Hypersensitivity Flashcards
What are the four main classes of hypersensitivity reactions
Type I - Allergy (IgE-mediated)
Type II - IgM or IgG-mediated (ABO blood groups, Rh)
Type III - Immune complex mediated (serum sickness eg)
Type IV - Delayed-type hypersensitivity
a) Type I hypersensitivity overview
b) IgE-mediated mast cell activation
c) Hygeine hypothesis
d) Development of allergy
a) Allergy (atopic disease). Caused by IgE and are very common (10-40% people). IgE evolved to protect against multicellular organisms like helminths, but in the absence of these immune challenges it is possible we have become hypersensitive to innocuous antigens instead. Anaphylaxis, urticaria, hay fever, asthma and food allergies are all different manifestations of allergy. They are all elicited by IgE that was generated through a prior Th2-mediated immune response.
b) Facilitates immune responses against worms and parasites. Binding of IgE to FcεR on mast cell leads to degranulation (only when helminth is bound to IgE), releasing histamine and other inflammatory mediators (good to remove helminths, not in inappropriate occasions)
c) Early exposure to pathogens and/or a rich commensal microflora may protect against atopic diseases and asthma
d) (see image) There is initial sensitisation where a dendritic cell presents a peptide of the innocuous antigen on MHC to naive T cells. Activated Th2 cells stimulate B cells to produce IgE, which is then captured by mast cells via their FcεR. When the peptide is re-exposed, it will bind to the captured IgE, causing immediate degranulation of the mast cell, and an allergic response
Type I hypersensitivity - Diagnosis of sensitivity to allergens
Determined by the skin-prick test.
A wheal and flare reaction appears at the site of infection within a few minutes (oedema and redness/erythema is from increased blood flow). Cause of this are immediate mediators released from mast cells - histamines, prostaglandins, leukotrienes, proteases, TNF-α
After ~6 hours, there may be a late-phase reaction, where the swelling spreads to involve the surrounding tissue. Symptoms are exacerbayed by additional recruitment of lymphocytes and myeloid cells. VEGF causes vasodilation and oedema. Late phase mediators - VEGF, CGRP, leukotrienes, prostaglandins, cytokines (IL-4), recruitment of basophils, eosinophils, monocytes, Th2 cells
Type I hypersensitivity
a) Allergic asthma
b) Treatments for type I hypersensitivity reactions
a) (see image). Inhalation of allergens trigger airway allergic immune responses. DCs sample the allergen and display peptides on their surface on MHCII. DCs then migrate to draining lymph node and activate allergen-specific T cells and induce clonal expansion and Th2 polarisation. Th2 cells produce inflammatory cytokines which induce allergic inflammation. Eosinophils, basophils and other cell types are also recruited by type 2 cytokines
b) Antihistamines, β-agonists, leukotriene receptor blockers - inhibit the effects of mediators on specific receptors and inhibit the synthesis of specific mediators.
Corticosteroids - general anti-inflammatory effects
Desensitisation therapy by injections of specific antigen - induction of Treg cells
Anti-IgE antibodies (omalixumab) - binf to IgE Fc region and prevent IgE binding to FcεR on mast cells
a) Type II hypersensitivity overview
b) ABO blood groups
c) Testing for blood groups
a) Caused by IgG or IgM binding to cells or tissues. eg drugs such as penicillin can bind to cell surfaces and elicit immune responses (anaemia if bound to RBCs, thrombocytopenia if bound to platelets).
b) RBCs are differentially glycosylated. The ABO gene encodes a glycosyltransferase. A variant adds N-acetylgalactosamine to the H antigen. B variant adds galactose to the H antigen. O variant is catalytically inactive. Group A displays A antigen, and has anti-B antibodies in the plasma. Group B display B antigen, and has anti-A antibodies in the plasma. Group AB displays A and B antigens, and has neither antibody in the plasma. Group O displays neither surface antigen, and has both anti-A and anti-B antibodies in the plasma. If a blood transfusion is given of an incompatible group, there will be a huge type II hypersensitivity reaction (lethal)
c) Use Coomb’s test - agglutination of RBCs with antigen of corresponding fixed antibody (see practical)
Type II hypersensitivity
a) The Rhesus antigen
b) prevention of this
a) RBCs are either rhesus positive (Rh+) or rhesus negative (Rh-). Rhesus negative individuals have anti-Rh antibodies. The Rhesus reaction is a haemolytic disease of the newborn. If a Rh- mother gives birth a Rh+ baby, it can generate IgG against the Rh antigen (mixing of blood during birth). IgG can cross the placenta and cause rejection of a subsequent Rh+ fetus and cause haemolytic anaemia
b) Administration of anti-Rh antibody (RhoGAM) prevents the mother from raising an immune response against Rh+ cells from the fetus, which masks or eliminates the Rh antigen before the mother can react. Additionally, RhoGAM may induce B cell tolerance for Rh+ by engaging the inhibitory FcγRIIB receptor on naive B cells. However, this treatment will only work if done during the first Rh+ pregnancy, otherwise memory B cells will be able to generate antibody responses the second time.
Type III hypersensitivity (immune-complex deposition)
a) The Arthys reaction
b) Serum sickness
c) Farmer’s lung
a) Caused by immune complex activation of mast cells by IgG binding to FcγRIII (a low affinity IgG receptor), leading to mast cell degranulation and inflammation. This can be a rare reaction to toxoid-containing vaccines (eg DPT) to individuals who already have high amounts of antibodies to these (see image)
b) Antibodies against bacterial toxins and snake bites were commonly generated by the immunisation of horses. When these antibodies (horse serum) were injected, there was sometimes a transient type III hypersensitivity reaction
c) Inhalation of large amounts of animal allergens that provoke IgG responses also precipitate type III hypersensitivity
a) Overview of type Iv hypersensitivity
b) Delayed type hypersensitivity (DTH)
a) T cell mediated. Required 10-100x more antigen compared to antibody-mediated. The antigen is processed by tissue macrophages and stimulates Th1 cells, which secrete chemokines (recruit further macrophages and leukocytes), IFNγ (activates macrophages to release inflammatory mediators), TNFα (local tissue destruction and increase expression of adhesion molecules on local blood vessels), IL-3 (stimulate monocyte production)
b) A contact-sensitising agent penetrates the skin and binds to self proteins, which are taken up by DCs. These present self peptides haptenated with the contact-sensitising agent to Th1 cells (secrete IFNγ, which activates macrophages to secrete mediators of inflammation)
Type IV hypersensitivity
a) The Mantoux test
b) Drug sensitivity
a) Test for Mycobacterium tuberculosis. A small amount of tuberculin is injected subcutaneously, which leads to local oedema - indicating prior infections or immunisation.
b) Some small drugs bind to MHC molecules and displace peptides. eg Abacavir sensitivity syndroms is a T cell mediated drug hypersensitivity that occurs in individuals possessing the HLA class I allele HLA-B57
