HYPERSENSITIVITY DISORDERS

Risk Factors for Immunopathological Disorders Immunogenetic predisposition Failure in autotolerance/self-tolerance Microbial and parasitic infections Drugs and environmental factors Risk Factors for Hypersensitivity Disorders Atopy-HLA linked hyperresponsiveness (HLA-B8 and HLA-Dw3) proportion about 10-20% population T cell deficiency sIgA deficiency Increased IgE levels (Th2 response) Mast cell instability

TABLE 24:
Hypersensitivity Type Type 1 Reactions

Classification and Characteristics of Hypersensitivity Disorders

Trigger Mechanism Allergen-IgE -mast cell interaction (15 min-1hr) IgM, IgG antibodies Clinical Examples

Designation

Immediate hypersensitivity

Asthma, bee sting reactions, urticaria, penicillin allergy and food allergies Blood transfusion reactions, haemolytic disorders of the new born, Goodpastures's syndrome, myasthenia gravis, Graves' disease Glomerulonephritis, serum sickness, SLE, rheumatoid arthritis. Contact dermatitis, tuberculin reaction, granuloma formation

Type II Reactions

Cytotoxic antibody hypersensitivity

Type III Reactions

Immune complex hypersensitivity

IgM, IgG and IgA immune complexes

Type IV Reactions

Delayed type hypersensitivity

T cells and macrophages (24-72 hrs)

Allergens
Environmental exposure:
Microbes and byproducts, animal faecal products, vegetable products, pollens,animal danders and fungal spores (mycotoxins) insects/venoms

Ingested allergens:
Cows milk, chicken egg, honey, fish, nuts legumes, cereal grains and prolifins (pollen proteins)

Drugs (penicillin, aspirin), antisera, metals, cosmetics and soap Infant allergy association with:
Elevated serum IgE levels; brief breast feeding; food allergens in milk; early solid food exposure; mites and pets; intrauterine exposure to tobacco

Mechanism of Allergy
Mast Cell Sensitization First exposure to allergen leads to Th2 (IL-4) dependent IgE production and
Sensitization of mast cells and basophils through binding their receptor in smooth muscle, blood vessels and mucosal lining

Reexposure to same allergen results in

Cross-linking of bound IgE on membrane Fc-R1 receptors leading to degranulation of mast cells and release of vasoactive and inflammatory mediators

Degranulation of mast cells Receptor aggregation Changes in membrane fluidity Methylation of phospholipids Increase in intracellular cAMP Influx of intracellular Ca++ ions Exocytosis of granule contents and release of preformed mediators such as histamines and proteolytic enzymes.

Early Phase Response

Release of preformed mediators trigger allergic symptoms including
Histamines, kininogenase, eosinophil chemotactic factor of anaphylaxis (ECF-A), proteolytic enzymes andTNF-

Release of mediators are associated with various clinical symptoms

Respiratory tract
Mucous production and smooth muscle contraction leads to runny nose, watery eyes, sneezing, coughing, sinus congestion and constricted airways

Gastrointestinal tract
Smooth muscle contraction and fluid release cause cramping, bloating gas diarrhoea and vomiting.

Dermatological symptoms
localized skin swelling causes hives (urticaria) angioedema, pruritus and erythematous macular rash

Late Phase Response

Further stimulation of mast cells and basophils by allergen IgE-FcRI complexes leads to synthesis of new mediators
Th2 response results in release of IL-4 and IL-13 Platelet activating factor attract leukocytes Arachidonic acid derivativese, leukotrienes (LT), prostaglandins and thromboxane

Systemic allergic reactions may also result in immediate lifethreatening systemic anaphylaxis leading to
Vascular shock. cardiac arrythmias, blocked airways and fluid accumulation in the respiratory system.

These massive IgE mediated responses may be caused by insect (bee) stings, drugs (penicillin) or various foods (shellfish and nuts)

 Clinical presentations: airway diseases or syndromes (asthma, rhinitis, chronic bronchitis); food allergy (oral allergy syndrome, food-induced colitis, malabsorption syndrome and celiac disease); allergic conjunctivitis; atopic dermatitis Diagnostic Tests History Skin prick test (SPT) RAST (Radioallergosorbent test): allergen specific serum IgE levels Basophil degranulation test Specific IgE levels Provocation challenge (bronchial, oral and nasal) Oral food challenge Control and Prevention

Avoidance of allergens: hyposensitization; use of corticosteroids and other immunosuppressive agents

Some allergic individuals to food, insect stings or medications may outgrow or spontaneously become tolerant to allergens

Desensitization Anti-IgE antibodies binding of IgE on mast cells prevented

By administering anti-IgE antibodies which block the receptor for IgE molecule

Prevention of IgE mediated allergies through

Injection of the patient with gradually increased doses of the putative allergen leading to a shift from Th2 to Th1 response

Hypotheses of the mechanism include

Shift of immune response from IgE to IgG that traps the allergen before triggering mast cells; induction of suppressor T cells (Th1) which block B cell activation and IgE synthesis in response to allergen

 Primary mediator of anaphylactic shock in histamine which bind to its receptors (H1) giving rise to signs and symptoms of anaphylaxis Binding to H1 receptors mediators pruritis, rhinorrhoea, tachyeardia and bronchospasm while both H1 and H2 receptors induce headach, flushing Arachadonic acid metabolites include prostaglandin/principally prostaglandin D2, PGD2 and leukotrienes (principally leukotriene C4 (LTC4) elaborated by mast cells and to a lesser extent basophils during anaphylaxis PGD2 mediates bronchospasm and vascular dilation, principal manifestations of anaphylaxis

 LTC4 is converted into LTD4 and LTE4 mediators of hypotension, bronchospasm, and mucous secrtioin during anaphylaxis in addition to acting as chemotactic signals for eosinphils and neutrophils. During anaphylaxis other active pathways include complement system, kallikrein-kinin system, the clotting cascade and the fibrinalytic system. Th2 cytokines (IL-4, IL-5, IL-9 and IL-13) enhance allergic response while Th1 cytokines (IFN, IL-12 and IL-18) inhibit allergy (anaphylaxis)

TABLE 27: IgE-Mediated Allergic Reactions

Clinical Syndrome

Common allergens

Route of entry

Clinical Response

Systematic anaphylaxis

Drugs Serum Venoms Peanuts Insect bites; allergy testing Pollens (ragweed, timothy, birch), dustmite faeces Pollens; dust-mite faeces

Intravenous (either directly or following rapid absorption) Subcutaneous

Edema; increased vascular permeability; tracheal occlusion; circulatory collapse and death Local increase in blood flow and vascular permeability Edema of nasal mucosa; irritation of nasal mucosa

Acute urticaria (wheal-and-flare) Allergic rhinitis (hay fever)

Inhaled

Asthma

Inhaled

Bronchial constriction; increased mucous production; airway inflammation Vomiting; diarrhoea; pruritis (itching), urticaria (hives) and anaphylaxis (rarely)

Food allergy

Shellfish Milk Eggs Fish Wheat

Oral

TABLE 24: Mediators of Immediate Hypersensitivity Reaction Mediator

Secretory granules (preformed): Histamines Serine Proteases, carboxypeptidase, proteoglacnas Heparin Neutrophil chemotactic factor (NCF)

Biological Activities
Vasolidation; vasopermeability; pruritis;

MEDIATORS OF IMMEDIATE HYPERSENSITIVITY REACTION

Mediator Secretary granules: Histamine Serine proteases; carboxypeptidase: proteoglacans Vaodilation: vasopermeability, pruritis; bronchoconstriction Degradation of blood vessels, basement membranes and proteins: generation of vasoactive complement and angiotension metabolites Formation of complexes with proteases Neutrophils chemotaxis Biological activities

Heparin Neutrophils chemotactic factor (NCF) Lipid mediators Membrane derived: Prostaglandin (PGD) Leukotrienes (LTB4, LTC4) Platelet/activating factor (PAF)

Vasopermeability: bronchoconstriction Vasopermeability: bronchoconstriction; stimulate influx and accumulation of PML and monocytes Aggregation of platelets: vasopermeability:; bronchoconstriction and neutrophil chemotactic factor Eosinophil chemotaxis: leukocyte adherence: fibroblast proliferation and collagen production; augments vascular permeability; constriction and dilation

Cytokines: IL-3, IL-4, IL-5, IL-6 & GM-CSF

Newly formed mediators Arachidonic acid metabolites Leukotrienes produced via the lipoxygenase pathway : Leukotrine B4 neutrophil chemotaxis and activation, augmentation C4 and D4 potent bronchoconstrictors, increase vacscular permeability, and cause arteriolar constriction : Leukotrienes E4 enhances bronchial responsiveness and increase vascular permeability (Leukotrienes C4, D4 and E4 comprise what was previously known as the slow-reacting substance of anaphylaxis) Cyclooxygenase products : Prostaglandin D2 produced mainly by mast cells; bronchoconstrictor; peripheral vasodilator; coronary and pulmonary artery vasoconstrictor; platelet aggregation inhibitor; neutrophil chemoattractant, and enhancer of histamine release from basophils : Prostaglandin F2 bronchoconstrictor; peripheral vasodilator, coronary vasoconstrictor; and platelet aggregation inhibitor - Thromboxane A2 causes vasoconstriction; platelet aggregation and bronchoconstriction

 Platelet-activating factor: : synthesized from membrane phospholipids via a different pathway from arachidonic acid. : It aggregates platelets but is also a very potent mediator in allergic reactions. : increases vascular permeability, : causes bronhcoconstriction, chemotaxis and degranulation of eosionophils and neutrophils. Adenosine: : a bronchoconstrictor and potentiates IgE-induced mast cell mediator release. Bradykinin: kininogenase released from the mast cell acts on plasma kinins to produce bradykinin. : bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain and activation of arachidonic acid metabolites. : role in IgE-mediated allergic reactions not clearly demonstrated.

CYTOTOXIC ANTIBODY HYPERSENSITIVITY

Antibody binds to cell surface antigen resulting in antigen-antibody complex eliminated through
Complement activation and lysis Fc-R mediated phagocytosis or Antibody dependent cell-mediated cyhtotoxicity (ADCC) involving
K cells NK cells, neutrophils, eosinophils and macrophages

Target Antigens Specific cell surfaces (RBC, lymphocytes, platelets, neutrophils, polymormphonuclear cells) Organs/tissues (gastric parietal cells, pancreatic islet cells, glomerular basement membrane, acetylcholine receptor, insulin receptor)

Clinical Examples
Hyperacute graft rejection
Preformed antibodies to blood gorup antigens or HLA cause immediate, severe and non-reversible damage to the graft

Drugs (aspirin and penicillin)

Form complexes with erythrocyte membrane proteins inducing synthesis of IgG which then bind drug-coated erythrocytes and damage them

Autoimmune diseases
Antibodies generated against membrane proteins
Acetylcholine receptor (myasthenia gravis), thyroid hormone receptor (Graves disease) and erythrocyte membrane proteins (autoimmune haemolytic anaemia)

Blood transfusion reactions due to ABO incompatibility

Clinical Conditions cont

Incompatible blood transfusions Haemolytic diseases of newborn (Rh alloimmunization) Spontaneous abortions Autoimmune haemolytic anaemias Autoantibodies against neutrophils (thyrombocytopenia); lymphocytes (lymphopenia); platelets (idiopathic thrombocytopenic purpura) Goodpastures syndrome (glomerular basement membrane)

Pemphigus (intracellular adhesion molecules)

Mysthenia gravis (acetylcholine receptor) Diagnostic Test Coombs Test - indirect and direct antibody test (DAT) results are positive in affected mothers.

Haemolytic Diseases of Newborn (HDN

HDN mediated by alloimmune antibodies to Rh and ABO antigens with indications of
Previous children with haemolytic disease; rising maternal antibody titres; rising amniotic fluid bilirubin contraction and ultrasonographic evidence of foetal bydrops

Rh blood group antigens include Kell (K and K), Duffy (Fyr), Kidd (Jka and Kkb) and MNSs (M, N, and S) systems that cause severe HDN
Risk of Rh immunization after delivery of first Rh-positive child to Rh-negative mother

Antibody-coated RBC are destroyed by spleen macrophages causing anaemia, release heme that is converted to unconjugated bilirubin
Hyperbilirubinaemia becomes apparent in the delivered newborn as the placenta effectively metabolizes bilirubin. Haemolysis and suppression of erythropoiesis occurs in Kell sensitization because the K cell antigen is expressed on the surface of erythroid progenitors

Rh Alloimmnization cont
Rh alloimmunization
Preventable through administration of Rh antibody that eliminates Rh+ foetal cells in maternal circulation

Haemolysis associated with ABO incompatibility

L,imited to O+ mothers with A or B blood group foetuses ( A and B positive mothers possess IgM antibodies while O positive mothers have predominantly IgG which cross the placenta)

Blood group A and B antigens

Widely expressed in a variety of tissues including RBC and only a small proportion of their antibodies cross the placenta Fetal RBC express few A or B antigen with less reactive sites thus giving rise to low incidence of haemolysis in affected neonates in comparison with a more severe HDN due to Rh alloimmunization

Other Type 11 Conditions

Immune Haemolytic Anaemia Antibodies generated against individuals own red blood cells leading to their lysis and producing anaemia Many drugs such as penicillin and quinidine may also trigger the disorder

Immune Thrombocytopenic Purpura (ITP)

Antibodies are produced against platelets (thrombocytes) causing external bleeding from the nose and internal bleeding into the skin causing purple patches (purpura) ITP is also triggered by prescription drugs like aspirin, digitoxin and sulfa drugs

Autoimmune Diseases
Myasthenia gravis, Thyrotoxicosis (Graves disease)

Immune Complex Hypersensitivity

Factors determining deposition of IC Immune complex (IC) size
Circulating small CIC diffuse into epithelial side of glomerular membrane Large CIC accumulate between the endothelium and basement membrane or mesangium, fix complement and eliminated

Increased blood vascular permeability High blood pressure and turbulence Antigen mediated affinity in deposition of circulating IC include
DNA anti-DNA complexes kidney in SLE IgG RF complexes (joint in rheumatoid arthritis)

Age and sex variation

Serum Sickness
Administration of large amount of foreign antigen (horse antiserum) results in
IC formation in Ag excess deposited in walls of blood vessels and glomeruli of kidneys

May also occur as a reaction to anti-lymphocyte globulin used as an immune suppresant for transplant recipients Reaction occurs 7 10 days after admn,
Complement activated, mast cells and basophils attracted releasing histamines and leukotrienes producing inflammation

Clinical presentations
Chills, rash, fever, arthritis and protein in urine and sometimes kidney damage

Arthus Reaction
IC formed in Ab excess and deposited in blood vessels IC binding to Fc-R on mast cells or leukocytes leading inflammatory reaction Releasing mast cell mediators and complement activation results
In local inflammation with swelling and reddening at the site of antigen introduction

Inflammation and Tissue Damage in Type III Hypersensitivity Reaction

CIC trigger inflammatory process through Complement activation leads to C5a and C3a generation which
Increases mast cell degranulation Increases vascular permeability Promotes neutrophil sequestration and increased respiratory burst activity

 Recruitment and activation of polymorphs and macrophages results into

Generation of ROI Increased lysozomal enzymes and acid hydrolases Increased neutrophil derived neutral serine proteases Activation of myeloperoxidase H2O2 lalide system (hypochlorous acid production) Elevated macrophage derived proinflammatory cytokines (L-1, TNF-, IL-6) Elevated prostaglandins, leukotrienes, serotin and thromboxane levels

Type 111 Damage cont

Platelet aggregation (basement membrane) leads to

Vasoactive amine release (C5a and C3a mediated) Glomerular membrane damage

IC Diseases
Persistent Infections Continued presence of certain infections (malaria, schisomiasis and flariasis, hepatitis B virus)
Provides renewable source of antigen to combine with synthesized antibodies resulting in deposition of immune complexes Farmers Lung

Repeated exposure to inhaled antigens (mold spores, hay, dust)

Elicit formation of antibodies and subsequently IC, inflammation of the alveoli in exposed farmers, sugarcane workers, mushroom growers :extrinsic allergic alveolitis condition (Farmers lung)

Patients develop cough, fever and difficulty in breathing

Autoimmune Diseases
Patients develop antibodies against a wide range of self components leading to formation of immune complexes
SLE (DNA-anti-DNA, ) Rheumatoid arthritis (IgG-rheumatoid factors) and
deposited in the skin and kidneys joints respectively , where they initiate inflammation.

IMMUNE COMPLEX DISEASES

Disease Origin
Persistent infections Viral infections Parasitic infections Fungal infections Autoimmune disorders Systemic diseases Drug/chemical induced

Examples
Post-streptococcal and straphylococcal; pneumococcal and Klebsiella infections; leprosy and tuberculosis Hepatitis, measles, CMV, AIDS, dangue haemorrhagic fever and rubella infections Malaria: leishmaniasis: toxoplasmosis: schistosomiasis and filariasis. Candidiasis and cryptococcosis Rheumatoid arthritis, SLE, polyarteritis, cryoglobulinaemia, polymyositis, dermatomysitis cutaneous vasculitis and fibrosing alveolitis Penicillin, sulphonamide, rifampiein

Metals/chemicals
Antisera products

Gold, cadmium, mercury penicillamine and hydrocarbons

Anti-venoms, anti-toxin

Localized diseases (Arthus type reactions)

Farmers lung, erythema nodosum (M. tuberculosis) erythema leprosum leprosy (M. leprae).

DELAYED TYPE HYPERSENSITIVITY REACTION

Hypersensitivity reaction mediated by antigen specific Th1 cells and activated macrophages characterized by
Induration, erythema (swelling) and neutrophil, T cell and monocyte infiltration into the site of lesion within 4872 hrs.

DTH mediated both by

Th1 CD4 T cell (produce-IFN, IL-6, TNF-, IL-17 proinflammatory cytokines) and Th1 CD8 CTL that secretes -IFN

Chemokines attract macrophages activated by

-IFN, IL-12 augments -IFN production by NK cells and T cells and promotes Th1 differentiation.

Expression of DTH
Local skin reactions to proteins in insect venom and injected mycobacterial protein, Contact sensitivities to poison ivy, nickel in coins and jewelry,
Re-exposure with same antigens activates memory (CD45RO) T cells releasing -IFN and IL-17 Keratinocytes respond to cytokines and secrete
IL-1, IL-6, TNF-, GM-CSF and chemokines that attract m and T cells into the site developing a characteristic itchy rash.

DTH Expression cont

In celiac disease, hypersensitivity to gliadin) causes atrophy of the intestinal villi, malabsorption of nutrients and diarrhoea Allograft rejection and graft-versus-host reaction are elements of DTH DTH is measured by skin testing (Mantoux test) using PPD
Memory Th1 cells secrete cytokines(attract ms and granulocytes causing induration and erythema) Positive test indicates previous exposure to mycobacteria while anergy results from infection or immunodeficiency

DELAYED HYPERSENSITIVITY REACTIONS

Type
Contact

Reaction time Clinical appearance

48-72 hr Eczema

Histology
Lymphocytes, later macrophages, oedmea of epidermis Lymphocytes monocytes, macrophages Macrophages, epithelioid cells giant cells and fibrosis

Antigen
Epidermal (nickel rubber, poison ivy)

Tuberculin

48-72 hr

Local induration

Intradermal (tuberculin)

Granuloma formation

21-28 days

Hardening (skin or lung)

Persistent infections

Contact Hypersensitivity
Langerhans cells in skin and lymph nodes process and present hapten DNCB bound to proteins. Sensitization and recruitment of CD4 T cells leads
- Production of Th1 -IFN and IL-17 which stimulate - Keratinocytes to release IL-1, IL-6, TNF- and IL-8 enhancing inflammatory response - Cell accumulation in dermo-epidermal junction and epidermis of
- Mononuclear cells (4-8 hrs) CD+ Th1 mainly and macrophages (48 hrs)

Tuberculin Type Hypersensitivity

Principally recal response to soluble antigen previously exposed to Intradermal PPD antigen challenge primes CD4T cells which produce Th1 cytokines Cellular infiltration occurs with
- Initially neutrophils (4 hrs) replaced by monocytes (12 hrs) 80 90% and T cells - Macrophages mainly APCs in DTH

Granulomatous Hypersensitivity

Major cause of immunopathological effect of DTH Persistence of intracellular pathogen in macrophages Granuloma demonstrates
- Epitheloid cells (activated macrophages) - Giant cells (fusion of epitheliod cells) - Lymphocytes accumulation and then fibrosis

Immune status and M. Tuberculosis infection

IMMUNOCOMPETENT Potent Protection Th1 Type Response
CD4 T cells
Primed ms Giant cells

IMMUNOSUPPRESSED Koch phenomenon Th2 Type Response

Eelevated CD8 suppressor T cells
Increased replication of bacteria in m Caseous necrosis (infected ms and cellular debrist at center and activated m and T cells at periphery)

Bacteria eliminated

Immune Status in M. leprae Infection

POTENT PROTECTION IMMUNOSUPPRESSED

Tuberculoid Borderline Borderline Lepromatous Leprosy Tuberculoid Lepromotous Leprosy (TL) Leprosy Leprosy (LL) (BT) (BL)
Efficient DTH Lymphocyte infiltration Disease Epitheloid cells/activated ms M. leprae vigorously eliminated Inefficient DTH Disseminated

Numerous M. laparae in m

Organs/Systems Disoders
Gastroenteropathy Disorders Coeliac disease (Type IV) Crohns disease (Type IV) Skin Disorders Contact dermatitis (Type IV) Atopic dermatitis (Type I) Bullous disease (Type I + III) Discoid lupus erythematosus (Type III) Psoriasis (Type IV)

Organs/Systems Disorders cont

Oscular Disorders Allergic Conjunctivitis (Type I)