Immunopathology Flashcards
1
Q
What is Type I hypersensitivity?
A
immediate
IgE, mast cells, and lipid mediators
2
Q
What is Type II hypersensitivity?
A
antibody mediated
IgM and IgG against cell-bound or extracellular matrix antigens
3
Q
What is Type III hypersensitivity?
A
immune complex
IgM and IgG immune complex deposition
4
Q
What is Type IV hypersensitivity?
A
delayed type
CD4 mediated
5
Q
What is an allergy?
A
- Type I/immediate hypersensitivity (associated with forms of Type IV)
- Immune-mediated inflammatory response to common environmental antigenst that are otherwise harmless
6
Q
What is an atopic individual?
A
- hihg levels of circulating IgE (normally barely detectible)
- ths vaires with condition
- elevated eosinophils in circulation in tissues
- elevated of Th2 cells secreting IL-4
7
Q
IgE is specialised to control…
A
Parasites
8
Q
What are the two phases of immediate (Type I) hypersensitivity?
A
- sensitization - rapid, usually not noticed
- response - varies
- local (common) - rhinitis, bronchoconstriction, conjunctivitis, hives, skin rashes, hay fever
- systemic (rare) - anaphylaxis
- immediate and late phase (both may be occuring at once)
9
Q
What are the 6 main contributors to the immediate/Type I hypersensitivity mechanism?
A
- allergens (antigens)
- Th2 cells - switch on B-cells to produce IgE
- IgE (antibody)
- FceRI (high affinity FceR) - IgE receptor
- mast cells - major player, FceRI receptors
- eosinophils
10
Q
What are the features of allergens?
A
- repeated exposure via mucosal route
- inhaled: highly soluble proteins, carried by small particles
- ingested: slowly degraded
- not easily broken down
- highly soluble in body fluids (causes systemic response)
- introduced at very low doses (favours Th2 response)
- allergens are often (not always) enzymes
- body might mistake them for parasite enzymes
11
Q
What are the acute and chronic responses to inhaled allergens?
A
- acute (pollens, Der p 1)
- rhinitis, conjunctivitis, hayfever
- chronic (+ danders)
- asthma
- shares some delayed type IV features
- asthma
12
Q
What is the sensitization mechanism of Th2 activation?
A
- Low dose Ag via mucosal route
- APC has taken it up and presented it
- in presence of IL-4 binds to T cell
- Differentiates to Th2
- Th2 produces IL-4, IL-5, and IL-13
13
Q
What is the sensitization mechanism IgE secretion?
A
- Th2 interacts with B-cells via CD40 ligand
- in presence of IL-4 and IL-13
- induces proliferation
- induces isotype switching to IgE
14
Q
How do dendritic cells contribute IL-4 to Th2 differentiation?
A
- indirectly (do not produce IL-4)
- some produce IL-33
- basophils are activated by IL-33 (and allergens) to secrete IL-4
- production of IgE
this is part of the sensitization phase
15
Q
How do basophils contribute IL-4 to Th2 differentiation?
A
- act as APCs
- express MHC I and II, PRRs
- interact w/Ag
- present Ag to CD4 Th2 via MHC II - TCR (signal 1)
- upregulation of co-stimulatory molecules (CD80/86 - CD28) (signal 2)
- secrete IL-4 (signal 3)
- activates Th2 cells
this is part of the sensitization phase
16
Q
How do dendritic cells and basophils contribute to Th2 differentiation and IgE production in the sensitization phase?
A
dendritic cells
- proudce IL-33
- induces basophils to release IL4
- Th2 differentiation
- +CD40L, IL-4, IL-5, IL-13 by Th2 cell
- binds CD40 –> IgE
basophils
- act as APCs
- present allergen/Ag on MHC II - binds to TCR on Th2 cell
- upregulate CD80/86 production - binds to CD28 on Th2
- upregulate IL-4 secretion
- Th2 differentiation
- +CD40L, IL-4, IL-5, IL-13 by Th2 cell
- binds CD40 –> IgE
17
Q
What are the properties of mast cells?
A
- mucosal and epithelial tissues, near interacting areas w/infectious agents e.g. blood vessels
- contain pre-formed granules
- bind IgE via high-affinity FceR (only receptor that binds Ab not bound to Ag)
- sensitizes the mast cell
- surface-bound IgE is very stable (lasts months or years; normal Ab is 24hrs)
- binding of IgE (Ab) to allergen induces cross-linking of FceRs
- degranulation (immediate)
- contain inflammatory mediators
- synthesis of more inflammatory mediators (lipid mediators, chemokines, cytokines)
18
Q
Activation of mast cells results in:
A
- secretion of preformed mediators from granules (immediate, 30-45s)
- histamine, heparin, enzymes (tryptase, chymase), TNF-a
- synthesis and secretion of lipid mediators on mast cell activation (still immediate, 10-30mins)
- prostaglandins and leukotrienes from arachidonic acid intermediates
- synthesis and secretion of cytokines (slow)
- mast cells make more mRNA for synthesis of cytokines, IL-3, IL-4, IL-13, IL-5, TNF-a
19
Q
What is a wheal and flare response?
A
- type I hypersensitivity (immediate)
- immediate phase (seconds to minutes)
- allergen introduced into skin
- components released from granules and synthesized by mast cells (e.g. histamines)
- blood vessels dilate, leak plasma –> swelling, pallor (wheal, squishy)
- further dilation leads to reddened area from blood (flare)
20
Q
What is the late phase of the wheal and flare response?
A
- type I/immediate hypersensitivity
- late phase (8-12 hours)
- much bigger response by the slowly produced mediators (chemokines, cytokines, leukotrienes)
- site is full of cells (neutrophils, Th2 cells, basophils, eosinophils)
- sustained oedema, hard to touch
- eosinophil presence is characteristic of atopic individuals
21
Q
What are the common allergic responses induced by mast cells?
A
- vasodilation
- vasopermeability
- smooth muscle contraction
- fluid secretion
22
Q
What is the reaction to the allergic response of mast cells in the GIT?
A
- +fluid secretion and +peristalsis
- leads to diarrhea and vomiting
23
Q
What is the reaction to the allergic response of mast cells in the skin?
A
- +fluid secretion (wheal) and +vasodilation (flare)
- leads to swelling, itching, urticaria (hives)
24
Q
What is the reaction to the allergic response of mast cells in the airways?
A
- -broncial diameter, +mucous
- nasal blockage, coughing, phlegm, asthma
25
What is the reaction to the allergic response of mast cells in the blood vessels?
* +blood flow, +permeability
* leads to +tissue fluid, +cell infiltrate
* can lead to anaphylactic shock (systemic)
* CO cannot keep up with +blood flow to hugely dilated vessels
26
What cell type is characteristic of the late effector phase of type I/immediate hypersensitivity?
**Eosinophils**
* normally in mucosal linings at low numbers to protect against parasites
* when activated (late only) they produce toxic granule-derived basic proteins and free radicals responsible for tissue damage and remodelling (meant for parasites, but instead is happening to us)
* produce chemical mediators that activate local tissues
* epithelial cell activation, inflammatory cell recruitment and activation
* normally, tightly controlled; bypassed in allergic responses
27
What happens when eosinophil control is bypassed in late allergic responses?
* part of type I/immediate hypersensitivity late effector phase
* IL-5 produced by early Th2 cells and by mast cells activates:
* eosinophils
* eosinophil **production** by bone marrow
* eosinophils are then **attracted** to and **infiltrate** tissues (inflamatory chemokines from epithelial cells)
* **activation** in tissues:
* release toxic granules
* upregulate FceRIs, boosting IgE binding and tf activation and degranulation (increased sensitivity, decreased threshold)
28
What are some symptomatic allergy treatements?
**these are non-antigen specific treatments**
* adrenaline/epinephrine in anaphylaxis
* inhaled B-aR agonists in asthma
* antihistamines for hives, allergic rhinitis
* corticosteroids
29
What is immunotherapy or desensitization?
* administration of increasing doses of allergen to achieve tolerance
* induces T-cell tolerance by:
* -allergen-induced proliferation
* switch from Th2 response to Th1 response (leads to deviation of secreted cytokines)
* switch T cells to kill themselves
* production of Treg cells to control Th2 cells
* new research is targeting basophils and eosinophils
30
What are the feautres of delayed type/type IV hypersensitivity?
* cell mediated: ++T-cells (particularly Th1, sometimes Th8) and macrophages
* it is a normal immune response
31
What elicits delayed type/IV hypersensitivity?
Persistent antigenic stimulation, e.g.
* mycobacterium TB
* mycobacterium perae
* actinomyces
* leishmania sp
* schistosoma sp
* hep B & C viruses
* picrylchloride
* hair dyes
* nickel salts
* poison ivy
* thiomersol
32
What is the mechanism of the sensitization phase in delayed type/IV hypersensitivity?
priming of the adaptive response
* allergen/Ag in skin or mucosa taken up by APCs
* APCs take it to lymph nodes
* APCs produce +IL-12:
* --\> T-cell differentiation to Th1
* --\> switches on CD8 T cells
* CD8 T cells & Th1--\> site of allergen/Ag but cannot remove it
* allergen/Ag persists
* this process continues on and on
33
What are the 3 main kinds of type IV/delayed type hypersensitivity?
* contact sensitivity (poison ivy, adhesives, tuberculin skin test)
* usually caused by chemicals
* previous sensitization, upon re-exposure central and effector memory cells are triggered
* infection (mycobacterium tuberculosis)
* inability to clear organism results in persistent activation of Th1 cells
* non-infectious disease: celiac disease
* exposure to wheat products induces Th1 dependent immunopathology of intestinal wall
34
What is the mechanism of contact hypersensitivity?
sensitization (e.g. poison ivy, pentacdecatechol = Ag)
* Ag picked up by DCs in skin
* broken down, displayed on MHC
* DC drains to local lymph node
* activates naive T cells
* T cells migrate back to skin as memory T cells (normal)
response
* on re-exposure more DCs are activated (as above) AND activation of memory T cells in skin
* huge increase in T cells at infection site = hard swelling (cells, not fluid)
* cells produce lots of IFNy (Th1s)
* massive macrophage activation at inflammatory site
* v. problematic
35
What is the mechanism of delayed type hypersensitivity responses in TB?
* inhaled in droplets --\> alveoli
* TB (facultative intracellular pathogen) survives in the alveolar macrophages
* some break down by macrophages, cytokines released (IL-12)
* DCs take bits of TB to lymph nodes --\> Th and CD + IL-12 --\> Th1
* TH1 stimualtes more macrophages via IFNy --\> cycle persists
* prolonged macrophage by IFNy activation produces:
* IL-8, Il-1, TNFa --\> endothelial activation, phagocyte and lymphocyte migration
* IL-1 --\> fever
* TNFa --\> weight loss, granuloma formation
* contains MNG cells, epithelioid cells, monocytes, CD4s, CD8s
* **normal response, controls infection (90%)**
* **can interrupt respiratory/alvelolar function (10%)**
* ****can burst BVs, cause hemoptysis (bloody sputum)
36
What is the mechanism of delayed type/IV hypersensitivity in celiac disease?
* gliadin, breakdown product of gluten (wheat, barley, rye)
* consists of glutamine & proline
* +ve glutamine cannot bind gliadin to +ve HLA peptide binding cleft
* tissue transglutaminase 2 (tTg2) in endomysial cells of intestinal lamina propria deamidate glutamine --\> glutamate (-ve)
* -ve glutamate binds HLA-DQ2 (& DQ-8)
* \>90% CD have HLA-DQ2 MHC
* APCs under mucosa can bind gliadin
* APCs --\> T cells in MALT --\> Th1
* Th1 --\> lamina propria --\> ++ IFNy --\> activate mø
* mø release toxic contents, damage villi
* elongated clefts, ablated villi, +immune cells
* \*\*we produce Abs to gliadin and tissue transglutaminase
* used for diagnosis (not involved in disease)
