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Immuno/Type 1 Allergy

Terms

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mast cell
major effector of immediate hypersensitivity reactions

derived from bone marrow precursors

reside in tissues adjacent to blood vessels

express a high affinity Fc receptor for IgE

contain numerous mediator-filled granules

antigen induced cross-linking of IgE bound to the mast cell Fc receptors causes:
- the release of their granule contents
- synthesis and secretion of other mediators
(immediate hypersensitivity reaction)
basophil
type of bone marrow-derived circulating granulocyte (structurally and fxnally similar to mast cells)
-has granules containing same inflammatory mediators as mast cells
-expresses high-affinity Fc receptor for IgE

recruited into tissue sites where antigen is present

may contribute to immediate hypersensitivity reaction
allergen
an antigen that elicits an immediate hypersensitivity (allergic) reaction

allergens are:
proteins or
chemicals bound to proteins that induce IgE antibody production in atopic individuals
sensitization
process by which IgE antibody production is stimulated

requires...

CD4 positive TH2 cells to:
-induce class switching of antigen specific B cells
-secrete IL-4 for B cell growth and differentiation
hypersensitivity
inflammation due to an exaggerated, inappropriate or ineffective immune response to antigens (that, in absence of immunity are often innocuous)
IgE
antibody which usually mediates type I hypersensivity reactions

serum concentration often higher in atopic individuals

made predominantly in plasma cells associated with the respiratory and GI tracts

foudn in external secretions

probably contributes to protection against helminths and certain protazoans

Fc portion of IgE bind to specific IgE receptors (FceR) on mast cells, basophils, lymphocytes and monocytes
FceR
IgE receptors

found on mast cells, basophils, lymphocytes and monocytes

bind Fc portion of IgE
cytotropic
"cell attracted"

refers to the immunoglobulins (usually IgE) involved in hypersensitivty

their attraction to IgE receptors (FceR) on particular cells enables them to initiate the cascade of events that result in tissue damage or disease
anaphylaxis
meaning against protection
(opp. of prophylaxis)

an extreme inflammatory reaction that includes:
- dilation and leakage of post-capillary venules
(causing edema and hypotension)
- constriction of airway smooth muscles (bronchoconstriction, which can result in hypoxia and death)
atopy
"strange"

refers to clincal features associated with allergies (asthma, hayfever, eczema)
histamine
mediator of immediate hypersensitivity rxn

bind to 2 types of receptors on target cells (H1 and H2 receptors)

via H1 receptors, histamine:
-contracts smooth muscle (eg in airways)
-increases vascular permeability
-increases mucous secretion by goblet cells

via H2 receptors, histamine:
-increases gastric secretion
-feeds back to decrease mediator release by basophils and mast cells

*histamine could aslo have important regulatory actions involving H2 receptors which are expressed on some T cells
prostaglandin
cause a wide variety of effects:

prostaglandin D2 is a:
-bronchoconstrictor
-peripheral vasodilator
-coronary and pulmonary vasoconstrictor
-inhibitor of platelet aggrecation
-neutrophil cehmoattractant
-also augments basophil histamine release
leukotriene
derived from the membrane fatty acids (primarily arachidonic acid) of mast cells, neutrophils and macrophages
SRS-A
slow reacting substance of anaphylaxis

aka: cysteinyl-leukotrienes (LTC4, LTD4, LTE4)
-bronchoconstrictors
-cause dilation and increased permeability of microvessels, leading to edema
-enhanced airway mucous secretion
-constriction of coronary and cerebral arteries
-decreased myocardial contractility
-increased gastric acidity
LTB4
LTB4- binds to different receptor than SRS-A, causes:
-neutrophil chemotaxis
-adhesion of neutrophils to endothelium of post capillary venules
-neutrophil degranulation
-also induces leakage of post capillary venules, leading to edema
*Pathologic Immune Mechanism

TYPE I Hypersensitivity
IgE antibody (HALLMARK)

also: Th2 cells, Mast cell, eosinophils

alergen binds to IgE on mast cell surface, crosslinking IgE and inducing release of mediators
Mechanisms of tissue injury and disease

TYPE I Hypersensitivity
mast cell-derived mediators:
vasoactive amines
lipid mediators
cytokines

cytokine-mediated inflammation:
eosinophils
neutrophils
*Pathologic Immune Mechanism

TYPE II Hypersensitivity
IgM and IgG antibodies (IMPORTANT)

against cell surface or ECM antigens
(eg transfusion reactions?)
Mechanisms of tissue injury and disease

TYPE II Hypersensitivity
complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils, macrophages)

Opsonization and phagocytosis of cells

Abnormalities in cellular fxn (e.g. hormone receptor signaling)
*Pathologic Immune Mechanism

TYPE III Hypersensitivity
IgM or IgG antibodies (IMPORTANT)

immune complexes of circulating antigens and IgM or IgG antibodies deposited in vascular basement membrane
Mechanisms of tissue injury and disease

TYPE III Hypersensitivity
complement and Fc receptor-mediated recruitment and activation of leukocytes

(eg autoimmune disease)
*Pathologic Immune Mechanism

TYPE IV Hypersensitivity
T cells (IMPORTANT)

1. CD4+ T cells (delayed hypersensitivity)
2. CD8+ T cells (T cell-mediated cytolysis)
Mechanisms of tissue injury and disease

TYPE IV Hypersensitivity
1. Macrophage activation, cytokine-mediated inflammation

2. Direct target cell lysis, cytokine-mediated inflammation
Type I Hypersensitivity
Immediate Hypersensitivity
IgE (on mast cells)
mast cell derived mediators
cytokine-mediated inflammation (eosinophils and neutrophils)
Type II Hypersensitivity
Antibody mediated diseases

IgM, IgG antibodies against cell surface or ECM antigens
complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils, macrophages)

opsonization and phagocytosis of cells

abnormalities in cellular fxn (e.g. hormone receptor signaling)
Type III Hypersensitivity
Immune complex-mediated diseases

Immune complexes (aka Antigen-Antibody complexes) made of circulating antigens and IgM or IgG deposited in vascular basement membrane

complement and Fc receptor mediated recruitment and activation of leukocytes
Type III Hypersensitivity characterized by:
Immune complexes (aka Antigen-Antibody complexes) made of circulating antigens and IgM or IgG deposited in vascular basement membrane

complement and Fc receptor mediated recruitment and activation of leukocytes
Type IV Hypersensitivity
T cell mediated diseases

1. CD4+ T cells (delayed-type hypersensitivity)

Macrophage activation, cytokine-mediated inflammation

2. CD8+ CTL (T cell-mediated cytolysis)

direct target cell lysis, cytokine-mediated inflammation
organs targeted by:
Anaphylactic (cytotropic) disease
respiratory tract
GI tract
skin
clinical symptoms of cytotropic disease
rhinitis, asthma, urticaria, atopic dermatitis, GI allergy
allergic rhinitis and sinusitis (clinical and pathologic manifestations)
increased mucous secretion
inflammationof upper airways, sinuses
food allergies (clinical and pathologic manifestations)
increased peristalsis due to contraction of intestinal muscles
bronchial asthma (clinical and pathologic manifestations)
bronchial hyper-responsiveness caused by SM contraction, inflammation and tissue injury caused by late phase reaction
anaphylaxis (cause can be drugs, bee sting, food)
fall in BP (shock) caused by vascular dilation
airway obstruction due to laryngeal edema
Th1 cells
functional subset of helper T cells

secretes set of cytokines (including IFNgamma)

principal function is to stimulate phagocyte-mediated defense against infections,

esp. with INTRACELLULAR MICROBES
Th2 cells
functional subset of helper T cells

secretes cytokines (including IL-4 and IL-5)

Principal functions are to:
-stimulate IgE and eosinophil/mast cell-mediated immune reactions and
-down-regulate Th1 responses
Activated T cells skewed to become Th1 cells if:
IL-12 binds (IL-12 secreted by activated macrophages, dendritic cells)
Activated T cells likely to become Th2 cells if:
IL-4 binds (either from activated T cells or other cellular sources)
How do T cells become Th1 and Th2 cells
Naive CD4+ T cell activated by APC
via CD28/B7 and MHC/TCR interactions

Activated T cell that binds:
IL-12 --> Th1 (produces IFNgamma)
IL-4 --> Th2 (produces more IL-4)
what does IFN-gamma from Th1 cell do?
MACROPHAGE ACTIVATION:
activates macrophages (enhanced microbial killing)

OPSONIZAITON AND PHAGOCYTOSIS:
enhances B cell production of complement and obsonizing antibodies
what do products of TH2 cells do?
IL-4:
increased IgE production by B cells
(LEADS TO MAST CELL DEGRANULATION)

IL-5: EOSINOPHIL ACTIVATION
Principal effector functions of:

IgM
complement activation
Principal effector functions of:

IgG (IgG1, IgG3)
Fc receptor-dependent phagocyte responses;

complement activation;

neonatal immunity (placental transfer)
Principal effector functions of:

IgE
immunity against helminths

mast cell degranulation = IMMEDIATE HYPERSENSITIVITY
Principal effector functions of:

IgA
mucosal immunity (transport of IgA through epithelia)
IgA production induced by
cytokines, eg: TGF-beta
Effect of Pollutants on IgE responses
successive injections of exhaust particles with Old Albumin

increased IgE antibody titre
greater anaphylaxis

individuals T cells skewed toward Th2 and IgE production
effect of bottle feeding on T cells and IgE levels
leads to increased serum IgE, esp in those with low T cell numbers
serum half life of IgE
2.5 days, but misleading becuase IgE can sit on mast cell for 3-6 monthes
serum half life of IgG1
21 days
structural features of IgE
5 heavy chain domains

heavily glycosylated (12% carbohydrate)
significance of IgE glycosylation in mast cell response
Lectins (eg from strawberries) can bind and crosslink sugar residues on IgE, leading to degranulation and secretion, but not classic adaptive immune response
IgE Levels and Atopic Disease
individuals with symptomatic levels of disease are more likely to have higher level of IgE in serum

but one can have symptoms in normal range of IgE for a particular antigen
genetic influces over allergen specific disease related to
HLA type
genetic influences over IgE
total production
FceRI
FceRII

more receptors, more likely to be triggered

if no APCs with receptors for particular antigen--> no rxn
HLA associations
in allergy to ragweed (ambrosia)
Antigen Closely Associated HLA class
Ra3 A2
Ra6 DR5
HLA class associatons with specific mushroom allergy
HLA class II DPB1, DQA1, DQB1, and DRB1
allergy skin test
test for cutaneous rxn to allergen at different dilutions (both for acute and prolonged reponse)
epinephrine
used to treat anaphylaxis

causes VSM contraction
increases CO (to counter shock)
inhibits further mast cell degranulation
corticosteroids
reduce inflammation

mainstay of treating hypersensitivity reaction
phosphodiesterase inhibitors
relax pronchial smooth muscles
desensitization
repeated administration of low doses of allergens

may inhibit IgE production and increase production of other Ig isotypes; may induce T cell tolerance
therapeutic use of anti-IgE antibody
neutralizes and eliminates IgE
(potential benefit in most allergic diseases)
antihistamines
block actions of histamine of vessels and SM
cromolyn
inhibits mast cell degranulation
primary mediators acting on:
smooth muscle and mucous glands

and (Rx)
-histamine (antihistamine)
-SRS-A [LTC4, LTD4] (LT Receptor antagonist, eg MONELUKAST)
-LTB4 [a chemotactic factor] (??glucocorticoids)
-Prostaglandins D2 and E2 (COX-1 inhibitors (NSAIDs) and COX-2 inhibitors (CELEBREX, VIOX)
-PAF= platelet activating factor
-Kinins (receptor antag ?HOE-140 inhibits late phase vascular leakage in trials)
chemotactic mediators
LTB4
ECF-A [histamine and mast cell peptides]
IL-8
mediators that cause tissue destruction
1. Toxic oxygen radicals released from neutrophils, macrophages and mast cells
2. acid hydrolases and neutral proteases (e.g. tryptase) from mast cells
3. Major basic protein: a very destructive protein from the larger eosinophil granule
Glucocorticoids suppress
TONS OF CYTOKINES, CHEMOKINES, INFLAMMATORY AGENTS, HORMONES, NEUROTRANSMITTERS, CELL ADHESION MOLECULES, etc...
Allergen Injections
repeated injections of allergen over a period of years

can decrease levels of IgE and increase levels of IgG and IgG4
how does IgG anti-allergen help?
1. intercepts allergen before it reaches mast cell; decreasing free allergen concentration
2. may block dominant epitope recognized by IgE preventing allergen binding to mast cell
3. promotes clearange by macrophage Fcgamma Receptors, decreasing total allergen concentration
4. can trigger inhibitory Fcgamma receptors on Mast cells, blocking mast cell activation
How can fusion proteins be used to treat cat allergy?
fusion protein made of:
allergen + heavy chain of IgG = GFD

or

allergen + IgG

IgG portion binds to FcReceptor
as antigen portion binds to IgE

IgG-Allergen-IgE corsslinking blocks mast cell activation (IgEs not crosslinked)

ITIM (inhibits activity of other crosslinked IgEs within mast cell)
serotonins rolle as a mediator of immediate hypersensitivity
found in platelets, but not in human mast cells

relatively weak inducer of vascular permeability
capillary dilation and SM contraction
Mediators that are pro-inflammatory by chemotactic properties
1. Eosinophil chemotactic factors of anaphylaxis (ECF-A: induces histamine and tetrapeptides from mast cell granules)
2. Neutrophil chemotactic factor of anaphylaxis (IL-8): a granule-derived protein of mast cells that attracts and activates neutrophils
3. Leukotriene-B4: derived from membrane fatty acids, potent chemotactic factor for polymorphonuclear cells, eosinophils and macrophages

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