Immuno/Type 1 Allergy
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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