Hypersensitivity (1/14)

Question 1

What is a hypersensitvity reaction?

Answer 1

Aberrant or excessive immune response to foreign antigens

Adaptive immune system = primary mediator

Damage is due to the same attack mechanisms that mediate normal immune responses to pathogen

Question 2

What are the 4 types of hypersensitivity?

Answer 2

Type 1 = IgE mediated

Type 2 = IgG/IgM monomers

Type 3 = IgG/IgM multimers

Type 4 = T cells

Question 3

What is sensitization? How is it related to the hypersensitivity reaction?

Answer 3

It’s an exposure that makes it easier to have an immune reaction later on

A sensitization (prior exposure) is reuqired for a hypersensitivity reaction (except in rare cases)

Sensitizaiton can be long lived in absence of reexposure due to immunologic memory

Question 4

What is a hapten?

Answer 4

A chemical moiety too small to elicit a T cell response alone forms a tight association with self proteins

Example: penicillin binds albumin –> “modified self” that can be presented to T cells

Question 5

What is Type 1 hypersensitivity? How does it occur?

Answer 5

Sensitization –> antigen contact –> IgE production

Sencond exposure –> IgE activation –> mast cell activation

This is fast: within minutes of exposure

Can be irritating (hayfever) or fatal (anaphylactic)

Question 6

How are IgE’s formed?

Answer 6

B cells class switch from IgM to to IgE, which requires T cell help: CD40L, IL-4, IL-13 (Th2 cytokines)

Some people have higher predisposition to form IgE responses = “atopic” individuals (to both food and inhaled allergens)

IgE has a half life of 2 days (contrast to IgG=30 days), bc it’s soaked up by mast cell receptors

Question 7

What is the early phase of IgE response in type 1 reaction?

What is the late phase?

Answer 7

Early: IgE crosslinks with antigen –> relase of histamine + other things –> smooth muscle contraction, vasodilation, vascular leak, GI motility, mucous secretion, sensory nerve activation

Then arachidonic acid products are released

Late: ~6 hours later, genes are activated –> cytokine production i.e. TNF alpha –> recruit inflammatory cells; IL-3, IL-5, GM-CSF –> eosinophil production; IL-4, IL-13 –> propagate Th2 response

Question 8

What is the receptor for IgE?

Answer 8

FcεRI & is found on mass cells, basophils and can be expressed on eosinophils

Has alpha, beta, 2 gamma subunits

ITAM = tyrosine sequence in the tail of the receptor, serves as docking site for Syk, a downstream activating kinase

Question 9

What is the role of eosinophils in type 1 reaction?

Answer 9

Chemotaxis attracts them from blood to tissue (IL-5, eotaxins) which prime them for activation

Increased expression of FcεR for IgG, IgA, IgE – crosslinking leads to activation

Low threshold for degranulation

Activation leads to exocytosis - bc they fight a beast bigger than they are

Question 10

What are the 5 main manifestations of type 1 hypersensitivity?

Answer 10

Question 11

What is anaphylaxis?

Answer 11

Response to systemic circulation of allergen– IgE cross linking on mast cells in peri-vascular tissue –> histamine, PG’s, LT’s –> vasodilation, vascular leak

Shock can occur! Also urticaria, wheeze, laryngeal edema, GI crampink, diarrhea

Treat with immediate epinephrine, antihistamines, then corticosteriods to prevent tissue edema from forming again, several hours down the line

Question 12

What is type II hypersensitivty?

Answer 12

Damage mediated by tissue specific IgG or IgM - monomers

Can be a hapten response (i.e. when penicillin modifies surface of RBC), molecular mimicry (proteins within us look like pathogen), or idiopathic (unknown)

Question 13

What is type III hypersensitivity?

Answer 13

Cross linking occurs between antibody and antigen = stoichiometric effect– at just the right conc of antigen/antibody

Ag-Ab complexis deposit on local BV walls

Complement makes C5a –> chemoattractant for neutrophils/ mast cell activator –> histamine release

Binds FcR on neutrophils/platelets

Question 14

What is serum sickness?

Answer 14

Clinical type III hypersensitivity, 2-3 weeks after infusion of antigen i.e. anti-serum of horse

Symptoms = fever, lymphadenopathy, urticaria, joint pain, proteinuria

Note that serum is the one exception to the rule that you have to have seen agent before you respond; here you respond right away, the first time, because the antigen hangs around long enough that we make an immune response to it the first time we see it

Question 15

What is type IV hypersensitivty?

Answer 15

T cell mediated –> direct killing of target cells by CD8, tissue damage via activation of macrophages via CD4

Requires sensitization, reaction occurs 1-3 days after re-exposure

T cells are necessary and sufficient

Question 16

What are examples of type IV reactions?

Answer 16

1. PPD (TB) test: local swelling at site
2. contact dermatitis: erythematous papular, scaling, blistering i.e. poison ivy, latex
3. drug rash - measles like rash - can be against almost any med

Question 17

What is the mechanism of type IV hypersensitvity?

Answer 17

Antigen crosses epidermis (can form hapten with self)

Dendridic cells process & load onto MHC I and II

DC migrate –> presentation to naive T cells –> T cell response –> production of interferon-gamma, chemokines, recruitment of macrophages –> TNF-alpha, inflammatory infiltration, local edema/erythema

** If hapten modifies extracellular proteins, these will be taken up by cutaneous macrophages

Hapten can easily cross cell membrane if it’s lipophilic, modifying cytoplasmic proteins, which makes effector T cells respond –> keratinocyte death, blistering

Question 18

Overview of hypersensitvity

Answer 18