Hypersensitivity Reactions 9/9 Flashcards
(28 cards)
1
Q
Type I Hypersensitivity = Immediate Hypersensitivity = Atopic
A
- Pathologic Immune Mechanisms: Th2 cells, IgE antibody, mast cells, eosinophils
- mechanisms of injury:
- mast cell-derived mediators (vasoactive amines, lipid mediators, cytokines)
- cytokine-mediated inflammation through activation of eosinophils and neutrophils
2
Q
Type II = Ab mediated diseases
A
- IgM, IgG antibodies against self cell surface or extracellular matrix antigens
- Mechanisms of tissue injury/disease:
- complement and Fc receptor-mediated recruitment and activation of leukocytes (neutrophils and macrophages)
- opsonization and phagocytosis of self cells
- abnormalities in cellular function (i.e. hormone receptor signalling)
3
Q
Type III = Immune complex - mediated diseases
A
- Immune complexes of circulating Ags and IgM or IgG Abs are deposited in vascular basement membrane
Mechanisms of injury:
- complement and Fc receptor mediated recruitment and activation of leukocytes
4
Q
Type IV: T cell mediated diseases
A
- CD4+ T cells (cytokine-mediated inflammation)
* results in macrophage activation and cytokine-mediated inflammation - CD8+ CTLS (T-cell mediated cytolysis)
* results in direct target cell lysis, and cytokine-mediated inflammation
5
Q
Properties of IgE
A
- has ability to bind both high and low affinity to mast cells
- once bound to cell receptors, the IgE 1/2 life is substantially increased
- from two days to ten days
- control of the switch from IgG to IgE is dependent upon T cells
- part of the adaptive immune response
- Mast cells and basophils have high affinity Fc receptors for IgE
- these are the only cells that contain histamine
- B cells have only low affinity receptors for IgE which is used for Ag presentation
6
Q
Cytokines resulting in Type I hypersensitity
A
- IgE production is T cell-dependent (adaptive immune response)
- requires IL-4/IL-13 to class switch
- IL-5
- IL-10
- Th1 is suppressive
- IFNgamma (macrophages)
- IL-12 (Th1)
7
Q
Allergens
A
Allergen = Ag that gives rise to immediate hypersensitivity
- most are proteins
Classical Allergens:
- Inhaled at small does
- eaten at “large” dose
8
Q
Type I reaction
A
- Upon first exposure to the allergen B cells bind via IgM receptors and activate TH2 cells.
- Acviation of TH2 cells results in IgE class switching in B cells and production of IgE Abs
- IgE Abs bind the FcR on mast cells (immunological priming)
- Upon repeated exposure to an allergen the mast cell is already primed and releases mediators:
- immediate hypersensitivity: releases histamine, heparin, tyrptase, arachidonic acid, LD4, PD2
- Late phase reaction: IL4, TNFalpha
9
Q
Results of activation of mast cells (basophils) and eosinophils
A
Activation of Mast cell/ basophil
- (Biogenic amines) histamines, PAF, PGD2 = vascular leakage, broncho-constriction, intestinal hypermotility
- (cytokines) TNF: inflamation
- (enzymes) tryptase: tissue damage
Activation of eosinophil:
- (cationic granule proteins) : killing of parasites and host cells
- Enzymes (eosinophil peroxidase): tissue damage
10
Q
wheal and flare reaction
A
- way to diagnose what people are allergic to
- wheal = extravasation of sera
- flare = axon reflex
11
Q
Clinical syndromes of Type I hypersensitivity
A
- Allergic Rhinitis Sinusitis (Hay Fever)
* increased mucus secretion, inflammation of upper airways and sinuses - Food Allergies:
* Increased peristalsis due to contractiion of intestinal muscles - Bronchial Asthma:
* Airway obstruction caused by bronchial smooth muscle hyperactivity: inflammation and tissue injury caused by late-phase reaction - Anaphylaxis (drugs, bee sting, food):
* fall in blood pressure (shock) caused by vascular dilation; airway obstruction due to laryngeal edema
12
Q
Late phase reaciton
A
- occurs 4-6 hours after initial type I reaction and persists for 1-2 days
- due to infiltration of PMNs (granulocytes), eosinophils, macrophages, lymphocytes and mast cells
- mast cells produce TNFalpha and IL-1 leading to increased expression of cell-adhesion molecules on venular endothelial cells
- IL-8 (neutrophil chemotactic factor)
- on-site release of IL-3, IL-5, IL-8 and GMCSF
13
Q
Hypersensitivity Type II: Antibody mediated binding to “surfaces”
A
- initiating antigen is a surface: Ab binds to surface, and results in damage of target cells
- in general the Ags are “fixed” and damage is localized to Ag binding cell
- Abs directed against cell surface Ags are usually pathogenic - Abs directed against internal Ags are usually not pathogenic
- it is initiated by IgG/IgM/FcR/C’ - results in damage of target cells bearing the Ag through three mechanisms:
- Abs are bound to cell surfaces/tissues and interact with Fc receptors on cells such as neutrophils, eosinophils and macrophages
- on fixed surface the macrophage goes through frustrated phagocytosis, releases all of its NOS into intravascular space and tissue is degraded
- Abs bound to cell surfaces can also cause the binding of C1 to IgG or IgM resulting in activation of the C’ cascade
- C3 receptor mediated damage to target cell via binding of C3b on target cell and and C3 receptor on neutrophils, eosinophils and macrophages
14
Q
Hemolytic Disease of Newborn
A
- Type II Hypersensitivity
- Mother is Rh(-) and baby is Rh(+): mom is primed for babies RBC - makes IgM against the Rh, and developes anti Rh memory cells.
- In next birth, mothers IgG anti-Rh Ab crosses the placenta via Rn receptor and attacks fetal RBC’s causing ertythroblastosis fetalis
- Rhogan = anti-D IgG: (RhD) binds blood cell markers and prevents IgG from binding the babies RBC’s
15
Q
Transfusion reaction
A
- when use whole blood, you are giving someones serum to another person
- Abs (usually IgM) cause agglutination, C’ activation and intravascular hemolysis
- fever, hypotension, nausea/vomiting, back/chest pain
16
Q
Autoimmune Hemolytic Anemias
A
- result of Abs binding RBC’s and activating lysis through the C’ system
- spontaneous, drugs, ABO
- often due to drug/RBC interactions: Drugs bind RBC’s, Ab binds to drug –> destruction of RBC’s
- PCN, quinine, sulfonamides
Warm/Cold Abs
- Warm: different epitopes than transfusion rxns. (Rhesus)
- Cold: high-titer IgM (Ii) (Usually in old people in winter)
Mycoplasma pneumonia
17
Q
Myasthenia Gravis
A
- type II hypersensitivity
- extreme muscle weakness
- make Abs to AcH receptors (IgG and C’)
- results in partial blocking of Ach receptors
18
Q
Type III hypersensitivity: Immune complexes with “soluble” Ag
A
- Ag is soluble: Ab mediated
- immune complexes of Ab/Ag/C’ are formed in circulation
- usually removed by the monophagocyte
- the complexes deposit in tissue (the bigger it becomes the more likelelihood of pathology) or vasculature
- usually immune complexes bind C’ and are removed by the liver after binding to CR1 on RBC’s- but this is the result of having too many complexes to be cleared
- This results in recruitment of basophils and platelets –> vasoactive amine release (histamine and tryptamine), which causes endothelial cell retraction and increase in vascular permeability –> complex deposition
- increased dposition in blood vessel walls induces platelet aggregation and C’ activation
- microthrombi form on the exposed collagen of BM of endothelium
- Neutrophils are attracted to site via C’3a/C5a and further damage the area
- this increases blood pressure and vascular turbulence, which further increases complex deposition.
- seen in three groups: Persistent infection, autoimmune, inhalation of Ag
19
Q
Arthus Reaction
A
- The Arthus reaction involves the in situ formation of antigen/antibody complexes after the intradermal injection of an antigen. If the patient was previously sensitized (has circulating antibody), an Arthus reaction occurs. It manifests as local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels.
- body is presensitized with IgG which induces an Ag reaction with marked edema and hemorrhave (4-10 hours)
- localized in and around the wall of small blood vessels
- Ag/Ab/C’ precipitation
- can lead to vascular occlusion and necrosis
- given “allergy shots” to try to build IgG to block and bind the Ag before it binds to IgE
20
Q
serum sickness
A
Induced by large injections of foreign antigen
Circulating immune complexes deposit in blood vessel walls and tissues
Leads to arthritis and glomerulonephritis
Complication of serum therapy (Equine) or Ag excess (acute infectious disease)
21
Q
Trends of Type II and Type III
A
Similar Mechanisms for Type II & III
Inflammatory pathways are identical
Differences in where the Ags are derived from & how the immune complexes form:
- Type II: “fixed” surfaces
- Type III: “soluble”
Complement is a major mediator
Inappropriate activation in both:
- Tissue damage
- Increase in inflammation
- Perpetuation of disease
22
Q
Type IV hypersensitivity: Delayed Type Hypersensitivity
A
- the result of sensitized Th1 cells releasing cytokines that activate macrophage or Tc cells which mediate direct cellular damage and edema
- Ts are sensitized during infection of adsoprtion through epidermins
- occurs 24-72 hours post exposure; triggers local inflamatory response
- if Ag persists can lead to granuloma formation (collection of macrophages)
Three types of DTH:
- Contact (Eczematous rxn - occurs at point of contact with allergen)
- Tuberculin (named after PPD) - induced by soluble Ags, used diagnostically
- Granulomatous - clinically most important
23
Q
2 stages of cantact sensitivity (seen in poison oak)
A
- Sensitization: takes 10-14 days
- occurs in dermis
- needs protein/hapten carrier
- protein hapten uptake by langerhans cells
- presentation in nodes/Class II HLA
- Results in EFFECTOR/MEMORY T CELLS
- Elicitation
- involves recruitment of CD4 T cells to site of contact
- driven by proinflammatory cytokines
- recruits monocytes and macrophages to the area
24
Q
PPD Test
A
Tuberculin Type DTH
Induced by soluble Ag
Used to test for T cell-mediated responses to organisms
Tuberculin Skin Test:
- Recall response to previously encounter Ag
- Infiltrate of cells: Neutro, Monos, T cells disrupt dermis
- General measure of cell-mediated immunity
25
Granulomatous DTH
Usually results from persistence within Macrophage of:
* Intracellular microorganisms able to resist Macrophage killing
* Other particles the cell is unable to destroy
- Occurs with chronic infections associated with Th1-like responses
- Occurs in the absence of infection
* Foreign body, non-immune
Core of epitheloid cells and Mfs surrounded by cuff of lymphocytes
Giant cells may be present
* Might have a central area of necrosis with complete destruction of cellular architecture
Substantial fibrosis
Common feature is persistent chronic, antigenic stimulus
Mfs may limit infection but may also lead to tissue damage.
--\> seen in mycobacterium leprae - macrophages can't kill the bacteria so they start to wall it off
26
summary slide 1
Hypersensitivity reactions are based on the classification of Coombs and Gell.
Immediate hypersensitivity, Type I hypersensitivity, is mediated by IgE.
IgE is distinct from the other dimeric immunoglobulins.
Production of IgE occurs in response to repeated low-dose exposure to inhaled allergens such as dust mite, cat dander, or grass pollen.
Allergens are the antigens that give rise to immediate hypersensitivity and contribute to asthma. Most are proteins.
IgE antibodies bind to FcɛRI on mast cells and basophils. When bound IgE is cross-linked by specific allergen, mediators including histamine and leukotrienes are released.
Skin tests are used for diagnosis and investigation.
Several different pathways contribute to the chronic symptoms of allergy.
IgE antibodies play a critical role in defense against helminths.
Type II hypersensitivity reactions are caused by IgG or IgM antibodies against cell surface and extracellular matrix antigens.
The antibodies damage cells and tissues by activating complement, and by binding and activating effector cells carrying Fcγ receptors.
Type II hypersensitivity reactions may target cells. Transfusion reactions to erythrocytes are produced by antibodies to blood group antigens.
Hemolytic disease of the newborn occurs when maternal antibodies to fetal blood group antigens cross the placenta and destroy the fetal erythrocytes.
27
summary slide 2
Type II hypersensitivity reactions may target tissues. Damage to tissues may be produced by antibody to functional cell surface receptors through Fab regions.
Cytotoxic antibodies are increasingly being used for therapeutic indications.
Diseases caused by immune complexes, Type III hypersensitivity, can be divided into three groups.
Immune complexes are formed every time antibody meets antigen and are removed by the mononuclear phagocyte system following complement activation. Persistence of antigen from continued infection or in autoimmune disease can lead to immune complex disease.
Immune complexes can trigger a variety of inflammatory processes. Fc–FcR interactions are the key mediators of inflammation. Most importantly, Fc regions within immune deposits within tissues engage Fc receptors on activated neutrophils, lymphocytes, and platelets to induce inflammation.
During chronic inflammation B cells and macrophages are the predominant infiltrating cell type, and activation of endogenous cells within the organ participates in fibrosis and disease progression.
Serum sickness can be induced with large injections of foreign antigen. Injection of antigen into the skin of presensitized animals produces the Arthus reaction.
The size of immune complexes affects their deposition. Deposition of circulating, soluble immune complexes is limited by physical factors, such as the size and charge of the complexes. Small, positively charged complexes have the greatest propensity for deposition within vessels. Large immune complexes are rapidly removed in the liver and spleen.
Immune complex deposition in the tissues results in tissue damage. Immune complexes can form both in the circulation, leading to systemic disease, and at local sites such as the lung. Charged cationic antigens have tissue-binding properties, particularly for the glomerulus, and help to localize complexes to the kidney. Factors that tend to increase blood vessel permeability enhance the deposition of immune complexes in tissues.
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summary slide 3
