Theme 5 - 5b (Hypersensitvity) Flashcards
what are the different classifications of hypersensitivity reactions
- I-IV
- I, II and II are ANTIBODY MEDIATED
- IV is CELL MEDIATED (T cells) and ‘delayed’ as the cells have to proliferate
describe type I hypersensitivity
- antibody IgE and MAST CELL mediated
- IgE isotype mediate it following sensitisation
- IgE targets SOLUBLE antigen
- antigen is picked up by APC and presented to B and T cells in the secondary lymphoid tissue
- Following FIRST exposure (sensitisation) to Ag, IgE remains bound by Fcε receptors on mast cells
- On subsequent exposures, Fcε receptor cross-linking triggers immediately, resulting in mast cell degranulation
- some antigen binds mast cell in periphery (eg in lung if antigen is from air)
- Granules contain potent inflammatory mediators (eg. histamine, prostaglandins and leukotrienes)
- Requires priming by Th2 cells to cause B cells to switch to IgE production
- This reaction is the basis of atopic (allergic) responses to environmental antigens
- tissue LOCATION governs disease symptoms
why do some people show an exaggerated response in Type I response
- could be due to
- receptors that bind IgE
- could be due to increased Interleukin 4 and 5 (IL4 and IL5) production
- MHC molecules that bind are meant to bind pathogenic peptides bind and present BETTER in some people
what kind of responses do Type I hypersensitivity responses cause
- allergic rhinitis (hayfever)
- if pollen is inhaled, it cuases the mass release of pro-inflammatory cytokines (eg TNFalpha)
- eosinophils, basophils and mast cells are involved
- symptoms: sneezing, rhinorrhea, itching, mucus productio, can affect the nerves as the histamine, leukotrienes are released in large amounts
how can type I responses in hypersensitivity cause asthma
- Allergen-specific Th2 cells in the lung promote release of IgE and activation of mast cells
- Th2 cytokines, such as IL-5 and eotaxin, recruit eosinophils to the lung
- Release of mediators such as histamine, LTC4, LTD4, LTE4, PAF (platelet activating factor) trigger bronchial CONSTRICTION and mucus production
- While some asthma-related allergens have been identified the underlying cause is unclear
what are the treatments for asthma
- either target MAST CELL and try and prevent release of mediators, such as (CROMOLYN, CORTICOSTEROIDS)
- EPI PEN (relax the brochioles)
- leukotriene antagonists (block leukotriene release)
describe type II hypersensitivity response
- mediated by IgG or IgM
- Antibodies (IgG or IgM isotype) can be directed against ANTIGEN on an individual’s OWN CELLS (target cell) (O there can be overlap here between hypersensitivity and autoimmunity)
- Antibody targets extracellular matrix proteins and connective tissues
- Can also be triggered by INNOCUOUS (normally harmless) foreign antigens, such as antigens on transfused red blood cells or platelets or even drugs (penicillin)
- IgG binding to antigen triggers opsonisation and complement fixation leading to recruitment of NEUTROPHILS and MACROPHAGES and eventual destruction of cell or tissue by antibody dependent cellular cytotoxicity (ADCC)
OR - IgG antibodies bind to signalling molecules or cell RECEPTORS, disrupting normal cell function (sometimes called Type V)
what is the pathology of type II hypersensitivity
- cell (eg RBC) has antigen on surface
- antibody binds to antigen on surface
- neutrophils or NK cells that have Fc receptors that recognise antibody can come and bind causing antibody dependent cellular cytotoxicity ADCC. neutrophils/NK cells can then release granzymes/perforins and granule contents causing cell lysis
- OR complement can be activated
- c1qrns activates the clasical complement pathway. other complement proteins are then attracted. C5a and C3a are released which can attract more neutrophils to the cell O inflammation is prormoted
what kind of diseases/syndromes are linked to type II hypersensitivity
1) Goodpasture’s syndrome
- Linked to viral infections
- viral antibodies target basement membrane collagenase IV in lung or kidney (glomerulonephritis)
- this attracts neutrophils/complement, which damages the tissues
- Can be visualised by immunofluorescence
2) Autoimmune haemolytic anaemia
- Antibodies target own RBCs via blood group Ags (Rh)
- Cause of transfusion reactions and hemolytic disease of newborn (reactive Ig crosses the placental barrier)
- Abs opsonize & fix complement, MAC lyses RBCs
- Diagnosed using Coomb‘s test
which diseases are type II/V mediated
1) Graves’ disease
- Caused by ‘auto’antibodies targeting the thymic stimulating hormone receptor
- Antibodies trigger receptor activation stimulating thyroid hormone synthesis, secretion, and thyroid growth (goitre)
- 50% of patients show opthalmopathy as Antibodies also target eye muscles
- Causes unknown (genetic/environment)
2) Myasthenia gravis
- antibodies block nicotinic acetylcholine receptors at the postsynaptic neuromuscular junction
- Causes muscle weakness and fatigue
- Weak genetic link to HLA-DR3 (MHCII gene)
- Often presents with other autoimmune disease eg. Diabetes type I and Rheumatoid Arthritis
describe the action of Type III hypersensitivity
- immune complex mediated
- Soluble antigens complex with IgG leading to immune complex formation which occurs during all immune responses and are normally removed by the phagocytes
- Activation of complement initially helps solubilise immune complexes by disrupting antigen-antibody bonds.
- COMPLEMENT DEFICIENCIES and AUTOIMMUNE disease are associated with INSOLUBLE IMMUNE COMPELXES AND DEPOSITION IN TISSUES
- Disease symptoms depend on site of complex deposition, which depends on complex size
- Small complexes preferentially deposit within vessels; large complexes accumulate in liver, spleen, and kidneys
- Immune complex deposition activates innate immune cells (macrophages & neutrophils) via activation of Fc receptors
describe the pathology of type III hypersensitivity
- pagocytosis and complement should clear circulating immune complexes but due to complement deficiency they aren’t cleared
- causes depostion of small complexes in vessels
- macrophages and monocytes release factors damages vessel causing inflammtion-> VASCULITIS. This can also happen in the liver/spleen etc
which diseases are associated with type III hypersensitivity
1) SERUM SICKNESS
- Sensitisation results in deposition of antigen:antibody complexes in blood vessel walls triggering neutrophil degranulation and vasculitis
- Triggered by injection of poorly catabolised foreign Ag (eg.anti-snake venom serum)
2) Arthus reaction
When symptoms are seen on the skin
Triggered occasionally after some diptheria vaccine or in autoimmune diseases
3) Systemic lupus erythematosus ‘the great imitator’
- Abs target cytoplasmic antigens eg. DNA, histones, RNA binding proteins (LSm proteins)
- Complexes can accumulate in the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system
- Hallmark of SLE is glomerulonephritis due to immune complex deposition at glomerular basement membrane
- Other symptoms - skin rash, arthritis
- SLE has a genetic component – runs in families, but is also linked to infectious agents
describe Type IV hypersensitivity
- T cell mediated
- delayed type, due to densitisation taking 1-2 weeks - mainly of Th1 helper cells
- following SECONDARY CONTACT with same antigen, sensitised T cells release inflammatory cytokines (eg IFN gamma) . this induces inflammtory reactions and activates MACROPHAGES
- sometimes Th2, Th17 and CTL (CD8+) mediated with eosinophil and mast cell activation
- activated macrophages are BETTER AT ANTIGEN PRESENTATION O perpetuating the response
describe type IV hypersensitivity and contact dermatitis
- eg contact dermatitis
- haptens: small molecules that are only able to elicit an immune response when bound to a large carrier molecule
- sensitizing agents (haptens) eg Poison Ivy, latex, nickel, gold, chromium, solvents
- eg nickel is a hapten
- nickel can move across into lower layers of skin
- it can bind to ‘own proteins’
- Langerhans cells are dendritic cells of the skin which pick up antigen
- Langerhans cells present self peptides HAPTENATED with the contact-senstising agent (eg nickel) to Th1 cells which secrete INF gamma and other cytokines
- activated keratinocytes secrete cytokines such as IL-1 and TNF alpha and chemokines such as IL8, IP9 and CXCL9 (Mig)
- the products of keratinocytes and Th1 cells activate macrophages to secrete mediators of inflammation
- Pentadecacatechol in poison ivy leaf is lipid soluble - can cross cell membranes and modify intracellular proteins and are picked up by APCs
- Modified self-proteins are presented on MHC class I (intracellular Ags) to CD8+ CTLs and MHC class II (extracellular Ags) to CD4+ Th1
- CD8+ CTLs kill Ag-expressing cells and Th1 cells activate inflammatory macrophages mainly via release of IFNg
