9. Immunopathology: Hypersensitivity Flashcards
Learning objective 1
Classify the hypersensitivity disease
The four types of hypersensitivity are:
Type I: reaction mediated by IgE antibodies.
Type II: cytotoxic reaction mediated by IgG or IgM antibodies.
Type III: reaction mediated by immune complexes.
Type IV: delayed reaction mediated by cellular response.
Learning Objective 2
Describe the immune reactants and effector mechanisms of 4 different kinds of hypersensitivity diseases
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Learning Objective 3
Provide examples of the 4 different kinds of hypersensitivity diseases
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Define Hypersensitivity
Inappropriate or heightened immune response to antigen (allergen)
- Cell mediated (T-cells) or humoral (B-cells)
- Requires: Resulting in tissue injury (or cell death depending on severity)
- Requires: Pre-sensitized host (secondary exposure results in reaction – Memory (B-cells) involved
- Four hypersensitivity types (I, II, III, IV)
Describe type 1 hypersensitivity
- Time to onset
- Main effectors (3)
- Define Atopy
Production of IgE antibodies that bind harmless allergens and induce mast cell degranulation resulting in allergic reaction
- Immediate hypersensitivity (can be local or systemic)
- eg Allergy
- MAIN EFFECTORS:
1. Mast Cells (tissue)/Basophils (plasma) = have high affinity receptor to IgE => degranulation => histamine release
2. IgE Ab
3. Histamine (component in granulocytes)
- Atopy -> genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema) invariably accompanied by +++ IgE production (abnormal)
Mast cell/Basophils = type of granulocyte = type of WBC
*Amplified by eosinophils and neutrophils
Define atopy
Atopy -> genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema) invariably accompanied by +++ IgE production (abnormal)
Type 1 Hypersensitivity Mechanism:
Primary Response
Secondary Response
- Primary response = priming event: 1st exposure to allergen; sensitizing event
1. Upon first exposure to allergen: Antigen presenting cell processes antigen and presents it to TH2 cell (Allergen bind to B-cell and TH cell helps create MEMORY CELLS and PLASMA CELLS (create IgE antibody)
2. Allergen specific IgE Abs persist in blood following allergen clearance - Secondary response
1. Upon second exposure to allergen:
2. Preformed IgE binds allergen = allergen antibody complex
3. Allergin-ab complex binds to FC receptor on basophils/mast cells = degranulation = release of pro-inflammatory molecules (histaine) into blood
4. Leads to: - Increased Vascular permeability; smooth mm contraction in airways (broncho
- large amounts of histamine and serotonin results in massive vasodilation, diminished blood pressure, and marked bronchoconstriction
Type 1 Hypersensitivity:
Primary Mediators
Secondary mediators
Primary Mediators: Minutes to hours
- Histamine
- Serotonin (5-HT)
- Eosinophil
- Neutrophil
- Chemotactic factor
- Proteases (Incr. mucus secretion (sniffing sneezing))
Secondary Mediators: (Called by incr. vasodialtion; Sustained response - starts 8-12 hrs after exposure; lasts days)
- Leukotrines
- Prostaglandins
- Bradykinin
- Platelet activating factor
- Cytokines (TNF; IL3; IL4/5)
Name clinical syndrome based on the clinical and pathologic manifestations. Which type of hypersensitivity are these?
1) Increased mucus secretion; inflammation of upper airways, sinuses
2) Increased peristalsis due to contraction of intestinal muscles
3) Broncial hyperresponsiveness caused by sm mm contraction; inflammation and tissue injury caused by late phase reaction
4) Fall in BP (shock) caused by vascular dilation; airway obstruction due to laryngeal edema
TYPE I HYPERSENSITIVITY
1) Increased mucus secretion; inflammation of upper airways, sinuses: Allergic rhinitis, sinusitis (hay fever)
2) Increased peristalsis due to contraction of intestinal muscles Food allergies
3) Broncial hyperresponsiveness caused by sm mm contraction; inflammation and tissue injury caused by late phase reaction Bronchial asthma
4) Fall in BP (shock) caused by vascular dilation; airway obstruction due to laryngeal edema Anaphylaxis (may be caused by drugs, bee sting, food)
Describe Type II Hypersensitivity
- mediated by?
- Main effectors (3)
- Effector functions of Ab
- Antibody mediated hypersensitivity
- Main effectors: IgG or IgM antibodies; Complement proteins (classic C3 convertase -> 3 key events to destroy cell
- Phagocytes
- Effector Functions of Ab: Lysing bacterial cells; opsonized bacteria engulfed more readily; Antibodies block binding of virus or exotoxin; cross-linked bacterial cell antigens
The membrane attack complex (MAC) is an important innate immune effector of the complement terminal pathway that forms cytotoxic pores on the surface of microbes.
What are antibody effector functions?
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Antibody effector functions are an important part of the humoral immune response and form an essential link between innate and adaptive immunity. Most of these effector functions are induced via the constant (Fc) region of the antibody, which can interact with complement proteins and specialized Fc-receptors
i) they can block ligand-receptor interactions;
ii) cause cell lysis through activation of complement dependant cytotoxicity (CDC);
iii) interact with Fc receptors on effector cells to engage antibody dependent cellular cytotoxicity;
iv) opsonization - signal for ingestion of a pathogen by a phagocyte.
SLIDE 11 PENDING: What is the classical complement pathway
1. Initiation by:
2. Formation of C4b convertase
3. Regulation of C4b
4. Formation of C-3 Convertase
5. C3b function and structure
6. Formation of C5 convertase and MAC (membrane attack complex)
*- Initiation: *
a) binding of antigen-antibody complexes to the C1q protein which has globular regions that bind to the Fc receptor of IgG or IgM
b) C1q is part of the inactive C1 complex
c) C1 complex consists of C1q, C1r and C1s
- Formation of C4b convertase:
a) C1q binding with pathogen or antigen-antibody complex => conformation change -> activation of serine protease C1r
b) activated C1r - cleaves and activates serine protease C1s -> cleaves C4 into C4a/b
- Regulation of C4b
a) C4b doesnt stay active due to reactive +++ thioester bond - cleaved by water = permanent deactivation THEREFORE C4b is restricted to only bind pathogen surfaces
- Formation of C-3 convertase.
a) Surface bound C4b acts as a receptor for the binding of C2 – results in cleavage of C2 by C1s into C2a/b
b) C2a diffuses into plasma as inflammatory mediator
c) C2b stays attached to C4b as C4bC2b (C3-convertase).
d) membrane-bound C3-convertase -> cleavage of many molecules of C3 into C3a and C3b
e) C3a = a potent inflammatory mediator.
-* C3b function and structure*.
a) C3b can act as an opsonin;
b) Phagocytes have receptors for C3b and as a result of receptor-ligand binding are able to more easily recognize and engulf pathogen molecules. While the anaphylatoxin C3a interacts with its C3a receptor (C3aR) to recruit leukocytes, C3b contributes to further downstream complement activation
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Formation of C5 convertase and MAC
a) C3b binds to the C3 convertase (C4b2b), to form C5 convertase (C4b2b3b). b) C5 convertase cleaves C5 into C5a and C5b.[3] -
c) C5a is also an anaphylatoxin that attracts leukocytes.
d) Subsequent interactions between C5b and other terminal components form the membrane attack complex or the C5b-9 complex which forms pores on the target cell membranes to lysing.[7]
Erythroblastosis Fetalis:
Type of Hypersensitivy?
Mechanism?
Type II Hypersensitivity
- In Rh- mother, first pregnancy: RBCs w/ Rh antigen mix with maternal blood
- Rh-specific B cell makes plasma cells -> Anti-Rh IgM and memory cells
- Second pregnancy, IgG anti-Rh Ab crosses placenta and attacks fetal RBCs causing erythroblastosis fetalis
Type II: cytotoxic reaction mediated by IgG or IgM antibodies.
In addition to Erythroblastosis fetalis, name and describe four Type II clinical syndromes:
1) Autoimmune hemolytic anemia: - Sim to Rh but w/ Igroup blood proteins through transfustion
2) Idiopathic thrombocytopenic purpura - antibodies against platelets; Reoccurrent platelet transfusion -> develop sensitivity -> hemorrhage
3) Goodpastures syndrome Protein in alveoli & glom mbrn; Ab-mediated destruction of lung alveoli; inflammation of kidney glomeruli -> kidney failure
4) Grave’s Disease: Antigen is receptor for TSH -> effect of hyperthyroid stimulation (crossover w/ autoimmunity)
Describe type III hypersensitivity
- Main effectors (3)
- Key element
Type III hypersensitivity:
Immune Complex Hypersensitivity (Larger eg IgM)
- Main Effectors:
- Ag-Ab complexes (large complexes floating around, can deposit in kidney) -> activate
- Complement system to cause
- Inflammation
Key Element: Inflammation
Think tissue injury from inflammation and the key mediaters ( see image)
Describe type IV hypersensitivity
- Main effectors (2)
- time of onsent
- Requires:
- Response characterized by:
- Caused by:
- Cell-mediated hypersensitivity
- Delayed hypersensitivity (weeks/months before response)
- Response characterized by significant infiltration of lymphocytes/macrophages -> leads to tissue damage
- Main Effectors:
1) CD8+ T-cells
2) Macrophages - Requires T-Helper Cells -> Mediate release of cytokines
- Caused by intracellular pathogens and contact allergens (nickel salts/hair dyes)
There are two major types of T cells: the helper T cell and the cytotoxic T cell. As the names suggest helper T cells ‘help’ other cells of the immune system, whilst cytotoxic T cells kill virally infected cells and tumours.
Cytoxic T-cells release what into virus infected cell? What is the ultimate result?
Release cytotoxic effector molecules (Perforin, granzymes, granulysin, Fas ligand) = To cause immediate Apoptosis
IFN-gamma; TNFalpha/beta = Cytokines => inflammation and immunity response
Inflammation in which Type of Hypersensitivity is characterized by infiltration of phagocytes and tissue injury?
Type IV Hypersensitivity
What is the type IV mechanism?
Antigen induces CD4+ and CD8+ T-cells to produce primed T-cells
- CD4+ T-cell leads to release of cytokines and proinflammatory factors to cause infiltration of phagocytes, proliferation of T-cell, Exudation and eduma, cytotoxicity
- CD8+ T-cell -> directly kill target cells
- INFLAMMATION characterized by infiltraion of phagocytes and tissue injury
