Hypersensitivity Flashcards
Define hypersensitivity
A harmful immunologic reaction developing in response to an otherwise harmless specific trigger
What is an arthus reaction?
- Hypersensitivity type III reaction
- Skin reaction when sensitized individuals are re-exposed to a specific antigen (hemorrhage/edema within 4-10 hrs)
- Repeated injection of vaccines cause localized inflammation and necrosis (already high IgG titers from previous vaccination)
What is serum sickness?
- Type III hypersensitivity reaction
- Systemic reaction following large quantities of foreign protein:
- Humans immunized with serum of immunized horses triggers illness (flu like; joint pain, swelling, fever, malaise, rash) a week later
- Onset 7-10 days after initial exposure (IgM to IgG class switch)… subsequent exposures have a more rapid onset
Define atopy
The predisposition to develop allergies (used interchangeably with “allergic”)
Summarize the 4 Gell and Coombs classifications of hypersensitivity reactions
- Immediate Allergy (IdE mediated)
- Direct antiBody mediated (cytolytic)
- Immune Complex mediated
- Delayed type (T cell mediated)
What are the two stages of the mechanism of hypersensitivity?
- Sensitization stage
Development of the immune response (requires adaptive immunity, symptoms silent) - Effector stage
Elicitation of the secondary immune response (symptoms evident)
Describe type I hypersensitivity
“Immediate type” hypersensitivity
Mast cells and basophils mediate the initial phase of anaphylaxis (IgE crosslinking by antigen triggers degranulation)
What are the steps of the type I hypersensitivity sensitization phase?
- BCRs on naive B cell bind antigen
- Antigen is also processed and presented by APCs to CD4+ T cells
- Naive CD4+ T helper cell matures into a Th2 antigen specific cell
- Th2 cell produces cytokines to support B cell class switching to IgE
- B cell and plama cell produce IgE
- Circulating IgE binds long-term onto Fc£RI on mast cells/basophils “priming” them for future activation
What are the steps of the type I hypersensitivity effector phase?
- Repeated exposure to allergen
- Antigen crosslinks antigen-specific IgE already bound to Fc£RI on mast cells/basophils
- Crosslinking triggers rapid extracellular release of preformed mediators -> immediate symptoms of anaphylaxis
- Hours later delayed phase symptoms develop
What are the 3 types of mediators in a type I hypersensitivity reaction? Give examples and their effects
- Preformed mediators (released in sec-min)
E.g. Histamine -> vascular dilation, smooth muscle contr
Tryptase -> tissue damage - Rapidly produced mediators (released in min-hr)
*From modification of arachidonic acid!
E.g. Prostaglandins (PGD2) -> vascular dilation
Leukotrienes -> smooth muscle contraction - Slowly produced mediators (released hrs-days)
*Transcriptional activation of cytokine genes!
E.g. Cytokines -> inflammation/leukocyte recruitment
What are the physiologic changes obsered in a type I hypersensitivity reaction?
- Leaky/dilated blood vessels
- Low BP
- Shock
- Cardiac effects
- Myocardial depression
- Tachy/bradycardia
- Smooth muscle spasm
- Bronchospasm
- GI/GU tract spasm
- Coronary spasm
What are the two main histamine receptors (note: at least 4 total)?
- H1R
- Itching
- Increased vascular permeability; edema
- Smooth muscle contraction; bronchospasm/cramping
- H2R
- Gastric acid secretion
What are the main preformed mediators of a type I reaction?
-
Histamine
*short half-life in serum, gone withing minutes -
Tryptase (mast cells only, not basophils)
*Immature constitutively released, mature only released with degranulation
*Found in serum up to 4 hrs after release (best clinical marker of mast cell activation), leads to connective tissue remodeling - Proteases (degrade toxin, lead to connective tissue remodeling)
Describe the crystalloid granule (of eosinophil)
Oval granule with major basic protein
Describe the origin and importance of IL5 in type I hypersensitivity
**Produced by Th2 CD4+ lymphocytes
- In vitro
- enhances surivival, leukotriene synthesis and parasite cytotoxicity
- promotes adhesion and transendothelial migration
- In vivo
- T cell production can cause hypereosinophilic syndrome
- Levels increased in fluids from allergic late-phase reactions
What is the therapeutic importance of corticosteroids in hypersensitivity?
They bind the glucocorticoid receptor (GR-a) which translocates to the nucles, inhibiting AP-1 and NFkB (pro-inflammatory transcription factors)
**Inhibits production of IL5
AKA “steroids seem to make eosinophils disappear”
Give 5 examples of type I hypersensitivity
- Allergic rhinitis
- Drug/food/venom allergies
- Asthma
- Urticaria/angioedema (hives and swelling)
- Mastocytosis (when mast cells accumulate in skin and/or internal organs such as the liver)
How can you clinically test for type I hypersensitivity?
Prick/scratch test, intradermal testing (never used for foods), and serum IgE ELISA
What are the first and second line treatments for asthma?
- First line:
- Trigger avoidance
- Inhaled corticosteroids
- SABA (short acting beta agonists- albuterol)
**Antihistamines ineffectual
- Second line:
- Montelukast (anti-leukotriene, LTRA)
- Omalizumab (anti-IgE)
- SCIT (subcutaneous immunotherapy- allergy shots)
- LABA (long acting beta agonists, only given with inhaled steroids)
Describe type II hypersensitivity
- “Tag you’re it”
- Antibody (IgG or IgM) binds cell or matrix bound antigen
- Bound Ab leads to future immunolgic attack and/or functional interference (inhibtion or activation)
**E.g. reaction to incorrect blood transfussion (ABO incompatibility)
What are the 4 ways an antibody triggers pathology in a type II reaction?
- Complement activation
- ADCC (Ab dependent cellular cytotoxicity, via CD8 and NK cells)
- Phagocytosis (via opsonization)
- Ab alteration of normal function (e.g. Ab inactivation of Ach receptors in myasthenia gravis)
What is goodpasture syndrome?
Hypersensitivity type II
Abs attack type IV collagen in basement membranes of glomeruli and lung alveoli
Leads to nephritis and lung hemorrhages
What is bullous pemphigoid?
Hypersensitivity type II
Abs attack epidermal basement membrane proteins
Leads to skin vesicles
What is pernicious anemia?
Hypersensitivity type II
Abs attack intrinsic factor (helps absorb vit B12) and gastric parietal cells
Leads to megaloblastic anemia
What is vasculitides?
Hypersensitivity type II
Abs attack cytoplasmic neutrophils
Varied disease presentation
What is thrombotic phenomena?
Hypersensitivity type II
Abs attack phospholipids
Varied disease presentation (can get clotting disorders)
What is acute rheumatic fever?
Hypersensitivity type II
Abs normally attacking streptococcal antigens cross-react with heart
Carditis/valvular disease
What is drug induced hemolytic anemia/thrombocytopenia?
Medicines may become antigenic when bound to RBCs/platelets (called hapten formation)
IgG targets the hapten
Ab-tagged RBC/platelet targeted for destruction (ADCC) in the spleen
E.g. cephalosporins, penicillins, quinidine, dapsone, nitrofurantoin, methyldopa
Describe fetal Rh incompatibility (erythroblastosis fetalis)
- Preventable fetal blood antigen type II hypersensitivity
- Rh negative mother is sensitized by first child’s delivery (mother develops IgG against fetal Rh)
- In next pregnancy, maternal anti-Rh IgG crosses the placenta, tags fetal RBCs, and marks them for destruction
- Fetal hydrops/still birth occurs from severe anemia
**treat mother with anti-Rh D antibody to prevent
Describe type III hypersensitivity
- IgG targeted against a soluble foreign antigen can form large polymeric immune complexes (linked antigen-antibody)
- IC formation and clearance is a normal process however certain circumstances can trigger self-injury
- IC formation is promoted when antigen:Ab ratio is close to 1:1 (the “zone of equivalence”)
- ICs deposit in preferential sites (kidneys, vessels, joints, skin)
**E.g. serum sickness
How do immune complexes trigger injury? What type of hypersensitivity is this?
Hypersensitivity type III
ICs trigger injury by activating FcγR expressing phagocytic cells and complement at sites of deposition
What are examples of antigens that cause type III hypersensitivity reactions?
- Exogenous
- Infectious agents (e.g. strep, hep B, etc)
- Drugs or chemicals (e.g. vaccines, heroin)
- Endogenous (for autoimmune patients)
- Nuclear antigens (e.g. in lupus)
- Immunoglobulins (e.g. in rheumatoid arthritis)
- Tumor antigens (e.g. in glomerulonephritis)
Describe type IV hypersensitivity
- “Cell mediated” delayed type
- Involves T cells (CD4 and/or CD8) NOT antibody
- Antigen binds self-proteins thus creating a haptenated self-protein (looks foreign to the immune system) which is processed/presented by APCs to T cells
- Triggers extensive macrophage mediate inflammation
**e.g. allergic contact dermatitis
What mediators are secreted by T cells in type IV hypersensitivity?
- IFNγ
- induces expression of adhesion molecules
- activates macrophages
- TNFα
- induces expression of adhesion molecules
- local tissue destruction
- IL3
- stimulates monocyte production from BM
- Chemokines
- recruit macrophages to site
What are some examples of type IV hypersensitivity?
- allergic contact dermatitis
- formaldehyde/preservatives
- rubber accelerators
- methacrylates
- nickel, gold, cobalt
- fragrances
- poison ivy (allergen=urushiol)
How do you usually test for a type IV hypersensitivity? How is it treated?
Confirm reaction by patch testing or intradermal diasnostic testing (e.g. TB test)… both slow to test positive
Improves with topical corticosteroids
Contrast autoimmunity, allergy, and anergy
Autoimmunity= reactivity to self antigens
Allergy= reactivity to harmless foreign antigens
(e.g. food/drug/venom/allergic rhinitis)
Anergy= ignorance/failure to clear harmful self or foreign antigens (e.g. cancer, HIV, TB)
(e.g. lupus, rheumatoid arthritis, MS)
What is the trend of disease in developed countries?
Immune dysregulation (autoimmunity and atopy) are rising
Infectious disease burdens continue to decrease
