Lecture 13 - allergy and autoimmunity Flashcards
Define allergy
harmful immunologically mediated hypersensitivity reactions in response to inherantly harmless antigens
What are the four types of hypersensitivity reaction?
I, II, III, IV
How is type I hypersensitivity characterised?
- immediate
- mediated by IgE
- usually chronic following initial sensitisation with antigen
What are five examples of IgE mediated allergic reaction?
1) Acute urticoria -animals, insects - entry through skin -> local increase in blood flow and vascular permeability edema
2) Seasonal rhinoconjunctivitus - pollens, dust mite faeces in contact with conjunctive of eye and nasal mucosa -> edema of conjunctiva and nasal mucosa, sneexing
3) Asthama - dander, pollen, dust mite faeces through inhalation leading to contact with mucosal lining of lower airways -> brochial constriction, increased mucus production, airway inflammation
4) Systemic anaphylaxis - druigs, venom, food, serum through intravenous entry -> edema, increased vascular permeability, laryengeal edema, circulatory collapse, death
5) food allergy - peanuts, treenuts, fish, milk though oral, -> vomiting, diarrhea, pruritis, urticavia, anaphylactis
What cells are allergic responses dependent upon?
Mast cells
How is IgE involved in activation of mast cell in an allergic response?
1) IgE secreted by plasma cells binds high affinity to Fc receptor FCeRI on mast cells
2) multivalent Antigen crosslinks bound IgE causing release of IgE and granule contents
What is released from an activated mast cell and what are the results?
1) enzymes e.g. trypsase - tissue damamge
2) Cytokines e.g. TNP, - inflammation
3) lipid mediators e.g.PAF, PGD2, LTC4 - intestinal hypermobility, bronchoconstriction
4) Biogenic amines e.g. histamines - vascular leak, vasodilation
What are the properties of allegen entry and mast cell activation when enter by skin?
- low dose
- through epidermis
- mast cell activation leads to local release of histamines in a ‘wheel and flare’ reaction, contraction of vessel and thickening
What are the properties of allegen entry and mast cell activation when enter by lungs?
- low doses
- mucus production
- muscle contraction
What are the physological effects of asthma?
- excess mucus secretion
- smooth muscle hypertrophy
- submucosal inflammatory infiltration with lymph
Who is affected by allergies?
- strong genetic component
- 40% western population prine to produce high IgE
- atopic individuals have enhanced allelic frequences e.g. IIqI2-12 (encode beta subunit of FcrRI)
What are the types of ashma susceptibilty genes?
1) genes triggering immune response or dictating CD4 Th1 cell differentiation
2) Genes regulating Th2 differentation and effector funtion
3) genes expressed in epithelial cells
4) genes identified by positional cloning
What are subtypes of ashma susceptibilty genes 1)triggering immune response or dictating CD4 Th cell differentation?
- pattern recognition receptors
- immunoregulatory cytokines
- transcription factors
- antigen presenting alleles
- Prostaglandin receptor
What are subtypes of ashma susceptibilty genes 2)genes regulating Th2 cell differentiation and effector function?
e.g. GATA-3, IL-4, IL-13
What are subtypes of ashma susceptibilty genes 3)genes expressed in epithelial cells?
- chemokines
- antimicrobial peptides
- CC16
- Epithelial cell barrier
What is the hygiene hypothesis?
genetic susceptibilty coupled with certain elements exposed to as a child increase chances of being allergic
-elements being ‘hygienic’ - not exposed to a range of microorganisms for immune system to deal with e.g early exposure to ubiquitous microorganisms, helminth infection
What is auto immunity?
failure to tolerate self antigens, the production of self reactive lymphocytes leading to tissue destruction, can be organ specific e.g. graves disease or non-organ specific e.g. MS, rheumatoid arthirtis
What is Insulin dependent diabetes mellitus?
destruction of insulin producing B cells
What happens in Insulin dependent diabetes mellitus?
1) cytotoxic T cells recognise peptides from B cell specific proten and attrack B cells
2) release IFNy, TNFalpha, IL-1B leads to influx of macrophages
3) cytokines and macrophage products lead to destruction of B cells
4) glucagon and somatostatin still produced by alpha and beta cells but no insulin
What happens in rheumatoid arthiritus?
1) IgM auto-antibodies bind to Fc receptor of serum IgG form an immune complex
2) immune complex binds to complement and complement receptor
3) phagocytosis and macrophage activated
4) leads to inflammation, acute phase cytokines ROI and enzymes, react against cartilidge and destroy
What happens in Multiple sclerosis?
autoreactive T cells and antibodies and activated macrophages irreplaceably destroy myelin sheath, caused by failure of central tolerence, failure to delete autoreactive cells
Why might immune cells be autoreactive against cells in the brain?
immune system doesn’t protect brain all the time and because of blood brain barrier may be ignorant to cells in brain
What factors are linked to disease susceptibility?
- Sex
- Genes
- Environmental
How is your gender related to disease susceptibility?
Females
- 3 times more likely to develop Rheumatoid arthiritus
- 10 times more likely do develop Systemic Lupus Erythematosus SLE
Same to develop Insulin dependent diabetes mellitus
BECAUSE women can have babies
-higher levels of antibodies
-more CD4 cells
-more Th1
What genes are related to disease susceptibility?
For IDDM,20 times more likely DR4/DR3
For MS 5 times more likely DR2
For SLE 5 times more likely if DR3
How can environmental conditions be related to disease susceptibility?
MS higher in europe, NZ, australis and north america
- sunlight induces vitamin D
- most immune cells express receptor for vitamin D
- ligation of VDR activates immune cells
- and induction of Tregs
What is central tolerance in the thymus followed by?
subsequent peripheral tolerance in tissues
What are types of T cell intrinsic mechanisms of peripheral tolerance?
- Ignorance
- Anergy
- Phenotypic skewing
- Apoptosis
What are types of T cell extrinsic mechanisms of peripheral tolerance?
- Tolerogenic dendritic cells
- Regulatory T cells
How does Anergy occur as a T cel intrinsic method to maintain peripheral tolerance?
stimulation with only signal 1
stimulation with repressor signals PD-1, PDL1/2
How does phenotypic skewing occur as a T cell intrinsic method to maintain peripheral tolerance?
Binds to and is activated by a non pathogenic cell, leading to an activated T cell with non-pathogenic cytokine/chemokine receptor profile
What do Tregs do?
control autoimmunity
- do not readily proliferate
- upregulate CTLA-4, down-regulate CD80
What do natural Tregs (CD4+ CD25+) secrete?
CTLA-4, FoxP3+
What do induced Tregs (Th3, Tr1) secrete?
IL-10 and TGF-beta
