Hypersensitivity and Allergy Flashcards
(35 cards)
What is 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
- Regulatory (blocking) antibody (IgG4) production
When do hypersensitivity reactions occur?
when immune responses are mounted against:
- Harmless foreign antigens (allergy, contact hypersensitivity)
- Auto-antigens (autoimmune diseases)
- Allo-antigens (serum sickness, transfusion reactions, graft rejection)
What is an allo-antigen?
an antigen present only in some individuals (e.g. of a particular blood group) and capable of inducing the production of an alloantibody in people that lack it
How is hypersensitivity classified?
- Type I: Immediate Hypersensitivity
- Type II: Antibody-dependent Cytotoxicity
- Type III: Immune Complex Mediated
- Type IV: Delayed Cell Mediated
When does type 1 hypersensitivity occur?
- anaphylaxis
- asthma
- rhinitis (seasonal and perennial)
- food allergy
What is the mechanism of type 1 hypersensitivity?
1st Antigen exposure:
- Sensitisation not tolerance
- IgE antibody production -> IgE binds to Mast Cells & Basophils
2nd Antigen Exposure:
- More IgE antibody produced -> Antigen cross-links IgE on mast cells and basophils
- leads to degranulation and release of inflammatory mediators
What are examples of type 2 hypersensitivity?
Organ-specific autoimmune diseases
- Myasthenia gravis (Anti-acetylcholine R antibodies)
- Glomerulonephritis (Anti-glomerular basement membrane antibodies)
- Pemphigus vulgaris (Anti-epithelial cell cement protein antibodies)
- Pernicious anaemia (Intrinsic factor blocking antibodies)
Pemphigus vulgaris:
- autoimmune attack of an antibody that cements epithelial cells together.
Bullous pemphigoid:
- blistering skin disorder (antibodies are against BM proteins)
- blisters tend to be a bit more robust - due to a deeper inflammation in the skin than pemphigus
Autoimmune cytopenias (antibody-mediated blood cell destruction)
- Haemolytic anaemia
- Thrombocytopenia
- Neutropenia
How can you test for specific antibodies?
immunofluorecence
ELISA e.g anti-CCP
What happens in type 3 hypersensitivity?
Immune Complex Mediated Hypersensitivity
- Formation of Antigen-Antibody complexes in blood (IMMUNE COMPLEXES)
- can’t get through the small blood vessels easily -> complexes deposit in the vessels and tissues
- leads to complement activation and cell recruitment/activation
- Activation of other cascades e.g. clotting
- Tissue damage (vasculitis) [most common sites = renal (glomerulonephritis), skin, joints and lung]
> Systemic lupus erythematosus (SLE)
> Vasculitides (Poly Arteritis Nodosum, many different types)
What are examples of type 4 (delayed) hypersensitivity?
- Chronic graft rejection
- Graft-versus-host disease (GVHD)
- Coeliac disease
- Contact hypersensitivity
- Many others: asthma, rhinitis, eczema
What do Th-1 and Th-2 do in hypersensitivity?
type 4
Th1 - characterised by producing lots of gamma-interferon. Th1 is important in most hypersensitivity reactions
Th2 releases: IL-4, IL-5 and IL-13.
- mediates allergic inflammation e.g. asthma, rhinitis and eczema
- Mechanisms involve either a transient antigen presence or a persistent antigen
- T cells then activate macrophages and CTLs. Much of the tissue damage is dependent upon TNF-alpha; hence why neutralising TNF-alpha has marked clinical benefits
What are the features of inflammation?
- Vasodilatation, increased blood flow
- Increased vascular permeability ( caused by C3a, C5a, histamine, leukotrienes)
- Inflammatory mediators & cytokines
- Inflammatory cells & tissue damage
o Cell trafficking – chemotaxis
o Neutrophils, macrophages, lymphocytes, mast cells
o Cell activation - Cytokine release: IL-1, IL-6, IL-2, TNF, IFN-γ
- Chemokines: IL-8/CXCL8, IP-10/CXCL10
What is atopy?
a form of allergy in which there is a hereditary of constitutional tendency to develop hypersensitivity reactions (e.g. hay fever, allergic asthma, atopic eczema) in response to allergens (atopens). Individuals with this predisposition - and conditions provoked in them by contact with allergens - are described as atopic
What are the genetic risk factors for asthma and eczema?
- The genetic component is polygenic: 50-100 genes associated with asthma/atopy
- Genes of the IL-4 gene cluster (chromosme 5) linked to raised IgE, asthma and atopy
- Genes on chromosome 11q (IgE receptor) are linked to atopy and asthma
- Genes linked to structural cells are linked to eczema (filagrin) and asthma (IL-33, ORMDL3)
What are the environmental risk factors of allergy?
- Age: increases from infancy, peaks in teens, and reduces in adulthood
- Gender: asthma is more common in males in childhood, and females in adults
- Family size: more common in small families
- Infection: early life infections protect
- Animals: early exposure protects
- Diet: breast feeding, anti-oxidants and fatty acids protect
What are the types of inflammation in allergies?
Anaphylaxis, urticaria, angioedema: type I hypersensitivity (IgE mediated)
Idiopathic/chronic urticaria: type II hypersensitivity (IgG mediated)
Asthma, rhinitis, eczema: mixed inflammation
- Type I hypersensitivity (IgE mediated)
- Type IV hypersensitivity (chronic inflammation)
Hw does sensitisation occur in atopic airway disease?
T cells are naïve before the have seen the antigen.
Once an antigen-presenting cell activates the CD4+ T cells, they then become specific to the presented antigen.
They could become Th1 (producing IFN-gamma).or Th2 cells, which leads to the activation of B cells. If the T cell was presented with a harmless antigen, they can become regulatory T cells.
subsequent exposure:
The allergens are presented by APCs to the memory Th2 cells cause degranulation of eosinophils by releasing IL-5. Th2 cells also release IL-4 and IL-13, which stimulate the production of IgE by plasma cells.
The IgE then becomes mobilised onto the surface of mast cells. The antigens then cross-link with the IgE on the surface of the mast cells and cause degranulation.
There is a massive release of inflammatory mediators, which gives rise to the effects seen in an allergic reaction.
What cells are invilved in allergies?
EOSINOPHILS - 0-5% of blood leukocytes - Recruited during allergic inflammation - Generated from bone marrow - Polymorphus nucleus: two lobes - Contain large granules full of toxic proteins Lead to tissue damage
MAST CELLS
- Tissue resident cells
- They have IgE receptors on cell surface
- Cross-linking of IgEs leads to mediator release:
> Pre-formed: Histamine, Cytokines, Toxic proteins
> Newly synthesized: Leukotrienes, Prostaglandins
*THIS ALL LEADS TO ACUTE INFLAMMATION.
NEUTROPHILS
- Important in virus induced asthma, severe asthma and atopic eczema
0 55-60% of blood leukocytes
- Multi-lobed nucleus
- Granules contain digestive enzymes
- Neutrophils also synthesis:
> Oxidant radicals
> Cytokines
o Leukotrienes
Describe the immunopathogenesis of asthma
mixture of type 1 + type 4
Mast cell activation and degranulation releases histamines (pre-stored mediators) and prostaglandins and leukotrienes (newly synthesised mediators) -> acute airway narrowing
airway narrowing is mainly caused by THREE processes:
- Vascular leakage leading to airway wall oedema
- Mucus secretion fills up the lumen
- Smooth muscle contraction around the bronchi
What are some clinical features of asthma?
- Reversible generalised airway obstruction – causes chronic episodic wheeze
- Bronchial hyper-responsiveness (they are much more sensitive to bronchial irritants)
- Cough
- Mucus production
- Breathlessness
- Chest tightness
- Response to treatment
- Spontaneous variation
- Reduced and variable peak expiratory flow (PEF)
What are the features of chronic asthma?
- chronic inflammation of the airways
- lumen of the airway is very narrow and the airway wall is grossly thickened
- cellular infiltration of Th2 lymphocytes and - Smooth muscle hypertrophy
- Mucus plugging
- Epithelial shedding
- Sub-epithelial fibrosis (if the inflammation has persisted for a long time)
What causes allergic rhinitis?
Seasonal – e.g. hay fever (grass and tree pollens)
Perennial – perennial allergic rhinitis (e.g. house dust mites, animal allergens)
What are the symptoms of allergic rhinitis?
- Sneezing
- Rhinorrhoea
- Itchy nose and eyes
- Nasal blockage, sinusitis, loss of small/taste
What are the features of allergic eczema?
- Chronic itchy skin rash
- Most commonly found in the flexures of the arms and legs
- can lead to house dust mite sensitisation - house dust mite proteins can get through the dry, cracked skin
- complicated by bacterial and (rarely) viral infections (e.g. HSV)
- 50% clears by 7 years
- 90% cleared by adulthood
