, which initiates the complement C1 to be
attached with FC portion of bound antibody this activates classical path way
there by destruction of RBC occurs in two
ways; they are opsionisation or
opsonized phagocytosis as a result of complement activation C3b complement can
be deposited on the cell surface, this C3b protein act as opsonin and form a coat on cell. As phagocytic cells such as
Macrophage have the specific C3b receptor, RBC with bound antibody cells can be
easily phagocytosed
Membrane attack complex
Membrane attack complex is the group of complement
proteins that are deposited on the
target cell surface it forms a pore in
the membrane of the cell which result in cell lysis.
Thrombocytopenic
purpura
The reaction time is
minutes to hours. Prolonged in take of drug
may be responsible for this reaction for example sedormid purpura . it is a sedative drug . when it is
continuously administered , it forms a coat over the platelets and altering
their surface antigenicity there fore auto antibodies are formed against this
coated platelet-antigens and lyse the platelets which results in
thrombocyto penic purpura.
TYPE III
HYPERSENSITIVITY
Type III
hypersensitivity is other wise termed as immune complex hypersensitivity since
immune complex or antigen antibody complex are involved. In this, deposition of
immune complexes triggers the inflammation, complement binding and platelet aggregation.
complement proteins
C3a, C4a, C5a plays an
important role in triggering this reactions.
. Complement system is getting activated when
the complement is fixed on immune
complexes.
. whenever the
antigen enters the body antibodies are
developed against the antigen and from antigen antibody complex. Once antigen antibody complex is formed
complement may fix on this complex. However
IgG antibodies are mainly involved in this reaction.
·
Antigen may arise from
either exogenous or endogenous.
Example : systemic
lupus erythematous .
Sequential Events
·
Antigen enter (may be
extrinsic or intrinsic ) in circulation.
·
Extrinsic means foreign
(bacteria , viruses) and intrinsic means auto antigen
·
Activate B cell in
circulation
·
B cells are
differentiated into plasma cells
·
Antibodies are released
·
Antigen is attached on
antibodies and from antigen antibody complex.
·
Once antigen antibody
complex is formed which allows the complements to be attached on the FC portion
of antibody and initiates complement activation.
·
CI recruits classical
pathway
·
The important
complement fragment is C3a and C5a.
·
Antigen antibody
complex with complements and freely circulating in blood or body fluids and
tissues.
·
Normally the immune
complex cells are phagocytosed when the
complex is formed with soluble antigen as well as smaller in size.
·
As result, complex is
deposited in vital organ, kidney and the blood vessels of the body.C3b produced
during activation would initiate membrane attack complex.
·
Where ever the complex
is formed, five lobed structure neutrophils come in contact to antigen antibody
complex.
·
Arrival of neutrophils
to the spot of reaction is due to C5a
·
Followed by inflammation lysomal
enzymes released from neutrophils then tissue damage is resulted.
Removal of immune
complex
·
Normally the
developments of antigen antibody complex
do not cause harm to host system since these complexes are getting phagocytosed
by macrophages.
·
Complement attached on
antigen antibody complex are easily engulfed and cleared.
·
Sometimes macrophage
fails to eliminate this complex if it is in excess.
·
Excess antigen antibody
complex may be resulted due to overwhelming
infection self antigen.
·
Thus more and more
immune complexes are formed.
·
Induce neutrophils to come and contact to spot .
·
Inflammatory reaction taken place resulting tissue damage.
Example
Arthus reaction
Serum sickness
Arthus reaction :
The reaction associated with the experimental set up was performed by
arthus in the year 1930. When an antigen
is injected intradermally into a hypersensitized animal (rabbit ), a localized
cutaneous inflammatory reaction occurs by initiating complement fixation.
Arthus reaction is due to ischemia that results from platelet induced thrombi
occluding the blood vessels at the site of the most intense reaction.
Serum sickness : It
develops mainly through serum transfusion when the serum ( horse ATS )is administered into host to
treat tetanus, the horse serum proteins being foreign and which induce antibody
formation in the host. Thus more and more immune complex are formed which casues unwanted consequences.
Symptom:
Fever, weakness, vasculities
, edema , erythema, and rarely lymphadenopathy.
Systemic lupus
Erythematosus:
It is developed due to
the formation of auto antibodies against nucleic acid.
system produces large
quantities of antibodies in response to initial exposure of profuse amount of antigen, when it enters
into blood. These antibodies are freely circulating in the blood. During second
exposure the same antigen enter for the second time that may reacts with
existing antibody to form antigen antibody
complex. This antigen antibody complex is inhibiting free flow of blood.
TYPE IV
HYPERSENSIVITY OR DELAYED HYPERSENSITIVITY
Definition : Type IV
hypersensitivity is often called delayed hypersensitivity as the reaction takes
two or three days to develop, unlike the other hypersensitivity, it is not
antibody mediated , but rather is a type of cell mediated immune response.
Type IV
hypersensitivity reactions are in appropriate
or excessive immune reactions that are mediated by specific subsets of
CD4 helper cells immune responses are themselves cause tissue injury and
disease. This is derived from the idea
that an immune responses are themselves
cause tissue injury and disease. This is
derived from the idea that an immune response to an antigen may result in
sensitivity to challenge with that antigen and therefore hypersensitivity
occurs . it includes two phases namely ,
sensation phases and effector
phase. As this reaction takes long time for T
cells to be sensitized , it is called delayed hypersensitivity.
In this CD4 TH cell, CD8 TCytotoxic cells are involved in accordance with type of
MHC molecule which presents the antigen . if peptide antigen is presented along
with MHC-II which interacts with CD4THCell while MHC-I CD8,
Tcytotoxic cells are involved.
Sequential events
Sensitation phase
It takes one to two weeks and is developed due to
antigenic stimulus. Whenever the antigen
( bacteria ) enters inside
the host system, which are taken up by the antigen presenting cells
( APCs ) such as dendritic
cells thereby antigens are digested
and display of antigen occurs on the surface of APC along with MHC-II
molecule.
Then these cells are
migrated into nearby lymph node where
there is an interaction takes place between APC and CD4 marker of T cell.
However in the presence of cytokine secreted by dendritic cells Macrophage
is getting activated thereby T cell is differentiated into THcell then
TH cell is further matured into THI cell and Ag specific memory T cell
then these cells are migrated the site of infection and do work towards the
elimination of pathogen . as the T cells are sensitized due to above
process this phases is known as
sensitization phase.
Effector phase
This phase is developed due to re exposure of same antigen. In this,
same way antigen is taken up by dendritic cell and presented it along with MHC II,
thereby resident Macrophage is getting
activated as a result cytokines are released then it activates Ag
specific Memory Tcell ( already
sensitized ). Then the memory T
cell is getting proliferated and differentiated into THI cell which releases Interferon gammalTumour necrosis factor and interleukin2
, which attracts and recruits
various inflammatory cells (macrophages)
at the spot of reactions and accumulation of these cells resulting
tissue damage.
Usually the cytokines derived from TDTH
are Interferon , Interleukin-2 ( IL2) ,MCAF ( monocyte Chemotactic and activating factor), TNF, MIF and IL3 all
these are effectively involved in delayed hypersentivity reactions.
Interferon-
Activating the resting macrophage for microbial killing.
Interleukin-2
– Stimulating the proliferation of TH cell
Contact Dermatitis :
Whenever the outer skin or skin layer
exposure to the allergen for the first skin time , the allergen can be
processed by skin macrophages and carried into T cells. As a result T cells are
getting activated . During the second exposure the allergen is attracted by
activated lymphocyte and macrophage to
the area, their intense response toward
antigen destroys epidermal cells in the immediate vicinity, which results in itchy papule,
blisters.
Tuberculin Test ( Mantoux test )
It is usually performed based on the principle of delayed
hypersentivity reactions. It is a test
to detect whether the patient has the
particular infection or not . take 0.1
ml of PPD ( purified protein derivative)
containing 5 TU. It is injected
intracutaneously on the flexor aspect of
forearm using a tuberculin syringe and
then the patient is allowed to be incubated for 48 to 72 hours. After this Diameter of induration has to be checked , if it is
more than 10mm the result is positive, if not it is negative.
Delayed Hypersensitvity
In this reaction, when the person exposure to
allergen for the first time which initiates the T cells to be activated. During the second exposure ,
of the same allergen , which activates already sensitized T cells there by
releasing of chemical substances from
the cell naturally lysis the tissues at the infected sites which results in
tissue damage and accumulation of macrophages . in the infected sites inflammation appears at 24 to 48 hours.
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