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inf & imm > (FE) Week 11 Hypersensitivity > Flashcards

(FE) Week 11 Hypersensitivity Flashcards

1
Q

What are the 4 types of hypersensitivity?

A

Type 1:
- Mediated by IgE
- Seen in allergic reactions
- Local vs systemic

Type 2:
- Mainly mediated by IgG
- Seen in autoimmunity

Type 3:
- Mainly mediated by IgG
- Seen in autoimmunity

Type 4:
- Mediated by T cells
- Seen in allergic reactions

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2
Q

How does Type 1 Hypersensitivity: IgE-mediated immediate allergy occur?

A

1) Allergens are first detected by DC, then presented to CD4+ T cells
- Activates B cells, with the help of T cells, activates Th2 cells
2) Th2 facilitates class switching of IgM to IgE
3) IgE binds to Fc receptors on mast cells
- Usually present under the skin and on mucosal surfaces
4) On 1st exposure, mast cell is sensitised
5) On re-exposure, cross-linking causes degranulation
- Release of vasoactive amines and lipid mediators
~ Leads to immediate hypersensitivity rxn (within mins)
- Release of cytokines
~ Leads to late-phase rxn (2-4 hrs after)

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3
Q

What physiological changes occur in immediate and late-stage Type 1 rxn?

A

Immediate:
- Vascular dilation
- Smooth muscle contraction
- Tissue damage
- Increased permeability leading to edema

Late-phase:
- Inflammation
- Recruitment of eosinophils, neutrophils, basophils and Th2 cells

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4
Q

What are the biological mediators stored in the mast cell granules?

A

1) Histamine
- Dilates small BV
- ^ vascular permeability
- Intestinal and bronchial SM contraction

2) Tryptase (protease)
- Cleaves fibrinogen
- Activates collagenase
- Cause damage to local tissues

3) Chymase (protease)
- Causes degradation of epidermal basement membrane
- Stimulates mucus secretion
- Causes damage to local tissues

4) Lipid mediators
- eg Prostalglandins, Leukotrienes and platelet activating factor (PAF)
- (P) Dilation and chemotaxis of neutrophils
- (L) Prolongs smooth muscle contraction
- (PAF) Bronchoconstriction

5) Cytokines and chemokines
- (TNF) Activates endothelial cells to become sticky
- (IL) Activates Th2 and eosinophils

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5
Q

What are some clinical syndromes of Type 1 hypersensitivity?

A

1) Allergic rhinitis/conjunctivis
- Mild allergies to inhaled Ag
- Mast cell activation beneath the nasal/eye epithelium
- Irritation of nose/eye due to histamine

2) Anaphylaxis
- Most severe

3) Acute urticaria

4) Food allergy

5) Asthma

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6
Q

What is asthma?

A
  • Allergen-induced activation of submucosal mast cells
  • In asthma attacks:
    ~ Bronchial constriction and ^ secretion of fluid of mucus
    ~ Chronic inflammation of the airways and continuous presence of leukocytes
    ~ Airway remodelling to prevent narrowing of the airways
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7
Q

What factors influences people to be atopic?

A

Atopic: sensitive to allergens
Atopic: High genetic susceptibility + Hygienic
Non-atopic: Low genetic susceptibility + Low

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8
Q

What are the different effector functions if degranulation occurs in various tissues?

A

GIT:
- ^ fluid secretion
- ^ peristalsis
- Leads to diarrhea and vomiting

Airways:
- Contracts
- ^ mucus secretion
- Leads to congestion and blockage
~ Wheezing and coughing damages tissues

Blood vessels:
- ^ blood flow
- ^ permeability
- Leads to ^ fluid in tissues

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9
Q

How does Type 1 Hypersensitivity: Anaphylaxis occur?

A

Entry through: (ie allergens go systemic)
- IV
- Following oral absorption into blood

Results in:
1) Loss of BP, Increase in vascular permeability
2) Difficulty in breathing (due to bronchoconstriction and mucus accumulation)
3) Suffocation (due to swollen epiglottis)
4) Edema

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10
Q

What are the different stages of anaphylaxis and anaphylactic shock?

A

Stage 1:
- Urticaria (generalised itching)

Stage 2:
- Swelling away from the sting (incontinence)

Stage 3:
- Difficulty in breathing

Stage 4:
- Fall in BP
- LOC

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11
Q

What is the mechanism of tissue injury in Type IV Hypersensitivity?

A

1) Cytokine-mediated inflammation
- APC presents Ag to CD4+ cell -> releases cytokines -> inflammation and chemotaxis of neutrophils, ROS
- Th1, Th2 and Th17 cause tissue injury
- Th1 activates macrophages in contact dermatitis, tubulin test
- Th2 activates eosinophils in chronic asthma, allergic rhinitis

2) T cell-mediated killing of host cells
- When CD8+ encounter Ag on cell, they initiate apoptosis -> cell dies

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12
Q

How does contact dermatitis occur?

A

1) Contact-sensitising agent penetrates the skin and binds to self-proteins
- Taken up by DC
2) DC present the peptides to Th1
- Secrets IFN-gamma and other cytokines
3) Activated keratinocytes secrete more cytokines and chemokines
4) Macrophages are activated and secrete mediators of inflammation

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13
Q

What is immune tolerance?

A

Unreactivity to self antigens

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14
Q

What are the steps in lymphocyte maturation in primary lymphoid organs?

A

1) Common lymphoid progenitor -> Pro-B/T cells
2) Pre-B/T cells expresses one chain of antigen receptor
- B cells: heavy chain
- T cells: Beta chain

3) Immature B/T cells acquires one more chain and expresses complete antigen receptor
- B: light chain
- T: Alpha chain

4) Weak antigen recognition w self (Positive selection)
- Progresses to mature B/T cell

5) Strong antigen recognition w self (Negative selection)
- Cell death or
- Acquires a new chain but of different specificity (to test against Ag again)

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15
Q

What happens when B/T cells leave the bone marrow/thymus?

A
  • When T cells are released from the thymus, they are already Mature T cells
  • When B cells are released from BM, they are still immature and need to go through 2nd negative selection and migrate to spleen
    ~ Matures in spleen
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16
Q

What is central immune tolerance?

A
  • Established in primary L.O.
  • Clonal deletion of self-reactive B/T cells
  • Clonal diversion/editing
    ~ Re-programming self-reactive T/B cell specificity
17
Q

What is peripheral immune tolerance?

A
  • Cell anergy/inactivation of B/T cells
  • Conversion into regulatory T cells (Treg)
    ~ Displays inhibitory function instead
18
Q

How does cell anergy occur?

A

1) T cells
- For a T cell to be activated, 2 signals are needed
~ MHC antigen
~ Costimulatory molecule or cytokines

  • When there is no 2nd signal, T cell is inactivated

2) B cells
- If B cell reacts to self-Ag, it reduces receptor expression
~ Signaling block leads to anergy

19
Q

How do Treg cells inhibit immune response?

A

1) Release of inhibitory cytokines
2) Killing of self-reactive cells by cytolysis
3) Metabolic disruption (death due to cytokine deprivation)
4) Inhibition of DC maturation
5) Expressing MHC-blocking molecules
6) Expressing CTLA4
- Competes with CD28 to bind to costimulatory molecules to inhibit T cell activation
- Cross-linking of CD28 delivers costimulatory signal during activation of naive T Cells and induces expression o f CTLA4
~ CTLA4 binds B7 more avidly than CD28 and delivers inhibitory signals to the activated T cells instead

20
Q

How is immune tolerance broken down?

A

1) Defects in tolerance + regulation
- Defect in clonal deletion of T/B cells + receptor editing in B cells
~ Autoimmune regulator/AIRE deficiency

  • Tregs are unstable
    ~ Number and functions
  • Defect in effector cell apoptosis after clearance triggering Ag (Fas and FasL)
  • Inadequate inhibitory receptor/CTLA4 activity

2) Abnormal exposure of self-antigens
- Enzymatic modifications/cryptic epitopes
- Structurally changed Ag (in SLE, RA)
- Defect in clearing apoptotic cells/intracellular Ag exposure (in SLE, Sjogren’s syndrome)

3) Inflammation/excessive innate immune response
- Tissue damage may overwhelm macrophages and other tissue cleansing mechanisms

4) Genetic susceptibility (failure of self-tolerance)
- AIRE: fail T cell negative selection
- Fas/FasL: defective deletion of B/T cells
- FOXP3: deficiency of Treg

21
Q

Why is autoimmunity chronic?

A
  • Amplification of response
    ~ Self-reactive cell releases cytokines which activates APC, which further release cytokines that activate more self T cells
  • Epitope spreading
    ~ When a self-reactive T cell presents Ag to APC and there is a tissue injury, more Ag are presented to T cells
22
Q

What is the role of infections in autoimmunity?

A
  • When a microbe activates DC that expresses a self-Ag, it expresses it to the T cells -> autoimmunity
  • Molecular mimicry: Infectious microbes may contain Ag that are antigenically similar to self-Ag
    ~ Immune responses to those Ag may cross-react with self-Ag which are usually unable to induce immune responses
    ~ eg streptococcal infx which is similar to heart Ag -> rheumatic fever and heart failure
23
Q

What are the Type 2 Hypersensitivity: Antibody-mediated autoimmune disease?

A

Px develop mostly IgG Ab that target cell surface receptors or extracellular matrix molecules

1) Pemphigus vulgaris
- Targets desmosomes/intercellular junctions of epidermal cells
- Leads to blistering

2) Goodpasture’s syndrome
- Targets basement membrane of glomerulus and lung alveoli
- Leads to nephritis and lung hemorrhage

3) Myasthenia gravis
- Auto-Ab block ACH receptors
~ Reduces number of receptors
- Leads to muscle fatigue, weakness and paralysis

4) Grave’s disease
- TSH-stimulating Ab leads to excessive thyroid hormone production
~ Thyroid hormones shut down TSH production but cannot affect auto-AB production

24
Q

What is Type 3 hypersensitivity: Immune-complex mediated systemic autoimmunity?

A
  • When antigen-antibody complexes (immune complexes) deposit in tissues throughout the body
    ~ Triggering an inflammatory response
  • In SLE:
    ~ IgG deposits in skin, along epidermal basement membrane (forming a lupus band)
    ~ Binds to the lupus nuclei of epidermal cells
25
Q

What is the pathogenic mechanism of antinuclear autoantibodies (ANA)?

A
  • Injury caused by anti-tissue antibody
    ~ ANA exits from blood into tissues, then binds to Fc receptors
    ~ Recruits and activates inflammatory cells
    ~ Enzymes and ROS damages tissues
  • Immune complex-mediated tissue injury
    ~ Immune complexes form in blood and deposit in vessel walls
    ~ Neutrophil granule enzymes and ROS cause vasculitis
26
Q

How do Type 4 hypersensitivity of T cell destruction lead to autoimmunity?

A
  • CD8 T cells attack pancreatic beta cells
    ~ Causes DM1

inf & imm (19 decks)

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