7. Hypersensitivity and Autoimmunity Flashcards
Define hypersensitivity.
Define autoreactivity.
What is an autoimmune disease?
Damage done to the body and its tissues by defence mechanisms, especially the immune system. Response can be directed against self or nonself. Types 1-5. Fuzzy definitions.
Interaction between variable regions of antibody and helper and cytotoxic T-cell receptors, and self components. (Not interaction between Fc portion of antibody and Fc receptors, between CD4/CD8 and HLA etc.)
A disease resulting from autoreactivity.
What is an allergy?
What is atopy?
Altered response to an antigen, following previous exposure; the response being damaging to self. The antigen is always nonself - autoreactivity is not involved.
An increased predisposition to form IgE antibodies against common environmental antigens. Strong inherited componet. Syndrome of asthma, allergic rhinitis and eczema.
List the 5 mechanisms of hypersensitivity.
Describe type 1 hypersensitivity.
I: allergy, 2: cytotoxic, antibody-dependant, 3: immune complex, 4: delayed-type hypersensitivity, cell-mediated immune immune memory response, 5: autoimmune disease
Antigen interacts with IgE, releasing mast cell products: histamine, leukotrienes, prostaglandins, eosinophil chemotaxins. Immediate type hypersensitivity: exposure to antigen causes mast cell degranulation, causes symptoms within minutes. BUT not all tpye 1 hypersensitivity occurs in atopic people.
What are some local phenomena that cause type 1 hypersensitivity?
Describe the general phenomena.
What is anaphylaxis?
Hayfever (antigens: pollen), asthma (pollen, house dust mite, fungal spores), some local urticaria (insect bites/stings), atopic eczema, abdo pain and diarrhoea (some food intolerence)
In highly sensitised people, trivial antigen exposure causes massive mast cell degranulation with systemic effects: anaphylaxis, general urticaria, angioneurotic oedema of skin and mucosa, asthma, hayfever, GI symptoms.
Oedema of larynx and bronchial tree plus profound fall in BP due to pooling in great veins. Insect bites/stings, some food and drugs = most common causes.
What did the Prausnitz-Kustner experiment show?
What are some other routes to mast cell degranulation (aside from general phenomena)?
Type 1 (immediate) hypersensiivity could be transferred by serum.
Degranulation can also be caused by C5a/C3a, nerves, physical/chemical, temperature/pressure can cause urticaria, food can cause local GI/systemic symptoms. Complement-mediated activation of mast cells (bt usually mixed with type 2/3)
Describe type 2 hypersensitivity and give some examples.
Antibodies attach to determinants on self strucutres, which are damaged by classical complement activation, phagocytosis and/or killer activity. E.g. haemolytic anaemia, haemolytic disease of the newborn, transfusion reactions, Goodpastures syndrome (Abs to BM in kidney and lung), myasthenia gravis (Abs to ACh receptor).
Describe type 3 hypersensitivity.
What is the experimental model for, and examples of:
a) the local form?
b) the systemic form?
Antigen-antibody immune complexes, +/- complement, damage neighbouring “innocent bystanding” tissue. The antigen may be self components (e.g. nuclear consituents as in SLE) or nonself (e.g. streptsoccal). Effects can be local (site of antigen introduction) or systemic (manifested whereever the complexes precipitate from the circulation).
a) Arthus reaction. Extrinsic allergic alveolitis.
b) Serum sickness (lots of horse serum injected IV). Clinial effects: vasculitis, glomerulonephritis, arthritis, plus fever and malaise. Clinical examples: SLE, many glomerulonephtitides etc.
What is the believed reason for most glomerulonephritides?
What factors determine whether immune complexes cause pathology?
Circulating immune complexes e.g. post-streptococcal nephritis, or SLE.
Duration and quantity of production, size, Ab:antigen, nature of lattice, identity of antigen, specificity of antibody and avidity for antigen, class/subclass of Ab, efficiency of phagocytes. IgA does not usually activate complement but if part of a precipated complex, it may.
Describe the mechanism in local and systemic forms of type 3 hypersensitivity.
What are the neutrophils further activated by in this mechanism?
Local thrombosis may also occur - describe this.
Immune complexes activate classical complement pathway, with activation of mast cells and inflammation, chemotaxis of neutrophils and monocytes, activation of the lytic sequence, with some innocent bystander damage, and phagocytosis of complexes by the neutrophils.
C5a and engagement of Fc and C3b receptors. Neutrophils generate oxidising agents and destructive enzymes which may leak and cause damage. They secrete leukotrienes, prostaglandins and PAF (platelet activating factor), which mediate further inflammation and chemotaxis.
Platelets have Fc receptors and adhere to immune complexes. They may degranulate b/c of the PAF, and through being “innocent bystanders” of the lytic sequence.
Describe type 4 hypersensitivity and give an example.
List some conditions that are under type 4 hypersensitivity.
Give 3 mechanisms of type 4 hypersensitivity.
Damage associated with activated CD4 T-cells and activated macrophages, activated by CD8 T-cells and NK cells. Delayed type hypersensitivity. E.g. TB: BCG vaccination in Mantoux-positive individual causes lesion that appears 12 or more hrs after antigen exposure.
Granulomata, T-cell infiltrates, contact dermititis, acute organ rejection. Cannot be transferred between individuals in serum.
1) presentation of antigen by macrophages to CD4 T-cells
2) activation of CD4 T-cells leading to secretion of IL2, IFN γ, TNF, and other cytokines
3) activation of macrophages with production of oxidising agents and destructive enzymes which are endocytosed causing local damage
Typer 4 hypersensitivity may cause granulomata formation - what is this?
Why might granulomatas form?
There are some lesions containing infiltrates of T-cells without granulomata and often rich in CD8 T-cells - why is there no granulomata?
Granulomata are freqently formed in chronic lesions: central area of necrosis (optional), surrounded by activated macrophages, epitheloid cells (long thin activated macrophages), or giant cells (fused macrophages) surrounded by lymphocytes.
They occur if the antigen is resistant (e.g. TB: tough cell wall, resists phagosome-lysosome fusion) and/or if there is some autoimmunity. The macrophages secrete TNF themselves = imp in mediating granuloma formation.
Antigen is of a different kind - a covert viral infection or a protein autoantigen e.g. islets in IDDM.
Describe type 5 hypersensitivity. Give an example.
Antibody stimulates hormone receptor e.g. Graves’ disease, where antibody to TSH receptors persistantly stimulates the thyroid, causing thyrotoxicosis.
Which is right?
a) class I HLA molecules present exogenous antigen to cytotoxic T cells, which express CD4
b) class II HLA molecules present endogenous antigen to helper T cells, which express CD8
c) class I HLA molecules present endogenous antigen to cytotoxic T cells, which express CD8
d) class II HLA molecules present exogenous antigen to cytotoxic T cells, which express CD4
e) class I HLA molecules present endogenous antigen to helper T cells, which express CD8
f) class II HLA molecules present exogenous antigen to helper T cells, which express CD8
C
a) Th1 CD4 T cell is likely to help?
b) Th2 CD4 T cell is likely to help?
c) Th1 CD4 T cells secrete which cytokines?
d) Th2 CD4 T cells secrete which cytokines?
a) Macrophages
b) B cells
c) IFN gamma, IL2
d) IL4
