Hypersensitive Reaction

Introduction
The immune response involves mobilization of a battery effector molecules to remove Ag. The effector molecules induce a localized inflammatory response that eliminates Ag without extensive damage of hosts tissue. Under certain circumstances this inflammatory response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity or allergy. The word hypersensitivity implies an increased response, the response is not always heightened but may, instead, be an inappropriate immune response to an antigen.

 Hypersensitive reactions may develop in the course of either HI or CMI response. The hypersensitivity reaction may be immediate

hypersensitivity if it occurs within the humoral branch &

initiated by Ab or Ag-Ab complexes because the symptoms are manifested within minutes or hours after a sensitized recipient encounters antigen. Delayed-type hypersensitivity (DTH) is so named in recognition of the delay of symptoms until days after exposure.

Several forms of hypersensitive reaction can be distinguished and classified according to the immune responses and the effector mechanisms responsible for cell and tissue injury.

Gell and Coombs Classification

Gell and Coombs proposed a classification scheme in which hypersensitive reactions are divided into 4 types:

Three types of hypersensitivity occur within the humoral branch

and are mediated by antibody or antigen-antibody complexes: IgE-mediated (type I) antibody-mediated (type II) immune complexmediated (type III)

A fourth type of hypersensitivity depends on reactions within the cell-mediated branch termed delayed-type hypersensitivity, or DTH (type IV). Each type involves distinct mechanisms, cells, and mediator molecules.

 Type I hypersensitivity reaction induced by antigens referred to as allergens. exhibits all the hallmarks of normal humoral response an allergen induces a humoral Ab response resulting in the generation of antibody-secreting plasma cells and memory cells. secretion of IgE by plasma cells makes it d/t from

normal humoral response.

 The IgE binds to Fc receptors on the surface of tissue mast cells and blood basophils. Mast cells and basophils coated by IgE are said to be sensitized.

A later exposure to the same allergen cross-links the

membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells .

 The pharmacologically active mediators released from the

granules act on the surrounding tissues. The principal effectsvasodilation and smooth-muscle contractionmay be either systemic or localized, depending on the extent of mediator release. Components of Type I Reactions ALLERGENS; IgE IgE receptors

Mast cells and Basophils

Pharmacologic Agents that mediate Type I reaction

The clinical manifestations of type I hypersensitive

reactions are related to the biological effects of the

mediators released during mast-cell or basophil

degranulation.
These mediators are pharmacologically active agents that act on local tissues as well as on populations of secondary effector cells:Eosinophils, neutrophils, T lymphocytes, monocytes and platelets.

 The mediators thus serve as an amplifying terminal effector mechanism much as the complement

system serves as an amplifier and effector of an

antigen-antibody interaction.

 When generated in response to parasitic infection, these mediators initiate beneficial defense processes,

including

vasodilatation

and

increased

vascular

permeability, which brings an influx of plasma and

inflammatory cells to attack the pathogen.

mediator release induced by allergens, results in unnecessary increases in vascular permeability and inflammation whose detrimental effects far outweigh any beneficial effect.

The mediators
The mediators can be classified as : primary or secondary Primary mediators are produced before degranulation and are

stored in the granules.

Secondary mediators are synthesized either after target-cell activation or are released by the breakdown of membrane

phospholipids during the degranulation process.

Difference in manifestations of type I hypersensitivity in different species or different tissues partly reflect variations in the primary and secondary mediators present.

Clinical Manifestations of Type I reaction

systemic or localized

range from life-threatening conditions, such as systemic

anaphylaxis and asthma, to hay fever and eczema, which are merely annoying.

Systemic Anaphylaxis
a shock-like and often fatal state whose onset occurs within minutes of a type I hypersensitivity reaction. induced in a variety of experimental animals and occasionally in humans.

wide range of antigens trigger this reaction in susceptible

humans: venom from bee, wasp, ant stings, drugs (penicillin, insulin &antitoxins) , Seafood, nuts.

 If not treated quickly, these reactions can be fatal. Epinephrine is the drug of choice for systemic anaphylactic reactions. -counteracts the effects of mediators

-improves cardiac output

-blocking further degranulation

Localized anaphylaxis
The reaction is limited to a specific target tissue or organ, often involving epithelial surfaces at the site of allergen entry. The tendency to manifest localized anaphylactic reactions is inherited and is called atopy.

Atopic allergies, which afflict at least 20% of the population in

developed countries, include a wide range of IgE-mediated disorders, including allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), and food allergies.

Regulation of Type I reactions

level of the IgE response induced by an antigen (i.e., its

allergenicity) depends on
-antigen dose -mode of antigen presentation - genetic constitution. the relative levels of the TH1 and TH2 subsets also are key to the regulation of type I hypersensitive responses TH1 reduce the response TH2 cells enhance it.

Controlling Hypersensitivity reaction (Type I)

to avoid contact with known allergens Immunotherapy repeated injections of increasing doses of allergens (hyposensitization). Use of drugs that block release of allergic mediators by interfering with various biochemical steps in mast-cell activation and degranulation.

Antibody-Mediated Cytotoxic (Type II) hypersensitivity reaction

 Type II hypersensitive reactions involve antibody-mediated

destruction of cells. Ab can activate the complement system creating pores in the membrane of a foreign cell or it can mediate cell destruction by antibody dependent cell-mediated cytotoxicity (ADCC).

In this process, cytotoxic cells with Fc receptors bind to the Fc

region of Abs on target cells and promote killing of the cells Antibody bound to a foreign cell also can serve as an opsonin.

enabling phagocytic cells with Fc or C3b receptors to bind and

phagocytose the antibody-coated cell.

Type II hypersensitivity reaction

Transfusion Reactions

Hemolytic Disease of the Newborn develops when maternal

IgG antibodies specific for fetal blood-group Ags cross the placenta and destroy fetal RBCs consequences can be minor, serious, or lethal. severe hemolytic disease of the newborn, called

erythroblastosis fetalis, most commonly develops when an

Rh+ fetus expresses an Rh antigen on its blood cells that the Rhmother does not express.

Drug-Induced Hemolytic Anemia

certain antibiotics (e.g., penicillin, cephalosporin, and streptomycin) can adsorb nonspecifically to proteins on RBC membranes, forming a complex similar to a hapten-carrier complex.

such drug-protein complexes induce formation of antibodies,

which then bind to the adsorbed drug on red blood cells. complement mediated lysis and thus progressive anemia. when the drug is withdrawn, the hemolytic anemia disappears.

Immune ComplexMediated (Type III) Hypersensitivity

 The reaction of antibody with antigen generates immune

complexes and this complexing of antibodies with antigen facilitates the clearance of antigen by phagocytic cells.

However, large amounts of immune complexes can lead to

tissue-damaging type III hypersensitive reactions. magnitude depends on : -the quantity of immune complexes -distribution within the body

The rxn could be localized if the complexes are deposited in

tissue very near to site of Ag entry. when the complexes are formed in the blood, a reaction develop wherever the complexes are deposited.

 Complex deposition is frequently observed on blood-vessel walls, in the synovial membrane of joints, on the glomerular basement membrane of the kidney, and on the choroid plexus of the brain. The deposition of these complexes initiates a reaction that

results in the recruitment of neutrophils to the site. The tissue

is injured as a consequence of granular release from the neutrophil. Type III hypersensitive reactions develop when immune complexes activate the complement systems array of immune

effector molecules

 The C3a, C4a, and C5a complement split products are

anaphylatoxins that cause localized mast-cell degranulation and consequent increase in local vascular permeability.

C3a, C5a, and C5b67 are also chemotactic factors for neutrophils,
which can accumulate in large numbers at the site of immunecomplex deposition.

 Much of the tissue damage in type III reactions stems from

release of lytic enzymes by neutrophils as they attempt to phagocytose immune complexes. The C3b complement component acts as an opsonin, coating immune complexes. A neutrophil binds to a C3b-coated immune

complex by means of the type I complement receptor, which is

specific for C3b. Because the complex is deposited on the basement membrane

surface, phagocytosis is impeded, so that lytic enzymes are

released during the unsuccessful attempts of the neutrophil to ingest the adhering immune complex.

 Further activation of the membrane-attack mechanism of the

complement system can also contribute to the destruction of

tissue. In addition, the activation of complement can induce aggregation of platelets, and the resulting release of clotting factors can lead to formation of microthrombi.

Manifestations of Type III hypersensitivity reactions. Localized

Injection of an antigen intradermally or subcutaneously into an

animal that has high levels of circulating antibody specific for that antigen leads to formation of localized immune complexes, which mediate an acute Arthus reaction within 48 h.

Generalized Type III Reactions

When large amounts of antigen enter the bloodstream and

bind to antibody, circulating immune complexes can form.

If antigen is in excess, small complexes form; because these are not easily cleared by the phagocytic cells, they can cause tissue-damaging type III reactions at various sites. Historically, generalized type III reactions were often

observed after the administration of antitoxins containing

foreign serum, such as horse antitetanus or antidiphtheria serum.

 In such cases, the recipient of a foreign antiserum develops

antibodies specific for the foreign serum proteins; these

antibodies then form circulating immune complexes with the foreign serum antigens. Typically, within days or weeks after exposure to foreign serum antigens, an individual begins to manifest a

combination of symptoms that are called serum sickness.

These symptoms include: Fever, weakness, generalized vasculitis (rashes) with edema and erythema, Lymphadenopathy, arthritis and sometimes glomerulonephritis.

 Manifestations of serum sickness depend on the

-quantity of immune complexes formed -overall size of the complexes, which determine the site of their deposition. The sites of deposition vary but, in general, complexes accumulate in tissues where filtration of plasma occurs this explains the high incidence of :

-glomerulonephritis
kidney),

(complex

deposition

in

the

- vasculitis (deposition in the arteries), -arthritis (deposition in the synovial joints) caused by serum sickness.

formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum sickness: Autoimmune Diseases; Systemic lupus erythematosus

Rheumatoid arthritis
Good pastures syndrome Drug Reactions Allergies to penicillin and sulfonamides

Infectious Diseases;
Post streptococcal glomerulonephritis Meningitis

Hepatitis
Mononucleosis Malaria Trypanosomiasis

Type IV or Delayed-Type Hypersensitivity (DTH)

 When some subpopulations of activated TH cells encounter certain types of antigens, they secrete cytokines that induce a localized inflammatory reaction called delayed-type

hypersensitivity (DTH).
The reaction is characterized by large influxes of nonspecific inflammatory cells, in particular, macrophages. The development of the DTH response begins with an initial sensitization phase of 12 weeks after primary contact with an antigen. During this period, TH cells are activated and clonally expanded.

 A subsequent exposure to the antigen induces the effector phase of the DTH response. In the effector phase, TH1 cells secrete a variety of cytokines that

recruit and activate macrophages and other nonspecific

inflammatory cells. A DTH response normally does not become apparent until an

average of 24 h after the second contact with the antigen; the

response generally peaks 4872 h after second contact. The delayed onset of this response reflects the time required for the cytokines to induce localized influxes of macrophages and their activation.

 Macrophages are the principal effector cells of the DTH response.

Cytokines elaborated by TH1 cells induce blood monocytes to adhere to vascular endothelial cells and migrate from the blood into the surrounding tissues. During this process the monocytes differentiate into activated macrophages.

Activated macrophages exhibit increased levels of phagocytosis

and an increased ability to kill microorganisms through various cytotoxic mediators.

In addition, activated macrophages express increased levels of

class II MHC molecules and cell-adhesion molecules and therefore function more effectively as antigen-presenting cells.

Autoimmune Diseases

DEFINITION An immune reaction against self-antigens is the cause of

certain diseases in human.

INTRODUCTION
immune system could go wrongly and, instead of reacting against foreign antigens, could focus its attack on self-antigens . While mechanisms of self-tolerance normally protect an individual from potentially self-reactive lymphocytes, there are failures. result in an inappropriate response of the immune system against self-components termed autoimmunity .

all self-reactive lymphocytes were eliminated during their

development in BM and thymus and that a failure to eliminate these lymphocytes led to autoimmune consequences.
50

Introduction
recirculating self-reactive lymphocytes have been shown. does not inevitably result in autoimmune reactions in the periphery. regulation through clonal anergy or clonal suppression.

breakdown in this regulation lead to activation of self-reactive

clones of T or B cells, generating humoral or cell-mediated responses against self antigens.

51

 reactions can cause serious damage to cells and organs,

sometimes with fatal consequences.

human autoimmune diseases can be divided into two broad categories:

organ-specific
systemic autoimmune disease.

Mechanism
1. Alteration of self-proteins (modification of the molecule) a. Partial degradation of autoantigens.

b.

Complexing of self-antigens with drugs or microorganisms.

4. Hidden antigens exposure.

5. Cross-reactions (molecular mimicry) Antibodies to streptococcal antigens may react with constituents of cardiac muscle or connective tissue in rheumatic fever. Rabies vaccine may rise to encephalitis.

CONT
(4) Breakdown of tolerance Bypass of helper T cell tolerance
Imbalance of suppressor-helper T cell function. Geneic fators Emergence of a sequestered antigen Polyclonal lymphocyte activation.

55

Organ-Specific Autoimmune Diseases

the immune response is directed to a target antigen unique to a single organ or gland, so that the manifestations are largely limited to that organ. cells of the target organs may be damaged directly by humoral or cell-mediated effector mechanisms.

56

CONT
alternatively, the antibodies may overstimulate or block the normal function of the target organ. Occur when lymphocytes or Abs bind to cell-membrane antigens, causing cellular lysis and/or an inflammatory

response in the affected organ.

Gradually, the damaged cellular structure is replaced by connective tissue (scar tissue), and the function of the organ declines.

HASHIMOTOS THYROIDITIS (DTH)

most frequently seen in middle-aged women, an individual produces auto-antibodies and sensitized TH1 cells specific for thyroid Ag. characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers. ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physiological response to hypothyroidism.

58

AUTOIMMUNE ANEMIAS
include pernicious anemia, autoimmune hemolytic anemia, and drug-induced hemolytic anemia.

Pernicious anemia is caused by auto-antibodies to intrinsic

factor, binding of auto-antibody to intrinsic factor blocks the intrinsic factormediated absorption of vitamin B12. in the absence of sufficient vitamin B12, which is necessary

for proper hematopoiesis, the number of functional mature

RBCs decreases below normal.
59

autoimmune hemolytic anemia

auto-antibody to RBC antigens is formed, triggering complement mediated lysis or antibody-mediated

opsonization and phagocytosis of the RBCs. Drug-induced hemolytic anemia

when certain drugs such as penicillin or the anti-hypertensive

agent methyldopa interact with RBCs the cells become antigenic.

60

GOODPASTURES SYNDROME
auto-antibodies specific for certain basement-membrane

antigens bind to the basement membranes of the kidney

glomeruli and the alveoli of the lungs. subsequent complement activation leads to direct cellular damage and an ensuing inflammatory response mediated by a build-up of complement split products.

61

 damage

to

the

glomerular

and

alveolar

basement

membranes leads to progressive kidney damage and pulmonary hemorrhage. death may ensue within several months of the onset of symptoms. biopsies stained with fluorescent-labeled anti-IgG and antiC3b reveal linear deposits of IgG and C3b along the

basement membranes

INSULIN-DEPENDENT DIABETES MELLITUS

disease affecting 0.2% of the population,
caused by an autoimmune attack on the pancreas. attack is directed against specialized insulin-producing cells (beta cells). attack destroys beta cells, resulting in decreased production of

insulin and consequently increased levels of blood glucose.

factors important in the destruction of beta cells: activated CTLs migrate into an islet and begin to attack the insulin producing cells. local cytokine production during this response includes IFNy, TNF-a, and IL-1.
63

INSULIN-DEPENDENT DIABETES MELLITUS

the first CTL infiltration and activation of macrophages, frequently is followed by cytokine release and the presence of

auto-antibodies, which leads to a cell-mediated DTH response

subsequent beta-cell destruction is thought to be mediated by cytokines released during the DTH response and by lytic enzymes released from the activated M. Auto-antibodies to beta cells may contribute to cell

destruction by facilitating either antibody-plus-complement

lysis or antibody-dependent cell-mediated cytotoxicity (ADCC)
64

Autoimmune Diseases are Mediated by stimulating or blocking auto-Abs

Abs act as agonists, binding to hormone receptors in the normal ligand and stimulating inappropriate activity. this usually leads to an overproduction of mediators or an increase in cell growth.

auto-antibodies may act as antagonists, binding hormone

receptors but blocking receptor function. this generally causes impaired secretion of mediators and gradual atrophy of the affected organ.
65

Autoimmune Diseases Mediated stimulating or blocking auto-Abs

Graves Disease: Production of auto-antibodies that bind the receptor for TSH and mimic the normal action of TSH, activating adenylate cyclase and resulting in production of the thyroid hormones

Unlike TSH, however, the autoantibodies are not regulated,

and consequently they over stimulate the thyroid. For this reason these auto-antibodies are called long-acting thyroid-stimulating (LATS) antibodies. Symptoms: Goiter (enlarged thyroid) and bulging eyes.
66

Autoimmune Diseases Mediated stimulating or blocking auto-Abs

Myasthenia gravis: is the prototype autoimmune disease mediated by

blocking antibodies.
auto-antibodies that bind the acetylcholine receptors on the motor end-plates of muscles, blocks the normal binding of acetylcholine and also inducing complement mediated lysis of the cells. progressive weakening of the skeletal muscles Affects mainly women. treated with drugs or immunosuppressants.
67

68

69

Systemic Autoimmune Diseases

the response is directed toward a broad range of target antigens and involves a number of organs and tissues. these diseases reflect a general defect in immune regulation that results in hyperactive T cells and B cells.

tissue damage is widespread, both from cell mediated

immune responses and from direct cellular damage caused by auto-antibodies or by accumulation of immune complexes.
70

Systemic Lupus Erythematosus

which typically appears in women between 20 and 40 years of age; the ratio of female to male patients is 10:1 characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction

more frequent in African-American and Hispanic women than

in Caucasians, although it is not known why this is so. affected individuals may produce autoantibodies to a vast array of tissue antigens, such as DNA, histones, RBCs, platelets, leukocytes, and clotting factors
71

Systemic Lupus Erythematosus

Interaction of these auto-antibodies with their specific

antigens produces various symptoms.

Auto-antibody specific for RBCs and platelets, for example,

can lead to complement-mediated lysis, resulting in hemolytic

anemia and thrombocytopenia, respectively

72

CONT.
when immune complexes of auto-antibodies with various nuclear antigens are deposited along the walls of small blood vessels, a type III hypersensitive reaction develops.

the complexes activate the complement system and

generate membrane-attack complexes and complement split products that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis.

Rheumatoid Arthritis
most often affecting women from 40 to 60 years old major symptom is chronic inflammation of the joints, although the hematologic, cardiovascular, and respiratory systems are also frequently affected.

Characterized by production of a group of auto-antibodies

called rheumatoid factors that are reactive with determinants in the Fc region of IgG.

74

 the classic rheumatoid factor is an IgM antibody with that reactivity. such auto-antibodies bind to normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints these immune complexes can activate the complement cascade, resulting in a type III hypersensitive reaction,

which leads to chronic inflammation of the joints.

Proposed Mechanisms for Induction of Autoimmunity

a variety of mechanisms have been proposed to account for

the T-cellmediated generation of autoimmune diseases

evidence exists for each of these mechanisms, and it is likely that autoimmunity does not develop from a single event but rather from a number of different events

76

CONT.
susceptibility to many autoimmune diseases differs between the two sexes

Hashimotos thyroiditis, systemic lupus erythematosus,

multiple sclerosis, rheumatoid arthritis, and scleroderma preferentially affect women. factors that have been proposed to account for this preferential susceptibility, such as hormonal differences

between the sexes and the potential effects of fetal cells in

the maternal circulation during pregnancy.

78

 The pancreatic beta cells of individuals with insulin-dependent diabetes mellitus (IDDM) express high levels of both class I and class II MHC molecules, whereas healthy beta cells express lower levels of class I and

do not express class II at all.

Similarly, thyroid acinar cells from those with Graves disease have been shown to express class II MHC molecules on their membranes.
this inappropriate expression of class II MHC molecules, which are normally expressed only on APCs may serve to sensitize TH cells to peptides derived from the beta cells or thyroid cells, allowing activation of B cells or TC cells or sensitization of TH1 cells against

self-antigens

79

Other evidence suggests that certain agents can induce some cells that should not express class II MHC molecules to express them (PHA) A number of viruses and bacteria can induce nonspecific polyclonal B-cell activation
Gram-negative bacteria, cytomegalovirus, and Epstein-Barr virus (EBV) are all known to be such polyclonal activators, inducing the proliferation of numerous clones of B cells that express IgM in the absence of TH cells

If B cells reactive to self-antigens are activated by this mechanism, auto-antibodies

can appear

Treatment of Autoimmune Diseases

Aimed at reducing only the autoimmune response while leaving the rest of the immune system intact

Current therapies for autoimmune diseases are not cures but merely palliatives, aimed at reducing symptoms to provide the patient with an acceptable quality of life

81

CONT
for the most part, these treatments provide nonspecific suppression of the immune system and thus do not distinguish between a pathologic autoimmune response

and a protective immune response

Immunosuppressive drugs (e.g., corticosteroids,

azathioprine, and cyclophosphamide) are often given with the intent of slowing proliferation of lymphocytes

Treatment of Autoimmune Diseases

By depressing the immune response in general, such drugs can reduce the severity of autoimmune symptoms general reduction in immune responsiveness, however, puts the patient at greater risk for infection or the development of cancer A somewhat more selective approach employs cyclosporin A or FK506 to treat autoimmunity

these agents block signal transduction mediated by the T-cell

receptor; thus, they inhibit only antigen-activated T cells while sparing nonactivated ones
83