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Immunology 2 > Lecture 5: Hypersensitivies > Flashcards

Lecture 5: Hypersensitivies Flashcards

1
Q

Genetic link assosicated to hypersensitivity reactions

A

Changes in constant domain of the TH

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2
Q

Mediators, timeframe and example of Type 1, Type 2, 3 and 4

A

Type 1: IgE mediated
Within an hour
Anaphylaxis

Type 2: IgG or IgM cytotoxic
Hours to Days
Haemolytic anaemia

Type 3: Immune complex mediated
1-3 weeks
SLE

Type 4: T cell mediated
Days to weeks
Rash

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3
Q

What causes type 1 hypersensitivity

A 
Genetic link
Environment
Lifestyle
Increased air pollution
Hygiene hypothesis (babies are not exposed to a wide enough range of antigens causing a weak immune response to antigens)
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4
Q

type 1 hypersensitivity facts

A

IgE mediated
Th2 and mast cells
Tissue reaction
- mediators act on blood vessels and smooth muscle (histamine, prostaglandins, leukotrines (prostaglandins and leukotrines increase mucous)
-cytokines recruit and activate inflam cells (IL-4,5,13)

Occurs within minutes

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5
Q

Pathophysiology of Type 1 hypersensitivity

A

Sensitization stage:

  1. APC recognize the allergen and presents to naïve T cells (APC could be B cell)
  2. T cells differentiate into Th2 which release the interleukins (IL-4/5/13)
  3. Interleukins stimulate B cells to produce IgE.
  4. Antigen-specific IgE binds to mast cells and basophils (mast cells have receptors that have high affinity for IgE receptors and
    therefore become sensitised ).
  5. Subsequent exposure to same antigen leads to degranulation and release of mediators. =

REACTION STAGE:
The immediate response:
- may be local or systemic
- induced by mast cell granule contents and lipid mediators (degranulation, histamines, leukotrienes, prostagladins)
- vasodilation, vascular leakage, edema, redness, itching and smooth muscle spasm
- starts within 5 to 30 minutes after exposure to an allergen and subsides by 60 to
80 minutes.

• Late-phase reaction

  • activated mainly by cytokines,
  • 2 to 8 hours after immediate response, it may last for several days. - inflammation and tissue destruction (epithelial cell injury).
  • eosinophils (predominant), neutrophils, and lymphocytes.
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6
Q

Clinical Features of Type 1 hypersensitivity

A

• Localised allergic reaction
- Rashes or blisters in the skin, pruritus (hives, atopic dermatitis, eczema)
- Increased eye and nasal secretions, itching, sneezing (allergic rhinitis/hay
fever, allergic conjunctivitis
- Oropharyngeal mucosal oedema (food allergies)
- Bronchospasm, wheezing (bronchial asthma)
- Gastrointestinal abnormalities such as abdominal pain, diarrhoea,
vomiting (food allergies)

Systemic reaction: Anaphylaxis

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7
Q

Anaphylaxis progess, treatment and cause

A

Rapidonset
Large quantities of inflammatory mediators released

➢ rapid systemic vasodilation and vascular permeability
➢ hypotension (shock) and extensive tissue oedema
➢ fluid in the lungs and constriction of airways
➢ shortness of breath and lethal suffocation
➢ cardiovascular collapse and loss of consciousness

Treatment
- immediate administration of adrenalin / epinephrine to reverse bronchoconstriction and vasodilation (EpiPen)

Causes – drugs, bee stings, certain foods, etc

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8
Q

Diagnosis type 1 hypersensitivity

A
  • Skin prick testing
  • Specific IgE testing (RAST, fluoroenzyme assays)
  • Tryptase (elevated after anaphylaxis)
  • A full blood count may show eosinophilia.
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9
Q

Type 1 hypersensitivity treatment

A
  • Avoidance of know allergen
  • Antihistamines
  • Topical steroid nasal sprays
  • Adrenaline (EpiPen)
  • Desensitisation
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10
Q

Type 2 Hypersensitivity

A

Antibody-mediated cytotoxic hypersensitivity

Involves IgG and IgM antibodies
• Binding to self-antigens, altered/modifiedself-antigens or
alloantigen
• activates the complement cascade.
• causes inflammation and damage to tissues

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11
Q

Type 2 Hypersensitivity mechanisms and Diagram

ADCC, opsonisation complement

A

Complement mediated cell lysis
• Opsonization
•Antibody dependent cell mediated cytotoxicity (ADCC)
• Antibody-mediated cellular dysfunction

Refer to diagram on lecture

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12
Q

Type 2 hypersensitivity: Examples of Pro and Inhibitory effects
eg thyroid cell

A

Causes over production of a cell, ie thyroid cell.

OR

Blocks the receptor on the cell membrane preventing cell function
ie, muscle receptors for Ach are blocked by antibody causing the Ach unable to cross to the muscle for an action potential.

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13
Q

Type 2 Hypersensitivity:

where does it occur

A

Lungs, skin, blood system, nerve, thyroid

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14
Q

Rheumatic Fever and autoimmune hemolytic anaemia

A

Rheumatic Fever:
Migratory polyarthritis, antibody target is Fc of IgG, pathophysiology: ADCC and diagnostic testing: clinical criteria

autoimmune hemolytic anaemia:
Fatigue, jaundice, antibody target: RBC cell membrane, pathiophysiology: Oponisation, diagnostic testing: Coombs test

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15
Q

Diagnosis of

Type II Hypersensitivity reactions

A

• Detection of causative antibodies - Eg Direct immunofluorescence

• skin biopsies
e.g. bullous pemphigoid and pemphigus vulgaris.

• General blood work
e.g. Renal and Liver function tests

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16
Q

Examples of Type 2 hypersensitivity reactions, diagnosis and management

A

Goodpasture Syndrome
o Diagnosis: clinical along with labs (anti neutrophil cytoplasmic antibodies, anti-glomerular basement membrane, renal biopsy
oManagement: plasmapheresis and immunosuppressive therapy

Grave’s Disease
o Diagnosis: TSH-receptor Ab confirms diagnosis; thyroid function tests
o Management: symptom control (beta-blockers) and reduction of thyroid hormone synthesis (antithyroid drugs)

Myasthenia Gravis
o Diagnosis: single-fiber electromyography (most sensitive) and immunologic studies
o Management: pyridostigmine, immunotherapies

Autoimmune haemolytic anaemia
o Diagnosis: haemolyses work-up; Coombs test
o Management (first-line): glucocorticoids; treat the underlying condition o Refractory cases may require immunosuppresive drugs

17
Q

Type III Hypersensitivity information and general overview

A

Immune complex mediated - soluble immune complexes

• IgG (mostly, some IgM) antibodies bound to soluble antigens in the blood

  • These antibody–antigen complexes get stuck in certain locations;
  • blood vessels in the skin, kidneys and joints
  • activation of the complement cascade which causes local damage
  • Can be localised (rare) or systemic

occurs when an antigen binds to an antibody forming a complex during typical infection etc and these complexes are removed by the immune system typically via phagocytosis. However, if there are not removed
they will collect in certain sites of the body and accumulate causing the implementation of complement and thus local tissue damage and thus inflammation.

18
Q

Type 3 hypersensitivity mechanism

A
  1. Intermediate sized immune complexes (antigen (self or foreign) to antibody causing soluble complex.
  2. Accumulation of complexes at certain locations in blood vessels.
  3. Activation of complement. C3a/C5a also cause degranulation of mast cells which release histamines which induces vascular permeability of blood capillaries. This facilitates deposition of immune complexes on wall of blood vessel.
  4. C3a and C5a also act as chemotatic factors for neutrophils, So it attracts neutrophils at the site of immune complex deposition.
  5. C3b acts as opsonin by binding with immune complex. Neutrophil binds to C3b coated immune complex by C3b receptor.
  6. neutrophils cant do phagocytosis due to complex size and therefore release lytic enzymes causing destruction of immune complex and also local tissue damage.
19
Q

Immune complex (IC) deposition depends on (3):

A

• Physical properties of the IC:
Affinity of antibody to complement, size, and charge of the IC

Increased rate of IC formation → overwhelms clearing mechanism → IC freely circulate out to organs

• Antigen-to-antibody ratio:
Low or excess antibodies → decreased effector activation

• Tissue-specific haemodynamics
ICs first localize within blood vessels → vasculitis
Common areas affected are “permeability”-susceptible tissues:
• Glomeruli (nephritis)
• Joints/synovium(arthritis)
• Small blood vessels (vasculitis)

20
Q

Factors that causes deposition of immune complex and increase susceptibility (4):

A

Persistent infection:
- large numbers of immune complexes are formed and deposited in tissues.

Complement deficiency:
- When complement
system is deficient, large amounts of immune complexes circulates in blood and deposits in tissues.

Autoimmunity:
- In autoimmune disease, large amounts of immune complexes are formed and deposited
in tissues.

Genetic defects:
- In certain genetic defects, small and soluble immune complexes are formed that cannot
be phagocytosed.

21
Q

Type 3 treatment

A

immunosuppression with systemic glucocorticoids -

disease-modifying drugs,
e.g. methotrexate

22
Q

Factors causing SLE

A
  • Genetic predisposition, including haplotype HLA-B8
  • Exposure to sunlight
  • Viral infection, particularly Epstein-Barr virus
  • Hormones
  • Toxins such as cigarette smoke
  • Drugs in drug-induced LE
23
Q

Lab findings for SLE

A

Raised ANA level and anti-dsDNA antibody level
• Presence of anti-Sm
• Positive antiphospholipid antibody (lupus anticoagulant, false positive rapid plasma reagin)
• Low complement levels
• Positive direct Coombs’ test

24
Q

Type 4 Hypersensitivity description

A

Delayed hypersensitivity reaction occurs 48–72 hours after exposure to the allergen

T cell mediated
• Recognition of antigen by T helper cells – release of cytokines - activation of CD8+
T cells – target cell destruction

Antigen can be autoantigens, Can be foreign agents alter self-antigens

25
Q

Common examples of cutaneous type IV hypersensitivity reactions include:

A
  • Contact dermatitis
  • The Mantoux test (used to detect active TB)
  • Delayed drug reactions
26
Q

Process of Type 4 hypersensivity

A

Sensitisation (1st exposure):
Antigen enters body (PRR to PAMP) and dendritic cell becomes APC and this presents to a naive T CD4+ cell and binds via CD4+/TCR on T cell to MCH 2 on APC and then CD28 on T cell to B7 on APC triggering the release of IL-12 from APC. Triggering the TH cell to differentiate into TH1 cells and memory T cells which are sensitised.

Effector Phase (second exposure): 
Upon re-expsoure to the antigen the APC presents to TH1 cell which quickly activates memory T cells and release IL-2 aiding proliferation of TH1 and IFN-y which activates macrophages. Activates macrophages release proinflammalory cyloHnes (TNF, 11-6, IL-1) forming inflammation reaction allowing monocytes to leave bloodstream and differeniate into macrophages.

Th1 cells produce
IL-2: increases T-cell production of Th1 cells
Interferon-gamma (IFNy): recruits macrophages Tumor necrosis factor (TNF): increases vascular permeability and recruits more leukocytes TH1 also produce: TNF, IL-1, IL-6 (pro-inflam) which further activate macrophages.

Cytotoxic T cells: react when there is MCH 1 on infected cells. After the APC presents to the CD4+ cell this releases cytokines which stimulate CD8+ cells.

27
Q

How to diagnose Contact Dermatitis

A

Confirmed through patch testing (also known as a contact delayed hypersensitivity allergy test)
• Small quantities of the potential allergens are applied to the skin
• They are left in situ for two days.
• A patch of eczema at the site of an allergen is a positive reaction

28
Q

Treatment for type 4

A

antihistamine and avoidance

29
Q

process of SLE

A
  • Nuclear proteins are not processed properly
  • Nuclear debris accumulates within the cell
  • This leads to the production of autoantibodies against nuclear proteins
  • Immune complexes are not removed
  • The complement system is activated
  • Inflammation leads to cell and tissue injury
30
Q

Type 3 clinical presentation affected from…

A
  1. route of entry
    2.site(s) of IC deposition
    3.persistence of antigens.

Immunology 2 (10 decks)

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