Immunologic mechanisms of tissue damage (hypersensitivity reactions)
Immunologic mechanisms of tissue damage (hypersensitivity reactions) Objectives1- Classify the hypersensitivity reactions (Gell & Coombs classification)2-Define (Illustrate) the Terms “Immediate hypersensitivity reaction, Reagin-mediated reaction, Atopy, Anaphylaxis, ". 3- Define the term ‘allergen’ & List some common allergens that cause type I activation4- Discuss the pathophysiology of type I hypersensitivity reaction5- Discuss the immediate & late-phase responses in type-I H.S.
6- List the predisposing factors to type-I H.S. reaction 7- list the clinical manifestations of some allergic diseases 8- Explain In-vitro & In-vivo diagnostic tests for Type-I hypersensitivity reaction 9- Describe the complementary approaches in treating allergic diseases (Avoidance, Immunotherapy, Pharmacological treatment) 10- Compare between Anaphylaxis & Anaphylactoid reaction
Immunologic mechanisms of tissue damage (hypersensitivity reactions)
Gell & Coombs (1963) have classified hypersensitivity reactions into four major types: Type I : Anaphylaxis H.S. Type II : Antibody-dependent cytotoxic H.S. Type III : Immune-complex mediated H.S. Type IV : Cell-mediated (delayed) H.S.Type I hypersensitivity:
Anaphylaxis H.S Immediate H.S Atopy The reaction may be mild & localized one, e.g. allergic conjunctivitis, or it may be severe generalized reaction, e.g. anaphylactic shock.Requirements of anaphylaxis:
1- IgE :Reagenic Ab, Homocytotropic Ab IgE receptors:- Fc epsilon receptor I (FcεRI) These are high affinity IgE receptors expressed on cell membrane of Basophils & mast cells (Langerhans cells).- Fc epsilon receptor II (FcεRII) CD23 These are low affinity IgE receptors Expressed on : T & B lymphocytes , monocytes, eosinophils, & platelets.2- Allergens:
a- Inhalants : animal danders . Plant pollens , fungal spore, house dust, house dust mites (Dermatophagoides) b- Ingestants :(foods, drugs ... etc.) egg albumin, fish, cheese, nuts, milk, food additive, penicillin, aspirin c- contactants: pollen, food, drugs ... etc.3- Mast cells & Basophils:
They represent a major source of potent chemical mediator implicated in a wide spectrum of inflammatory & immunological processes.They express membrane receptors (FcεRI) that specifically bind the Fc portion of IgE (binding site) Ab. Complements are not involved in this type of reaction.
4- Intra-cellular biochemical events (mast cell degranulation):
Mast cell & basophil mediators of atopic disease (vasoactiveamines):1- Preformed (stored) mediators: -Histamine -ECF-A Eosinophil chemotactic factor of anaphylaxis 2- Synthesized mediators -PAF -SRS-A -Bradykinin
5- Vasoactive amines:
a- Histamine: - smooth muscle contraction of human bronchioles. - increase permeability of capillaries (vasodilatation). - increase secretions by nasal & bronchial mucous glands.b- ECA-A (Eosinophil Chemotactic Factor of Anaphylaxis)
- preformed in basophils & mast cells. - causes influx of eos. to area of allergic inflammation. (eosinophil chemotaxis) * role of eosinophils in allergy: They control allergic reactions by releasing histaminase and arylsulfatase , which degrade two important mediators, histamine and SRS-A, respectively. Eosinophil may therefore reduce the severity of type I response.C- Kinin- Generating proteases
Smooth muscles contraction of bronchioles.↑ vascular permeability↑ secretion of mucous glandsStimulate pain fibersd- PAF (Platelet Activating Factor) e- HMW-NCF (High Molecular Wt. Neutrophil Chemotactic Factor)
f- Arachidonic acid metabolitites
Clinical manifestations:
- Skin urticaria , angioneurotic oedema , atopic dermatitis - Respiratory system Hay fever, asthma , allergic conjunctivitis - Gastro-intestinal tract Vomiting , abdominal pain , diarrhoea Urinary tract Frequency , dysuria , hematuria Vascular involvement:Factors predisposing to type I H.S.:
Genetic factors (atopic allergies -hay fever, asthma, food allergy)Atopic individuals have IL4-gene coding for high level for IL4a- IL4 gene ---- IL4 ↑ no. Th2 ↑isotype switching ↑IgE level b- HLA allele at (maternal & paternal) DR loci e.g. allergy to grass pollen : HLA-DR3 allergy to rag weed pollen : HLA-DR2 , HLA-DER5 - Environmental FactorsAir pollutants (S02, car exhaust, fumes, passive cigarette smoking) increase permeability of epithelial cells of respiratory tract for allergens.Diagnosis:
- In Vitro : PRIST , RAST -In vivo (skin test)Wheal & flare
Treatment & Prevention:1-Avoidance of responsible allergens 2-Immunotherapy a- Desensitization , Hyposensitization (IgG-blocking Abs) * allergy shots(repeated inj+ dose) b- Immunotolerance
3- Drugs
a- Anti-histamins : Tavist-D (clemastin fumerate)b- Mast cell & basophil stabilizing drugs: Adrenaline : increase intracellular level of cAMP Theophylline : inhibits brake down of cAMP by phosphodiesterase Sodium chromoglycate : inhibits calcium influx c- General anti-inflammatory agents : corticosteroids