Hypersensitivity

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Hypersensitivity and Types of Hypersensitivity reaction

MEGI KHABAZI
Hypersensitivity:
 When immune system works properly, it helps in elimination or removal of
antigens from host body by means of effector molecules.
 The effectors molecules generally induce local inflammatory response and
removes antigen without extensively damaging host tissues.
 However in certain conditions such as when immune system does not work
properly or over activated, it causes deleterious effects resulting in
significant tissue damage, serious disease and even death. Such unwanted,
inappropriate and damaging immune response is termed
as hypersensitivity.
 Hypersensitivity reaction may develops in course of either cell mediated or
humoral immune response
 Various autoimmune disorders as well as allergies fall under the umbrella of
hypersensitivity reactions, the difference being that allergies are immune reactions
to exogenous substances (antigens or allergens), whereas autoimmune diseases
arise from an abnormal immune response to endogenous substances
(autoantigens).
Gell and Coomb’s Classification of Hypersensitivity
reaction

 Hypersensitivity reactions are classified as Immediate or delayed type on the basis


of time required by sensitized host to response to shocking dose of antigen.
 Hypersensitivity reactions can be distinguished by immune response and
difference in effectors molecules generated in course of reactions.
Immediate and Delayed hypersensitivity reactions

Immediate hypersensitivity reaction:


 Immediate hypersensitivity reaction is mediated by humoral antibody and manifests
within minutes to few hours.
 The anaphylactic reaction initiated by antibody or Ag-Ab complex are referred as
immediate hypersensitivity because it occurs within minutes or few hours after a
sensitized host encounter with antigen
 Type-I, II and III hypersensitivity reaction are immediate
Delayed hypersensitivity reaction:
 Delayed hypersensitivity reaction is mediated by sensitized CD4 T cells and manifests
slowly usually after 24 hours or more.
 It is called delayed because symptoms appears days after exposure to antigen.
 In delayed hypersensitivity reaction, the effector molecules are various cytokines
secreted by activated CD4 T cells themselves.
 Type-IV hypersensitivity depends upon activation of T cells and occurs within cell
mediated branch of immune response and termed as delayed type hypersensitivity
reaction (DTH).
Type I hypersensitivity reaction:
 Type-I hypersensitivity reaction is an immediate type of
reaction mediated by IgE.
 It is also known as anaphylactic reaction or allergy. It is
induced by certain types of antigen called allergens such as
pollengrains, dandruff, dusts, food components etc.
 Allergens induces humoral antibody response by the same
mechanism as other soluble antigens in the generation of
antibody secreting plasma cells and memory cells but the
difference is that the plasma cell secretes IgE class of
antibody.
Development of allergy or anaphylactic reaction requires two dose of antigen. 1 st dose is known as
sensitizing dose and 2nd dose is known as shocking dose.
Mechanism of Type I hypersesnsitivity
reaction:
1. Production of IgE antibody:
 At first allergen is processed and presented by antigen presenting cells (APCs) to
CD4 T cells.
 Activated CD4 t cells divides to form T helper cell and memory cell.
 T helper produces IL4.
 At the same time B cell bind to antigen in presence of APC and IL4 and gets
activated.
 Activated B cells divide to form plasma cells and memory cells.
 Up to this step, mechanism is similar to that of normal humoral immune
response. The difference between Type I hypersensitivity and normal immune
response is that the plasma cell produces IgE antibody instead of IgM or IgG.
2. Sensitization:
 Fc region of IgE antibody has receptor on the surface of tissue mast cells and blood
basophils. So the IgE antibody binds to FcRI of mast cells and basophils.
 This binding of IgE to mast cell and basophil is known as Sensitization and the mast cells
and basophils are said to be sensitized.
3.Shocking dose of antigen:
 When the same antigen (allergen) enter into same host for second
time in life, antigen cross linked with Fab region of IgE molecules on
the surface of mast cell or basophils.
4. Degranulation of mast cell:
 The cross-linking of antigen (allergen) to IgE antibody  causes
degradation of mast cell and basophils releasing various
pharmacological active chemicals such as histamine, heparin,
serotonin, cytokines, leucotriene, prostaglandin etc.
5. Allergic reaction:
 These active chemical mediators acts on surrounding tissue
producing various symptoms of allergy such as vasodylation, smooth
muscle contraction, mucus production, sneezing, etc.
 The allergic reaction may be localized or systemic depending upon
types of allergen.
First
ex posure
6
1
Second
ex posure Cytokines
and

2 3
 Transmission electron micrograph showing a skin mast cell containing many
prominent electron-dense granules

E, Anaphylactic mast cell


degranulation with fusion of
mast cell granules. F
Piecemeal mast cell
degranulation in asthmatic
bronchial
mucosa
Type II hypersensitivity reaction:
Mechanism and examples
 Type II hypersensitivity reaction involves
antibody mediated destruction of cells. It is
also known as cytotoxic reaction.
 In this hypersensitivity reaction, specific
antibody (IgG or IgM) bound to cell surface
antigen and destroy the cell.
 The killing of cell can occurs by one of the
three mechanisms. They are-
1.Complement mediated cell lysis
2. Antibody dependent cell mediated cytotoxicity
(ADCC)
3. Opsonization
1. Complement mediated lysis of cell:

 Complement system is a system of lytic enzyme which are


usually inactive in blood.
 Enzymes of complement system are activated by antigen-
antibody complex.
 When antibody binds to antigen (microorganism or RBC) they
form Ag-ab complex.
 Ag-ab complex can activate complement system by three
different mechanism-classical pathway, alternate pathway and
lectin pathway.
 Activated complement proceeds in cascade mechanism.
 When complement is activated on the surface of cell (RBC) it
causes lysis of cell.
2.Antibody dependent cell mediated
cytotoxicity (ADCC)
 Antibody binds with antigen by its Fab portion. However Fc
region of antibody has receptor on cytotoxic cells. So, antibody
cross link target cell (microorganism or RBC) with cytotoxic
cells and promote killing.
 Most cytotoxic cells contain storage of hydrolytic and digestive
enzymes. These enzymes are released on the surface of target cell
, killing them.
 Here antibody itself does not kill or destroy cell but rather
mediate killing by presenting antigen to cytotoxic cell. Similarly
cytotoxic cell depends upon antibody to bind antigen. So this
mechanism is known as Antibody dependent cell mediated
cytotoxicity.
3. Opsonization
 When antigen enters into host body, antibodies are produced.
 Antibody binds to antigen through Fab region. Fc region of
antibody remains free.
 Phagocytic cells such as Neutrophils, macrophages and
monocytes have receptors that can bind to Fc region of
antibody
 In this case antibody molecule directly cross links antigen
(Microrganism or RBC or target cell) with phagocytic cells.
This cross-linkage activates phagocytic cells and increases
the rate of phagocytosis.
 This increased rate of phagocytosis by binding of antibody
to antigen is called Opsonization.
Some examples of Type II hypersensitivity
reaction:
 Acute hemolytic transfusion reaction
 Autoimmune hemolytic anemia
 Bullous pemphigoid
 Pemphigus vulgaris
 Rheumatic fever
 Drug-induced neutropenia and agranulocytosis
 Goodpasture syndrome
 Graves disease
 Hemolytic disease of the fetus and newborn
 Immune thrombocytopenia (ITP)
 Hyperacute transplant rejection
 Myasthenia gravis
 Pernicious anemia
Type III hypersensitivity reaction:

 The reaction of antibody with antigen generates immune complex. In most of the cases, these immune
complexes are removed from blood circulation. Some immune complexes are removed by phagocytic action of
phagocytic cells in blood. Most other immune complexes are first carried by blood to spleen where they are
destroyed by macrophages. Complement system is also needed for removal of immune complexes from blood
to spleen.
 In some cases large amount of immune complexes are formed and deposited on various body parts and leads to
tissue damage resulting in Type III hypersensitivity reaction.
 If immune complexes are not removed from blood, they accumulate on wall of blood vessels and on tissue .
 Type III hypersensitivity reaction is characterized by deposition of immune complexes on various tissues such
as wall of blood vessels, glomerular basement membrane of kidney, synovial membrane of joints and choroid
plexus of brain.
 Deposition of immune complexes initiates reaction resulting in damage of surrounding tissue and cause
inflammation.
 Type III hypersensitivity reaction is characterized by deposition of immune complexes on various tissues
such as wall of blood vessels, glomerular basement membrane of kidney, synovial membrane of joints
and choroid plexus of brain.
 Deposition of immune complexes initiates reaction resulting in damage of surrounding tissue and cause
inflammation.
 In some cases large amount of immune complexes are formed and deposited on various body parts and
leads to tissue damage resulting in Type III hypersensitivity reaction.
 If immune complexes are not removed from blood, they accumulate on wall of blood vessels and on
tissue .
Factors that causes deposition of immune complex and increase
susceptibility to Type III hypersensitivity reaction:

1. Persistent infection:
 In persistent infection such as Malaria, large number of immune complexes are formed and deposited
in tissues.
2. Complement deficiency:
 Complement removes immune complexes from blood, but when complement system is deficient,
large amount of immune complexes circulates in blood and deposits in tissues.
3. Autoimmunity:
 In autoimmune disease, large amount of immune complexes are formed and deposited in tissues.
4. Genetic defects:
 In certain genetic defects, small and soluble immune complexes are formed that can not be
phagocytosed.
Types of Type III hypersensitivity
reaction:
 1. Localized Type III hypersensitivity reaction:
 2. Generalized Type III hypersensitivity reaction:
1. Localized Type III hypersensitivity
reaction:
 Acute Arthus reaction is an example of localized Type
III hypersensitivity reaction.
 When antigen is injected or enters intradermally or
subcutaneously, they bind with antibody to form
localized immune complexes which mediate acute
Arthus reaction within 4 to 8 hours.
 As the reaction develops, localized tissue damage and
vascular damage results in accumulation of fluids
(edema) and RBCs (erythema) at the site of antigen
entry.
 The severity of reaction can vary from mild swelling
and redness to tissue necrosis.
2. Generalized Type III hypersensitivity
reaction:
 Serum sickness is an example of generalized Type III hypersensitivity reaction.
 When large amount of antigen enter blood stream and bind to antibody, circulating immune
complexes forms.
 If antigens are in significantly excess compared to antibody, the immune complexes formed are
smaller and soluble which are not phagocytosed by phagocytic cells leading to Type III
hypersensitivity reaction.
 The manifestation of serum sickness depends on the quantity of immune complex as well as
overall site of deposition. The site may vary but accumulation of complexes occurs at site of
blood filtration.
 Generalized Type III hypersensitivity reaction at different site results in different diseases such
as Glomerulonephritis (Kideny), vasculitis (arteries), Arthritis (synovial joints).
Serum sickness
 The cardinal features of serum
sickness are rash, fever, and
polyarthralgias or polyarthritis,
which begin one to two weeks after
the first exposure to the responsible
agent and resolve within a few
weeks of discontinuation.
 Although patients may appear very
ill and uncomfortable during the
acute febrile stage, the disease is
self-limited, and prognosis is
excellent once the responsible drug
is stopped.
Type IV hypersensitivity reaction or
Delayed type hypersensitivity (DTH)
 Type IV hypersensitivity reaction is also known as delayed type hypersensitivity (DTH).
 When some subpopulation of activated T helper cells encounters certain antigen, they
secrete cytokines that induce a localized inflammatory reaction called delayed type
hypersensitivity (DTH).
 The reaction is characterized by influxes of non-specific inflammatory cells particularly
macrophages.
 DTH occurs slowly and reaches a peak level within 48-72 hours after 2 nd encounter of
antigen.
 In DTH tissue damage is mediated by Th cells and macrophages but not by antibodies.
 Although DTH causes some tissue damage, it is very important defense mechanism
against intracellular microorganisms such as Mycobacterium tuberculosis,
Mycobacterium leprae,
DTH occurs in two phases:

1. Sensitizing phase of DTH:


2. Effector phase of DTH:
1. Sensitizing phase of DTH:
 DTH begins with initial sensitization by primary contact with
antigen. At first antigen is processed and presented by
antigen presenting cells (APCs) to CD4+T cell.
 CD4 +T cells are activated to form TH cells.
 During this TH cells are clonally expanded by binding with
MHC-II molecule carrying antigen by appropriate APCs.
Varieties of APCs have been shown to be involved in activation
of DTH response including langerhans cell and macrophages.
 CD4+ T cell are the primary cell activated during sensitizing
phase of DTH response. However in some cases CD8 + cells are
also found to induce DTH response.
2. Effector phase of DTH:
 A subsequent or second time exposure to antigen induces the effector
phage.
 In this phase, TH1 cell secretes varieties of cytokines that recruits and
activates macrophages and other non-specific inflammatory cells to
the site of antigen injection.
 Macrophages are the principle effector of DTH response. The
activated macrophages exhibit increased level of phagocytosis and
increased ability to kill the antigen (microorganisms) by various
cytotoxic lytic enzymes.
 Activated macrophages releases lytic enzymes that damage
surrounding tissues and intracellular bacteria.
 The influx and activation of macrophages in DTH is important in host
defense against intracellular bacteria and parasite, where circulating
antibodies cannot reach them.
2. Effector phase of DTH:

 Increased phagocytic activity and build up lytic enzyme from macrophages in the
area of infection leads to non-specific destruction of tissues and intracellular
pathogens.
 Generally pathogens are killed rapidly with little tissue damage. However in some
case, especially if the antigen is not easily cleared, a pro-long DTH response can
itself become destructive to host as intensive and chronic inflammation develops
into a visible granulomatous reaction.
 A granuloma develops when continuous activation of macrophages induces the
epitheloid shape and some time fusion of macrophages to form multinucleated
giant cells. These giant cells displace normal cells forming palpable nodules and
release high concentration of lytic enzymes which destroy surrounding tissues
leading to necrosis.
Some examples of Type IV
hypersensitivity reaction:
 Acute and chronic transplant rejection
 Contact dermatitis (e.g., nickel, poison ivy, cosmetics, rubber gloves)
 Drug reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with
eosinophilia and systemic symptoms (DRESS)
 Graft-versus-host disease
 Mantoux tuberculin skin test for latent tuberculosis
 Candida skin test
 Multiple sclerosis
 Guillain-Barré syndrome
 Hashimoto's thyroiditis
 Rheumatoid arthritis
 Type 1 diabetes mellitus
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