Hypersensitivity Reactions basics

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Hypersentivity Reactions
Allergies Greek = altered reactivity

1906 von Pirquet coined term: hypersensitivity

Hypersensitivity reactions over reaction of the immune system to harmless environmental antigens
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Definition
Definition : Hypersensitivity refers to the injurious consequences in the sensitized host ,Following contact with specific Antigen
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How we classify Hypersensitivity

Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity reactions require a presensitized (immune) state of the host. Hypersensitivity reactions can be divided into four types: type I, type II, type III and type IV, based on the mechanisms involved and time taken for the reaction.
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Hypersensitivity
Immunity protects against
Infections, Toxins. Many other functions. But Immunity can be Injurious, When exaggerated causes Tissue Damage, Disease and Death
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Immune response is altered

In hypersensitivity Antigen is not Important But what happens as a result of Immune reaction Allergy a Synonym for Hypersensitivity.
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What happens in Hypersensitivity

Initial contact sensitizes the Immune system. The antigen acts as priming dose
Causes the priming of B/T Lymphocytes,

Subsequent dose a shocking dose.

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Classification of Hypersensitivity Coombs and Gell

Classified into 4 types on Mechanism and Pathogenicity Type I Generalized Anaphylactic shock. Localized - Hay fever, Asthma Type II Cytotoxic ( Antigen + Antibody ) Type III Immune complex Type IV Cell Mediated.
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Hypersensitivity reactions
Type I Mechanism Antigen Onset IgE-Ag triggers Allergen minutes Mast cell mediators IgG or IgM binds to Cell surface Few cell surface; ADCC molecule hours or complement Immune complexes, Soluble or Few inflammation particulate hours Cytokines (T cells, Chemicals, 1-3 Macrophages, CTL) intracellular days Dr.T.V.Rao MD

II

III
IV

Classification of Hypersensitivity
Immediate and Delayed. Immediate type Also called as Immediate Hypersensitivity Popularly called as B cell Mediated Hypersensitivity
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Examples of Immediate Hypersensitivity

Anaphylaxis Atopy, Antibody mediated cell damage. Arthus Phenomenon Serum sickness
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Hypersensitivity-1
Inappropriate immune responses Type I are immediate type, in which antigen binds to IgE on mast cells, histamine released.
Histamine: smooth muscle contraction, vasodilatation. Results in asthma, diarrhea, shock depending on where antigen enters body. Ex. Bee sting
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Type II Hypersentivity
Type II are cytotoxic reactions like the Rh factor problem and bad blood transfusions.
Rh is one of many blood groups, like ABO An Rh+ fetus in an Rh- mother means she gets immunized by babys blood cells, makes Antibodies. Second pregnancy, fetal RBCs are attacked. Solution: give Rho-gam during 1st pregnancy.

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Type III and IV

Type III are immune complex disorders, where too many agnaby clumps cause inflammation Type IV are delayed type, T cell produces various cytokines which affect macrophages.
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Type IV
Type IV are delayed type, T cell produces various cytokines which affect macrophages.

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The bar fight scenario: come, stay, get angry. Angry macrophages cause much tissue damage. Ex. Poison ivy; urushiol-coated cells killed.
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Delayed Hypersensitivity T Cell Mediated

Tuberculin type. Contact dermatitis.

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Type I Hypersensitivity

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Examples of Immediate Hypersensitivity Anaphylaxis Atopy, Antibody mediated cell damage. Arthus Phenomenon Serum sickness
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Type I hypersensitivity
Anaphylaxis = Ana means without Phylaxis protection ( Rich ) Sensitizing dose more effective when given parentally Antigen can hapten also may take 2-3 weeks to produce sufficient IgE Shocking dose is effective if given IV The nature of antigen should correspond to antibodies
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Type I
Anaphylactic Ig E ( Reagin ) Antibodies are fixed on Tissue cells Eg Mast cells and Basophils Antigen + Antibody combination causes release of Pharmacologically active substances Occurs in Acute and Chronic or recurrent form (Non Fatal and localized Atopy)
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Anaphylaxis
Classical Immediate Hypersensitivity Experiments in dogs with Sea anemones Guinea pigs By any route with Antigens and Haptens 2-3 weeks later with sensitizing or shocking dose I V

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The type I anaphylaxis involves

The target organs are several vital organs and tissues, On the target tissue, causes oedema,decreased coagabulity of Blood Leads to fall of Blood pressure Leucopenia and thrombocytopenia Guinea pigs are highly sensitive Human are intermediate in reactivity
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Experiment in Guinea pig

A guinea pig is injected with small dose of antigen eg Egg albumin no reaction observed. The same animal injected with egg albumin after 2 weeks by IV route
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2nd dose produces Anaphylaxis

The 2nd produced anaphylactic shock Manifested with Restlessness Chewing and rubbing nose Wheeze Developed convulsions Animal died
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Same is experienced in Humans With bee sting Penicillin administration Happens in sensitized individuals
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Local reactions happen

Asthma Hay fever The reactions depend on the level of IgE The biologically active molecules are present in in the mast cells and Basophilic granules synthesize to active production after triggering with antigenic stimulations.
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Nature of IgE
Present in low fractions compared with other Immunoglobulin's IgE is heat sensitive inactivated at 560c in 2 4 hours heat causes damage to Fc particle
IgA deficiency produces excessive IgE
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The biological mediator on effect stage

1. Histamine:
Dilate blood vessel Increase vascular permeability

2. Leukotriene's:
Bronchial smooth muscles contract Asthmas

3. Prostaglandin:
High concentration of PGE low concentration of PGE
Inhibit the secretion of histamine

promote the release of histamine

4. Platelet activating factor (PAF) :

Agglutinate and activate platelets to release histamine

5. Eosinophil chemotactic factorECF-A: 6. Bradykynin :

Vasodilator function
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Important chemical and substances produced to cause reaction

Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. Leukotriene's: Bronchial spasms.

Anaphylactic shock: Massive drop

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4. Common

disease of type I hypersensitivity

1. Systemic anaphylaxis: a very dangerous syndrome

1) Anaphylactic drug allergy penicillin 2) Anaphylactic serum allergy

2. Respiratory allergic diseases :

1) Allergic asthmaacute response, chronic response

2) Allergic rhinitis

3. Gastrointestinal allergic diseases :

The lack of SIgA protein hydrolase Undigested protein Allergen

4. Skin allergy:

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Atopy
When the antigen and antibody IgE react produce certain pharmacologically active substances Can cause Conjunctivitis, Rhinitis G E involvement Dermal involvement Urticaria
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Primary Mediators of Anaphylaxis

Histamine an vasoactive in human Anaphylaxis Histidine on Decarboxylation to Histamine Stimulates the sensory nerves Causes burning and itching Causes vasodilatation and hyperemia Smooth muscle stimulation Affects the Intestines, Uterus, Especially bronchioles
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Effects of type I reactions

Systemic anaphylaxis Respiration becomes difficult Blood pressure drops Smooth muscles of bladder and GI tract contract Bronchoconstriction Countered by epinephrine relaxes smooth muscles decreases vascular permeability improves cardiac output
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Mechanism of Anaphylaxis
Ig E cell fixed on Mast cells and Basophiles. Antigen + Antibody Bridges the gap Leads to deregulation Releases Biologically active substances from granules of the cells.
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Histamine release occurs within minutes Binds to receptors on target cells

smooth muscles contract

eosinophil's attracted mucus secretion platelet activation blood vessel dilation

Blocked by various compounds: antihistamines, Epinephrine, corticosteroids
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Secondary mediators of Anaphylaxis

Prostaglandins Leukotriene's Thromboxane's, Lead to manifestation with 1Transient constriction of Bronchioles 2 Dilatation of capillaries, 3 Platelet activation factor,
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Serotonin
Produces on Decarboxylation of Tryptophan Found in Intestines, Mucosa, Brain tissue, Platelets Causes smooth muscle contraction Increases capillary permeability Vasoconstriction Human ?
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Other factors
Heparin Not in human Enzymatic mediators proteases and hydrolases

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Effects of Histamine

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Many of us suffer

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Secondary factors in anaphylaxis

Prostaglandins and Leukotriene's releases from disrupted cell membranes Mast cells and other leukotriene's Slow reacting substances Prostaglandins affects secretion by mucosal glands Platelet activating factor aggregates platelets ad release vasoactive amines
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Other Mediators
By complement activation Bradykynin Anphylactoid reactions can be caused due to IV Peptone, Trypsin by IV routes
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Clinical effects
Causes smooth muscle contraction. Increased vascular permeability Many organs Target organ shock organ Causes Edema Fall of BP, Coagulation of Blood, Leucopenia, thrombocytopenia Guinea pigs most susceptible Humans Intermediate Bee stings, Penicillin, Causes the constriction of smooth muscles( Bronchioles )

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Clinical effects in Humans

Itching of scalp, Tongue Flushing of skin, Bronchial spasm Hypotension Loss of consciousness and Death Previously with serum Now with Antibiotics. Adrenaline is life saving 0.5 ml 1:1000 dils
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Clinical effects Cutaneous Anaphylaxis

Intradermal Injection in sensitized host Wheal and flare reaction Useful in skin testing ( But dangerous ) Passive cutaneous anaphylaxis.

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Skin tests
Skin test via intra dermal injection of allergens: if an individual is allergic to the substance injected, local mast cells de granulate producing a wheel and flare response within minutes
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Secondary Mediators of Anaphylaxis

Slow reacting substances Prostaglandins, Platelet activating factors Cytokines IL3, IL4, IL5
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Atopy
Agent Inhaled Pollens /Dust Ingested Egg , Milk Contact with skin Conjunctiva Ig E is over produced Bottle fed infants Estimation of Ig E by RAST
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5. Therapy of type I hypersensitivity

1. Allergen avoidance : Atopy patch test

2. Desensitivity therapy / Hyposensitization :

1) Allogenic serum desensitivity therapy: Repeated injection small amounts of allergen, Temporality

2) Specific allergen desensitivity therapy IgG+allergen Neutralizing antibody,

Blocking antibody

3. Drug therapy
1) Stabilization of triggering cells sodium cromoglycate stabilize the membrane, inhibit mast cell degranulation

2) Mediator antagonism
Chlor-Trimeton Antihistamine

Acetylsalicylic acid Bradykinin antagonism 3) Improve the responsibility of target organs

4. New immunotherapy
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Hypersensitivity type II Reactions

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Type II Hypersensitivity
Type II hypersensitivity or cytotoxic hypersensitivity is caused by antibody-mediated reactions. When the immune system reacts to antigens it produces various Immunoglobulin's or antibodies, usually long-lasting immunoglobulin G (IgG) antibodies.
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Type II (Cytotoxic) Reactions Involve activation of complement by IgG or IgM binding to an antigenic cell. Antigenic cell is lysed. Transfusion reactions:

ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream.
Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells.
Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.

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What Happens in type II

Ig G and Ig M combines with antigenic determinants on the cells. Leads to cytotoxic and catalytic effects Eg - Anti erythrocyte antibodies in autoimmune anemia's and hemolytic disease of the new born. Other free antigens or hapten may be absorbed on the cell surface Subsequent reactions will lead to cell damage Drugs too behave in the same way
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Type II Hypersensitivity
LATS Antibodies stimulate determinants on Thyroid Leads to excessive secretion of Thyroid hormones
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Haptens too can produce type II Hypersensitivity

. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity.

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Type II Hypersensitivity
The binding of these antibodies to the surface of host cells then leads to: opsonization of the host cells whereby phagocytes stick to host cells by way of IgG, C3b, or C4b and discharge their lysosomes
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Type II Hypersensitivity
(Contd)
Anti erythrocyte antibodies Autoimmune Anemia's Hemolytic anemia's. Antigen + Antibody =Cell damage Even Hap tens act in the place of Antigen Disrupts the normal function Graves disease , Myasthenia gravis.
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Opsonization During Type-II Hypersensitivity, Step-1

The Fab of IgG reacts with epitopes on the host cell membrane. PhagocytesMD Dr.T.V.Rao bind to the Fc portion

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Opsonization During Type-II Hypersensitivity,

Step-2

Phagocytes binding to the Fc portion of the IgG Dr.T.V.Rao MD and discharge their lysosomes causing cell

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Examples of Type II Hypersensitivity.

Pemphigus: IgG antibodies that react with the intracellular substance found between epidermal cells. Autoimmune haemolytic anaemia (AHA): This disease is generally inspired by a drug such as penicillin that becomes attached to the surface of red blood cells (RBC) and acts as hapten for the production of antibody which then binds the RBC surface leading to lysis of RBCs. Dr.T.V.Rao MD 63 .

Good pasture's syndrome

Good pasture's syndrome: Generally manifested as a glomerulonephritis, IgG antibodies that react against glomerular basement membrane surfaces can lead to kidney destruction
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Type II Hypersensitivity
Salmonella , and Mycobacterium can produce Hemolytic crisis

Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence
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Type III Hypersensitivity Reactions

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Introduction
Immune complexes(Ag and Ab) deposit in tissues such as blood vessels and glomeruli. activate complement, and cause tissue injury or dysfunctional responses.
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Arthus reaction
Injecting repeatedly sc Normal horse serum Later injections leads edema, indurations hemorrhagic necrosis manifest as localize from of generalized hypersensitivity Damage is caused due to Antigen and antibody complexes, leads to activation of complement Release of inflammatory molecules Vascular permeability, infiltration of neutrophils. Causes tissue necrosis Eg Inhalation of Actinomyctes from mouldy hay grain causes Farmers lung
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Type III Hypersensitivity

Example of a Type III hypersensitivity is serum sickness, a condition that may develop when a patient is injected with a large amount of e.g. antitoxin that was produced in an animal. After about 10 days, anti-antitoxin antibodies react with the antitoxin forming immune complexes that deposit in tissues.
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Type III hypersensitivity

Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematous, Arthurs reaction), kidneys (e.g., lupus nephritis), lungs (e.g., Aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganism
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Type III Hypersensitivity

Antigen and Antibody complexes Accumulate around the small blood vessels cause damage to cell Arthus Reaction Occurs as a local manifestation Antigen + Antibody complexes Releases Inflammatory molecules, Infiltration with Neutrophils Reduces blood supply Other example Inhaled antigens produce Farmers lung

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Type III Hypersensitivity mechanism

Neutrophil C3a & C5a C3 C3b & C5b
C4 C2 C1

C5-C9

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2- Serum Sickness
* A systemic immune complex phenomenon * Injection of large doses of foreign serum * Antigen is slowly cleared from circulation * Immune complexes are deposited in various sites fever urticaria Arthralgia lymphadenopathy splenomegaly glomerulonephritis antidiphtheritic serum penicillin Dr.T.V.Rao MD sulphonamides

* 10 days after injection

e.g. treatment with

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Mechanism of damage in type-III hypersensitivity

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Deposition of immune complexes in blood vessel walls

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Disorders of the Immune System: Immune Complex Disease

Glomerular basement membrane of kidney

Large complex

Endothelial cell

Small complex

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Type III Hypersensitivity (Cont )

Serum Sickness Systematic form of Type III Diphtheria Antiserum produces antibodies Produces Fever, Lymphadenopathy Splenomegaly Arthritis Glomerulonephritis Endocarditis and Vasculitis Mechanism Foreign serum and antibodies Deposit in Endothelial Lining on Blood vessels. Many times self limited.

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Serum Sickness
May last for 7-10 days. Bacterial Viral and Parasitic infection produce serum sickness. Important Diseases Post Streptococcal Glomerulonephritis Hepatitis B Infections Auto immune conditions. Disseminate malignancies.
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Diagnosis and Treatment

The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (Nephelometry), binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes antiinflammatory agents.
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Type IV Hypersensitivity

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Type IV Hypersensitivity
Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response
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Type IV Reaction Delayed Hypersensitivity

Also called as Cell Mediated Immunity, Stimulates Sensitizes CD4/CD8. Secretion of Lymhokines Fluid/Phagocytes accumulate. Not Induced by antibodies T Cell Th1 Th2 Tc Take active part
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Delayed hypersensitivity.
The reaction elicited by antigen occurs relatively slowly (hence the name "delayed hypersensitivity"). The hypersensitivity is mediated via Tcells and macrophages. The hypersensitivity illustrates both antigen-specific (T-cell) and antigen nonspecific (macrophage) characteristics
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Type IV hypersensitivity is T cell mediated

The type IV hypersensitivity differs from the other three types of reactions in that it is not caused by antibodies, but by immunocompetent cells (lymphocytes). These lymphocytes are immunologically specific with receptors for the antigens, which can be different tissues (tissue antigens) or small molecular substances which, when fixed to the cell membrane, can function as antigens.
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Type IV Reactions
Type IV reactions, which are also called delayed hypersensitivity reactions, as a rule occur 12 - 48 hours after exposure to the antigen. Type IV reactions lead to inflammatory tissue damage and infiltration of cells, which are principally mononuclear (lymphocytes and macrophages).
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Type IV reactions
The inflammatory reaction leads to irreversible damage with deterioration of the tissue. The classical examples of type IV hypersensitivity are the positive tuberculin reaction, contact dermatitis (e.g. caused by nickel or chrome) and rejection of tissues transplanted from other individual
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Mechanisms of damage in delayed hypersensitivity

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Several diseases based on Delayed Hypersensitivity

Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, Histoplasmosis, toxoplasmosis, leishmaniasis, etc.) granulomas due to infections and foreign bodies

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Tuberculin Type ( IV )
Tuberculin reaction. Tuberculin Injection Sensitized to Tuberculin protein. Indurations develop at the site < 48 hours. Unsensitized No response Bacteria, Fungi, Viruses, Parasites

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Tuberculin Test

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Measurement of Induration

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Immune Complex Mediated Hypersensitivity

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Other agents stimulating Type IV Hypersensitivity

Topical application of Penicillin in creams Lange ham cells in epidermis absorb the drug or chemical T Cells are stimulated Lymph nodes acts as store houses Repeated applications leads to Eczema like conditions
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3. Common disease of type IV hypersensitivity

1) Infectious delayed type hypersensitivity
OT( Old Tuberculin ) test

2) Contact dermatitis :
Paint, drug red rash, papula, water blister, dermatitis

3) Acute rejection of allogenic transplantation and immune response in local tumor mass
Same disease (SLE), multiple immune injury ,hypersensitivity involved
Same drug (penicillin), several types of hypersensitivity

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DTH as a result of a contact-sensitizing agent* Contact Dermatitis

Can be caused by poison ivy and mango sap

*a contact-sensitizing agent is usually a small molecule that penetrates the skin then binds to self-proteins, making the protein look foreign

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Contact dermatitis
Contact dermatitis or Irritant dermatitis is a term for a skin reaction resulting from exposure to allergens (allergic contact dermatitis) or irritants (irritant contact dermatitis).
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Contact Dermatitis ( IV )
Delayed hypersensitivity Skin contact. Cell Mediated response. Nickel, Chromium, Dyes , Penicillin's Antigens absorbed, Langerhams cells capture Migrate to draining lymph nodes, Present the processed Antigens with MHC molecules to Immune cells.
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