Def: When an immune response results in exaggerated or inappropriate reactions harmful to the host then it is called as hypersensitivity or allergy.
Antigens are called allergens They occur on contact with specific antigen get sensitized, & the subsequent contacts elicit the allergic response.
Types of hypersensitivities are determined by their time, course and whether T cells are the principal immune elements involved.
Initial contact with the allergen is necessary. This leads to sensitization to that allergen- sensitizing dose
Subsequent contacts with same allergens known as shocking dose
Hypersensitivity reactions can be of Type I (Immediate or Anaphylactic) Reaction Type II (Cytotoxic) Reaction Type III (Immune Complex) Reaction Type IV (Delayed or Cell Mediated) Reaction
Type I: Immediate (Anaphylactic) Hypersensitivity This is an immediate hypersensitivity reaction. It occurs when an antigen (allergen) binds to IgE on the surface mast cells with consequent release of several mediators. IgE is present in very low levels in serum in most people Its' half life in serum is only 2-3 days but much of the IgE in the body is bound to high affinity receptors In the bound state the half-life is ~3 weeks.
Type I (Anaphylactic) Reaction
– Immediate hypersensitivity – Anaphylaxis – IgE-associated immune responses
High affinity Fc receptors are found on mast cells and basophils with wide spectrum of antigen specificities.
The cells are activated when antigen bind to the IgE molecules bound to tissue cells (mast cells & basophils). Such binding leads to rapid degranulation (60-300 secs) of the mast cells and the release of primary inflammatory mediators stored in the granules.
These mediators cause all the normal consequences of an acute inflammatory reaction.
o increased vascular permeability o smooth muscle contraction o granulocyte chaemotaxis and extravasation(process of exuding or passing out of a vessel into surrounding tissues ) The secondary mediators also are released
If the challenge is cutaneous it produces the so-called
'wheal and flare'–
Raised patch surrounded by a pink effusion.
Induction and effector mechanisms in type 1 hypersensitivity
Clinical manifestation depends on:
1. The route of entry of the allergen 2. Location of mast cells bearing the IgE for allergen e.g. exposure to pollen in air – hay fever ingest of allergen in food – diarrhea. Shocking dose is most effective when given- Intravenously less effective - subcutaneously least effective - intradermally.
• Immediate (Anaphylactic) Hypersensitivity
• Clinical symptoms of type I hypersensitivity: • Immediate manifestations: Severe dyspnoea (shortness of breath) Hypotension Vascular collapse leading to deatho Vasodilatation o Increased vascular permeability o Smooth muscle contraction.
The late response seen after some hours is characterised by cellular infiltrate which gives a hard but barely pigmented nodule in the case of skin. It can be in various formsurticaria eczema rhinitis conjunctivitis asthma.
Type : 1. Anaphylaxis 2. Atopy
Anaphylaxis: It is a classical example of type I It is acute, potentially fatal & systemic form. It is IgE mediated reaction. Mechanism: The sensitized individual comes in contact with a shocking dose of antigen. Sensitization can occur through: Parenteral route- effective route Inhalation Ingestion
Interval of 2-3 weeks is required between sensitizing & shocking dose. IgE is produced attaches to the surface receptors of mast cells & basophils by their Fc end. Once sensitized the individual remains so for a long period.
When shocking dose of the same is given – the antigen combines with cell bound IgE antibody on the mast cell rapidly.
The Ag-Ab complex stimulates mast cells and basophils to release mediators that cause clinical manifestation of anaphylaxis.
Sensitization against allergens and type-I hypersensitivity
Histamine, tryptase, kininegenase, ECFA
Leukotriene-B4, C4, D4, Newly prostaglandin D, PAF synthesized mediators
Mediators are of two typesi) Primary mediators:
Histamine: Vascular permeability, smooth muscle contraction Serotonin: Vascular permeability, smooth muscle contraction Eosinophils chemotactic factor of anaphylaxis (ECFA) : A eosinophil chaemotaxis Neutrophil chemotatic factor of anaphylaxis (NCFA) : A neutrophil chaemotaxis Proteases: Mucus secretion, connective tissue degradation
ii) Secondary mediators: Leukotrienes: Vascular permeability, smooth muscle contraction Prostaglandins & thromboxane : Vasodilation, smooth muscle contraction, platelet activation Bradykinin: Vascular permeability, smooth muscle contraction Cytokines such as IL3 – IL6, INF-γ,INF-α : numerous effects - activation of vascular endothelium, eosinophil recruitment and activation Both the types of mediators are active only for sometime, after which they are enzymatically broken down.
Mast cell activation products
Newly formed mediators Leukotriene B4:
attract neutrophils and basophils
Leukotriene C4 & D4:
same as histamine but 1000 x potent
kinins - vascular permeability, vasodilatation, edema
Platelet Activating Factor (PAF):
platelet aggregation, microthrombi formation, heparin release
Features of Anaphylaxis: i) Anaphylaxis occurs within a few seconds to few minutes following shocking dose of antigen. ii) Cytotropic IgE antibody is responsible. iii) Tissues or organs which are affected in anaphylaxis are called “Target tissues” or “Shock organs”. Lung is the principle shock organ in humans. iv) It can be induced artificially by serum of sensitized individual. v) It is not related to heredity.
Types of Anaphylaxis: 1. Systemic Anaphylaxis 2. Local Anaphylaxis 3. Mixed Anaphylaxis Systemic type is the most severe form. The common allergens areAntibiotics Biological products – antiserum Insect bite – Bee venom, scorpion venom Symptoms: Urticaria, skin rashes, laryngeal edema, diarrhoea, bronchospam, hypotension can be life threatening.
Localised anaphylaxis: Allergic rhinites Asthma Food allergies Atopic dermatitis Symptoms are localized to particular organ or part of the body. e.g. mosquito bite Symptoms include wheal & flare reaction.
Anaphylactic shock :
Rare but is basically systemic anaphylaxis where – Bronchioles constrict Edema occurs Circulatory shock may occur resulting in death within minutes. Treated with epinephrine.
• These reactions appear clinically similar to anaphylactic ones and are not IgE mediated. • The inticing agents are drugs. •Precise immunological mechanism not known. •Leads to direct histamine release from mast cells without the involvement of IgE.
Atopy: Atopic disorders like hay fever, asthama, eczema, urticaria exhibit a strong familial predisposition and are associated with elevated IgE levels.
Common allergens include: Inhalants- pollen, house dust. Ingestants- shellfish, milk, egg Contact allergens- skin & conjunctiva may be exposed.
The atopic sensitization occurs spontaneously following natural contact with atopens. Predisposition to atopy is genetically determined, probably linked to MHC genotypes.
Features of Atopy: 1. Atopy runs in families. These individuals have tendency to produce IgE antibody in large amounts.
2. Reactions occur at the site of entry of the antigens. • Inhalation of pollens effects lungs- bronchial asthma • Ingestion of fish, milk, eggs, drugs etc.gastrointestinal disorders or cutaneous erruptions • Contact leads to local allergy- conjunctivitis.
3. It is IgE mediated hypersensitivity reaction. IgE is homocytotrophic i.e. species specific. Only human IgE can fix to the surface of human cells.
4. Induction of atopy is difficult artificially because atopens are poor antigens. Mechanism: •The atopen combines with cell bound IgE antibodies fixed on the surfaces of mast cells & the basophils. •This antigen antibody complex stimulates these cells to release mediators resulting in clinical features of atopy.
IgE levels in immediate hypersensitivity
Atopic diseases allergic asthma allergic eczema hay fever Helminthic (worm) infections
Immunodeficiency hyper-IgE syndrome Wiscott-Aldrich syndrome
Miscellaneous diseases Bronchopulmonary Aspergillosis IgE myeloma
• Prausnitz- Kustner (PK) reaction:
This was the original method for detecting atopic antibody. The test serum from an atopic individual is injected intradermally into a normal subject. The normal subject is challenged 24-48 hours later with the antigen suspected of causing the immediate hypersensitivity reaction in the atopic individual. Wheal and flare reaction is seen at the site of injection within mins. This test is not done due to risk of transmission of serum hepatitis.
Detection : Small amounts of allergens injected intradermally Person is allergic local mast cells degranulate producing wheal and flare reaction with in 30 mins
Multiple allergens can be tested at the same time IgE levels in serum can be measured by RADIO ALLERGOSROBENT TEST (RAST)
Detection of Allergies • Skin Test
• Blood Test • Elevated IgE (ELISA) • RIST Test - Radioimmunosorbant test • RAST Test - Radioallergosorbent test
Close-up view of intradermal skin test with multiple positive allergen responses
• RIST and RAST Tests
Detects nanograms amts of Total IgE
Detect nanogram amts of allergen specific IgE
Treatments for allergy
Receptor blockers antihistamine, antileukotriene Bronchodialators β-agonists (inhahants)
Prevent mast cell degranulation
Ca influx inhibitor (chromolyn sodium) Phosphodiesterase (theophylline)
Hyposensitization Anti-IgE(Fc) Ab
Type II: Cytotoxic Hypersensitivity: Hypersensitivity due to IgG (or rarely IgM) antibodies against cell surface Ag resulting in cell damage. It is a cytotoxic reaction. This may be mediated by classic complement cascade or cellular mechanisms. The antibody (IgG or IgM) attaches to the antigen via Fab region and acts as a bridge to complement via its Fc region. As a result, there is complement–mediated lysis.
e.g. hemolytic anemias, ABO transfusion reaction or Rh hemolytic disease. Complement activation attracts phagocytes to the site, leading to release of enzyme that damage cell membranes.
Drug reaction: Drug can attach to the surface proteins on RBC & initiate antibody formation. These autoimmune antibodies then interact with red blood cell surface & result in hemolysis e.g. penicillin, phenacitin, quinidine
• Sedromid purpura is a classical example.
• Sedromid is a sedative drug, it combines with platelets and antibodies are formed against these sedromid coated platelets. – On subsequent exposure to drug, antibodies attack the platelets leading to thrombocytopenic purpura. • Other drugs are – sulphonamide, thiazide diuretcs
Type II hypersensitivity
role of complement and phagocytes
Antibodies bind to an antigen on the cell surface and cause1. Phagocytosis of the cell through opsonic or immune adherence
2. Cytotoxicity by natural killer (NK) cells.
3. Lysis through activation of complement system.
• Type II cytotoxicity hypersensitivity reaction
Other examples of type II hypersensitivity
i. Myasthenia gravis: An autoantibody against the patient's own acetylcholine receptors in which the antibody removes and internalizes the receptors.
ii. Goodpasture syndrome: An autoantibody produced against the patient's own type IV collagen present in basement membranes of kidney and lung.
iii. Autoimmune hemolytic anemia: An autoantibody produced against the patient's own red blood cell antigens.
iv. Autoimmune thrombocytopenic purpura: An autoantibody produced against the patient's own platelet integrin.
v. Hyperacute graft rejection: The recipient of a graft already has pre-formed antibody against the graft; after receiving the graft it is rejected within hours.
Demonstration of Type II reaction:
Coombs test (direct antiglobulin test) is positive.
Type III: Immune – Complex Hypersensitivity
It is characterized by deposition of antigen- antibody complexes in tissues, activation of complement & infilteration of polymorphonuclear leucocytes leading to tissue damage.
Types: 1. Arthus reaction 2. Serum sickness
• This type of hypersensitivity occurs when antigenantibody complexes induce an inflammatory response in tissues.
• The immune complexes when deposited on tissues it results in several disorders. • Immune complexes deposited on tissues activates the complement system. Polymorphonuclear cells are attracted to the site and inflammation and injury occurs.
• The self antigens (in autoimmune disease) elicit antibodies that bind toorgan antigen or deposit in organs as complexes
• Joints - arthritis • Kidneys - nephritis • Blood vessels- vasculitis
Types of immune complex disease
persistent infection inhaled antigens injected material
bacterial, viral, parasitic, etc.
site of deposition
infected organ, kidney
mold, plant or animal antigen
kidney, skin, arteries, joint
kidney, joint, arteries, skin
Mechanism of damage in immune complex hypersensitivity
Arthus reaction: It is named after Dr. Arthus who first described the inflammatory response that occurs under the following conditions.
If animals are given an antigen repeatedly until they have high levels of IgG antibody & that antigen is then injected subcutaneously or intradermally, intense edema & hemorrhage develop, reaching a peak in 3-6 hours.
Ag, Ab, & C are deposited in vessel walls. Polymorphonuclear cell infiltration & intravascular clumping of platelets then occur. These reactions can lead to vascular occlusion & necrosis.
Clinical manifestation: Hypersensitivity pneumonitis (allergic alveolitis) associated with inhalation of thermophilic Actinomycetes (farmer’s lung) growing on hay. e.g. of occupation- related hypersensitivity pneumonitis Cheese-workers lung Wood worker’s lung Wheat-millers lung
It is a systemic inflammatory response to the presence of immune complexes deposited in many area of the body. It appears after a single dose of high concentration of foreign serum (it serves as both sensitizing and shocking dose).
Abs reach high titers by 7-12 days. The excess Ag remain in circulating blood.
• Immune complex get deposited on the endothelial lining of blood vessels in various parts of the body, causing inflammatory infilteration.
• Complex is also deposited on glomerulo basement membrane & the damage to the membrane is caused by the enzymes released by polymorphonuclear cells. • Massive complement activation & fixation by antigenantibody complexes leads to fall in complement concentration.
Fever, urticaria, arthralgia, lymphadenopathy, splenomegaly. Some important Immune complex diseases areBacterial infection- Post streptococcal glomerulonephritis Rheumatoid arthritis Endocarditis Viral infections - Hepatitis B Dengue haemorrhagic fever Parasitic infections- Malaria Autoimmune disease- Systemic Lupus Erthematosus
• Systemic Lupus ErthematosusIt affects several organs like – Skin of the face Joints Kidneys
• Antibodies are formed against DNA and other components of the nucleus of cell. • Antigen antibody reaction activates complement which attracts the neutrophils that release enzyme to damage the cells.
Systemic lupus erythematosus
Type IV hypersensitivity
Delayed reaction 36 to 48 hours Characterized by induration and erythema Also known as cell mediated hypersensitivity Tuberculin test is the most common example
Type IV : Delayed or Cell mediated Hypersensitivity. Delayed hypersensitivity is a function of T lymphocytes.
The response is “delayed”, it starts hours or days after contact with the antigen.
The reaction is mediated by sensitized T- Lymphocytes On contact with specific antigen it releases lymphokines This causes biological effects on macrophages, leucocytes & tissue cells.
Types: Tuberculin (Infection) type: When a patient previously exposed to M. tuberculosis is injected with a small amount of tuberculin (PPD) intradermally. Little reaction is seen in first few hours. Gradually induration & redness develop & reach a peak in 48-72 hrs. A positive skin test indicates that the person has been infected with the agent but does not confirm the presence of current disease. Histologically the reaction site would most probably show helper T cells & macrophages.
Contact hypersensitivity: Manifestation of cell mediated hypersensitivity occurs after sensitization with Chemicals- Nickel, Formaldehyde. Plant materials- Poison Ivy, poison oak. Topically applied drugs- Sulfonamides, neomycin Some cosmetics, soaps etc. The haptens enter the skin attach to body proteins & become complete antigen. The haptens alters the protein to such an extent that the body immune system recognizes it as foreign.
The sensitized person will develop erythema, itching, vesicles, eczema or necrosis of skin within 12- 48 hrs.
Detection is done by Patch test.
Contact dermatitis reaction to leather
Poison ivy / poison oak reaction
active hapten molecule
Contact dermatitis vs tuberculin reaction
Delayed hypersensitivity reactions
type time of reaction
antigen and site
T cells, later macrophages
epidermal: heavy metals, poison ivy, rubber, latex intradermal: tuberculin, lepromin, etc. persistent antigen stimulus, chronic infection
48-72 hours 21-28 days
local induration hardening
lymphocytes, monocytes giant cells, epitheloid cells, fibroblasts
Type IV hypersensitivity the three forms
INITIATION MECHANISM EXAMPLES
Ag induces crosslinking of IgE bound to mast cells with release of vasoactive mediators
Systemic anaphylaxis, Local anaphylaxis, Hay fever, Asthma, Eczema
Antibody-mediated cytotoxic hypersensitivity
Ab directed against cell-surface antigens mediates cell destruction via ADCC or complement Ag-Ab complexes deposited at various sites induces mast cell degranulation via FcI, PMN degranulation damages tissue
Memory TH1 cells release cytokines that recruit and activate macrophages
Blood transfusion reactions, Haemolytic disease of the newborn, Autoimmune Haemolytic anaemia Arthus reaction (Localised); Systemic reactions disseminated rash, arthritis, glomerulonephritis
Contact dermatitis, Tubercular lesions
Immune-complex mediated hypersensitivity
1. The major effector molecules involved in type IV hypersensitivity reactions are: A. Antibodies. B. Complement components. C. Cytokines. D. Prostaglandins.
E. 5-hydroxytryptamine (5-HT).
2. The Arthus reaction is characterized by an intense infiltration by: A. Mast cells. B. Neutrophils. C. Eosinophils. D. Macrophages.
E. Langerhans' cells.
3. Rhesus hemolytic disease of the newborn involves:
A. IgE. B. Antibody to cell surfaces. C. Soluble immune complexes. D. Cytokine release from T-cells.
E. Stimulatory antibodies.
4. Anaphylaxis can be triggerred by cross-linking of IgE receptors on: A. Monocytes.
B. Mast cells. C. B-cells. D. Eosinophils. E. Neutrophils.
5. Which type of hypersensitivity cannot be transferred with serum antibody?:
A. Type I. B. Type II. C. Type III. D. Type IV.
6. The term reactive lysis usually refers to a sequence of events involving: A Natural killer (NK) cells.
B Cytotoxic T-lymphocytes (CTL). C Antibody-dependent cellular cytotoxicity (ADCC). D Th1 cells. E Complement.
7. Your patient in the emergency room was stung by a bee about 15 minutes ago. She says that a few minutes after being stung she became very short of breath and saw hives (urticaria) appear in several places on her skin. Which one of the following is the most likely immunological mechanism for these clinical findings?
A. Sensitized helper T cells release large amounts of IL-2 B. Immune complexes consisting of IgG and hapten precipitate in the lung and skin. C. Activated macrophages produce large amounts of tumor necrosis factor. D. Membrane attack complexes of complement damage cells in the lung and skin.
E. IgE-coated mast cells release histamine and leukotrienes
Levinson- 7th edition- chapter 65 Jawetz – 23rd edition- chapter 8