Immunology Flashcards
What is an appropriate immune response?
Occurs to foreign harmful agents such as viruses, bacteria, fungi and parasites
- Required to eliminate pathogens
- Maybe concomitant tissue damage as a side effect, but as long as pathogen is eliminated quickly it will be minimal and repaired easily
Involves antigen recognition by cells of the immune system and antibody production
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 and regulatory (blocking) antibody (IgG4) production
- Antigen recognition in context of “danger” signals leads to immune reactivity, absence of “danger” to tolerance
What is a hypersensitivity reaction?
Occur when immune responses are mounted against:
- Harmless foreign antigens (allergy, contact hypersensitivity)
- Autoantigens (autoimmune diseases)
- Alloantigens (serum sickness, transfusion reactions, graft rejection)
What are the different types of hypersensitivity reaction?
Type I: Immediate hypersensitivity
Type II: Antibody-dependent cytotoxicity
Type III: Immune complex mediated
Type IV: Delayed cell mediated (Delayed-type hypersensitivity)
Types I, II and III depend upon the interaction of antigen with antibody
Type IV involves T cell recognition
Give examples of type I hypersensitivity
Immediate:
- Anaphylaxis
- Asthma
- Rhinitis
- Seasonal
- Perennial
- Food allergy
How does antigen exposure contribute to type I hypersensitivity?
1° antigen exposure - Sensitisation not tolerance - IgE antibody production - IgE binds to mast cells and basophils 2° antigen exposure - More IgE antibody production - Antigen cross-links IgE on mast cells/basophils - Degranulation
What is the clinical presentation of type II antibody-dependent hypersensitivity?
Depends on target tissue
- 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 Ab) - Autoimmune cytopenias (Ab mediated blood cell destruction)
- Haemolytic anaemia
- Thrombocytopenia
- Neutropenia
What tests can you do for specific autoantibodies in type II hypersensitivity?
- Immunofluorescence
- ELISA e.g. anti-CCP (Cyclic Citrullinated Peptide Abs for rheumatoid arthritis)
What is type III immune complex mediated hypersensitivity?
- Formation of antigen-antibody complexes in blood
- Deposition of complexes in a tissue
- Complement and cell recruitment/activation
- Activation of other cascades e.g. clotting
- Tissue damage (vasculitis)
• Systemic lupus erythematosus (SLE)
• Vasculitides (Poly Arteritis Nodosum, many different types
Where do the immune complexes deposit and cause vasculitis in type III hypersensitivity?
- Renal (glomerulonephritis)
- Skin
- Joints
- Lung
Give examples of conditions associated with type IV hypersensitivity.
- Chronic graft rejection
- CVHD
- Coeliac disease
- Contact hypersensitivity
What are the varieties and mechanisms of type IV hypersensitivity?
Three main varieties: - Th1 - Cytotoxic - Th2 Mechanisms - Transient - T cell activation of macrophages, CTLs - Much of tissue damage dependent upon TNF
What is the common cause of type IV contact hypersensitivities?
Nickel
What is the immune reactant in hypersensitivity reactions?
Type I: IgE
Type II: IgG
Type III: IgG
Type IV: Th1, Th2 and CTL
What is the effector mechanism in hypersensitivity reactions?
Type I: Mast-cell activation
Type II: Complement, FcR cells (phagocytes, NK cells); antibody alters signalling
Type III: Complement phagocytes
Type IV: Macrophage activation; eosinophil activation; cytotoxicity
What are the features of inflammation?
- Vasodilation, increased blood flow
- Increased vascular permeability
- Inflammatory mediators and cytokines
- Inflammatory cells and tissue damage
What are the signs of inflammation?
- Redness
- Heat
- Swelling
- Pain
- Loss of function
What causes increased vascular permeability in inflammation?
- C3a
- C5a
- Histamine
- Leukotreines
What cytokines are involved in inflammation?
- IL-1
- IL-6
- IL-2
- TNF
- IFN-γ
What chemokines are involved in inflammation?
- IL-8 / CXCL8
- IP-10 / CXCL10
What is the prevalence of atopy in young adults in the UK?
50%
What are the different severities of atopy?
- Mild occasional symptoms
- Severe chronic asthma
- Life threatening anaphylaxis
What are the risk factors for atopy?
Genetic
- ~80%
- Polygenic
• 50-100 genes linked to asthma/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 linked to structural cells linked to eczema (filaggrin) and asthma (IL-33, ORMDL3)
Environmental
- Age (increases from infancy, peaks in teens, reduces in adulthood)
- Gender (more common in males in childhood, females in adulthood)
- Family size (More common in small families)
- Infections (Early exposures protect)
- Diet (breast-feeding, anti-oxidants and fatty acids protect)
What are the types of inflammation in allergy?
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)
What is required for expression of disease?
- Development of sensitisation to allergens to sensitise instead of tolerance (primary response - usually in early life)
- Exposure to produce disease (memory response- any time after sensitisation
What is the process of sensitisation and subsequent exposure in atopic airway disease?
Sensitisation
- Processed allergen presented to CD4⁺ cell
- CD4⁺ activates Th2 cell but Treg and Th1 is inactive
- Th2 secrete IL-4 and IL-13 which activates B cells
- B cells proliferate and differentiate into plasma cells
- IgE synthesis and release
Subsequent exposure
- Allergen presented to Th2 (memory)
- Th2 produce IL-5 which activates eosinophils which produce inflammatory mediators
- Th2 produce IL-4 and IL-13 which causes B cell differentiation to plasma cells
- Plasma cells produce IgE which binds to mast cells and causes degranulation
What are eosinophils?
- 2-5% of blood leukocytes
- Present in blood but most reside in tissues
- Recruited during allergic inflammation
- Generated from bone marrow
- Polymorphous nucleus - two lobes
- Contains large granules (toxic proteins)
- Lead to tissue damage
What are mast cells (allergy)?
- Tissue resident cells
- IgE receptors on cell surface
- Crosslinking of IgEs leads to:
• Mediator release of preformed- histamine
- cytokines
- toxic proteins
and newly synthesised - leukotreines
- prostaglandins
What are neutrophils role in allergy?
Important in: - virus induced asthma - severe asthma - atopic eczema 55-70% of blood leukocytes - Nucleus contains several lobes - Granules contain digestive enzymes - Also synthesise: • oxidant radicals • cytokines • leukotreines
What is the immunopathogenesis of acute asthma?
Acute inflammation of the airways
- Mast cell activation and degranulation
• pre-stored mediators (histamine)
• newly synthesised mediators (prostaglandins, leukotreines)
- Acute airway narrowing
• Vascular leakage (airway wall oedema, mucus secretion)
• Smooth muscle contraction
What is the response to a single allergen challenge in asthma?
- Early response (~30 mins)
- Late response (5 hours)
What is the immunopathogenesis of chronic asthma?
Chronic inflammation of the airways:
- Cellular infiltrate (Th2 lymphocytes, eosinophils)
- Smooth muscle hypertrophy
- Mucus plugging
- Epithelial shedding
- Sub-epithelial fibrosis
What is asthma? What are the symptoms?
Reversible generalised airway obstruction - Chronic episodic wheeze - Broncial hyperresponsiveness - Bronchial irritability Cough Mucus production Breathlessness Chest tightness
Response to treatment
Spontaneous variation
Reduced and variable peak flow (PEF)
What are the types of allergic rhinitis?
- Seasonal: hayfever- grass, tree pollens
- Perennial: perennial allergic rhinitis
• HDM, animal
What are the symptoms of allergic rhinitis?
- Sneezing
- Rhinorrhoea
- Itchy nose, eyes
- Nasal blockage, sinunsitis, loss of smell/taste
What is allergic eczema?
- Chronic itchy skin rash
- Flexures of arms and legs
- HDM sensitisation and dry cracked skin
- Complicated by bacterial and (rarely) viral infections (herpes simplex)
- 50% clears by 7 years
- 90% by adulthood
What are common food allergies among infants (<3 years)?
Egg
Cows milk
What are common food allergies among children and adults?
Peanuts Shellfish Nuts Fruits Cereals Soya
What are the symptoms of mild and severe allergies?
Mild - Itchy lips - Itchy mouth - Angioedema - Urticaria Severe - Nausea - Abdominal pain - Diarrhoea - Anaphylaxis
What is anaphylaxis?
Severe, generalised allergic reaction
- Uncommon, potentially fatal
- Generalised degranulation of IgE sensitised mast cells
What are the symptoms of anaphylaxis?
- Itchiness around mouth, pharynx, lips
- Swelling of the lips, throat and other parts of the body
- Wheeze, chest tightness, dyspnoea
- Faintness, collapse
- Diarrhoea and vomiting
- Death is severe and untreated
What systems are involved in anaphylaxis?
Cardiovascular: - vasodilation - cardiovascular collapse Respiratory: - bronchospasm, - laryngeal oedema Skin: - vasodilation - erythema - urticaria - angioedema GI - vomiting - diarrhoea
What investigations are conducted into anaphylaxis to make a diagnosis?
- Careful history essential
- Skin prick testing
- RAST (blood specific IgE)
- Total IgE
- Lung function (asthma)
What is the treatment of anaphylaxis?
Emergency treatment - EpiPen and Anaphylaxis kit • antihistamine, steroid, adrenaline • Seek immediate medical aid Prevention - Avoidance of the known allergy - Always carry a kit and EpiPen - Inform immediate family and caregivers - Wear a MedicAlert bracelet
What is the treatment for allergic rhinitis?
- Antihistamines (sneezing, itching, rhinorrhoea)
- Nasal steroid spray (nasal blockage)
- Cromoglycate (children, eyes)
What is the treatment for eczema?
- Emollients
- Topical steroid cream
What is the treatment for SEVERE rhinitis and eczema?
- Anti-IgE mAb
- Anti-IL4/13 mAb
- Anti-IL-5 mAb
What is the treatment for asthma?
Step 1:
Use short acting β₂ agonist drugs as required by inhalation
- Salbutamol
Step 2:
Inhaled steroid low-moderate dose
- Beclomethasone/Budesonide (50-800μg/day)
- Fluticasone (50-400μg/day)
Step 3:
Add further therapy
- Add long acting β₂ agonist, leukotreine antagonise
- High dose inhaled steroids - up to 2mg/day via a spacer
Step 4:
Add a course of oral steroids
- Prednisolone 30mg/day for 7-14 days
- Anti-IgE, anti-IL4/13, anti-IL-5 mAbs
What are the uses of immunotherapy?
Effective for single antigen hypersensitivities
- Venom allergy (bee or wasp stings)
- Pollens
- HDM
- Antigen used is purified
What are the different types of immunotherapy? Describe them.
- Subcutaneous immunotherapy (SCIT)
- 3 years needed
- Weekly/monthly 2 hour clinic visit - Sublingual immunotherapy (SLIT)
- Can be taken at home
- 2-3 years is enough
Why do corneas “fail”?
- Degenerative disease
- Infections
- Trauma
Why does skin “fail”?
- Burns
- Trauma
- Infection
- Tumours
Why does bone marrow “fail”?
- Tumours
- Hereditary disease