L26 Hypersensitivity and Auto-immunity Flashcards
Describe the mechanisms of Type 1 hypersensitivity reaction (allergy/anaphylactic)
- Divalent allergen crosslinks two IgE molecules previously passively bound to high affinity FcE receptors on mast cell
(also triggered by C3,C5a complement and some drugs)
- This causes mast cell to release preformed/newly formed mediators
- Chemoattractants
- Activators: vasodilation, complement and platelets
- Spasmogens: SM contraction, mucus secretion
- Results in vasodilation/leakiness, pruritis and SM contraction, which may be localised to the site (less severe allergy) or multi organ in anaphylaxis (emergency)
Describe the common sites for allergy and the presentation there
- Resp Tract:
- Allergic rhinitis
- sinusitis
- conjunctivitis
- Asthma - if severe life threatening - Skin
- Urticaria
- Angioedema - Gut
- Food allergy: diarrhoea, abdominal cramps, vomiting
What makes a patient Atopic
They have increased levels of IgE antibodies, and tend to make IgE antibodies to multiple allergens which runs in families
What is the treatment for allergies
- Avoidance
- Antihistamines for mild forms
- Corticosteroids for chronic conditions (eg. asthma)
- sodium cromoglycate: stabilises Mast cells to reduce degranulation
- Sympathomimetics: epinephrine in Anaphylaxis
- Desensitisation (in select people) gradually increasing doses of allergen to induce high affinity IgG antibodies to compete with IgE.
Describe the mechanisms of Type 2 hypersensitivity reaction (Cytotoxic)
eg. haemolytic disease of the newborn
- IgG Antibodies are formed against cell surface antigens and they bind, exposing their Fc region
- Fc region is bound by K cells that undergo antibody dependent cellular cytotoxicity - releasing things that damage the cell surface
- Due to formation of immune complexes (antigen bound to antibody) there is activation of Complement which forms MAC (damage cell surface) and releases C3b
- IgG Fc receptor + C3b allows neutrophils to attach and be activated and because they can’t ingest they will release their granules and cause damage to cell surface (frustrated phagocytosis)
Describe the mechanisms of Type 3 hypersensitivity reaction (immune complex mediated)
- Following chronic infection there is a period where conc of soluble antigen in blood is still high while antibodies are starting to appear.
- This leads to formation of large lattice immune complexes which can deposit in vessels
- This leads to activation of complement. Which leads to platelet activation and recruitment of neutrophils leading to neutrophil mediated damage in the vessels
4.a)
Can lead to Systemic disease - depositions in skin, joints, kidney (rash, arthritis, nephritis) - non human Mab SE
b) can be localised disease within tissues - eg. Extrinsic allergic alveolitis: IgG antibodies meet inhaled actinomycete fungi in alveoli leading to complement /neutrophil mediated lung function compromise
Describe the mechanisms of Type 4 hypersensitivity reaction (Delayed type) - Contact sensitivity
- Small molecule (eg. nickel) diffuses into the skin where it binds with a Hapten (normal protein) which makes it antigenic
- Uptake, processing and presentation of this antigen by dendritic cell in skin to T helper memory cell in nearby lymph node.
- T lymphocyte (mainly CD4) secretes cytokines which recruits/activates macrophages and lymphocytes-> inflammation
What are the 4 mechanism of Tolerance of self - removal of self reactive lymphocytes
- Clonal deletion (central) after self reacting to antigens in the bone marrow / thymus
- Clonal regulation (peripheral) No co-stimulation when presenting peripheral self antigen leading to anergy
- Suppression (peripheral) T regulator cells keep self reactive b/t cells in check
- Immunological ignorance:
self-reactive cells are present but antigens sequestered in immunologically privileged sites or lacking T cell help
What are natural autoantibodies and why don’t they cause disease (5) - give example
Natural antibodies are usually IgM, and have a regulatory role / disposing of breakdown products.
They don’t cause disease because
- low titre and/or low affinity
- directed against antigens not normally accessible in significant amounts
- the patient does have disease but its still subclinical
- they may need help from a corresponding self reactive CD4 lymphocyte to get a stronger response going
- the antibody isn’t actually causing damage
Both seen in elderly but also present in specific disease
eg. A-nuclear antib: SLE
eg. A-thyroid antib: thyroid disease
How can a tolerised T lymphocyte still cause an autoimmune disease and give eg.
Molecular mimicry where T cells think that the HLA +self peptide combo looks the same as HLA + bacterial/viral RNA/DNA peptide so there is a cross reaction
- Means that HLA haplotype is important
eg. Salmonella, shigella, chlamydia infection can trigger reactive arthritis
What are the two hypersensitivity reactions that have roles in autoimmune diseases give an example and the treatment
- Type 2: antib mediated cytotoxicity
= Organ specific autoimmune disease
eg. Addison’s disease:
Treatment: Replacement of glucocorticoid and mineralocorticoids
- Type 3: immune complex mediated
= Systemic autoimmune disease
eg. Systemic Lupus Erythermatous
Treatment: Immune suppression
- Corticosteroids, Azathioprine, Cyclophosphamide
What are the risk factors for developing Auto-immune conditions (5)
- Genetic predisposition- mutations in
- Antigen receptor genes–> Ig and TCR
-Antigen presentation genes–> some HLA haplotypes are associated with certain diseases,
eg. B27: ankylosing spondylitis
maybe due to peptide binding, molecular mimicry
- Complement genes (impaired immune complex clearance)
- Regulatory genes: cytokines + co-stimulators
2. Females in childbearing ages (hormonal component?) are the most common to have AA conditions
