L30: Allergy and Hypersensitivity Flashcards
Hypersensitivity
Adaptive immune response which occurs in an inappropriate or exaggerated way, resulting in tissue damage of some other detrimental response in the host
Type 1 Hypersensitivity
Immediate hypersensitivity. Antigens (allergens) often environmental. IgE and mast cells are central mediators, end results ranges from discomfort to death.
Anaphylactic reactions
- Rapid response (2-30mins)
- Due to interaction of antigen with IgE associated with surface of Mast cells and basophils
- Activates either to cause production of effectors responsible for various types of anaphylaxis
- Vary in extent and severity
- Systemic reaction termed anaphylactic shock - affects breathing and blood pressure
- Localised reactions less severe - hay fever, hives, asthma
Type 1 Hypersensitivity Mechanisms (5)
- Exposure
- Antigen presentation
- Activation of Th2 helper cells
- IgE production
- Binding of IgE to mast cells
Type 1 Hypersensitivity mechanisms in GIT, Airways and Blood Vessels
GIT: increase fluid secretion and peristalsis - expulsion of GIT contents
Airways: decrease diameter, increase mucous secretion - congestion and blockage of airways; swelling and mucus secretion in nasal passages
BV: increase blood flow and permeability - increase fluid in tissues = increase flow of lymph to LN, increase cells and protein in tissues and effector responses in tissues.
Degranulation of mast cells (3)
- Chemoattractants: e.g. cytokines
- Activators: e.g. histamine
- Spasmogens: e.g. histamine, leukotrienes and prostaglandinds
Type 2 Hypersensitivity
Anitbody dependent cytotoxic hypersensitivity. Occurs when antibodies bind to either self antigens (cell surface and ECM) or foreign antigens on cells. Cell death occurs from phagocytosis, NK cell activity or complement-mediated lysis. Pathology occurs when destruction of the tissues leads to illness in the host.
Examples of Type 2 reactions (3)
- Reactions against blood cells and platelets (transfusion reactions, haemolytic disease of the newborn, certain drug reactions)
- Reactions against tissue antigens (Myasthenia Gravis)
- Hyperacute graft rejection (from a few minutes to 48h after transplantation)
Five major blood groups involved in transfusion reactions (5)
- ABO
- Rhesus
- Kell
- Duffy
- MN
ABO blood group reactivities (genotypes, antigens on RBCs and antibodies in serum)
A: AA, AO; A; anti-B
B: BB, BO; B; anti-A
AB: AB, A and B; none
O: OO, H, anti-A & anti-B
Universal donor/recipient
Donor: The RBCs of O donors have no A, B or Rh antigens therefore can be accepted by any person
Recipient: The serum of AB+ patients contain no antibodies to A, B or Rh antigens, therefore they can accept RBC from any person.
Haemolytic disease of the newborn (HDNB):
Erythroblastosis fetalis, occurs when Rh- mother bears an Rh+ child, usually only occurs on second and subsequent pregnancy, antibodies made by pregnant women cross placenta and react with foetal RBCs. Rh+ antigens don’t cross over into the mother in the first birth, but after they are exposed to Rh antigens and develop a sensitisation response. If the mother has a subsequent pregnancy, she has a primed response to the Rh antigens. The maternal antibodies can cross the placenta and lyse the foetal RBCs. To prevent this, the mother can be injected with anti-Rh antibodies after the first birth to eliminate any Rh+ cells and prevent sensitisation.
Type 3 Hypersensitivity
Immune-complex (IC) disease: caused by the deposition of immune (IgG/IgM/Ag complement) complexes in blood vessels and tissues. Under appropriate conditions, IgG and soluble Ag can precipitate, causing large aggreagtes which activate platelets, neutrophils, mast cells and basophils.
Types of Type 3 reactions (route of ag delivery, resulting disease and site of IC deposition)
- Intravenous (high dose): vasculitis, nephritis, arthritis; blood vessel walls. renal glomeruli, joint spaces
- Inhaled: farmer’s lung; alveolar/capillary interface
- Subcutaneous: arthus reaction; perivascular area
Immune complex process
ICs form every time an antibody encounters an antigen. In primates, CR1 receptors (bind C3b) on erythrocytes (RBCs) bind ICs that have fixed complement. ICs bound to RBCs are transported to liver and spleen for removal by fixed tissue macrophages. Larger complex are cleared most efficiently
Issues with clearing IC
Clearance of RBC-bound ICs removes most of the active CR1 from circulation, therefore when IC formation is continuous, efficiency of IC clearance is impaired. Patients with low level of complement have poor binding of IC to RBH, thus there is reduced removal by the liver and spleen. Problems arise when uncleared ICs deposit in blood vessels and other tissues.
Examples of IC disease:
- Serum sickness
- Post-streptococcal glomerulonephritis
- Rheumatoid arthriris
- Farmer and Pigeon Fancier’s lung
- Arthus reacton
Serum sickness
Occurs when foreign serum proteins are introduced. Long-lasting nature of serum proteins results in prolonger Ab production and formation of ICs. ICs deposit in the kidneys, blood vessels and joints causing arthritis, nephritis and vasculitis. Symptoms disappear when ICs cleared.
Type 4 (Cell mediated) reactions
Takes longer - delayed type hypersensitivity. Delay is due to the time required for T cells to migrate and accumulate at site of reaction. Delayed type hypersensitivities are due to TD cells. Cytokines attract macrophages and initiate tissue damage
Contact hypersensitivity
Contact dermatitis. Antigen are simple chemicals (haptens) like nickle, plant material, soaps and cosmetics, initial contact sensitises while second contact leads to erythema, itching etc. within 12-48hr
Central role of Th1 cell in DTH (4)
Antigen is processed by tissue macrophages and stimulates Th1 cells:
- Chemokines: recruit macrophages to site of antigen deposition
- IFN-y: induces expression of vascular adhesion molecules, activates macrophages, increasing release of inflammatory mediators
- TNFa/b: cause local tissue destruction, increases expression of adhesion molecules on local blood vessels
- IL-3/GM-CSF: stimulate monocyte production by bone marrow stem cells
Stages of DTH reaction
- Ag uptake, processing and presentation by APC
- TH1 effector cell recognises antigen and releases cytokines which act on vascular endothelium
- Recruitment of phagocytes and inflammatory cells
Granulomatous hypersensitivity
Occurs in lungs in response to microbacterium tuberculosis. TB lives intracellularly in macrophages, inducing a granuloma response. A typical granuloma has a core of epitheloid cells and macrophages. Centre may be necrotic as in TB. Core is surrounded by cuff of lymphocytes and there may be fibrosis.
General mechanism of DTH
- Contact-sensitising agent penetrates the skin and binds to self protein taken up by Langerhan cells
- Langerhan cells present self-pepides haptenated with contact-sensitising agents to Th1 cells which secrete IFN-y and other cytokines
- Activated keratinocytes secrete cytokines such as IL-1 and TNF-a and chemokines such as CXCL8 (IL8), CXC11 (IP-9) and CXCL9 (Mig)
- Products of keratinocytes and Th1 cells activate macrophages to secrete mediators of inflammation
