Immune Pathology 11 to 20
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1. Delayed type hypersensitivity
TH1cells are activated and secrete cytokines that are responsible for the delayed type reaction – IL-12, IFN-(gamma), TNF, lymphotoxin, chemokines. Accumulation of mononuclear cells around small veins and venules, perivascular cuffing, increased microvascular permeability, escape of plasma proteins and deposition of fibrin in interstitium
Typical example = tuberculin reaction
2. T cell mediated cytotoxicity
Sensitised CD 8+ T cells (cytotoxic T lymphocytes) kill Ag bearing target cells
Pass: 2/4 Bold[/symple_toggle]
How does it differ in a naïve individual?
In naïve individual, CD4+T cells differentiate into TH 1cells after recognising antigen presented on APCs in association with class II MHC molecules. TH1cells can enter the circulation and remain in the memory pool of T cells for long periods (years)
What is Type 1 Hypersensitivity?
It is the acute or immediate potentially life-threatening type of allergic reaction
Typified by anaphylaxis, bronchial asthma (atopic) 3. 1GE mediated
Describe the 2 phases that occur.
Prompt: what are the mediators?
Phase 1 — initial rapid with vasodilation, vascular leakage, smooth muscle spasm and glandular secretion 5-30 mins subsides 60 mins Mediators —biogenic amines, enzymes, eg proteases, proteoglycans eg heparin, cytokines
Pass: 2 with time frame and at least 2 mediator
Phase 2 -2 -24 hours infiltration of basophils, eosinophils, neutrophils, G04+ with tissue destruction esp mucosal
Pass: Time Frame
What is type IV hypersensitivity?
It is a cell mediated type of hypersensitivity initiated by specifically sensitised T lymphocytes. It includes the classic delayed type of hypersensitivity reactions initiated by CD4+ M-I1) cells and direct cell mediated cytotoxicity mediated by CD8+ (CTL) cells.
What is a delayed type of hypersensitivity reaction?
Prompt: Please give an example
Tissue antigen on antigen presenting cell encounters CD4+ (THI) secrete specific cytokines — IL12, IFN-y, IL2 and TNFa. Examples — classic tuberculine reaction, response to fungi, protozoa, parasites, contact skin sensitivity and allograft rejection, diabetes multiple sclerosis & rheumatoid arthritis, GB.
8-12 hours starts peaks at 24- 72 hours and thereafter subsides
These cytokines mediate injury by (additional information for the high performing candidate)
• activating antigen non-specific monocytes and macrophages
• Secretion of PDGF and TGFI3
• Paracrine proliferation of T cells which includes CD4+ T cells
• Local vasodilatation
• Increased expression of ELAI%4-1 — increased attachment of passing lymphocytes and monocytes
• Secretion of low molecular weight with chemotactic factors — IL8
• Extravasation of lymphocytes and monocytes
• With persistent non-degradable antigens nodules of activated epitheloid macrophages form a granuloma with characteristic perivascular (perivenular) cuffing.
What is T cell mediated cytotoxicity?
Principle pattern of response to viral infections, tumour cells and allograft rejection. The CD8+ – CTLs directly kill tissue cells and antigen presenting cell via perforin — granzyme and Fas-FasL pathways which causes apoptosis.
Describe the pathogenetic sequence of events in septic shock.
Infection, producing particularly gram negative endotoxin (bacterial wall lipopolysaccharides LPS) but also gram positive exotoxin binds with leucocytes and endothelial cells causing cell damage as well as initiating a cascade of mediators from plasma or cells .
Major mediators from the mononuclear phagocyte system are IL-I and TNF- a. Others include PAF,NO, complement prostaglandins, leukotrienes etc
Effects on multiple organ systems
How are specific organ systems affected in septic shock
• Heart — dysfitnction/depression/dilation
• Vascular system — hypotension and vasodilation
• Microcirculation — endothelial injury and activation, leucocyte aggregation
• Coagulation system — DIC
• Lungs — ARDS
• Liver – failure
• Kidney – ARF
• CNS — confusion/coma
What is meant by the term atopic asthma?
1. Asthma triggered by environmental factors – dust, pollen, dander, food
2. Type 1 IgE mediated hypersensitivity reaction
Outline the events occurring in the immediate phase.
a. Antigen + IgE = mast cell degranulation
b. Release of preformed mediators – open epithelial tight junctions – allow antigen access to mucosa
c. Activates mucosa] mast cells and eosinophils – more mediator release
d. Directly or thru’ neuronal reflexes – bronchospasm, inc vascular permeability, mucus production, additional cell recruitment.
Pass: At least 3
Which mediators are involved in atoplc asthma?
- “Putative” mediators – effective pharmacological interventions
- Leukotrienes 04, Da, E4
- Acetylcholine – bronchoconstriction.
- Mediators found in atopic asthma, but with ? minor role – Histamine, PGD2, PAF.
- Suspected mediators – cytokines (IL-1, TNF, IL-6), chemokines, neuropeptides, NO, bradykinin, endothelins
What are the phases in the pathogenesis of systemic immune complex disease?
- Formation of antigen antibody complexes in circulation
- Deposition of immune complexes in various tissues
- Inflammatory reaction leading to tissue injury
Pass: 2 of 3
What chemical mediators contribute to immune complex mediated tissue injury.
Prompt: What cell types are involved — what factors might they liberate? Any other systemic processes?
- Complement cascade — classical pathway:
opsonins C3b — resulting in phagocytosis
Chemotactic factors C5 fragments C5b67
Anaphylotoxins C5a C3a
Membrane attack complex C5-9
- Inflammatory mediators liberated from neutrophils and macrophages, Histamine, PAF, protaglandins
- Hageman factor, kinins
- Oxygen free radicals
Pass: 1 and 2 with reasonable coverage of each.
What are the major mechanisms involved in Type 2 hypersensitivity reactions?
Prompt: How is complement involved in this process?
- Phagocytosis mediated by opsinisation and complement
- Membrane attack complex by complement activation
- Antibody Dependent Cell mediated Cytotoxicity (ADCC)
- Inflammation ( tissue damage) induced by complement and Fc receptor binding of leucocytes
- Antibody mediated cellular dysfunction
Pass: 2 of 4
How does type 2 hypersensitivity bring about changes in cellular function?
Prompt: What is their effect on receptors?
Antibodies directed against cell surface receptors may bind to the receptors and either
Upregulate their function — ie Graves disease
Downregulate ie myesthenia gravis
Where are B lymphocytes located?
- Bone Marrow
- Lymph nodes
- Peripheral Lymphoid Tissue
Pass: 4 of 5
How do B cells respond to antigenic stimulation?
- Specific Receptor Complex (IgM)
- Transformation to Plasma Cell
- Production of Specific immunoglobulins
How are B cells activated in a graft vs host reaction?
- (CD4+) T helper cells
- Cytokines (Interleukin 4&5)
- B cell stimulated by antigen in presence of cytokines
What is the role of complement in systemic immune complex disease?
- Opsonisation (c3b)
- Chemotaxis (c5 & b67)
- Anaphylotoxins (c3a & 5a)
- Membrane Attack Complexes (c5-9)
Pass: 3 of 4
What is an Arthus Reaction?
- Excess of antibody
- Large immune complexes – precipitates – vasculitis
An obese 50 year old woman presents to ED with an anaphylactic reaction to penicillin. What type of hypersensitivity reaction is involved?
- Type 1
What are the sequences of events involved in type I hypersensitivity reactions following re-exposure to an allergen?
- Mast cells armed with pre-formed IgE antibodies -> on re exposure to specific to specific antigen -> release of mediators from mast cells
- Pre-formed mediators e.g. histamine/proteases/chemotactic factors
- Lipid mediators e.g. leukotrienes C4 and D4/ PG D2/ PAF
- Cytokines e.g. TNF and chemokines
- -> Immediate and late phase reactions
What changes occur at the tissue level?
- Increased vascular permeability
- Smooth muscle spasm/bronchospasm
- Cellular infiltration
- Epithelial damage
- 3 of 5 to pass