Immunopathology: Allergy & Delayed Type Hypersensitivity Flashcards
What are some ways that things can go wrong with the immune system?
1. Failure of all or part of the Immune system Syndrome: Immunodeficiencies Outcome: - recurrent infections - overwhelming infections - opportunistic infection - tumours
2. Abnormal or unwanted responses Hypersensitivities, Types I- IV Inflammation Outcomes: - Immunopathology - Allergies - Autoimmune disease - Graft rejection
What are the four types of hypersensitivity?
Immediate Hypersensitivity/ Type I
(IgE, mast cells and lipid mediators)
- in response to allergens
- induce rapiddegranulation (histamine –> anaphylactic response)
Antibody mediated/ Type II
(IgM and IgG against cell-bound or extracellular matrix Ag)
Immune Complex/ Type III
(IgM and IgG immune complex deposition)
Delayed Type Hypersensitivity/ Type IV
(CD4 mediated delayed type hypersensitivity)
Explain the hypersensitivity reaction involved in allergy?
Immediate Hypersensitivity (Type I): Allergy: immune-mediated inflammatory response to common environmental antigens that are otherwise harmless
What are some features of an Atopy/atopic individual?
Atopy/atopic individual:
- high levels of IgE (varies with condition) (linkage between allergy and IgE levels however it is not always causative, it only increases susceptibility)
- large numbers of eosinophils
- large numbers of IL-4 secreting Th2 cells
- Inflammatory response to antigens (allergens) mediated by IgE (IgE is the antibody class specialised to control parasites)
- Sensitization phase followed by response
- Responses may be local (common) or systemic (rare)
– Local - rhinitis, bronchoconstriction, conjunctivitis
– Systemic - anaphylaxis
- Responses have both an immediate and a late phase.
Contributors to effector (allergic) mechanism include: Allergens, Th2 cells, IgE, FcεRI (high affinity FcεR), Mast cells, Eosinophils
What are some examples of allergens/antigens?
Examples: pollens, house dust mite, food etc.
- Allergens share some common features:
- Individuals are repeatedly exposed via a mucosal route
- inhaled allergens: highly soluble proteins carried by small particles
(can be associated with pollution)
- ingested allergens: slowly degraded molecules
- very stable - not broken down easily and persist for long periods)
- high solubility in body fluids
- introduced in very low doses (favors Th2) eg
What are the phases of type I hypersensitivity?
Type I Hypersensitivity can be separated into two phases:
1. Sensitization - primes the response 2. Response (effector Phase)
What are some features of sensitization in Type I hypersensitivity?
This is the typical pathway which produces IgE from the allergen exposure
Allergen Interaction with APCs facilitates activated CD4 Th to different to TH2 T cells.
- Th2 Differentiation occurs in skin and mucosa.
- DCs don’t produce IL-4, but do produce IL-33.
- Basophils (found in tissues and LNs) can be activated by allergens directly to secrete IL-4 or to secrete it after binding IL-33.
- Signal 3 (IL-4) is provided
- -> Differentiation to Th2
- -> Production of IgE
- Basophils are key APCs for the initiation of allergen-specific Th2 responses.
- Basophils can act as APC’s (express MHC I and II, PRR, and secrete IL-4 after interaction with allergen
- In all cases, the signals required for the activation T cells are now present.
What are some responses/features of the effector phase?
Mast Cells, IgE and Type I Responses (Effector Phase)
Location/properties:
– Mucosal and epithelial tissues, and near blood vessels
– Contain pre-formed granules
– Bind IgE using high affinity FcεR – mast cell are now sensitized
– Surface-bound IgE very stable
Allergen-mediated IgE/ FcεR cross-linking causes:
– granule exocytosis (LTs etc.)
– synthesis of inflammatory lipid mediators & cytokines & chemokines
What does mast cell activation result in?
Mast Cell ActivationResults in:
- Secretion of preformed mediators
- histamine, heparin, tryptase + chymase, TNF -α (30 – 45 secs) - Synthesis and secretion of lipid mediators
- prostaglandins and leukotrienes (10 – 30 mins) - Synthesis and secretion of cytokines
- IL-3, IL-4, IL13, IL-5, TNF -α (slow)
Immediate and Late Phases
Intradermal antigen - allergy tests, insect bites
Immediate (minutes)
- Redness - vasodilation
- Soft Swelling - leakage of plasma from venules
- Dependent upon IgE
Late (hours - days)
- Hard Swelling - accumulation of leukocytes
- Neutrophils, Th2 cells, Eosinophils
What are the immediate and late responses to allergy tests?
Immediate Phase - Wheal and Flare
- Occurs in seconds – minutes
- Due to preformed mediators (histamines etc), which are rapidly metabolized
- Blood vessels dilate and leak plasma
- Localized swelling around site of challenge (wheal)
- Blood vessels in area further dilate and engorge with blood (flare)
Late Phase
- 8-12 hours
- induced mediators (chemokines, cytokines, leukotrienes)
- involve cell infiltrates and sustained edema and/or smooth muscle contraction (neutrophils, Th2 cells, eosinophils)
During the effector phase of allergy, what occurs with eosiophils?
Eosinophils:
– Normally present in mucosal linings
- usually play protective role against parasites
– found late in allergic response
– produce toxic granule-derived basic proteins and free radicals
- responsible for tissue damage/remodeling
– produce chemical mediators
- Epithelial cell activation, inflammatory cell recruitment and activation
Normally, the eosinophil numbers are highly regulated due to their toxicity etc however eosinophil control is bypassed in allergy:
– Increased production of eosinophils in bone marrow and release into circulation
- IL-5 produced by Th2 and mast cells
– Attraction, infiltration and activation of eosinophils into tissues
- production of CC chemokines (eotaxins) by epithelial cells at inflammatory site
– Decreased threshold of activation and degranulation (increased senstivity)
- after activation get ↑ number of FcERI on surface and IgE binding
What are some typical allergy treatments?
Symptomatic treatment:
– Adrenaline (Epinephrine) - anaphylaxis
– inhaled β-adrenergic receptor agonists (asthma)
– Antihistamines (hives, allergic rhinitis)
– Corticosteroids
– Provide a broad, non-antigen specific treatment of symptoms and not the cause of the allergy.
Explain the principles of immunotherapy/desensitization for allergy?
- Involves administration of increasing doses of allergen to achieve tolerance
- Induces T cell tolerance
– Decreased allergen-induced proliferation (anergy) (turn off those cells)
– Deviation of secreted cytokines (a more normalised ratio)
– Stimulation of apoptosis
– Production of Treg cells
What are the features of Type IV hypersensitivity?
Delayed Type Hypersensitivity (Type IV)
-Cell mediated with heavy involvement of T cells (and macrophages)
– Classically Th1 but sometimes CTL
- Elicited by persistent antigenic stimulation such as:
- microbial infection
- intradermal injection of protein antigens
- contact with chemicals etc. absorbed through skin
- including:
- Mycobacterium tuberculosis - Picrylchloride
- Mycobacterium leprae - Hair dyes
- Actinomyces - Nickel salts
- Leishmania sp - Poison ivy
- Schistosoma sp - Thiomersol
- Hepatitis B and C viruses
- Type IV Hypersensitivity is cell mediated inflammation due to persistent antigen and does not have an immediate phase due to the necessity of T cells response developing time.
Give some examples of Type IV hypersensitivity reactions>
- Contact sensitivity – (poison ivy, adhesives, tuberculin skin test)
- Previous sensitization, upon re-exposure central and effector memory cells are triggered - Mycobacterium tuberculosis
- Inability to clear organism results in persistent activation of TH1 T cells. - Celiac Disease
- Exposure to wheat products induces TH1 dependent immunopathology of intestinal wall.
