Immune Pathology 1 to 10
What are the features of Type 1 hypersensitivity?
- Immediate reaction, previously sensitised individuals, IgE mediated
- Mast cell and or basophils involved
- Mediators involved include Histamine, other amines, enzymes proteases, proteoglycans, heparin, leukotrienes, C4, PAF, Prostaglandins, Cytokines
- 3 out of 5 bold
What are the actions of mast cell mediators in Type I Hyeprsensitivity (and give examples)?
- Cellular infiltration – leukotrienes, chemotaxis, PAF, Cytokines
- Vasoactive effects – Hist, PAF, Leukotrienes, PG D4
- Smooth muscle spasm – leukotrienes, histamine, PG, PAF
- Histamine PLUS 2 others
What is the late phase reaction?
- Ongoing inflammatory reaction without additional exposure to triggering antigen
What is a Type I hypersensitivity reaction?
- Rapid immunologic reaction (minutes)
- Antigen – antibody
- Mast cells
- Previously sensitised individual
- Bold to pass
What are the Primary mediators within the mast cell granules and their actions?
- Biogenic amines/histamine. The most important vasoactive amine is histamine.Histamine causes intense smooth muscle contraction, increased vascular permeability, and increased secretion by nasal, bronchial, and gastric glands.
- Enzymes. (named) These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement (e.g. C3a) by acting on their precursor proteins.
- Proteoglycans. These include heparin, a well-known anticoagulant, and chondroitin sulfate. The proteoglycans serve to package and store the other mediators in the granules
- Pass – 2 out of 3 groups must include biogenic amines and example of each
What characterizes the second, late-phase reaction?
- The late phase reaction is characterized by infiltration of the tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial cell damage.
- Time course 2-24 hours later without additional exposure – may last for days
What is antibody -mediated hypersensitivity?
- Caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix.
- Antigens can be intrinsic to the membrane or matrix or extrinsic eg. Drug metabolite
- Bold points
Describe the mechanisms which mediate the hypersensitivity response.
Prompt: List an example or examples for each mechanism.
- Mechanism of hypersensitivity response
- Opsonisation and phagocytosis: IgG antibodies opsonise cells plus complement activation generates C3b and C4b recognized by phagocyte Fc and protein receptors resulting in phagocytosis and destruction of opsonised cells
- Examples: transfusion reaction, erythroblastosis fetalis, autoimmune haemolytic anaemia, agranulocytosis, thrombocytopaenia, drug reactions when a drug acts as a hapten
- Complement and Fc receptor mediated inflammation: antibodies bind to fixed tissue such as basement membranes, extracellular matrix … activates complement … generate by-products particularly chemotactic agent C5a … direct PMN migration and C3a and C5a = increase vascular permeability. PMNs activated by C3a and Fc receptors… release of pro- inflammatory substances like prostaglandins, production of lysosomal enzymes, reactive O2 species
- Examples: glomerulonephritis, vascular rejection in organ grafts, vasculitis caused by ANCA, Goodpastures
- Antibody mediated cellular dysfunction: antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation
- Examples: myasthenia gravis, Graves’s disease, insulin resistant diabetes, pemphigus vulgaris
- Antibody dependant cellular cytotoxicity.
- Examples: IgG coats cells, effector cells such as monocytes, neutrophils, eosinophils and NK cells then bind and lyse cells without phagocytosis, role in specific diseases uncertain.
- 2 out of 4
What are the normal barriers to infection by ingested pathogens in the gastrointestinal tract?
- Acid gastric secretions;
- viscous mucosal layer;
- lytic pancreatic enzymes;
- bile detergents;
- secreted IgA antibodies;
- competition for nutrients with commensal bacteria;
- clearance by defaecation
- 3 out of 7 to pass
Describe the barriers to infection that exist within the respiratory tract.
- Mucociliary blanket within upper airways for trapping large microbes
- Coughing (clears microbes from trachea)
- Ciliary action within trachea and large airways (moves them up to be swallowed)
- Alveolar macrophages or neutrophils attack and destroy microbes
- 2 out of 4 to pass
What processes can disrupt the normal protective mucociliary action?
- cystic fibrosis (viscous secretions);
- aspiration of stomach contents;
- trauma of intubation;
- viral infection;
- bacterial infection
- 3 out of 6 to pass
Give some examples of Antibody-mediated (Type 2) hypersensitivity?
- Transfusion reaction;
- Erythroblastosis fetalis;
- Certain drug reactions;
- Autoimmune haemolytic anaemia, thrombocytosis & agranulocytosis;
- Myaesthenia gravis;
- Grave’s Disease;
- Pemphigus vulgaris;
- Glomerulonephritis (some forms);
- vascular rejection in organ grafts
- 3 to pass
By what mechanisms is Type 2 hypersensitivity mediated?
- Opsonisation & Complement- and Fc Receptor-mediated Phagocytosis: Cells are coated (opsonized) with molecules attractive to phagocytes. Complementactivation resulting in by-products (C3b and C4b). Phagocytosis results
- Antibody-dependent cellular cytotoxicity (ADCC): no complement activation, leucocyte driven.
- Complement- and Fc Receptor-mediated inflammation: Extracellular tissue inflammation – mainly antibody deposited activation of complement (by-products C5a; lesser C4a and C3a), which recruit neutrophils and monocytes. Fc receptors also bind the antibodies releasing enzymes and oxygen intermediates
- Antibody mediated cellular dysfunction: antibodies against cell-surface receptors impair or dysregulate function without causing cell injury or inflammation
- 2 groups to pass
What is the pathogenesis of type III hypersensitivity?
- Antibodies bind antigens & then induce inflammation directly or by activating complement. The recruited leukocytes produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals
- 3 phases (systemic diseases)
- a) Formation of antigen antibody complexes in circulation
- b) Deposition of immune complexes in various tissues
- c) inflammatory reaction at the site of deposition
- Bold to pass
What are the common sites for immune complex deposition?
- Renal glomeruli, joints, skin, heart, serosal surfaces, small blood vessels
- 3 to pass
Give some examples of diseases caused by Type III hypersensitivity.
- SLE, polyarteritis nodosa, post strep GN, Acute GN, reactive arthritis, serum sickness, arthus reaction
- 3 to pass
Describe the role of complement in inflammation.
- Vascular phenomena
- Leucocyte adhesion, chemotaxis and activation
- 3/3 to pass
Of the complement components, which are the most important inflammatory mediators?
- Must name both
What is type 2 hypersensitivity?
- Type 2 hypersensitivity is mediated by antibodies directed toward antigens present on the surface of cells or other tissue components
- Antibody mediated
- One of cell surface & extracellular matrix
Describe the different types of type 2 hypersensitivity reactions and give examples of each.
(A) Opsonisation, Complement & Fc Receptor Mediated Phagocytosis
- Ig G,M activate complement, C3b & C4b recognised by phagocytes
- activates complement system & membrane attack complex causing lysis of cells
- Ig G recognised by phagocytes
- Ab dependent cellular cytotoxicity (ADCC) Mono, Macro, Neut, Eosin, NK
- transfusion reactions
- erythroblastosis foetalis
- auto immune haemolytic anaemia
- certain drug reactions
(B) Complement and Fc receptor Mediated Inflammation
- C5A (+C4A & C3A) stimulate Neutrophil and Monocyte attack via Fc receptors releasing enzymes and Oxygen free radicals
- Vascular Organ graft rejection
(C) Antibody Mediated Cellular Dysfunction
- Antireceptor antibodies disturb the normal function of receptors without causing cell injury.
- myasthenia gravis (ACh receptor antibodies)
- Graves Disease
- pemphigus vulgaris
- 2 of 3 types with one example
- Able to describe complement dependant reaction plus one other with examples
What is Type 111 hypersensitivity?
- Immune complex disease
- Humoral Abs bind Ags and activate complement.
- Complements attract neutrophils which damage tissues by release of lysosomal enzyme and toxic free radicals
What kinds of antigens cause it?
- Foreign protein (serum sickness)
- Bacteria (endocarditis, Glomerular Nephritis)
- Viruses (Polyarteritis Nodosum),
- Autoimmune diseases SLE, Rha, GN
Name some environmental triggers for atopic asthma.
- Animal dander (old skin scales)
- At least 2
What are the pathological steps of the acute response?
Prompt: Various mediators are released. What do they do?
- Ag cross links mast-cell bound IgE
- Release of preformed, and newly-formed mediators, with opening of tight junctions between epithelial cells
- Cause bronchospasm, mucus production, increased vascular permeability, recruitment of additional cells, vagal receptors
- 2 out of 3 to pass
What cells are involved in the late phase response?
- Eosinophils – major basic protein
- Bold PLUS 1 other
Please describe some of the inflammatory mediators involved.
- 5 Eosinophil cationic protein; – eotaxin [ same as eosinophil chemotactic factor (ECF)];
- IL-1 and IL-6, TNF, nitric oxide, bradykinin