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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
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
Type IV Reactions
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
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.
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
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
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)
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
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
Inhaled
Asthma
Inhaled
Bronchial constriction; increased mucous production; airway inflammation Vomiting; diarrhoea; pruritis (itching), urticaria (hives) and anaphylaxis (rarely)
Food allergy
Oral
Biological Activities
Vasolidation; vasopermeability; pruritis;
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
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.
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
Autoimmune diseases
Antibodies generated against membrane proteins
Acetylcholine receptor (myasthenia gravis), thyroid hormone receptor (Graves disease) and erythrocyte membrane proteins (autoimmune haemolytic anaemia)
Mysthenia gravis (acetylcholine receptor) Diagnostic Test Coombs Test - indirect and direct antibody test (DAT) results are positive in affected mothers.
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
Autoimmune Diseases
Myasthenia gravis, Thyrotoxicosis (Graves disease)
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)
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
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
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
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.
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
Farmers lung, erythema nodosum (M. tuberculosis) erythema leprosum leprosy (M. leprae).
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.
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.
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
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)
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
Bacteria eliminated
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)