Hypersensitivity Flashcards
Hypersenstivity
Exaggerated immune responses that cause inflammation and tissue damage
The 4 types of hypersensitivity reactions are classified by thier ____
Effector mechanisms
Type 1 Overview
IgE mediated hypersensitivity to harmless antigens (soluble)
- mas cell activation
- allergic rhinitis, asthma, systemic anaphylaxis
Type 2 Overview
Antibody mediated destruction of cells
- IgG
- self antigen
- FcR+ cells, phagocytosis by NK cells
- autoimmune diseases
Type 3 Overview
Immune complex mediated
- IgG
- soluble antigen
- FcR+ cells, complement
- serum sickness, arthus reaction
Type 4 Overview
T cell mediated
- Th1 cells –> soluble antigen, macrophage activation, DTH
- CTL –> cell- associated antigen, cytotoxicity, contact dermatitis
Type 1 mechanism
Allergic response to harmless environmental antigen
- sensitization
- germinal center formation in 2nd week of primary response
- isotype switching to IgE
- memory B cells and long lived plasma cells
- mast cells express high-affinity Fc receptor for IgE and bind free IgE from blood
Sensitization
Initial exposure generates a primary immune response
Allergy
State of hypersensitivity to a non-harmful antigen
Type 1 what happens with a second exposure to the original allergen?
Early phase: immediate
- effector function of IgE-mediated activation of mast cells = degranulation and release of histamine and TNF-alpha, leading to an inflammatory response at the site of allergy exposure
Allergen specific IgE
Mast cells express Fc-receptors for IgE
- found in connective tissues surrounding blood vessels and in the mucosa of the gut and airways
Mast cell degranulation effect on tissues
GIT: increased fluid secretion, increased peristalsis = expulsion of GIT contents
Airways: decreased diameter, increased mucus secretion = expulsion of airway contents
Blood vessels: increased blood flow, increased permeability = edema, inflammation, increased lymph flow and carriage of antigen to lymph nodes
Late phase (6-8 hours)
Mast cell synthesis
- prostaglandins and leukotrienes = vasodilation and vascular permeabiltiy
- cytokines and chemokines = leukocyte recruitments
- eosinophils: respond to mast cell derived cytokines, release damaging proteases
- basophils: IgE mediated activation or respond to mast cell derived cytokines= histamine release
What is the goal of the late phase response?
Recruit leukocytes with anti-parasite effector functions (eosinophils and basophils)
- could result in narrowing of airway or sustained edema
Type 1 systemic response
Allergen enters blood stream
- IgE mediated activation of mast cells (CT mast cells associated with blood vessels throughout the body
Anaphylaxis
Immediate type 1 hypersensitive reaction causing circulatory shock and suffocation due to bronchiole constriction
Histamine release by mast cells
- vasodilation and vascular permeability = decrease in blood pressure
- bronchial smooth muscle contraction
- intestinal smooth muscle contraction
Examples of allergens
- drugs
- insect venom
- foods
Heart/vascular system systemic response
- increased capillary permeabilty and entry of fluid into tissues
- swelling of tissues including tongue
- loss of blood pressure
- reduced oxygen to tissues
- irregular heartbeat
- anaphylactic shock
- loss of consciousness
Respiratory tract systemic response
- contraction of smooth muscle and constriction of throat and airways
- difficulty in swallowing
- difficulty in breathing, wheezing
GIT systemic response
- contraction of smooth muscle
- stomach cramps
- vomiting
- fluid outflow into gut
- diarrhea
Type 2 drug-induced hemolytic anemia
- sensitization
- some drugs can bind to self proteins and induce a primary immune response in allergic individuals
- ex: antibiotics (penicillin)
Type 2 mechanism
- drug binds to self proteins to generate a new epitope (could include proteins expressed on surface of RBCs)
- activation of a primary response to a new epitope
- germinal center formation results in high affinity IgG
Type 2 second exposure
- antibiotics bind to self proteins expressed on RBCs
- drug induced IgG binds to the surface of RBCs
- drug induced hemolytic anemia: RBCs are opsonized by IgG and activated complement (C3b) = removal of opsonized RBCs by macrophages in the spleen
Is there a type 1 hypersensitivity to penicillin in some people?
Yes
Is type 3 hypersensitivity due to an allergy?
No, its immune complex mediated
Type 3 local response
Arthus reaction: immune complexes form in tissue, cause localized inflammation
- ex: booster vaccine sometimes results in swelling and/or pain at injection site due to residual antibodies from previous vaccine forming immune complexes with vaccine antigen
Immune complexes activate what pathway of complement?
Classical
- complement activation is proinflammatory
- mast cells degranulate in response to C5a and signals through the Fc recptor for IgG
- activation of Fc-gamma-R3 on mast cell induces degranulation
= local inflammation, increased fluid and protein release, phagocytosis, and blood vessel occlusion (within 2 hrs)
Type 3 systemic response
Serum sickness: immune complexes form in the bloodstream in capillaries of various tissues and induce inflammation
Type 3 systemic example
Snake bite treatment
- antiserum from horses immunized with snake venom occurs with injection of a large amount of poorly catabolized foreign antigen (horse IgG)
- excess of antigen will cause formation of small immune complexes which are depositied in blood vessel walls, leading to activation of complement in vessel wall and inflammation
- later in immune response, large complexes are rapidly cleared form bloodstream by macrophages in liver and spleen
Early in type 3 response there is little _____ and excess of _____
Antibody; antigen
= small immune complex formation
- do NOT fix complement and are not cleared
Late in type 3 response there is large amount of ____ and little ____
Antibody; antigen
= medium-sized immune complexes that fix complement and are cleared from circulation
Type 4 (delayed-type)
- sensitization phase: primary immune response
- elicitation phase: mediated by memory T cells
Is type 4 in response to an allergy?
NO
Type 4 mechanism
- antigen is introduced into sub q tissue and processed by local APCs
- Th1 effector cell recognizes antigen and releases cytokines which act on vascular endothelium
- recruitment of T cells, phagocytes, fluid, and protein to site of antigen injection causes visible lesion
Type 4 example
Turberculin skin test
- requires previous infection with Mycobacterium tuberculosis or vaccination with the attenuated M. bovis vaccine
- mediated by memory Th1 T cells
- Others: anthraxin test or candidin test
Is type 4 contact hypersensitivity in response to an allergen?
Yes!
- T cell mediated, allergic response to chemically modified self proteins
Contact hypersensitivity example
Poison ivy
- chemical from leaf can form covalent bonds and modify extracellular skin proteins (presented by MHC2) or enter cell and modify intracellular proteins (MHC1)
Allergic contact dermatitis
- activation of memory Th1 cells = proinflammatory cytokines
- activation of memory CTL = cellular cytotoxicity and IFN-gamma
Contact hypersensitivity mechanism
- contact sensitizing agent penetrates skin and binds to self proteins, which are taken up by Langerhans cells –> Langerhan cells present self peptides haptenated with contact sensitizing agent to Th1, which secrete IFN-gamma –> activated keratinocytes secrete cytokines (IL-1, TNF-alpha) and chemokines (CXCL8, CXCL11, CXCL9) –> product of keratinocytes and Th1 cells activate macrophages to secrete mediators of inflammation
2 types of contact dermatits
- allergic: immunological form, allergic response to antigen
- irritant: non-immunological, response to chemicals that irritate or traumatize skin (no sensitizaiton, occurs immediately, chemicals activate keratinocytes to produce pro-inflammatory cyo/chemokines)
