Hypersensitivity: allergy and autoimmunity

Question 1

tut review

What is the sequence of events in a typical immediate hypersensitivity reaction? What is the late-phase reaction, and how is it caused?

Answer 1

immediate: body fluid trapping/swelling late: Leukocyte infiltration
FcεRI cross-linking by allergens triggers:
1) IIgE-mediated mast cell `immediate’ degranulation
2) Immediate generation and release of lipid mediators
3) Later secretion of cytokines

Question 2

tut review

What are the major types of hypersensitivity reactions?

Answer 2

1. Type I hypersensitivity: mediated by IgE
   antibodies [allergy]
2. Type II hypersensitivity: mediated by mainly
   mainly IgG antibodies [autoimmunity]
3. Type III hypersensitivity: mediated by mainly
   mainly IgG antibodies [autoimmunity]
4. Type IV hypersensitivity: mediated by T cells
   (CD4 or CD8) [allergy and autoimmunity]

Question 3

tut review

What is the sequence of events in a typical immediate hypersensitivity reaction?

Answer 3

Type I hypersensitivity: allergy
Immediate (in minutes):

IgE-mediated mast cell `immediate’ degranulation. IgE important molecule, need Th2 (not an antibody)

Fc εRI cross -linking by allergens triggers (through signalling pathways):

1) Immediate degranulation of mast cell (above)

2) Immediate generation and release of lipid mediators

Question 4

tut review

What is the late-phase reaction, and how is it caused?
Type __: ___-___, delayed tissue injury
-later secretion of ___
Delayed inflammatory reactions due to
- Continuous synthesis and release of inflammatory mediators by ___ cells
- Recruitment of immune cells including: ___,___, ___, ___ cells

Answer 4

Type IV: Cell-mediated, delayed tissue injury
-later secretion of cytokines
Delayed inflammatory reactions due to
- Continuous synthesis and release of inflammatory mediators by mast cells
- Recruitment of immune cells including: Eosinophils, neutrophils, basophils Th2 cells

Question 5

tut review

What are some examples of immediate hypersensitivity disorders, what is their pathogenesis?

Answer 5

Th1, Th2 and CTL mediated allergy
asthma
Allergen-induced activation of submucosal mast cells
Symptoms: Chest tightness, wheezing, difficulty breathing
asthma attack
- Bronchial constriction and increased secretion of fluid and mucus
- Chronic inflammation of the airways: continuous presence of leukocytes
- Airway remodeling: permanent narrowing of the airways

allergic rhinitis:
- Mild allergies to inhaled antigen such as pollen
- Mast cell activation beneath the nasal epithelium
- Irritation of nose due to histamine
- Intense itching and sneezing, nasal passage blockade, nasal discharge

allergic conjunctivitis: A similar reaction to airborne allergen
on the conjunctiva of the eye

Question 6

tut review

How is anaphylaxis caused and why can it be life-threatening?

Answer 6

Causes
1) Anaphylactic drug allergy ：penicillin
2) Anaphylactic serum allergy：insect venom

Loss of blood pressure: increase in vascular permeability
Difficulty in breathing: airways constrict, outpouring of mucus
Suffocation: swelling of the epiglottis
Stage I Generalised itching, (Urticaria)
Stage II Swelling away from the sting, (Incontinence)
Stage III Difficulty in breathing
Stage IV Fall in blood pressure, loss of consciousness

Question 7

tut review

What are some examples of hypersensitivity reactions caused by T cells, what is their pathogenesis?

Answer 7

Type IV, cell-mediated, delayed-type hypersensitivity: diseases caused by T lymphocytes
Autoimmunity: against cellular antigens with restricted
tissue distribution
Environmental antigens: contact sensitivity to chemicals,
including drugs, plants (poison ivy), microbial proteins

Type IV Hypersensitivity – allergic diseases (II): contact dermatitis

Question 8

tut review

Hypersensitivity v.s. normal immune response
Normal: T helper (Th) cells determine IgE, IgG and IgA
production by __ cells

Type IV Hypersensitivity – allergic diseases (II) (contact dermatitis)
1. contact sensitising agent penetrates skin and bind to self proteinswhich are taken up by ___ cell.
2. langerhans cell present ___ __ with contact sensitising agents on them to ___ –> IFN ___ and other cytokines secreted
3. activated keratinocytes secrete cytokines IL-1 and TNF alpha and chemomkines
4. these products from Th1 and keratinocyte action activate macrophages to secrete mediators of inflammation

Answer 8

Normal: T helper (Th) cells determine IgE, IgG and IgA
production by B cells

Type IV Hypersensitivity – allergic diseases (II) (contact dermatitis)
1. contact sensitising agent penetrates skin and bind to self proteins which are taken up by langerhans cell.
2. langerhans cell present self peptides with contact sensitising agents on them to Th1 –> IFN gmma and other cytokines secreted
3. activated keratinocytes secrete cytokines IL-1 and TNF alpha and chemomkines
4. these products from Th1 and keratinocyte actionactivate macrophages to secrete mediators of inflammation

Question 9

tut review

Immediate v.s. delayed hypersensitivity

Answer 9

Type I: Immediate type tissue injury
Type IV: Cell-mediated, delayed tissue injury

Question 10

tut review

Allergen v.s. autoantigen

Answer 10

Allergens:
Microbes, insects, and other non-infectious
environmental antigens

Self-antigens:
Soluble, extracellular matrix, and cell surface antigens
with failed self-tolerance (autoimmunity)

Question 11

tut review

Organ-specific v.s. systemic autoimmunity

Answer 11

organ specific immunity: kidney glomerulus
systemic autoimmunity: Systemic lupus
ethythematosus (SLE)

Question 12

tut review

Causes for autoantibodies: Antinuclear autoantibodies (ANA) v.s. anti-desmosome (cell-cell junction)

Answer 12

Underlying immunological abnormalities (I)
Ø Abnormal exposure of self antigens
Ø Defect in clearance of apoptotic cells (intracellular
antigen exposure): SLE, Sjogren’s syndrome, etc
Ø Structurally changed antigens (arginine deamination or
citrullination): rheumatoid arthritis, SLE, etc.
Ø enzymatic modifications or cryptic epitopes
Ø Inflammation or an excessive innate immune response
(infection or injury)

Ø Defects in tolerance or regulation:
Ø Defect in clonal deletion of T or B cells or receptor
editing in B cells during their development in the generative lymphoid organs (e.g. autoimmune regulator/AIRE deficiency)
Ø Defect in regulatory T cells (CD4+CD25+Foxp3+) number and functions
Ø Defect in effector cell apoptosis (Fas-FasL) after clearance of triggering antigens
Ø Inadequate inhibitory receptor (CTLA-4) activity

Mechanisms of autoimmunity remain partially explained
Ø General characteristics of autoimmune diseases
Ø Immunological abnormalities in autoimmune diseases
Ø Genetic basis of autoimmunity
Ø Role of infections in autoimmunity
Ø Other factors in autoimmunity

Question 13

tut review

Anti-TSH v.s. anti-acetylcholine receptor: functional differences

Answer 13

Anti-acetylcholine receptor antibodies interfere with neuro-muscular synapse functions leading to muscle fatigue [Myasthenia gravis]

Pathological anti-thyroid stimulating hormone (TSH) receptor antibodies
are found in Grave’s Disease leading to excessive thyroid hormone production that is no longer regulated by negative feedback [Grave’s disease]

Question 14

tut review

Why and how Antinuclear autoantibodies (ANA) affects many organs?

Answer 14

WHY?
IgG deposition in patient skin:
1) along the epidermal basement membrane (“lupus band”)
2) binding to the nuclei of epidermal cells

Indirect immunofluorescence (IIF): incubating SLE patient
sera with substrate cells (Hep2 cells)
leads to disruption in mRNA splicing, ribosome production, centromeres, histones and DNA

HOW?
1) Urine dipstick and blood work showed evidence of renal dysfunction (proteinuria)
2) A kidney biopsy is performed
3) ANA and anti-DNA tests in patient blood

Pathogenic mechanisms of antinuclear autoantibodies (ANA)
1) injury due to anti-tissue antibody
- ANA exit blood into tissues
- ANA binding to cell debris
- Antibody binding to Fc receptor
- Neutrophil/macrophage activation
- Enzymes, reactive oxygen intermediate (ROI), etc. damage tissues
- Complement activation

2) Immune complex mediated tissue injury
- Immune complexes form in blood
- Deposition on vessel walls
- Activation of neutrophils
- Enzymes, ROI, etc. damage tissues

Question 15

quiz

When a person responds to an antigen by producing histamine, this person is more likely to develop the following disease:
A) Contact dermatitis
B) Grave’s disease
C) Systemic lupus erythematosus (SLE)
D) Allergic rhinitis
E) Type I diabetes

Answer 15

D
allergic rhinitis is Irritation of nose due to histamine

A: due to environmental antigens
B: due to Pathological anti-thyroid stimulating hormone (TSH) receptor antibodies
C: due to ANA. IgG deposition (arrows) in patient skin:
1) along the epidermal basement membrane (“lupus band”)
2) binding to the nuclei of epidermal cells
E: is not an immune response. is coz not enuf insulin

Question 16

quiz

All but one of the following occurs in the first few minutes of an allergic reaction:
A) Vascular dilation
B) Increased smooth muscle contraction
C) Mast cell secretion of cytokines
D) Macrophage secretion of proteases
E) The blood vessels near the allergens exhibit increased endothelial
permeability

Answer 16

C
1) Immediate degranulation
2) Immediate generation and release of lipid mediators
- Histamine: Dilation of small blood vessels (A),* Increase vascular permeability (E)*
Intestinal and bronchial smooth muscle contraction (B)
- Protease (D): tryptase and chymase: Chymase can cause degradation of epidermal basement membrane and simulate mucus secretion, Cause damage to local tissues

3) Later secretion of cytokines (C)delayed!

Question 17

quiz

What defines an allergen is whether it can productively activate:
A) CD4 T cell so that they differentiate into Th1 cells
B) CD8 T cells so that they become cytotoxic T lymphocytes
C) B cells so that they produce IgG antibodies
D) the differentiation of CD4 T cells into Th2 cells
E) macrophage production of inflammatory cytokines

Answer 17

D
by elimination: either A or D is wrong.
TH1 cells: A functional subset of helper T cells that secretes a particular set of cytokines, including interferon-γ, and whose principal function is to stimulate phagocyte-mediated defense against infections, especially with intracellular microbes.

TH2 cells: A functional subset of helper T cells that secretes a particular set of cytokines, including IL-4 and IL-5, and whose principal functions are to stimulate IgE and eosinophil/mast-cell mediated immune reactions and to down-regulate TH1 responses. (allergic reaction)

Allergens are proteins, or chemicals bound to proteins, that induce IgE antibody production in atopic individuals.

E wrong because it’s a normal response by macrophage

Question 18

quiz

Systemic anaphylaxis can be triggered in a person when:
A) He/she contacts with the antigen for the first time
B) The antigen simply fall on his/her skin
C) The antigen enters her blood
D) He/she produces IgM antibodies against the antigen
E) The antigen induces antinuclear autoantibodies (ANA)

Answer 18

C
Stage I Generalised itching, (Urticaria)
Stage II Swelling away from the sting, (Incontinence)
Stage III Difficulty in breathing
Stage IV Fall in blood pressure, loss of consciousness

A and B: superficial
D: IgM is largest antibody isotype. normal immune response
E: Antinuclear autoantibodies (ANA): a hallmark of systemic lupus erythematosus (SLE)

Question 19

quiz

The number and activities of self-reactive T/B lymphocytes are NOT regulated through:
A) Deletion of most of them in the thymus, bone marrow or spleen
B) The induction of an anergic state when they bind to self-antigens when co-stimulatory stimulation is absent
C) Conversion of some of them into immunosuppressive cells like regulatory T cells
D) The production of the cytokine IL-2
E) The expression of inhibitory receptors like CTLA-4

Answer 19

D
IL-2: A cytokine produced by antigen-activated T cells, that acts in an autocrine manner to stimulate T cell proliferation and also potentiates apoptotic cell death of antigen-activated T cells. Thus, IL-2 is required for both the induction and regulation of T cell-mediated immune responses. IL-2 also stimulates proliferation and differentiation of natural killer cells and B cells.

Question 20

quiz

All but one of the following mechanism is known to contribute to autoimmunity:
A) Some people have increased genetic susceptibility
B) Infections
C) Tissue injuries
D) Fas/Fas ligand (FasL) expression on activated lymphocytes
E) Molecular mimicry

Answer 20

D

A: Most autoimmune diseases are genetically complex, or polygenic diseases
B: Role of infections in autoimmunity: A sore throat can lead to a broken heart (pericarditis)

C: Type III: Immune complex-mediated tissue injury
Type IV: Cell-mediated, delayed tissue injury

D: ONLY MUTATION of FAS/FASL: defective deletion of self-reactive B and T cells, autoimmune lymphoproliferative syndrome (ALPS). normal expression does NOT cause autoimmunity!!

E: Molecular mimicry:
Ø Infectious microbes may contain antigens that are antigenically similar to self-antigens
Ø Immune responses to these microbial antigens may cross-react with self antigens which are unable to induce immune responses