IMMUNO; Lecture 1, 2, 3, 4 and 5 - Hypersensitivity, Transplantation, Tolerance and Autoimmunity, Tumour immunology and immunotherapy of cancer, Inflammatory dermatoses Flashcards
Immuno
When do appropriate immune reactions occur and what do they involve?
To foreign harmful agents = viruses, bacteria, fungi and parasites -> concomitant tissue damage as side effect, but as long as pathogen removed quickly, then minimal and easily repaired. Involve antigen recognition by cells of immune system and Ab production
Immuno
What is appropriate immune tolerance and what does it involve?
Occurs to self and other harmless proteins (food, pollens, plant proteins, animal proteins). Involves Ag recognition and generation of Treg and regulatory Ab production (IgG4) -> sense of ‘danger’ cna lead to tolerance (if none) and reactivity (if present)
Immuno
When do hypersensitivity reactions occur?
When IR are mounted against -> foreign Ag (allergy, contact hypersensitivity), autoAg (AI disease), alloantigens (serum sickness, transfusion reactions, graft rejections)
Immuno
What are the classifications of hypersensitivity reactions?
I = immediate hypersensitivity; II = Ab-dependent cytotoxicity; III = immune complex mediated; IV = delayed cell mediated -> I-III depend on interaction of Ag with Ab; IV involves T cell recognition and because of longer time scale = delayed type hypersensitivity
Immuno
Which diseases have Type I immediate hypersensitivity?
Anaphylaxis, asthma, rhinitis (seasonal and perennial), food allergy
Immuno
What is the mechanism of action of type I immediate hypersensitivity?
1ry Ag exposure -> IgE production, sensitisation not tolerance, IgE binds to mast cells and basophils; 2ry Ag exposure -> more IgE is produced, Ag cross-links with basophils/mast cells and degranulation occurs
Immuno
What is the clinical presentation of Type II Ab-dependent hypersensitivity?
Depends on target tissue -> organ specific AI disease [myasthenia gravis (anti-ACh R Ab), glomerulonephritis (anti-glomerular basement membrane Ab), pemphigus vulgaris (anti-epithelial cell cement protein Ab), pernicious anaemia (IF blocking Ab)] and AI cytopenias (thrombocytopenia, haemolytic anaemia and neutropenia - Ab mediated blood cell destruction)
Immuno
How do you test for Type II sensitivity?
Test for specific autoAb, immunofluourescence, ELISA (anti-CCP for Rheumatoid arthritis)
Immuno
What is the mechanism of Type III Immune complex mediated hypersensitivity?
Formation of Ag-Ab complexes in blood, deposition of the complexes in tissue, complement and cell recruitment/activation, activation of other cascades and clotting leading to tissue damage (vasculitis - commonly in renal, skin, joints and lung) = e.g. SLE, Vasculitides (polyarteritis nodosum)
Immuno
Which diseases have Type IV delayed hypersensitivity response?
Chronic graft rejection, graft vs host disease, coeliac, contact hypersensitivity, asthma, rhinitis, eczema
Immuno
What is the mechanism of Type IV hypersensitivity?
Th1 = gamma interferon and is important in most hypersensitivity reactions; Th2 releases IL-4,5 and 13, mediating allergic inflammation (asthma, rhinitis and eczema)
Immuno
How can you distinguish between hypersensitivity types 1-3?
All mediated by Ab and distinguished by type of Ag that they recognise. Type 2 recognises cell surface/matrix bound antigens; type 3 soluble Ag
Immuno
Summarise the 4 types of hypersensitivities?
x
Immuno
What is inflammation?
Body’s response to tissue injury, rapid attempt to bring body’s defences to the site of injury and once immune cells reach the site of damage then release cytokines that lead to features of inflammation
Immuno
What are the features of inflammation?
Vasodilation, increased blood flow, increased vascular permeability (C3a, C5a, histamine and leukotrienes), inflammatory mediators and cytokines, inflammatory cells and tissue damage -> with redness, heat, pain and swelling
Immuno
Which cell mediators are used in inflammation?
C3a, C5a, histamine and leukotrienes cause increased vascular perm; cytokines = IL-1,6,2, TNF, IFN-gamma; chemokines = IL-8/CXCL8, IP-10/CXCL10
Immuno
Which inflammatory cells infiltrate and take part in inflammation?
Cell trafficking by chemotaxis; neutrophils, macrophages, lymphocytes, mast cells -> cell activation is caused
Immuno
What is atopy?
Form of allergy where there is a hereditary or constitutional tendency to develop hypersensitivity reactions in response to allergens -> very common, in 50% of YA in UK -> risk factors = genetic and environmental
Immuno
How does severity of atopy vary?
Mild, occasional symptoms, severe chronic asthma, life threatening anaphylaxis
Immuno
What are the genetic risk factors for atopy?
x
Immuno
What are the environmental risk factors for atopy?
x
Immuno
What are the types of inflammation in allergy and which type of hypersensitivity caused it?
x
Immuno
What is needed to express a disease?
Development of sensitisation to allergens instead of developing tolerance; exposure to produce disease (memory response)
Immuno
How does sensitisation in atopic airway disease occur?
Naive T cells haven’t seen the Ag; when CD4+ Tcells are activated by APC hey become specific to Ag and become -> Th1 (IFN-g), Th2 (activate B cells) and i Ag is harmless then become Treg
Immuno
How does subsequent exposure after sensitisation affect inflammation?
Allergens presented by APC to Th2, which release IL-5 causing degranulation of eosinophils;
also release IL-4 and 13 which stimulate IgE production by plasma cells. IgE then mobilised onto mast cell surface ->
Ag cross-link wiith IgE onto surface of mast cells and causes degranulation ->
massive release of inflammatory mediators, giving rise to effects seen in allergic reaction
Immuno
What are eosinophils?
2-5% of blood leukocytes, present in blood but more reside in tissues; recruited during allergic inflammation; generated from bone marrow; polymorphous nucleus (2 lobes); contains large granules full of toxic proteins; leads to tissue damage
Immuno
What are mast cells?
Tissue resident cells which have IgE receptors on surface, crosslinking of IgE leads to mediator release -> pre-formed: histamine, cytokines and toxic proteins; newly synthesised: leukotrienes, prostaglandins -> all leading to acute inflammation
Immuno
What are neutrophils?
Important in virus induced asthma, severe asthma and atopic eczema; 55-60% of blood leukocytes, multilobed nucelus, granules contain digestive enzymes and neutrophils can also synthesise: oxidant radical, cytokines and leukotrienes
Immuno
What is the acute asthma immunopathogenesis?
Mixture of type I and IV
Immuno
What are the 3 processes leading to airway narrowing in acute asthma?
Vascular leakage leading to airway wall oedema, mucus secretion filling up the lumen and smooth muscle contraction around the bronchi
Immuno
What is the chronic asthma immunopathogenesis?
Chronic inflammation of the airways, with the lumen being very narrow and airway wall grossly thickened; cellular infiltration of Th2 and eosinophils; smooth muscle hypertrophy, mucus plugging, epithelial shedding and sub-epithelial fibrosis
Immuno
What are the important clinical features of asthma and what’s a typical day like?
x
Immuno
What is allergic rhinitis and what are the symptoms?
Seasonal = hay fever (grass, tree pollens), perennial (house dust mite, animal) -> sneezing, rhinorrhoea, itchy nose and eyes, nasal blockage, sinusitis, loss of smell/taste
Immuno
What is allergic eczema?
Chronic itchy skin rash, most commonly found in flexures of arms and legs; lead to house dust mite sensitisation -> complicated by bacterial and viral (rare) infections -> 50% cleared by 7y, 90% by adulthood
Immuno
What are food allergies?
Type 1 -> IgE mediated; common foods change with age -> infancy-3y = egg, cows milk; children/adults = peanuts, shellfish, nuts, fruits, cereals, soya
Immuno
What are the mild and severe reactions to food allergies?
Mild: itchy lips and mouth, angioedema, urticaria; severe: nausea, abdo pain, diarrhoea, anaphylaxis
Immuno
What is anaphylaxis?
Severe generalised allergic reaction -> uncommon and potentially fatal = generalised degranulation of IgE sensitised mast cells
Immuno
What are the symptoms and systems involved in anaphylaxis?
x
Immuno
What investigations can you carry out to diagnose allergies/hypersensitivity?
Careful history = essential -> skin prick test, RAST (tests for amount of specific IgE in blood), IgE total measure, lung function in asthma
Immuno
How do you treat anaphylaxis?
EMERGENCY = epipen and anaphylaxis kit; if mild = antihistamine (backed with steroid injection), if severe = adrenaline injection. PREVENTION= avoidance of known allergen, always carry anaphylaxis kit and epipen, inform immediate family and caregivers, wear medicalert bracelet
Immuno
How do you treat rhinitis and eczema?
Allergic rhinitis: anti-histamines (help sneezing, itching and rhinorrhoea) nasal steroid therapy (nasal decongestant) and cromoglycate (in children, eyes). Eczema: emolients (maintain moisture to reinforce barrier function) and topic steroid cream. SEVERE: anti IgE mAb, anti IL4/13 mAb, anti-IL5 mAb
Immuno
How do you treat asthma?
x
Immuno
What is immunotherapy?
Effective for single Ag hypersensitivities = venom allergy (bee/wasp stings), pollens, HDM; Ag used is purified. Subcut (SCIT) = 3 y needed with weekly/monthly 2 hr clinic visits; sublingual (SLIT) = 2-3y enough and can be taken at home
Immuno
What are the 2 reasons for transplantation?
Life saving (other life-supportive methods aren’t fully developed (heart and liver)) or life enhancing (other life supportive methods are less good (kidneys with dialysis, pancreas where in some cases it can be better than insulin injections)
Immuno
Why do organs (cornea, skin, bone marrow, kidney, liver, heart) fail?
x
Immuno
What are the different types of transplantation?
Xenografts -> heart valves from pigs/cows, skin;
allografts -> solid organs (kidney, liver, heart, lung, pancreas), small bowel, free cells, temporary (blood, skin), cornea, framework (bone, cartilage, tendon, nerve), composite (hands, face, larynx)
Immuno
What are the kinds of donors of allografts?
Deceased donor, living donor (bone marrow, kidney, liver; geneticall related/unrelated)
Immuno
What are the 2 types of deceased donors?
Donor after brain death (RTA, massive cerebral haemorrhage, confirm brain death; harvest organs and cool to minimise ischaemic damage), donor after cardiac death (heart stopped before organ harvest, longer period of warm ischaemia time and suitable for kidneys)
Immuno
How do you confirm brain death?
x
Immuno
What needs to be done for all donors before transplantation?
x
Immuno
What are the steps that recipients take part in when receiving transplants?
Transplant selection (access to waiting list) and transplant allocation (access to organ)
Immuno
How is transplant selection carried out?
x
Immuno
How is transplant allocation carried out?
x
Immuno
What are the steps to allocate a kidney to a patient?
x
Immuno
How can you decide whether they should allocate the organ locally or nationally?
Heart needs very little cold ischaemic time and lungs need to be a size match
Immuno
What strategies can increase transplantation activity?
Donor transplant coordinators (registered trained nurses in critical care); increase donations (marginal donors = DCD, elderly patients, sick), living donation (transplant across tissue compatibility barriers and exchange programmes), xenotransplantation? stem cell research?
Immuno
What are the most important and variable protein variations in clinical transplantation?
ABO blood groups; HLA coded on chromosome 6 by MHC
Immuno
What is the difference between each ABO blood group?
x
Immuno
How does Ab-mediated rejection occur?
Circulating, pre-formed, recipient anti-B antibody binds to B blood group antigens on donor endothelium.
Abs Recruit complement and macrophage activation which then fix onto endothelium; complement makes holes in endothelium, thrombus.
Immuno
How do we do ABO-incompatible transplantation?
Remove the antibodies in the recipient (plasma exchange) Good outcomes (even if the antibody comes back) Kidney, heart, liver
Immuno
What is HLA?
Cell surface proteins Highly variable portion Variability of HLA molecules important in defense against infections and neoplasia Foreign proteins are presented to immune cells in the context of HLA molecules recognised by the immune cells as “self”
Immuno
What is rejection?
Most common cause of graft failure
Diagnosis = histological examination of a graft biopsy
Treatment = immunosuppressive drugs
Immuno
How does T-cell mediated rejection occur?
Interstitial infiltrate ; CD4+ T cells recruit CD8+ cells and macrophages
Immuno
Which cells are involved in t-cell mediated rejeciton?
x
Immuno
What do we monitor for rejection post-transplant?
x
Immuno
What are the targets of immunosuppressant drugs?
Target T cell activation and proliferation; target B cell activation and proliferation and Ab production
Immuno
What is the standard immunosuppressive regime?
x
Immuno
How are foreign antigens recognised by T cells?
See peptides exhibited on a definite framework
Immuno
How is antigen presented on APC in rejection?
Presenting HLA on HLA molecule, causing a delayed hypersensitivity response
Immuno
What are the different HLA molecules and how does this affect transplantation?
Class I (ABC) - on all cells; class II (DR DQ DP) - on all APC but can be upregulated on other cells -> all are highly polymorphic with lots of alleles for each locus, with each individual often having 2 types for each HLA molecule.
Most important for transplants are A, B and DR as they are the most likely to produce an immune response (most polymorphic)
Immuno
How are HLA mismatches dealt with in transplantation?
Should only be from 0 to 6 mismatches
Immuno
Why is related living donation a good idea?
Mother and father you will share 3 loci; siblings have high chance of having up to 6 in common
Immuno
What are the targets in the B-cell/Ab complex that drugs can target?
x
Immuno
What are the 3 main factors that affect transition from normal AI to AI disease?
Genetic suscepitibility, infections, environmental factors -> leading to breakdown of self-tolerance and progression to AI disease
Immuno
What are the mechanisms of autoimmunity?
x
Immuno
What is the impact of AI diseases - epidemiology?
More common in females, but some like T1DM is more common in men -> oestrogen is a hypothesis for high incidence in females
Immuno
What are some important AI diseases?
x
Immuno
What is the spectrum of autoimmune diseases and how do they fit in the spectrum of organ specific vs multi-systemic AI disease?
x
Immuno
What are the AI diseases which are a type II reaction?
x
Immuno
What is the difference between type II and III hypersensitivity?
- Difference in type II and III is that Ag is insoluble in type II and soluble in type III;
- both types can recruit inflammatory cells which bind via Fc receptors to Fc portion of Ab.
- Type II: causes more localised tissue injury;
- Type III: immune complexes can deposit in various sites, effector mechanisms are same as type II
Immuno
Which diseases are type IV T cell mediated?
Normal response of T-cell to antigens: Ag presented to T cells by MHC expressed on surface of APC, with CD4=MHCII and CD8=MHCI, and costimulation from APC is needed for activation and proliferation
Immuno
How does MHC II affect susceptibility to AI disease?
MHC are the strongest genetic link to AI disease, with mostly class II genes and good evidence that T cells are involved in AI disease
Immuno
What is central tolerance?
Mechanism of deletion of autoreactive T and B cells in primary lymphoid organs.
All lymphocytes come from stem cells in the bone marrow, with precursors of T cells then migrating to thymus where they develop into mature T cells, undergoing rigorous selection process in thymus (B cells occur in bone marrow)
Immuno
How are T cells selected in the thymus?
Involves extent of binding of TCR to the MHC molecules, with 2 cell popn (CD4+ and CD8+) depending on which MHC molecule they bind to best; with 3 possible outcomes that can occur; only 5% of thymocytes survive selection
Immuno
How does B cell selection occur?
- Selection takes place in bone marrow; NOT MHC restricted, selected based on interaction between the B cell receptor and the Ag present in bone marrow;
- no self reaction and B cells go on to become mature B cells which express IgD and IgM -> if they do recognise self Ag they will usually die by apoptosis;
- Receptor editing (second chance for B cells to amend themselves) occurs;
- if they recognise soluble autoAg, they will migrate to the periphery but don’t express normal levels of IgM and they are anergic.
- If they have a weak interaction with soluble Ag the B cells will develop fine and there will be normal levels of cell surface receptors;
- cells that recognise self weakly have the potential to cause AI disease
Immuno
How does APECED come about?
Failure to delete T cells in thymus, due to mutations in the AIRE gene (important for expression of tissue specific genes in the thymus, involved in negative selection of self reactive T cells in thymus)
Immuno
What processes are affected in SLE’s immune system?
Genes can affect multiple biologicl pathways and may lead to failure of immune tolerance -> main processes affected are induction of tolerance, apoptosis and clearance of antigen
Immuno
Summarise central tolerance
x
Immuno
What is anergy?
Subsequent stimulation even in the presence of costimulation leads to anergy
Immuno
When does immunological ignorance occur?
x
Immuno
What happens if there is failure of immunological ignorance?
Sympathetic ophthlmia as an example
Immuno
What is suppression/regulation of the immunological response?
Treg are specialised cells that regulate activity of other T cells, expressing CD4, CD25 (IL-2 receptor), CTLA-4 and FOXP3 (transcription factor used as marker for Treg
Immuno
What is IPEX?
ACCUMULATION OF AUTOREACTIVE T CELLS
Immuno
Which AI diseases are caused by infections?
x
Immuno
How do infections affect the tolerant state?
APCs present self peptides always, which T cells are tolerant to;
APCs when activated by pathogens, present pathogen AND self peptide at the same time, and upregulation of costimulatory molecules occurs, which could trigger T cell activation for self protein, leading to AI
Immuno
Summarise peripheral tolerance
x
Immuno
What is Paraneoplastic cerebellar degeneration?
Immune response against tumour (breast for e.g.) which resulted in degeneration of cerebellum leading to dizziness, vertigo, untintelligible speech truncal and appendicular ataxia;
cerebellum degeneration-related Ag 2 detected in serum.
Spontaneous immune response was acting somewhere else in body with self tissue, in this case led to elimination of Purkinje cells in brain.
Certain tumours can express antigens which are absent from corresponding normal tissues, immune system can detect such abnormally expressed Ag and launch an attack against tumour, which may result in AI destruction of normal somatic tissues
Immuno
What is the cancer-immunity cycle?
- Release of Ag from cancer cells, which are captured by professions APCs which then migrate to local draining lymph nodes;
- if enough costimulation then you will get activation of T cell response, which brings an Ab response;
- T cell responses are particularly important against tumours because the Ag are intracellular and once T cells activated, they return to tumour (tumour infiltrating T cells), with processed tumour Ag recognised by T cells which can kill cancer cells ->
- immune selection pressure on tumour cells, cause a form of antibiotic resistance, which makes them able to evade killing by Tcells.
- After being exposed to same Ag several times T cell expresses PD-1 receptor;
- tumour cells upregulate expression of ligand PDL-1 which can bind to PD-1 and downregulate T cell response ->
- blocking of PD1-PDL1 interaction could help stimulate T cell response
Immuno
Which mediators are involved in the cancer-immunity cycle stages?
x
Immuno
How does cancer formation initiate?
- Results from multiple sporadic events over time: irradiation, chemical mutagens, spontaneous errors during DNA replication, tumour virus induced changes (inflammation amount varies) in genome which induces mutations in cellular DNA.
- Viral = lots of pattern recognition receptors, lots of cytokines and lots of inflammation;
- tumour = NOT very inflammatory, so can be missed by the immune system, but once sufficient inflammation then innate immune cells recruited (dendritic, macrophages and NK cells) DC capture Ag from tumour cells and go to lymph nodes, present to circulating T cells, followed by recruitment of adaptive, Ag-specific immunity
Immuno
What are the different cancers of viral origin that exist?
Tumour cells in cervical cancer express viral proteins, so there are tumour specific viral Ag and the immune system can detect these tumour cells and can kill them, with most people generating this immune system quite well
Immuno
What is the relation between consequences of cervical HPV infection and HPV specific T cell immunity?
Most people generate a good immune response against HPV and have no problems and no tumours, but for a small minority, they don’t and could go on to have immune failure and develop neoplasia
Immuno
What are tumour associated antigens (TAA)?
Generally derived from normal cellular proteins which are aberrantly expressed (timing, location or quantity), and immune system isn’t tolerant and they become immunogenic when expressed by tumour -> abnormal expression of normal cellular protein -> examples =
Immuno
Give some examples of tumour associated antigens
x
Immuno
What is the problem with tumour associated antigens?
If immune response is generated against TAA then it could cause AI type problems as the TAAs are normal proteins that are expressed elsewhere in the body;
IR may be good at dealing with the cancer, but could cause AI;
e.g. in melanoma patients taking a cancer ‘vaccination’, this frequently causes AI depigmentation in melanoma patients
Immuno
What are the different types of monoclonal Ab-based therapy for cancer?
x
Immuno
What is the name of the therapeutic cancer vaccination and what does it do?
x
Immuno
How does immune checkpoint blockade work in cancer immunotherapy?
x
Immuno
What is adoptive transfer of cells in cancer immunotherapy?
x
Immuno
What are Chimaeric antigen receptors?
x
Immuno
How is the skin organised and how do the cells evolve from basal cell?
Basal Cell -> Prickle Cell -> Granular Cell (at Granulosum) -> Keratin
Immuno
What cells are present in the epidermis?
x
Immuno
What is the structure of the epidermis?
x
Immuno
What is atopy?
Atopy = tendency to develop hypersensitivty; diseases inc. atopic eczema (relapsing and remitting), asthma and hayfever -> atopic march is shows tendency for each atopy to progress with age to different diseases
Immuno
How is atopic asthma biologically caused?
- Defective barrier function of the skin, leading to dry skin.
- Filagrin gene mutations in 10% of cases.
- Filagrin is an epidermal protein important in maintaining barrier function of the skin.
- Filagrin mutation is denoted by palmar hyperlinearity.
- Causes Intrinsically dry and flakey skin.
- Defective barrier function allows penetration of irritants, allergens (eg house dust mite particles) and pathogens eg staph aureus.
- S. Aureus infection exacerbates eczema.
- Inflammation of the skin then occurs as APCs take up allergens and present them to T cells (sensitisation). ->
- HSV can also attach to eczematous skin forming widespread lesions, small punched out ulcers which are 3-4 mm
Immuno
How is psoriasis caused?
Genetic susceptibility and environmental triggers are the underlying cause.
Many genes are implicated including PSOR1.
Immune process occurs where T lymphocytes move out of blood vessels into the dermis and initiate the release of cytokines, eg TNF Alpha.
The Epidermis becomes thickened and produces more keratinocytes than normal, neutrophils infiltrate the epidermis and lymphocytes infiltrate the dermis.
Triggers include infections, drugs and stress.
Hyperkeratosis = thickening of stratum corneum with keratinocytes; parakeratosis = failure to denucleate keratinocytes before reaching stratum corneum; acanthosis = generalised increased thickening of epidermis, esp at S. basale and spinosum
Immuno
Where does psoriasis affect?
Can on present on soles of feet with tick yellowish scales, with symmetry; can also affect the nails causing subungual hyperkeratosis, dystrophic nail (external - oncholysis), loss of cuticle
Immuno
What is acne?
A very common condition which mainly affects teenagers and young adults.
Commonly occurs on the face, chest and back.
Disease of the pilosebaceous unit of the skin.
Dead cells accumulate and trap bacteria within the unit.
Bacteria then accumulate protruding as a pimple (whitehead).
Upon bursting inflammation is triggered by exposed bacterial antigens (blackhead). Pathogenesis is multifactorial:
- Hyperkeratinisation of the epidermis in the infundibulum of the hair follicles
- Accumulation of dead keratinocytes in the lumen of the hair follicle
- Increase sebum production stimulated by androgens
- Proliferation of propioni bacterium acnes within the pilosebaceous unit
- Rupture of the inflamed pilosebaceous unit, with further inflammation of the surrounding skin
Immuno
What are the clinical features of acne?
- Whiteheads (closed comedone)
- Blackheads (open comedone)
- Papules (lesions)
- Pustules (pus filled papules)
- Nodules (large papules)
Immuno
What is the pathophysiology of bullous pemphigoid?
- IgG autoantibodies to basement membrane antigens BP180 (type XVII collagen) or BP230 result in cleavage of the skin at the dermo epidermal junction leading to sub epidermal blisters.
- Basement membrane zone is integral to holding the ectoderm (epidermis) and mesoderm (dermis) together.
- Treatment is via PO and Topical steroids.
- Note: epidermolysis bullosa – conditions characterised by any genetic defect of a BMZ protein. Skin is easily eroded and heals with scarring.
Immuno
What is the pathophysiology of pemphigus vulgaris?
IgG autoantibodies to epidermal cell surface proteins desmogleins 1 and 3 lead to loss of cell-cell adhesion (acantholysis) within the epidermis causing flaccid blisters in the skin or mucous membranes.
These proteins help join keratinocytes together in the deeper stratum.
