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Yr 2 MCD - Immuno > 1 - Hypersensitivity and Allergy > Flashcards

1 - Hypersensitivity and Allergy Flashcards

1
Q

When do appropriate immune responses occur?

A

Appropriate immune responses occur to foreign harmful agents such as:

  • viruses
  • bacteria
  • fungi
  • parasites

Required to eliminate pathogens

May be concomitant tissue damage as a side effect, but as long as pathogen is eliminated quickly will be minimal and repaired easily

Involves antigen recognition by cells of the immune system and antibody production

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2
Q

When do hypersensitivity reactions occur?

A

Hypersensitivity Reactions occur when immune responses are mounted against:

  • Harmless foreign antigens
    • allergy
    • contact hypersensitivity
  • Autoantigens (self antigens)
    • autoimmune diseases
  • Alloantigens (foreign antigens)
    • serum sickness
    • transfusion reactions
    • graft rejection
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3
Q

How are hypersensitivity reactions classified?

A

Classified by Gell & Coombs:-

  • Type I : Immediate Hypersensitivity
  • Type II : Antibody-dependent Cytotoxicity
  • Type III : Immune Complex Mediated
  • Type IV : Delayed Cell Mediated

Each involves distinct parts of the immune system reacting

NOTE: many diseases involve a mixture of types

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4
Q

What hypersensitivity conditions are classified as Type 1?

A

Anaphylaxis

Asthma

Rhinitis

  • Seasonal
  • Perennial (year-round)

Food Allergy

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5
Q

What events lead to a Type 1 hypersensitivity reaction?

A

STEP 1: PRIMARY Antigen Exposure

  • Sensitisation not tolerance
  • In allergy, you develop sensitisation
  • If no allergy, you develop tolerance
  • IgE antibody production
  • IgE binds to Mast Cells & Basophils

STEP 2: SECONDARY Antigen Exposure

  • More IgE Ab produced
  • Antigen cross-links IgE on Mast Cells/Basophils
  • Degranulation
  • Allergic reaction ensues
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6
Q

What does the clinical presentation of Type 2 hypersensitivity depend on?

A

Clinical presentation depends on target tissue

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7
Q

What conditions are classified as Type 2 hypersensitivity?

A

Organ-specific autoimmune diseases

  • Myasthenia gravis (Anti-acetylcholine R Ab)
  • Glomerulonephritis (Anti-glomerular basement membrane Ab)
  • Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
  • Pernicious anaemia (Intrinsic factor blocking Abs)

Autoimmune cytopenias (Ab mediated blood cell destruction)

  • Haemolytic anaemia
  • Thrombocytopenia
  • Neutropenia
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8
Q

How do you test for Type 2 hypersensitivity?

A

Type 2 = Antibody-Dependent Hypersensitivity

Test for specific autoantibodies

  • Immunofluorescence
  • ELISA e.g. anti-CCP (Cyclic Citrullinated Peptide Abs for Rheumatoid Arthritis)
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9
Q

What is Type 3 Hypersensitivity?

A

TYPE 3 = Immune Complex Mediated Hypersensitivity

  • Formation of Antigen-Antibody complexes (immune complexes) in blood
  • Complex deposition in blood vessels/tissue
  • Complement & cell activation in site where complexes have been deposited
  • Activation of other cascades egclotting
  • Tissue damage (vasculitis)
    • Systemic lupus erythematosus (SLE)
    • Vasculitides (Poly Arthritis Nodosum, many different types)
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10
Q

In what conditions do you get Type 4 Hypersensitivity responses?

A

TYPE 4 = DELAYED HYPERSENSITIVITY RESPONSES

Th1 Mediated

  • Chronic graft rejection
  • GVHD
  • Coeliac disease
  • Contact hypersensitivity (on the skin)
  • Many autoimmune diseases….

Th2 Mediated

  • Asthma
  • Rhinitis
  • Eczema
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11
Q

What is the mechanism behind Type 4 Hypersensitvity responses?

A

THREE MAIN VARIETIES OF THESE RESPONSES

  • Th1
  • Cytotoxic
  • Th2

MECHANISMS

Th1 Mechanism

Antigen taking up by Antigen-Presenting Cell

Presented to Th1 cell

Produces lots of IFN-γ

This leads to:

  1. Macrophage activation and then TNF production
  2. Activates fibroblasts, leading to angiogenesis and fibrosis
  3. Leads to IL-2 production which activates CTLs which produce proteins perforin which kills cells

General Mechanism

Transient/Persistent Ag

T cell activation of macrophages, CTLs

Much of tissue damage dependent upon TNF and CTLs

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12
Q

What is Type 4 Hypersensitivity?

A

Delayed Hypersensitivity Responses

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13
Q

Give an example of a Type 4 Delayed-Type Cell-Mediated Hypersensitivity response

A

Nickel

  • Contact Hypersensitivity
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14
Q

Summarise the different forms of hypersensitivity reactions

A
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15
Q

What are the features of inflammation?

A

IMMUNE CELL

  • recruitment to sites of injury/infection
  • activation

INFLAMMATORY MEDIATORS

  • complement
  • cytokines
  • etc.

Features of Inflammation

Vasodilatation (increased blood flow)

Increased vascular permeability

Inflammatory mediators and cytokines

Inflammatory cells and tissue damage

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16
Q

What are the signs of inflammation?

A

Redness

Heat

Swelling

Pain

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17
Q

What occurs in inflammation?

A

Immune cell recruitment to sites of injury and/or infection

Immune cell activation

Inflammatory mediators also have a role e.g. complement, cytokines etc.

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18
Q

What cytokines are pro-inflammatory?

A
  • IL-1
  • IL-6
  • IL-2
  • TNF
  • IFN-γ
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19
Q

What chemokines are involved in attracting inflammatory cells?

A
  • IL-8/CXCL8
  • IP-10/CXCL10
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20
Q

What caused increased vascular permeability in inflammation?

A

Caused by:

  • C3a
  • C5a
  • Histamine
  • Leukotrienes
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21
Q

By what mechanisms do inflammatory cells infilitrate tissues?

A

Cell Trafficking (Chemotaxis)

  • Neutrophils
  • Macrophages
  • Lymphocytes
  • Mast Cells

Cell Activation

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22
Q

List some common allergens

A

Animal fur

Pollen

House dust mites

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23
Q

What is atopic?

A

Denoting a form of allergy in which a hypersensitivity reaction such as eczema or asthma may occur in a part of the body not in contact with the allergen.

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24
Q

Outline the prevalence of atopy in UK

A

Prevalence of atopy is 50% in young adults in UK

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25
Q

Explain how the severity of atopy can differ

A

SEVERITY CAN VARY

Mild

  • e.g. occasional symptoms

Severe

  • e.g. chronic asthma

Life-Threatening

  • e.g. life threatening anaphylaxis
26
Q

What are the overall risk factors for allergy?

A

Genetic

Environmental

27
Q

Outline genetic risk factors that can cause allergies

A

80% of atopics have a family history

Polygenic

  • 50-100 genes liked to ashtma/atopy
  • genes of IL-4 gene cluster (chromosome 5) linked to raised IgE, asthma, atopy
  • genes on chromosome 11q (IgE receptor) linked to atopy and asthma
  • genes liked to structural cells linked to eczema (flaggrin) and asthma (IL-33, ORMDL3, CDHR3)
28
Q

Outline environmental risk factors that can cause allergies

A

AGE

  • increases from infancy
  • rare in infancy
  • peaks in teens
  • reduces in adulthood

GENDER

  • asthma more common in males in childhood and females in adults

FAMILY SIZE

  • more common in small families
  • only child has higher risk of allergy/asthma

INFECTIONS

  • early life infections are protective

ANIMALS

  • early exposure is protective
  • children that grow up on farms have very low incidence of allergies

DIET

  • breast-feeding = protective
  • anti-oxidants = protective
  • fatty acids = protective
29
Q

What is happening to the prevalence of allergies in the UK?

A

Allergies are increasing in the UK

  • asthma, hayfever and eczema have all increased
  • believed to be due to environmental changes
  • especially, decreased infectious disease incidence
30
Q

What are the types of inflammation in allergy?

A

Anaphylaxis/Urticaria/Angioedema

  • type 1 hypersensitivity (IgE mediated)

Idiopathic/Chronic Urticaria

  • type 2 hypersensitivity (IgG mediated)

Asthma/Rhinitis/Eczema

  • mixed inflammation
  • type 1 hypersensitivity (IgE mediated)
  • type 4 hypersensitivity (chronic inflammation)
31
Q

What does expression of atopy require?

A
  • Development of sensitisation to allergens instead of tolerance (primary response - usually in early life)
  • Further allergen exposure to produce disease (memory response - any time after sensitisation)

DIAGRAM:

Lumen of the airway depicted

Smooth muscle cells lining airway

Dendritic cells just under surface of epithelium

  • Sample allergens using their processes
  • Process allergen
  • Present peptides from allergen

Presented to naive T cells

Tolerance: Becomes Treg cell

Autoimmunity: Th1 response

Allergy (Sensitisation): Th2 response

Th2 response (Allergy)

Th2 cells proliferate

Cytokines IL-4 and IL-13

These cytokines tell B cells to produce IgE instead of IgG

IgE is specific to the peptide allergen

IgE binds to plasma cells

More IgE producion

Subsequent Exposure

IgE already being produced and present on mast cells

Intake of allergen

Allergen peptide presented by dendritic cells

T cells become Th2

More IL-4 and IL-13

More IgE

IL-5 also produced which leads to eosinophil recruitment and activation

Eosinophils produce mediators of inflammation

This combines with mast cell response which is degranulation and inflammatory mediator recruitment

Expression of allergic disease

SENSITISATION NOT TOLERANCE

32
Q

What are eosinophils?

A

0-5% of blood leukocytes

Present in blood, most reside in tissues

Recruited during allergic inflammation

Generated from bone marrow

Nucleus

  • two lobes

Contain large granules

  • toxic proteins

Lead to tissue damage

33
Q

What are mast cells?

A

Tissue resident cells

IgE receptors on cell surface

Crosslinking of IgEs leads to:

Multiple granules in cytoplasm

  • Mediator release
    • Pre-formed:
      • histamine
      • cytokines
      • toxic proteins
    • Newly synthesized:
      • leukotrienes
      • prostaglandins
34
Q

What are neutrophils?

A

Important especially in:

  • virus induced asthma
  • severe asthma
  • atopic eczema

55-70% of blood leukocytes

Polymorphonuclearcells (PMNs)

  • nucleus contains several lobes

Granules contain

  • digestive enzymes

Also synthesize

  • oxidant radicals
  • cytokines
  • leukotrienes
35
Q

What is the immunopathogenesis of asthma?

A

Acute inflammation of the airways

  1. Mast Cell Activation and Degranulation
  • Pre-stored mediators
    • histamine
  • Newly synthesised mediators
    • prostaglandins
    • leukotrienes
  • Acute airway narrowing
  • Airway wall oedema
36
Q

Outline the two-phase response to single allergen challenge

A

Initially, PEF is still lower than average due to pre-exisiting condition (e.g. asthma)

Pathogen inhalation

Acute rapid response due to:

  • Mast cell activation
  • Degranulation
  • Mediators:
    • Prostaglandins
    • Histamine
    • Leukotrienes
  • These cause airway narrowing due to:
    • Mucus
    • Smooth muscle
    • Oedema

This recovers fairly rapidly within an hour

Then there’s another late response without inhalation of the allergen as a cell-mediated response

  • Lymphocyte driven inflammation
  • Eosinophil driven inflammation

Occurs 2-8 hours after a single large-dose inhalation

37
Q

What are the important clinical features of asthma?

A

Reversible generalised airway obstruction

  • chronic episodic wheeze

Bronchial hyperresponsiveness

  • bronchial irritability

Cough

Mucus production

Breathlessness

Chest tightness

Response to treatment

Spontaneous variation

  • due to variation in allergen exposure

Reduced and variable peak flow (PEF)

38
Q

Outline the daily PEF of a person with poorly controllled asthma

A

Use inhaler in order to increase PEF

Exercise decreases PEF

PEF decreases during sleep normally due to house dust-mites

39
Q

What can cause allergic rhinitis?

A

SEASONAL

  • ​​hay-fever (grass, tree pollens)

PERENNIAL (year-round)

  • perennial allergic rhinitis (HDM, pets)
40
Q

What are the symptoms of allergic rhinitis?

A

Sneezing

Rhinorrhoea

Itchy nose

Itchy eyes

Nasal blockage

Sinusitis

Loss of smell/taste

41
Q

What is allergic eczema?

A

Chronic itchy skin rash

  • Common in flexures of arms and legs

House dust-mite sensitisation

  • HDMs can enter dry cracked skin so this makes it worse
  • HDM sensitisation and dry cracked skin

Complicated by bacterial and (rarely) viral infections (early childhood, herpes simplex)

50% clears by 7 years

90% by adulthood

42
Q

What percentage of allergic eczema cases are cleared by the age of 7 and what percentage by adulthood?

A

50% cleared by 7 years old

90% cleared by adulthood

43
Q

What forms of food allergy most commonly affect infants and children/adults?

A

INFANTS (3 YEARS)

  • eggs
  • cows milk

CHILDREN/ADULTS

  • peanuts
  • nuts
  • shell-fish
  • fruits
  • cereals
  • soya
44
Q

What are the symptoms of mild food allergies?

A

Itchy lips

Mouth

Angiodema

Urticaria (generalised all over body)

45
Q

What are the symptoms of severe food allergies?

A

Nausea

Abdominal Pain

Diarrhoea

Collapse

Wheeze

Anaphylaxis

46
Q

What is anaphylaxis?

A

Severe generalised allergic reaction

Uncommon

Potentially fatal

47
Q

What causes anaphylaxis biologically?

A

Generalised degranulation of IgE sensitised mast cells

48
Q

What are the symptoms of anaphylaxis?

A

Itchiness around:

  • mouth
  • pharynx
  • lips

Swelling of:

  • lips
  • throat
  • other parts of body

Wheeze

Chest tightness

Dyspnoea

Faintness

Collapse

Diarrhoea

Vomiting

Death (if severe and untreated)

49
Q

What is the effect of anaphylaxis on different body systems?

A

CARDIOVASCULAR

  • vasodilatation
  • cardiovascular collapse

RESPIRATORY

  • bronchospasm
  • laryngeal oedema

SKIN

  • vasodilatation
  • erythema
  • urticaria
  • angioedema

GI

  • vomiting
  • diarrhoea
50
Q

How are allergies investigated and diagnosed?

A

Careful history is essential

Skin-prick testing

  • Wheel of 3mm is diagnostic of allergy
  • Flare surrounds the wheel

RAST (blood specific IgE):

  • Total IgE - not very specific
  • Lung function (asthma)
51
Q

How do you treat anaphylaxis?

A

EMERGENCY TREATMENT

​EpiPen and Anaphylaxis Kit

  • antihistamine
  • steroid
  • adrenaline (epinephrine)

Then seek immediated medical aid

52
Q

How do you prevent anaphylaxis?

A

Avoidance of known allergen

Always carry a kit and EpiPen

Inform immediate family and caregivers

Wear a MedicAlert bracelet

53
Q

How do you treat rhinitis and eczema?

A

ALLERGIC RHINITIS

  • anti-histamines (sneezing, itching, rhinorrhea)
  • nasal steroid spray (nasal blockage)
  • cromoglycate (children, eyes)

ECZEMA

  • emollients (keep skin barrier healthy without cracking so HDMs can’t enter)
  • topical steroid cream

IF SEVERE:

  • anti-IgE
  • anti-IL-4
  • anti-IL-13
  • anti-IL-5 mAb

These are very effective, however they are also very expensive. Therefore, they are restricted to severe disease.

54
Q

Outline asthma treatment

A

STEP 1

Use short-acting β2 agonist drugs as required by inhalation

  • Salbutamol

STEP 2

Inhaled steroid low-moderate dose

  • Beclomethasone/Budesonide (50-800μg per day)
  • Flucticasone (50-400μg per day)

STEP 3

Add further therapy

  • Long-acting bronchodilators, leukotriene antagonist
  • High dose inhaled steroids - up to 2mg per day via a spacer

STEP 4

Add course of oral steroids, SLIT, azithromycin

  • Prednisolone - 30mg daily for 7-14 days
  • Anti-IgE, Anti-IL-5, Anti-IL-4/-13 monoclonal Abs
55
Q

What is immunotherapy effective for?

A

Effective for single antigen hypersensitivities

  • Venom allergy - bee or wasp stings
  • Pollens
  • HDM

This is done via subcutenous injection

Build it up from low dose to high dose

Helps to build tolerance

Need to do the subcutaneous version it for 3 years to build good tolerance

Antigen used is purified

56
Q

What is SCIT?

A

Subcutaneous Immunotherapy (SCIT)

  • 3 years needed
  • weekly/monthly 2 hour clinic visits
  • still relatively expensive
57
Q

What is SLIT?

A

Sublingual Immunotherapy (SLIT)

  • Can be taken at home
  • 3 years needed
58
Q

When does appropriate immune tolerance occur?

A

Appropriate immune tolerance occurs to self, and to foreign harmless proteins:

  • food
  • pollens
  • other plant proteins
  • animal proteins
  • commensal bacteria

Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production

  • Antigen recognition in context of “danger” signals leads to immune reactivity, absence of “danger” to tolerance
59
Q

What kinds of responses would someone with asthma undergo daily?

A

Mixture of early Type 1 response and ongoing late, cell-mediated response at the same time

60
Q

What are the features of asthma?

A

Chronic inflammation of the airways

Cellular infiltrate

  • Th2 lymphocytes, eosinophils

Smooth muscle hypertrophy

Mucus plugging

Epithelial shedding

Sub-epithelial fibrosis

This is all in addition to ongoing acute inflammation features

61
Q

What is rhinorrhea?

A

Runny nose

Nasal cavities filled with mucus

Yr 2 MCD - Immuno (5 decks)

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