Immunology Flashcards
What is the acute phase response following recognition of pathogens?
- Innate immunity sense non self
- Cytokines produced
- Acute phase reactants produced
- Measures to localise the spread of infection and enhance systemic resistance
What do PRPs recognise in infections and tissue damage?
Infections: pathogens associated molecular patterns (PAMPS)
Tissue damage: danger/damage associated molecular patterns
Where are TLR-like and NOD-like receptors located?
TLR - on cell surface
NOD - cytosolic
What are pro-inflammatory cytokines?
IL-1B, IL-18, IL-6, TNF-alpha - all induced by TLR activation
What do pro-inflammatory cytokines lead to? 4
1/ activation of complement opsonisation
2/ phagocytosis
3/ decreased viral/bacterial activation
4/ initiate adaptive immune response
How do steroids suppress pro-inflammatory genes?
In nucleus - steroids induce expression of anti-inflammatory genes and suppress pro-inflammatory genes
Why is C reactive protein the best marker for an acute phase response?
- it is pro-inflammatory
- important opsonin
What are the 3 pathways in complement system?
- alternative - activated by microbe
- Classical - activated by Ab-Ag immune complexes
- Lectin - activated by MBL
What are the physiologic activities of complement once it recognises pathogens?
- host defence: opsonisation for phagocytosis, chemotaxis and lysis of bacteria and cells (MAC)
2 interface between innate and adaptive immune systems - Disposal of waste
How can abnormalities in complement be detected?
Assessmemt of C3 and C4 serum levels
What is classical complement deficiency associated with?
Pyogenic infection and SLE
What are the 3 major classes of innate phagocytes?
- Granuloctyes
- Macrophages
- immature D.C’s
What cells are involved in cell-mediated immunity and what do they do?
Intracellular organisms
T helper cells (CD4+) - activate macrophages to kill phagocytksed microbes
Cytotoxic T cells (CD8+) - bind infected cells and kill them directly
What is central and peripheral tolerance?
Central - Self antigens are presented to T cells in the thymus before they are released into periphery
Peripheral - T cells with self recognition are killed in the periphery
What cells are involved in humoral mediated immunity?
B cells - recognise extracellular
Follicular b cells: T cell dependent and produce a/b
Marginal zone B cells and B1 B-cells: T independent (IgM and short lived plasma cells) and they are important in polysaccharide and lipid responses
What are the 2 types of immunodeficiency?
Primary: inherent defect
Secondary: acquired problems as a result of another disorder (infection, drugs, haematological)
When should a Primary immunodeficiency disorder be suspected?
- Patients with infections - recurrent, opportunistic
- Family history of PID
- Other complications associated with immune deficiency - failure to thrive, facial features, cardiac abnormalities
How can PID’s be categorised?
B cell defects:
- XLA
- CVID
Combined immunodeficiencies
1. SCID
Phagocyte defects
1. CGD
What is X-linked agammaglobulinaemia?
Disorder of defective B cell development
- No B cells due to mutation in BTK
- usually present at 6months when maternal IgG disappears
- commonly get pneumonia and otitis media
What is common variable immunodeficiency?
Defective B cell differentiation
- sinopulmonary and GI infections
Diagnosis: low Ig’s of at least 2 isotopes
Treatment: Ig replacement therapy/prophylactic antibiotics
What is severe combined immunodeficiency?
Defect of T and B cells characterised by absence of T cells.
- proofed susceptibility to infection
What are the groups of genetic defects that can cause SCID?
- cytokines not signalling properly
- recombination of antigen receptors
- premature lymphocytic death
- defects in TCR
- defects affecting thymus development
What is chronic granulomatous disease?
Disordered phagocyte killing
- defective killing mechanism allows the microbe to survive causing granuloma formation and ongoing sterile inflammation
- skin, bone, liver, GI tract most susceptible
What are 4 unwanted immune responses and examples?
- Autoimmune - SLE, RA
- Alloimmune - rejection of transplants
- Immune-mediated inflammatory disorders - sarcoidosis
- Allergic - asthma, atopic excema
What do these drugs have in common: cyclosporine, tacrolimus, sirolimus, everolimus
Inhibit lymphocyte signalling
What are some cytotoxic agents?
Anti-metabolite: MTX, AZA, mycophenolate
Alkylating: cyclophosphamide
What are patient considerations when choosing an immunosuppressant?
Age, gender, comorbidities, fertility status, genetics, medications
How do steroids act as immunosuppressants?
Bind to cystolic receptors, enter nucleus, alter gene expression of lymphocytes (inhibit NFkB)
Why is stopping steroids a slow process?
Steroids are adrenal suppressors so the body may take time to produce its own again
How does azathioprine act?and what are the side effects?
Inhibits DNA production and lymphocyte proliferation
Side effects: hypersensitivity, GI upset, hepatotoxicity, BM toxicity and infection
How does methotrexate act as an immunosuppressant? side effects
MTX inhibits folic acid metabolism, which is needed for DNA replication
Side effects: teratogen, BM suppression and infection, nausea, mouth ulcers, hepatotoxicity
How does mycophenolate act? and side effects
Inhibits the enzyme needed for production guanosine in lymphocytes
side effects - GIT upset, BM suppression, infection, teratogenic
How does cyclophosphamide act?
Potent alkylating agent - cross links DNA helix preventing division and replication= SEVERE drug
What is an example of a mono-clonal antibody and how does this class act?
Rituximab - antiCD20 antibody causes B cell depletion as it is a marker on B cells
May also stop T reactive responses as CD20 is on APCs that present to T cells
What are some TNF-alpha inhibitors? and their side effects?
Infliximab, etanercept, adalimumab
Side effects - infection, HF, Demyelinating disorders, infection, cytopenias
What are some hallmarks of endocrine autoimmunity?
- auto reactive T cells
- chronic inflammatory infiltrate (lymphocytes, plasma cells, macrophages, germinal centres)
What are autoimmune diseases of the thyroid?
Hyperthyroidism - thyrotoxicosis
- Grave’s disease
- Toxic multi nodular goitre
- Toxic adenoma
Hypothyroidism - thyroiditis
- Hashimoto’s thyroiditis
- Atrophic thyroiditis
What is the disease process in Grave’s disease?
- Autoantibodies to TSH receptor
- stimulate hypertrophy and hyperplasia
- auto-antibody binds TSH receptor and mimics TSH
What are signs of Grave’s disease?
- weight loss
- nervous
- weakness
- sweating
- heat intolerance
- enlarged thyroid
- fast pulse
- tremor
- exophthalmos and periorbital myxoedema
What are the eye signs of Grave’s?
Stare and lid-lag
Exophthalmous - swelling of eye tissue = bulge
What is the laboratory diagnosis of Grave’s?
High T4
Low TSH
Diffuse increase in radio iodine uptake
- anti-thyroid peroxidase TPO and anti-thyroglobulin TG confirms autoimmunity and predicts eventual thyroid failure
- anti-TSH receptor antibodies confirm Grave’s
What is the treatment for Grave’s?
If it does not resolve - Ablative = surgery or large dose of radio iodine
Anti-thryoid drugs - most cases remit in 1-2yrs so these drugs can help in the meantime (neomercazole, propylthiouracil)
What is hashimoto’s thyroiditis?
- antibodies may stimulate TSH receptor but don’t cause increase in TH production
- enlarged thyroid with inflammatory infiltrate + high levels of autoantibodies TG and TPO
- Inevitably progress to thyroid failure = require TH replacement
What is atrophic thyroiditis?
- autoimmune disease that may result in thyroid failure
- antibodies to TPO and TG
How is thyroid autoimmunity detected?
Presence of thyroid peroxidase antibodies = anti-TPO via:
- immunofluorescence on human thyroid tissue
- haemagglutination
- proportion of ‘healthy people’ with these a/b progress to thyroid failure
What is predictive of IDDM?
Autoantibodies to pancreatic islet cells:
- islet cell antibodies
- anti-glutamic acid decarboxylase
- anti-tyrosine phosphatase
What is addisonian pernicious anaemia?
Autoimmune disease - malabsorption of B12 due to autoimmunity to parietal cells = gastric atrophy = lack of intrinsic factor
How is addisonian pernicious anaemia diagnosed and treated?
Diagnosis:
- malabsorption of B12
- Anti-parietal cell a/b
- intrinsic factor antibody
Treatment - B12 injections
What is coeliac disease?
Hypersensitivity to food protein (gluten) and autoimmunity to enzyme (trans glutamase) in the gut
Ingestion of gluten = atrophy of small bowel = malabsorption
What is the mechanism of hypersensitivity in coeliac disease?
- Gliadin is rich in glutamine and proline and resists digestion
- tissue transglutaminase tTg removes amine from glutamine in the peptide
- peptide can now bind groove of HLA-DQ2 or 8
- this antigen is presented to a non-tolerant immune system, eliciting strong T cell and antibody response
- vigorous T cell response damages mucosa
What is the revised ARA criteria for classification of SLE?
Skin and mouth: malar rash, discoid rash, photosensitivity, oral ulcers
Joints: arthritis
Lungs and heart: pleuritis or pericarditis
Kidney: proteinuria or casts
Nervous system: seizures or psychosis
Blood: low WBC/platelets/lymphocytes or haemolytic anaemia
Immune system: anti ds DNA/Sm/cardiolipin/anticoagulant and antinuclear antibody
How does SLE affect the skin and joints?
Skin - malar/butterfly rash (photosensitivity), discoid rash and lesions
Joints - arthritis and tenosynovitis
How does SLE affect the lungs and heart?
Lungs - fibrinoid effusions and adhesions, infections, interstitial pneumonitis, embolism/infarction
Heart - pericarditis, myocarditis
How does SLE affect the kidneys, blood vessels and CNS?
Kidneys - immune complexes trapped in capillary walls, glomerulonephritis, renal failure (blood/protein in urine)
BV - micro thrombi and thromboembolism
CNS - micro infarcts, immune complexes deposited in choroid plexus
What is Sjrogen’s and Sicca syndrome?
Sicca - dry eyes and mouth
Sjrogen - SICCA + connective tissue disease (arthritis and photosensitive rashes, lymphadenopathy, lymphoma, vasculitis)
What is scleroderma (systemic sclerosis) characterised by?
- chronic inflammation thought to be result of autoimmunity
- widespread damage to small blood vessels
- progressive interstitial and perivascular fibrosis in the skin and multiple organs
What is diffuse and limited scleroderma?
Diffuse - widespread skin involvement, rapid progression and early visceral involvement, presence of Raynaud’s, renal failure, GI and myocardial involvement (autoantibodies target nucleolus and RNA polymerase)
Limited - skin involved is on hands fingers, arm and face, visceral involved late and sometimes CREST syndrome (calcinosis, raynauds, esophageal dysmotility, sclerodactylyl, telangietasia) and antibody against centromere
What is Raynaud’s phenomenon?
Thickening of walls of small blood vessels supplying hands
- white = sharp demarcation, artery spasm or narrowing
- Blue = slow flow in dilated venues
- Red = capillary dilation in anoxic tissue
What are 5 features of polymyositis/dermatomyositis?
Idiopathic inflammatory myopathy:
- symmetrical weakness of limb girdle muscles
- muscle fibre necrosis, phagocytosis, regeneration
- muscle enzymes in serum
- EMG changes
- DM rash = Gottron’s papules
What is vasculitis and what are the typical features?
Vasculitis - vessel wall inflammation causing narrowing, thrombosis, rupture and multi system involvement
Features - constitutional signs and fever, myalgia, arthralgia and malaise
What is mixed cryoglobulinaemia?
Small vessel vasculitis affecting the skin, peripheral nerves and kidneys (Associated with HepC)
Serum proteins precipitate in the cold and solubilise when re-warmed
Diagnosis - cryoglobulins in serum and complement is low
Treat - underlying HCV infection and immunosuppressants
What are immune complexes?
Small vessel vasculitis
- antigen bound to a/b
- form in slight antigen XS
- deposit in sub endothelium in high concentrations
- fix and activate complement
- recruit, activate and degranulate neutrophils
What do anti-neutrophil cytoplasmic antibodies (ANCA) do?
Small vessel vasculitis
- directed against enzymes in primary granules of neutrophils
- results from dysregulated T and B autoimmunity to these enzymes
- ANCA activate neutrophils causing degranulation, sequestering acute inflammatory cells and causing inflammation
Treatment: prednisolone, rituximab, cyclophosphamide
What is a type of medium vessel vasculitis? what are the clinical features and investigations?
Polyarteritis nodosa - systemic disorder affecting all parts of the body
Investigations -
Biopsy: necrotising vasculitis
Angiography: stenoses and aneurysms of medium sized arterioles
What is large vessel primary vasculitis?
Chronically persistent inflammatory infiltrates within arteries in the 3 layers of the walls
Results from dysregulated innate and adaptive
Results in occlusion or aneurysm
What is giant cell arteritis?
Large vessel vasculitis
- driving factor - IL6
- Panarteritis with transmural T cell and macrophage infiltrates
- macrophages in different layers produce pro-inflammatory cytokines, reactive oxygen intermediates or growth factors
- multinucleate giant cells - provide growth and angiogenic factors that promote intimal hyperplasia and luminal occlusion
What are clinical features of giant cell arteritis, investigations and treatment?
Clinical features - headache, jaw claudication, scalp tenderness, malaise, weight loss, ocular symptoms
Investigations:
- blood - acute phase response
- imaging - stenosis or aneurysm
- biopsy - diagnostic for GCA
Treatment: high dose corticosteroids over 18-24 months with low dose aspirin
What are causes of secondary cellular immunodeficiencies?
- Diseases affecting T cells/cytokines
- Medications/procedures
- Organ transplantation
- Progressive multifocal leukoencephalopathy (PML)
rare - Idiopathic CD4 lymphopenia
- Autoantibodies to interferon gamma
What is progressive multifocal leukoencephalopathy?
- results from reactivation of JC virus during immunosuppression
- gradually demyelinates nerves = loss of coordination and weakness
- JC virus infection/previous immunosuppressant therapy = risk factors
What are common causes of secondary antibody immunodeficiency?
- disease affecting b cells/plasma cells - lymphoproliferative, myeloma, thymoma associated immune defects
- medications/medical procedure - immunosuppressant/rituximab, HSC transplant
What is secondary hypogammaglobulinaemia? and when is Ig therapy recommended?
After solid organ transplant, some patients have IgG serum of <4g/L = 4x risk of infection
Therapy - if patient has recurrent or persistent infections with bacteria/enteroviruses
What is asplenia-associated immunodeficiency?
Asplenic patients are predisposed to acute overwhelming post splenectomy infection (OPSI) - with encapsulated bacteria and blood borne parasites like malaria
- functional spleen required for maturation and differentiation of B cells (marginal zone)
What is thymoma associated immune dysfunction?
Thymomas are associated with production of cytokine auto-antibodies, can cause:
- b cell deficiency
- cellular immunodeficiency
- autoimmune disease - myasthenia gravis, SLE
- lichen planus
`What is an allergy?
Harmful, misguided and excessive immune response to antigens that causes tissue damage and disease
What are the 4 types of hypersensitivity reactions?
Type I - immediate - IgE - mast cells - anaphylaxis
Type II - Cytotoxic - IgG - complement/phagocytes - AIHA
Type III - immune complex disease - IgG - immune complexes - SLE
Type IV - delayed - T cells (4 different types)
What type of hypersensitivity is allergic rhinitis? and what is it mediated by?
Immediate hypersensitivity (type 1)
- mediated by degranulation of mast cells and eosinophils
- degranulation triggered by cross linking for IgE antibodies bound to mast cell by divalent hapten AND cross linking of IgE by anti-IgE
What substances are released on degranulation of mast cells and eosinophils?
Preformed mediators - histamine, heparin, PAF, eosinophil and neutrophil chemotactic factors
Newly synthesised mediators - leukotrienes, PGD2, thromboxanes
TH2 cytokines - IL3, 4, 5, 6, GM-CSF
What hypotheses explain the recent rise in allergy?
- Hygeine hypothesis
- Microbiota hypothesis
- Biodiversity hypothesis
What type of hypersensitivity reaction is asthma?
Type 4b - TH2
What are the 3 components of airway inflammation in asthma?
- cellular infiltration - eosinophils, TH2, IgE
- changes in resident cells
- changes in non-cellular components of airway wall
What is the airflow limitation in asthma caused by?
- chronic mucous plug formation
2. airway remodelling - irreversible due to structural airway matrix changes
What are the two phases of the allergic response in asthma?
- ACUTE: <1hour
- binding of allergen to IgE pre bound to FcER1 on surface mast cells leads to degranulation and release of mediators such as histamine –> inflammation, redness, swelling - CHRONIC
- 6-12 hours after allergen exposure
- recruitment of T cells, eosinophils and more mast cells to exposure site
- recruited cells release enzymes, toxic proteins and more cytokines leading to increase inflammation
How is the TH2 pathway involved in the allergic inflammatory response?
In allergy, a persons response is shifted towards the TH2 pathway (instead of TH1), which favours the development of IgE from B cells (class switching from IgM)
What are regulatory T cells?
- either thymic or induced in periphery
- express FoxP3 transcription factor
- control/inhibit proliferation of CD4/8 cells once they’ve done their job
- maintain balance between immunity and tolerance
What cells are involved in late allergic inflammation at:
6 hours
24 hours
>24 hours
6 hours - neutrophils
24 hours - eosinophils
>24 hours - lymphocytes, monocytes, DC, basophils, mast cells (result in altered epithelial and smooth muscle cells)
- chemokine induce migrations of eosinophils which release granules that cause direct damage to bronchial tissue
What happens in early inflammation in the allergic response (asthma)?
- TH2 cells cause favouring of IgE to develop from B cells (class switching from IgM)
- this is controlled by the cytokines they’re exposed to
What is urticaria?
Red, raised, itchy rash from vasodilation, increased blood flow and vascular permeability
- affects the superficial skin layers
- wheals/hives can vary in size
- usually spontaneous and resolve within 24hours
What is angioedema?
- involves submucosa, deeper reticular dermis and subcutaneous tissue
- can persist for days
What is the mechanism of urticaria and angioedema?
- mast cells degranulate, releasing vasoactive mediators like histamine
- leukotrienes and prostaglandins then released
- extravasation of fluid into the superficial tissues
What is the management of chronic and acute intermittent urticaria?
non sedating antihistamines leads to significant relief in about 45% of patients
What is the aim of immunotherapy? and which form is recommended for asthma and allergic rhinitis?
Aim - shift from a TH2 response (IgE) to TH1 response (IgG4)
Asthma - Subcutaneous
Allergic rhinitis - sub lingual
What are the pro’s and con’s of sublingual and subcutaneous immunotherapy?
Sublingual
Good - safe
? - long term benefits?, daily admin, more expensive, more difficult to treat multiple
Subcutaneous
Good - evidence, suited to multiple sensitisations, better compliance and cheap
? - systemic adverse reactions 2%, contraindicated in severe asthma
What is the most common cause of contact dermatitis?
Nickel metal
What is contact dermatitis?
Allergic contact dermatitis - allergen induces hypersensitivity immune reaction
Irritant contact dermatitis - substance directly damages skin
What is the pathogenesis of type IV allergy? - dermatitis
- antigen engulfed by APC and presented to naive T cells in lymph node
- sensitised CD4/8 cells are produced and released
(sensitisation process takes 10-14 days) - re-exposure - antigen presented to sensitised lymphocytes which release cytokines and cause inflammation
- dermatitis in sensitised individual occurs within 12-48 hours after exposure
What is the clinical presentation of contact dermatitis?
Typically a very itchy rash up to 2 weeks after exposure, papillary, erythematous, with indistinct margins
What is the management of dermatitis?
- avoid allergen/identify
- alternative product
- treat skin inflammation with topical steroids
- restoration of skin barrier - emolient/moisturiser
- skin protection
How can drug hypersensitivities be classified?
type 1 drug reactions - IgE mediated
Immediate <1 hour
- anaphylaxis, hypotension, laryngeal edema, wheezing
Accelerated 1-72 hours
- urticaria, angioedema, laryngeal edema
Non-IgE mediated - late >72 hours,
- rash, fever, haemolytic anaemia, commonly T cell mediated
What is a penicillin allergy? How is it tested for?
- IgE molecules against the beta-lactam core or against R groups
Testing - penicillin skin testing is gold standard for IgE mediated penicillin allergy but gives no info on non-IgE mediated allergy
What are type IV drug reactions?
Delayed hypersensitivity - occurs days to 6/8 weeks after drug initiation
- often due to viral infections
Severe cutaneous drug reactions (SCAR)
- DRESS - drug reaction with eosinophilia and systemic symptoms
- DIHS - drug induced hypersensitivity - fever, rash, internal organ involvement
- Steven’s-johnson syndrome - <10% skin detachment
- toxic epidermal necrolysis - >30% skin detachment
- SJS-TEN together
- acute generalised exanthematous pustulosis
How should Steven’s johnson syndrome and toxic epidermal necrolysis be identified and managed?
Identify - prick/intradermal WONT pick up, must use patch testing
MGMT - desensitisation is contraindicated, permanent drug discontinuation
What syndrome is associated with Abacivir Flucloxacillin Carbamazepine Allopurinol
Abacivir - hypersensitivity syndrome - HLA-B-5701 Flucloxacillin - Hepatitis - HLA-B-5701 Carbamazepine - SJS/TEN : through HLA-B-1502 -HLA-A-3101 Allopurinol - SJS, TEN, DRESS, DIHS
What investigations would you do for SLE
- C3 low
- C4 low
- +ve ANA
- +ve Anti-dsDNA
