Hypersensitivity & Allergy Flashcards by Rama Jha

• Explain Appropriate Immune Tolerance

Can occur to SELF & FOREIGN harmless proteins - involves:
• antigen recognition
• generation of T-reg cells
• regulatory (blocking) Ab production (IgG4)

Antigen recognition in absence of “danger” = immune tolerance

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Broadly, give the classifications of Hypersensitivity Reactions

Classified by Gell & Coomb:

o Type 1
• Immediate Hypersensitivity (allergic)

o Type 2
• Ab-dependent Cytotoxicity

o Type 3
• Immune Complez Mediated

o Type 4
• Delayed Cell Mediated

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Explain against what are hypersensitivity reactions responding to?

Hypersensitivity reactions occurs when responses are mounted against:

 Harmless foreign antigens
• e.g. pollen

 Auto-antigens
• e.g. Auto-immune

 Allo-antigens
• e.g. transfusion reactions

Allo-antigens are antigens present in only SOME individuals (i.e. ABO blood groups).

Note – many diseases involve a mixture of the different types of hypersensitivity reactions

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What is Type 1 hypersensitivity mediated by and examples?

Mediated by:
IgE

Example:
 • Anaphylaxis
 • Asthma
 • Rhinitis
 • Food Allergy

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Explain how Type 1 hypersensitivity comes about

 1st exposure:
• SENSITISATION rather than tolerance
• IgE AB production = binds to mast cells and basophils

 2nd exposure:
• MORE IgE produced
• antigens crosslink IgE on mast cells and basophils = degranulation = release of inflammatory mediators

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What is Type II hypersensitivity mediated by and what does clinical presentation depend on?

Mediated by:
• Abs responding to cell-surface OR matrix-bound antigen (INSOLUBLE)

Clinical Presentation depends on TARGET TISSUE

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Give examples of Clinical presentations in Type II Hypersensitivity

 Organ-specific AI diseases - reactions associated with Abs directed against:

Anti-ACh R AB –> Myasthenia gravis
Anti-glomerular basement membrane AB –> Glomerulonephritis
Anti-epithelial cell cement protein AB –> Pemphigus vulgaris
Intrinsic factor blocking AB –> Pernicious anaemia

 AI cytopaenias – AB-mediated blood cell destruction:

Haemolytic anaemia.
Thrombocytopaenia.
Neutropenia

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What tests can you carry out for Type II Hypersensitivity to test for specific Abs?

(1) Immunofluorescence

(2) ELISA
• e.g. anti-CCP (Cyclic-Citrullinated Peptide) Abs for RA

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What is Type III hypersensitivity mediated by and what does this result in?

Mediated by:
• antigen-Ab complexes

Abs respond to SOLUBLE antigens
• these can NOT traverse vessel walls very easily
SO
• are DEPOSITED in various TISSUES

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Explain what the deposition of the antigen-Ab complexes in the various tissues leads to in Type III Hypersensitivity

Leads to:
• complement activation
&
• cell recruitment

Leads to activation of cascades such as clotting & leads to tissue damage:
• e.g. SLE
• e.g. Vasculitis (in kidneys, skin, joints, lungs)

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What is Type IV hypersensitivity mediated by and examples?

Mediated:
• T-cells

Examples:
 • Chronic GRAFT rejection
 •  Chronic graft rejection
 • Graft-versus-Host disease (GVHD)
 • Coeliac disease
 • Contact hypersensitivity
 • Allergic inflammation – asthma, rhinitis, eczema

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Explain the mechanisms of Type IV Hypersensitivity Responses

Three main Varieties:
• Th1 - produces lots of GAMMA-IFN (activates macrophages - producing TNF-a which causes tissue damage)

Cytotoxic
Th2 - releases IL-4/5/13 (allergic inflammation)

Mechanisms:
• transient or persistent antigen presence = T-cell activation of macrophages & CTLs = TNF-a damage

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Nickel and hypersensitivity?

Nickel can cause a Type IV Hypersensitivity

• CONTACT HYPERSENSITIVITY

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What causes inflammation?

CYTOKINES released by the immune cells leads to features of inflammation

Cytokines which INCREASE PERMEABILITY include:
• C3a, C5a
• histamine
• leukotrienes

Other cytokines involved:
• IL-1/2/6
• TNF
• IFN-gamma

Also brought about by CHEMOKINES which mediate cell-trafficking:
• neutrophils, macrophages, lymphocytes & mast cells undego chemotaxis & active cells
• IL-8
• IP-10

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Define Atopy

Form of Allergy

Hereditary/constitutional tendency to develop hypersensitivity reactions
• e.g. hay fever, allergic asthma, atopic eczema

Severity varies:
• Mild - occasional symptoms
• Severe - chronic asthma
• Life threatening - anaphylaxis

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What are the broad Risk Factors for Allergies?

(1) Genetic

(2) Envrionmental

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Explain the Genetic Risk Factor for Allergies

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Genetic – 80% of atopies have a family history:
• Polygenic

 50-100 genes are associated with asthma and atopy

 IL-4 gene cluster – Chr5
• linked to raised IgE, asthma and atopy.

 Chr11q IgE Receptor
• genes linked to atopy and asthma.

 Genes linked to eczema (filaggrin) and asthma (IL-33, ORMDL3).

Explain the Envrionmental Risk Factor for Allergies

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 Age
• increases in infancy to a peak in teens and then drops into adulthood.

 Gender
• more common in males (childhood) and females (adulthood).

 Family size
• more common in small families.

 Infections
• lends to early life protection from infections

 Animals
• early exposure protects against them

 Diet
• breast feeding, anti-oxidants and fatty acids protects against atopy.

What are some types of inflammation in allergy and the associated hypersensitivity reaction?

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 T1-hypersensitivity (IgE-mediated):
• Anaphylaxis
• Urticaria
• Angioedema

 T2-hypersensitivity (IgG-mediated):
• Idiopathic/chronic urticaria

 Mixed T1 (IgE), T4 (chronic inflammation) hypersensitivity:
• Asthma
• Rhinitis
• Eczema

What does Expression of Disease require?

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Requires:
• development of sensitisation to allergens INSTEAD of tolerance (1o response - usually in early life)

• further allergen exposure to produce disease (memory response - any time after sensitisation)

Explain the Expression of Disease in Atopic Airway Diseases - FIRST STEP?

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SENSITISATION!

APC presents the allergen to the naïve T-cell which then becomes:
 •	Th1 cell 
 (produce IFN-g).
 •	Th2 cell 
 (lead to activation of B-cells).
 •	Treg cells 
 (if presented with a harmless antigen).

Explain the Expression of Disease in Atopic Airway Diseases - SECOND STEP?

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SUBSEQUENT EXPOSURE!

APC presents the allergen to the Th2 memory cells which leads to:
 •	Degranulation of eosinophils
 via IL-5.
 •	Production of IgE plasma cells
 via IL-4, IL-13.

 IgE then mobile onto the surface of mast cells and degranulate the mast cells.
• mediators released inc. histamine, cytokines, leukotrienes, PGs

Main Allergic Cell Mediators?

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Eosinophils

Neutrophils

Mast Cells

Explain Eosinophils as Allergic Cell Mediators

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o 2-5% of blood leukocytes.
o Present in the blood but most are in the tissue

o Recruited during allergic inflammation.
o Generated from bone marrow.

o Have polymorphic nuclei – bi-lobed.
o Have large granules full of toxic proteins.

Explain Neutrophils as Allergic Cell Mediators

Important in • virus induced • severe & atopic asthma o 55-70% of blood leukocytes. o Multi-lobed nuclei with digestive enzyme granules. ``` Synthesise: • oxidant radicals • cytokines and • leukotrienes ```

Explain Mast Cells as Allergic Cell Mediators

Tissue resident cells. IgE receptors on the cell surface: • cross-linking with IgEs leads to release of inflammatory mediators:  Pre-formed: • Histamine. • Cytokines. • Toxic proteins.  Newly synthesised: • Leukotrienes. • Prostaglandins. o Leads to ACUTE inflammation.

Explain Acute Asthma

Asthma is a mixture of T1 and T4 hypersensitivities: • Mast cell activation & degranulation releases histamines, prostaglandins and leukotrienes = narrowing airway Airway narrowing caused by:  Vascular leakage – airway wall oedema.  Mucus secretion – fills lumen.  Smooth muscle contraction. o There is a two-phase response to single allergen challenges with an early and then late response.

Explain Chronic Asthma

o Airway wall is grossly thickened with a narrow lumen. o Cellular infiltrations of Th2 lymphocytes and eosinophils. o Smooth muscle (SMC) hypertrophy. o Mucus plugging. o Epithelial shedding. o Sub-epithelial Fibrosis

Important clinical features of Asthma? | •

o Reversible airway obstruction • = chronic episodic wheeze o Bronchial hyperresponsiveness o Cough, dyspnoea, chest tightness o mucus production o responds to treatment, BUT has spontaneous variation o a REDUCED PEF and VEF.

What are the symptoms of Allergic Rhinitis

Seasonal • e.g. hay fever Perennial • e.g. perennial allergic rhinitis (house mites etc.) ``` Symptoms: • sneezing • rhinorrhoea • itchy nose & eyes • nasal blockade • sinusitis • loss of smell/taste ```

Explain Allergic Eczema

Chronic itchy skin rash • found in flexures of the arm & legs Can lead to house dust mite (HDM) sesitisation & dry cracked skin • HDMs through cracked skin It is complicated by bacterial & viral infections

Explain what type of allergy food allergies are, the common ones and the reaction types you can get

Type I Hypersensitivity Reaction Common food allergies change with age: • Infancy (3yo) – eggs and cow’s milk. • Children/adults – peanuts, shellfish, nits, fruits, cereals, soya.  Reaction types: • Mild – itchy lips and mouth, angioedema, urticaria. • Severe – nausea, abdominal pain, diarrhoea, anaphylaxis.

General information regarding anaphylaxis

A severe generalised allergic reaction:  Uncommon but are potentially fatal.  Caused by generalised degranulation of IgE-sensitised mast cells.

Symptoms of anaphylaxis?

``` o Itchiness at mouth. o Wheeze/chest tightness. o Diarrhoea & vomiting. o Swelling if lips & throat o Fainting/collapse. o Death. ```

What systems can be affected in anaphylaxis?

o CVS – vasodilation, CVS collapse o Respiratory – bronchospasm, laryngeal oedema. o Skin – vasodilation, erythema, urticaria, angioedema. o GI – vomiting and diarrhoea.

What investigations and diagnosis can be done to detect allergies?

``` o Skin prick testing. o RAST – blood specific IgE ABs in blood. o Measure total IgE. o Careful history. o Lung functions (asthma). ```

What is the treatment in place for Anaphylaxis?•

Emergency: • epi-pen & anaphylaxis kit – anti-histamine (mild), steroids, adrenaline (severe) ``` Prevention: • avoidance • emergency kits to hand • inform • medicalert bracelet. ```

Treatment for Allergic Rhinitis?

o Anti-histamines. o Nasal steroid therapy. o Cromoglycate – for children in the eyes.

Treatment for Eczema?

o Emollients – maintains moisture of skin • reinforces barrier function o Topical steroid cream.

If either Allergic Rhinitis or Eczema is severe, what can be given?

Anti-IgE Anti-IL4/13 Anti-IL5 mAbs!!

Treatment for Astham?

Astham: 4 Steps: 1. Short-acting beta2 agonist drugs • SALBUTAMOL 2. Inhaled steroids (low-moderate dose): (a) Beclomethasone /Budesonide (b) Fluticasone. 3. Add further therapy: (a) Long-acting beta2 agonist (bronchodilators) OR a leukotriene antagonist. (b) High dose inhaled steroids. 4. Add courses of oral steroids. (a) Prednisolone. (b) Anti-IgE, anti-IL-4/13, anti-IL-5 mAb.

Explain how Immunotherapy works for Allergies and Asthma

Effective for SINGLE ANTIGEN hypersensitivities • induces tolerance by exposure to very small amounts of purified antigens • e.g. venom allergy, pollens, HDM Given SUBCUTANEOUSLY • 3 years needed • weekly/monthly 2hr clinic visits Can also recieve it SUBLINGUALLY • can be taken at home • 2-3years is enough

Hypersensitivity & Allergy Flashcards

(42 cards)