1
Q
What are involved in appropriate immune tolerance?
A
- regulatory T cells
- regulatory antiody production
2
Q
What are hypersensitivity reaction?
A
o immune responses are mounted against:
- harmless foreign antigens -> allergy, contact hypersensitivit
- auto-antigens -> autoimmune diseases
- allo-antigens -> serum sickness, transfusion reactions, graft rejection
3
Q
Describe the Gell and Coombs classification of hypersensitivity.
A
o Type I: Immediate Hypersensitivity
o Type II: Antibody-dependent Cytotoxicity
o Type III: Immune Complex Mediated
o Type IV: Delayed Cell Mediated
- many diseases involve a mixture of different types of hypersensitivity
4
Q
Name some examples of type 1 hypersensitivity.
A
- anaphylaxis
- asthma
- rhinitis -> seasonal (pollen/hay fever) or perennial (cat/dust mite allergy)
- food allergy
5
Q
What is the mechanism of type 1 hypersensitivity?
A
o 1st antigen exposure -> sensitisation occur and not tolerance -> IgE antibody production -> IgE binds to mast cells and basophils
o 2nd antigen exposure -> more IgE antibody produced -> antigen cross-links IgE on mast cells and basophils -> degranulation and release of inflammatory mediators
6
Q
Name some examples of type 2 hypersensitivity.
A
o organ-specific autoimmune diseases:
- myasthenia gravis (anti-acetylcholine receptor antibodies)
- glomerulonephritis (anti-glomerular basement membrane antibodies)
- pemphigus vulgaris (anti-epithelial cell cement protein antibodies)
- pernicious anaemia (intrinsic factor blocking antibodies)
o autoimmune cytopenias (antibody-mediated blood cell destruction) leads to haemolytic anaemia, thrombocytopenia and neutropenia
7
Q
What tests can be ran to test for specificauto-antiboides?
A
- immunofluorescence
- ELISA -> e.g. anti-CCP
8
Q
What is the mechanism of type 3 hypersensitivity?
A
- formation of antigen-antibody complexes in blood -> immune complexes
- immune complexes can’t fit through the small blood vessels -> complexes deposit in the vessels and tissues
- leads to complement activation and cell recruitment/activation and clotting cascade activation -> tissue damage (vasculitis-destruction of blood vessels by inflammation)
9
Q
What are the common sites of vasculitis?
A
- renal -> glomerulonephritis
- skin
- joints
- lungs
10
Q
Name some examples of type 4 hypersensitivity.
A
- chronic graft rejection
- graft-versus-host disease (GVHD)
- coeliac disease
- contact hypersensitivity
- many others: asthma, rhinitis, eczema -> Th2 mediated unlike the rest which are Th1
11
Q
What are the features of inflammation?
A
- vasodilatation
- increased vascular permeability
- inflammatory mediators & cytokines
- inflammatory cells & tissue damage
12
Q
What are the signs of inflammation?
A
- redness
- heat
- swelling
- pain
13
Q
What cause increased vascular permeability in inflammation?
A
- C3a, C5a, histamines, leukotrienes
14
Q
What mediates allergic inflammation?
A
- Th2 -> either by transient antigen presence or persistent antigen
15
Q
What is atopy?
A
- a form of allergy in which there is a hereditary of constitutional tendency to develop hypersensitivity reactions in response to allergens
- e.g. hay fever, allergic asthma, atopic eczema
16
Q
What are the genetic risk factors for atopy?
A
o 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)
17
Q
What are the environmental/uncontrolable factors for atopy?
A
- age -> increases from infancy, peaks in teens, and then reduces in adulthood
- gender -> asthma is more common in males in childhood, after puberty that switches
- family size -> more common in small families
- infection -> early life infections protect
- animals -> early exposure protects
- diet -> breast milk, anti-oxidants and fatty acids protect
18
Q
Name some examples of mixed inflammation hypersenitivities.
A
o asthma, rhinitis, eczema
- are mix of type 1 (IgE mediated) and 4 (chronic inflammation)
19
Q
Describe sensitisation in atopic disease.
A
- 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
- if the antigen is deemed harmful 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
20
Q
If sensitisation occur, describe a subsequent exposure to the same antigen.
A
- allergens are presented by APCs to the memory Th2 cells -> causes 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 –> IgE then becomes mobilised onto the surface of mast cells
- antigens then cross-link with the IgE on the surface of the mast cells and cause degranulation -> massive release of inflammatory mediators, which gives rise to the effects seen in an allergic reaction
21
Q
Where are eosinophils found?
A
- in blood (0-5% of blood leukocytes)
- most reside in tissue
22
Q
Briefly describe the appearance of eosinophils.
A
- polymorphus nucleus -> two lobes
- contains large granules full of toxic proteins
23
Q
What does the activation of eosinophils lead to?
A
- toxic granules kill cells presenting the antigen -> leads to tissue damage -> obviously unwanted in allergy
24
Q
Where are neutrophils found?
A
- tissue resident cells
25
Describe the organisation of mast cells?
o have IgE receptors on cell surface
o cross-linking of IgEs leads to mediator release:
- pre-formed -\> histamine, cytokines, toxic proteins
- newly synthesized -\> leukotrienes, prostaglandins
26
What is the consequence of mast cell activation?
- acute inflammation
27
Describe the organisation of a neutrophil?
- multi-lobed nucleus
- granules contain digestive enzymes
28
What allergic diseases are neutrophils thought to be particularly important in?
- virus induced asthma
- severe asthma
- atopic eczema
29
Where are neutrophils found?
- predominantly in the blood -\> 55-60% of blood leukocytes
30
What do neutrophils synthesise?
- oxidant radicals
- cytokines
- leukotrienes
31
What are the three main processes leading to airway narrowing?
- vascular leakage leading to airway wall oedema
- mucus secretion fills up the lumen
- smooth muscle contraction around the bronchi
32
Describe chronic asthma.
o chronic inflammation of the airways -\> lumen of the airway is very narrow and the airway wall is grossly thickened
o cellular infiltration of Th2 lymphocytes and eosinophils
o smooth muscle hypertrophy
o mucus plugging
o epithelial shedding
o sub-epithelial fibrosis -\> takes a while to occur
33
What are the important clinical features of asthma?
- reversible generalised airway obstruction -\> causes chronic episodic wheeze
- bronchial hyper-responsiveness
- cough
- excess mucus production
- breathlessness
- chest tightness
- reduced and variable peak expiratory flow (PEF)
- good response to treatment
34
What are the symptoms of allergic rhinitis?
- sneezing
- rhinorrhoea
- itchy nose and eyes
- nasal blockage, sinusitis, loss of small/taste
35
Where is allergic eczema most commonly found?
- the flexures of the arms and legs
36
What is the most common cause of allergic eczema?
- house dust mite sensitisation -\> house dust mite proteins can get through the dry, cracked skin
37
What is the prognosis of allergic eczema?
o far more common in young children
- 50% clears by the age of 7
- 90% by adulthood
o may complicated by bacterial and viral infections
38
What type of hypersenitivity is food allergy?
- type 1 -\> IgE mediated
39
What are the symptoms of food allergy?
o mild reaction
- itchy lips and mouth
- angioedema
- urticaria
o severe reaction
- nausea
- abdominal pain
- diarrhoea
- anaphylaxis
40
What is anaphylaxis?
o severe generalised allergic reaction due to generalised degranulation of IgE sensitised mast cells
- anaphylaxis is uncommon but potentially fatal
41
What are the symptoms of anaphylaxis?
- itchiness around mouth, pharynx and lips
- swelling of the lips, throat and other parts of the body
- wheeze with chest tightness and dyspnoea
- faintness or physical collapse
- diarrhoea
- vomiting
42
What is the emergency treatment of anaphylaxis?
- EpiPen and anaphylaxis kit
- if mild = antihistamine which can be backed up with a steroid injection
- if SEVERE = ADRENALINE
43
What are the prevention/precautional steps to avoiding anaphylaxis?
- avoidance of the known allergen
- always carry an anaphylaxis kit and EpiPen
- inform immediate family and caregivers
- wear a MedicAlert bracelet
44
What are the techniques in investigation and diagnosis of an allergic reaction?
o careful history is essential
- skin prick testing -\> only available in common ones -\> if these aren't positive more history is required before it can be tested
- RAST (radio-allergosorbent test) -\> tests for specific IgE antibodies in the blood
- measure total IgE
- lung function (in asthma)
45
What is the treatment for allergic rhinitis?
- anti-histamines -\> help the sneezing, itching and rhinorrhoea but not blocked nose
- nasal steroid therapy/spray -\> nasal decongestant
- cromoglycate -\> in children and for itchy eyes (most common symptoms in teenagers)
46
What is the treatment for eczema?
- topic steroid cream
- emollients (maintain the moisture in skin thus reinforcing its barrier function)
- if severe -\> anti-IgE mAb, anti-IL4/13 mAb, anti-IL5 mAb
47
What is the treatment for asthma?
STEP 1: Use a short-acting beta-2 agonist by inhalation e.g. SALBUTAMOL
STEP 2: Inhaled steroid low-moderate dose
STEP 3: Add long-acting beta-2 agonist or a leukotriene antagonist as well as high dose inhaled steroids -\> up to 2 mg/day via a spacer
STEP 4: Add courses of oral steroids, SLT, azithromycin, prednisolone 30 mg/day for 7-14 days and anti-IgE, anti-IL4/13, anti-IL5 mAbs
48
Describe immunotherapy for allergy.
- develop tolerance by exposing them to small amounts of the allergen they are allergic to
- effective for single antigen hypersensitivities -\> venom allergies, pollens, house dust mites
- subcutaneous immunotherapy (SCIT) - 3 years needed (weekly/monthly) -\> 2hrs clinic visits each time to ensure anaphylaxis doesn't occur
- sublingual immunotherapy (SLIT) - can be taken at home, 2-3 years enough
49
What factors influence the chance of suffering from an autoimmune disease?
o genetics -\> genes and sex -\> 80% of al AI are females -\> thought to be due to the fact that females have a more vigorous immune response
o environment
- infections -\> generate an inflammatory environment
- diet -\> obesity, high fat, effects on gut microbiome
- stress -\> physical and psychological, stress-related hormones play a role
- microbiome -\> gut/oral microbiome helps shape immunity, perturbation may trigger autoimmune disease
50
What are the mechanisms of autoimmunity?
- adaptive immune reactions against self use the same mechanisms as normal immune reactions
- ALL autoimmune diseases involve breaking of T-cell tolerance
- disease mediated by antibodies is almost always IgG
- effector mechanisms resemble those of hypersensitivity reactions types II, III, and IV
51
What immune reactions are knwon to play a direct role in the pathology of human autoimmune disease?
- antibody response to cellular or extracellular matrix antigen -\> Type II hypersensitivity
- immune complex formed by antibody against soluble antigen -\> Type III hypersensitivity
- T-cell mediated disease (delayed type hypersensitivity reaction) -\> Type IV hypersensitivity
o often it is a mixture
52
Name some type II autoimmune diseases?
- autoimmune haemolytic anaemia
- Goodpasture’s syndrome
- Grave’s disease
- Myasthenia gravis
53
What is Goodpaster's syndrome?
- a rare autoimmune disease in which antibodies attack type IV collagen in the basement membrane in lungs and kidneys, leading to bleeding from the lungs and kidney failure
54
What is Grave's disease?
- an autoimmune disease in which an antibodies that is agonistic to the TSH receptor is produced -\> hyperthyroidism
55
Name a type III autoimmune disease.
- SLE -\> results in glomerulonephritis, vasculitis and arthritis
56
What is the difference between type II and III hypersensitivity?
- in both cases, we see antibody binding to antigen -\> the effector mechanisms are the same = activation of complement and recruitment of inflammatory cells, particularly neutrophils
- type II = DIRECT BINDING of the antibody in situ, either on cell surfaces or on ECM
- type III = soluble immune complexes form, they can circulate around the body and become deposited in various sites
57
Name some type IV autoimmune diseases.
- insulin-dependent diabetes meliltus
- rheumatoid arthritis
- multiple sclerosis
o autoantibodies are still involved but aren't thought to be in the initial mechanism of the disease
58
Mutations in what genes increases your susceptibility to autoimmune diseases?
- MHC class II
59
Define immunological tolerance.
- the acquired inability to response to an antigenic stimulus
60
What are the 3 A's of immune tolerance?
- acquired = involves cells of the acquired immune system and is 'learned'
- antigen specific
- active proess in utero and as neonates -\> its effects are maintained throughout life
61
What are the 2 main types of tolerance?
- central
- peripheral
62
Summarise central tolerance.
o ELIMINATION of self-reactive lymphocytes during lymphocyte development in the thymus and bone marrow
63
What are the 3 mechanisms of peripheral tolerance?
- anergy
- active suppression -\> regulatory T cells
- immune privilege (ignorance of antigen)
64
How is central tolerance maintianed by the bone marrow?
o no self reaction = B cells go on to become mature B lymphocytes -\> mature B cells express their surface receptors (IgD and IgM)
o recognise self antigens = usually die by apoptosis
65
What is the selection process for T cells that provides central tolerance?
- useless = TCRs don’t recognise MHC at all -\> death by apoptosis
- useful = weakly associate with MHC -\> receive signal to survive/'positive selection'
- dangerous = associate with MHC too strongly -\> death by apoptosis/'negative selection'
66
What is receptor editing, in the case of B cells?
o a second chance for B cells to amend themselves
- recognise soluble autoantigens, they will still migrate to the periphery, but they are ANERGIC = non-responsiveness, cannot be activated by T helper cells
- are expressed at LOW levels of surface IgM and they are anergic
- have a short half life, and tend to die out due to competition
67
How does the bone marrow occasional produce antigen against self?
- if an antigen has a weak interaction with soluble antigens the B cells will develop fine -\> normal levels of cell surface receptors -\> have the potential to cause autoimmune disease
- can also happen because the protein it recognises isn't present in the bone marrow
68
What is APECED?
- results from a FAILURE to delete T cells in the thymus due to a mutations in the transcription factor AIRE (autoimmune regulator) gene
- AIRE is important for the expression of “tissue-specific” genes in the thymus -\> peptides derived from these gene products are being presented on cells in the thymus -\> developing T cells can be exposed to these peptides y -\> involved in the negative selection of self reactive T-cells in the thymus
- if AIRE doesn’t work properly, we don’t have expression of tissue specific proteins in the thymus -\> developing T cells aren’t exposed, so they can end up becoming self-reactive -\> often are self-reactive to endocrine glands
69
What is co-stimulation?
- naïve T-cells require co-stimulation for full activation
- co-stimulatory molecules expressed on APC are absent on most cells of the body
- without co-stimulation, cell proliferation and/or factor production does not proceed -\> T cell becomes ANERGIC -\> is non functional and it is harder to activate this T cell -\> leads to a refractory state termed ‘ANERGY’
70
Describe immunological ignorance.
- antigen concentration is too low in the periphery for lymphocytes to recognise it -\> may also occur by physical segregation of antigen from lymphocyte (immunologically privileged sites - e.g. testes, peripheral nerves or eye)
71
What happens is immune ignorance is broken, such as in sympathetic opthalmia?
- some sort of physical trauma to the eye -\> release of proteins (antigens) in the eye -\> proteins can enter nodes, and antigens can be presented to re-circulating T cells in the lymph nodes
- if T cells do become activated, adhesion molecules on the T cells change, and the T cells go back to the eyes -\> both eyes can show symptoms of the disease despite damage in only one
72
What is FOX P3?
- encodes a transcription factor critical for the development of regulatory T-cells
73
What is IPEX?
o a genetic condition resulting in failure of the regulation of peripheral tolerance
- onset of autoimmune symptoms and accumulation of auto-reactive T cells
- is a fatal recessive disorder presenting early in childhood resulting from a mutation in the FOXP3 gene -\> regulatory T cells don’t work properly or develop properly
74
What are the symptoms of IPEX?
- early onset insulin dependent diabetes mellitus
- severe enteropathy (disease of the intestines)
- eczema
- variable autoimmune phenomena
- severe infections
75
How can infections affect the tolerant state?
- molecular mimicry of self molecules -\> where the microbe has a similar structure to self molecules -\> immune response against the microbe = response will attack the self molecule
- infections can induce changes in the expression and recognition of self proteins
- infection can cause induction of co-stimulatory molecules or inappropriate MHC class II expression -\> results in a pro-inflammatory environment
- failure in regulation -\> effects on regulatory T-cells (potential to alter regulation of auto-reactive T cells)
- immune deviation -\> shift in type of immune response e.g. Th1-Th2
- tissue damage at immunologically privileged sites
76
What are the 5 types of transplantation?
- autografts
- isografts
- allografts
- xenografts
- prosthetic grafts
77
What is autograft transplantation?
- transplanting tissue from an individual from one area if the boody to another area of the body -\> reconstruction etc
78
What is isograft transplantation?
- transplant between two genetically identical individuals of the same species
79
What is allograft transplantation?
- transplant between different individuals of the same species
80
What is xenograft transplantation?
- transplant between different species -\> used for heart valves and surgical skin replacement -\> has lots of ethical issues
81
What is a prosthetic graft?
- a graft made from plastic or metal
82
What are the 2 types of deceased organ donation?
o DBD -\> donor after brain death (brain dead, heart-beating) -\> must be confirmed brain dead
- people who have had road traffic accident and massive cerebral haemorrhage
o DCD -\> donor after cardiac death (non-heart beating donors)
- have a longer period of warm ischaemia time so aren't suitable for all transplants -\> can be used for kidney transplant
83
How is a brain dead diagnose made?
o irremediable structural brain damage has to be of a KNOWN cause -\> apnoeic coma can'tbe due to anything that may be potentially reversible:
- depressant drugs
- metabolic or endocrine disturbance
- hypothermia
- neuromuscular blockers
o patient must demonstrate a lack of brain stem function:
- pupils both fixed to light
- corneal reflex absent
- no eye movements with cold caloric test
- no cranial nerve motor responses
- no gag reflex
- no respiratory movements on disconnection (with PaCO2 \>50 mmHg)
84
What are organs checked for before the transplantation procedure can take place?
- viral infection (HIV, HBV, HCV)
- malignancy
- drug abuse/overdose
- poison
- disease of the transplanted organ
85
WHat is tranplant allocation based on?
o equity -\> what is fair?, time on waiting list, super-urgent transplant - imminent death (liver, heart), what else?
Efficiency -\> what is the best use for the organ in terms of patient’s survival and graft survival?
86
Describe the chain of events that leads to organ rejection due to blood groups.
- A and B proteins are found on red blood cells and also ENDOTHELIAL LINING of blood vessel in transplanted organs
- if a transplant from a blood group B donor to a blood group A recipient the recipient has pre-formed anti-B antibodies that bind to the B antigen present on the endothelial cells
- leads to activation of complement and thrombosis -\> IMMEDIATE, ACUTE REJECTION (mediated by antibodies)
87
How can ABO-incompatible tranplants take place now?
- removal of antiboides form the recipient by plasma exchange
- good outcome even if the antiboides return
- used in heart, kidney, liver etc transplants -\> mainly when the organ donator is living
88
How does HLA play a role in transplant rejection?
- rather than presenting a foreign viral/bacterial peptide, the APC presents a fragment of the donor’s HLA peptide in the context of the recipient’s HLA molecule
- leads to T cell activation for T cells that are allo-specific, and can recognise the antigen in this context -\> immune response to the transplanted organ
89
How many HLA mismatches are feasible with a potential donor? How is this displayed in the notes?
- 0-6 are possible
- HLA-A, HLA-B and HLA-DR are the most polymorphised HLA genes and are therefore the most likely to cause damage -\> are shown by the number of mismatches from each of these categorys: HLA-A = 1, HLA-B = 2, HLA-DR = 0
- this method is only as clinical short-hand -\> all HLA are tested an matched
90
What is the most common type of graft failure?
- rejection -\> most commonly due to exposure to foreign HLA molecules
91
What is the treatment for rejection?
- if rejection is confirmed by histological examination of a biopsy IMMUNOSUPPRESIVE DRUGS are given as treatment
92
What can rejection be due to?
- T-cell mediated
- antibody mediated
93
How are rejections classified?
- hyperacute -\> immediate
- acute -\> days to weeks
- chronic -\> gradual build up over a number of years
94
Explain the mechanism of T-cell mediated graft rejection.
- in a transplanted organ, both the recipient and donor APCs will take up fragments of the donated organ antigens -\> circulate to the lymph nodes
- at lymph nodes, APC sit and present antigen -\> T cells circulate through the lymphatic system, and have contact with the APCs in this way until some T cells that can mount an allo-specific response against the specific antigens come into contact -\> these specific T cells recycle to the organ, and will infiltrate
- also recruit inflammatory cells to help them cause organ damage.
- initial response is through CD4 positive T cells, they then begin to recruit other cells this is the effector phase: CD4 cells recruit CD8+ (cytotoxic) T cells and macrophages -\> immune cells cause injury to the graft
- injury to the graft is through a variety of mechanisms: secretion of enzymes, production of free radicals, apoptosis etc
95
Decribe antibody-mediated rejection.
- antibody against graft HLA and AB antigen arise -\> pre-transplantation (“sensitised”) and post-transplantation (“de novo”)
- is predominantly an intravascular process/stays within capillaries -\> endothelium is the main site that is being targeted
- antibodies trigger the complement system which cause the immune response
96
What are the signs of kidney transplant rejection?
- risee in creatinine
- increased fluid retention
- hypertension
97
What are the signs of liver transplant rejection?
- rise in LFTs
- increased coagulopathy
98
What are the signs of lung transplant rejection?
- breathlessness
- pulmonary infiltrate
99
What organs often have subclinical signs of rejection?
- kidney
- heart -\> no good test for dysfunction -\> required regular biopsies
100
What are the main target cells for immunosuppressive drugs?
- T and B cells
- also target antibody production
101
What is the standard immunosuppressive regime?
o pre-transplantation -\> induction agent (T-cell depletion or cytokine blockade)
o from time of implantation -\> base-line immunosuppression
- signal transduction blockade, usually a CNI inhibitor: Tacrolimus or Cyclosporin
- sometimes mTOR inhibitor (Rapamycin)
- antiproliferative agent: MMF or Azathioprine
- corticosteroids
o if needed -\> treatment of episodes of acute rejection
- T-cell mediated: steroids, anti-T cell agents
- antibody-mediated: IVIG, plasma exchange, anti-CD20, anti-complement
102
What are more likely to occur due to tranplantation?
- as patients are on immunosuppressors
- \> infections
- \> tumours and malignant cancers -\> partcularly vunerable to skin cancers and EBV driven cancers
- \> drug toxicity
103
What evidence exists thats shows the immune system can mount a response to cancer?
- auto-antiboides to tumours -\> can causes auto-immune diseases which are recognised
- autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease -\> controlled by self
- patients treated for melanoma, after many years apparently free of disease, have been used as donors of organs for transplantation -\> recipients have developed melanoma -\> donor had developed ‘immunity’ to the melanoma, but the transplant recipients had no such ‘immunity’
- deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy
- men have twice as great chance of dying from malignant cancer compared to women -\> women typically mount stronger immune responses
104
Describe the cancer-immunity cycle.
1. begin with a tumour -\> some of the tumour cells may be dying, or releasing antigens -\> these antigens may be captured by APCs (dendritic cells), and may migrate to local draining lymph nodes
2. antigen is presented to T cells -\> T cell activation -\> after the T cell response, T cells go via the circulation to the site of the tumour -\> T cells leave the circulation to infiltrate the tumour, to respond to it
3. cells that leave the bloodstream and go into tumours are tumour-infiltrating lymphocytes (TILs) -\> TILs include T cells and monocytes
4. if there is recognition, it puts a lot of immune selection pressure on the tumour -\> T cells select cancer cells that have LOST the ability to present MHC and peptide to the T cells -\> mutations in the cancer cells (highly unstable) leads to the outgrowth of tumour cells that are no longer capable of being recognised by the immune system -\> once the T cells are killing these cells, there is release of antigen again
105
What is required for activation of an adaptive anti-tumour immune response?
o co-stimulation must occur
1. local inflammation in the tumour (“danger signal”)
2. expression and recognition of tumour antigens
106
What are the problems with immune survelliance of cancer?
- takes the tumour a while to cause local inflammation -\> gets to a large size before it is detectable
- anti-genic differences between normal and tumour cells can be subtle (e.g. a few point mutations)
107
What molecules make ideal molecules for cancer immunotherapy?
o must be specific to the cancer cells
- viral proteins that acts as tumour specific antigens -\> EPV and B cell lymphomas and HPV and cervical cancer
- known mutated proteins -\> e.g. TGF-beta receptor III
108
Describe some cancers of viral origin.
o opportunistic malignancies/immunosuppression
- EBV-positive lymphoma due to post-transplant immunosuppression
- HHV8-positive Kaposi sarcoma in unmanaged HIV
o immunocompetent viral cancers
- HTLV1-associated with adult T cell leukaemia/lymphoma
- hepatitis B and Hepatitis C virus associated hepatocellular carcinoma
- human papilloma virus (HPV) positive genital tumours
109
Describe the HPV vaccine.
- vaccines do not usually target the E6 and E7 oncoproteins directly -\> deemed to dangerous as there is a risk of causing cancer
- use surface proteins (late genes) which are expressed and incorporated into viral-like particles
- Gardasil is the commonly used recombinant vaccine -\> has the coat proteins from 9 different types of HPV, to protect against essentially all types of genital tumours
110
What are tumour-associated antigens?
- are derived from normal cellular proteins -\> but are aberrantly expressed (timing, location or quantity)
- because they’re normal, self proteins, tolerance may need to be overcome for an immune response -\> is harder to produce an immune response against self proteins
111
Name some tumour-associated antigens.
- cancer-testis antigens -\> expressed early in life, but not in adults -\> are silent in normal adult tissues except male germ cells (some expressed in placenta)
- human epidermal growth factor receptor 2 (HER2) -\> overexpressed in some breast carcinomas
- mucin 1 (MUC-1) -\> membrane-associated glycoprotein, overexpressed in very many cancers
- carcinoembryonic antigen (CEA) -\> normally only expressed in foetus/embryo, but overexpressed in a wide range of carcinomas
- prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP)
112
What are two major problems with targeting of tumour-associated auto-antigens for T cell-mediated immunotherapy of cancer?
1. auto-immune responses against normal tissues
2. immunological tolerance -\> MUST be overcome
- normal tolerance to auto-antigens
- tumour-induced tolerance
113
What approaches are being used/developed for tumour immunotherapy?
- antibody-based therapy
- therapeutic vaccination
- immune checkpoint blockade
- adoptive transfer of immune cells
- combinations of all above
114
What are the different types of monoclonal antibody-based therapy?
- naked
- conjugated
- bi-specific antiboides
115
What is 'naked' monoclonal antibody-based therapy?
- antibody is administrated with nothing attached
- e.g. trastuzumab (Herceptin) -\> anti-HER2 antibody -\> used in breast cancer
116
What is 'conjugated' monoclonal antibody-based therapy?
o antibodies which have been bound to another form of treatment
- radioactive particle -\> e.g. anti CD20 linked to yttrium-90
- drug -\> e.g. anti-HER2 linked to a cytotoxic drug
117
What is 'bi-specific' monoclonal antibody-based therapy?
- genetically engineered to combine 2 specificities, e.g. anti CD3 and anti CD19
- \> e.g. Blinatumomab -\> approved for use in patients with some B cell tumours
118
Describe therapeutic cancer vaccination.
- is one FDA approved vaccine to treat cancer (licensed for sale in the UK, but not NICE approved due to cost-benefit ratio)
o is called Provenge® (sipuleucel-T) for advanced prostate cancer
- patient’s own WBCs are treated with a fusion protein between PAP and the cytokine GM-CSF -\> stimulates dendritic cell maturation and enhances PAP-specific T cell responses
119
Describe personalised tumour specific cancer vaccines.
- involves tailoring the vaccine for each person -\> starts with tissue from the patient (some from the tumour and some from the equivalent normal cell)
- techniques sequence all the RNA/DNA in the tissue and HLA typing takes place.
- mutations specific to the tumour cell can be identified -\> RNA sequencing confirms expression of mutated genes.
- can predict which peptides can be presented via the HLA molecules (each HLA molecule has a peptide binding motif) -\> end up with some candidate neo-antigens (variants of normal cellular proteins)
- vaccinating the patient with these antigens in some way with an inflammatory signal (adjuvant) -\> this is a personalised vaccine response in the patient
o to routinely do this is a very expensive process -\> theoretically, it is possible to generate personalised vaccines against individual tumours in individual patients
120
Describe immune checkpoint blockade therapy.
- redcues/removes the negatively regulated controls on existing T cell response
- acts via the CTLA-4 and PD-1 pathways
- can causes autoimmune consequences -\> immune response is down-regulated for a reason
121
Describe adoptive transfer of cells as an anticancer treatment.
o genetically modified T cells can be used
- remove cells from a patient (e.g. from blood) and expanded them in vitro (by stimulating them with antigen, or non-specifically with cytokines)
- is the potential for introducing new molecules using genetic engineering, including new antigen receptors with different specificities
- expanding these cells and putting them back into the patient is the idea behind adoptive transfer
122
Describe chimaeric antigen receptors (CARs).
- chimaeric antigen receptors are molecules that are FUSIONS between the variable parts of a T cell receptor, and the signalling part of the costimulatory molecule anchored into the membrane
- if the CAR binds something, the T cell becomes fully activated -\> because it receives both signals (signal from CD3 and costimulatory molecule) at the same time
- have been really effective in blood cancers particularly using CD19 fragment for binding to B cells
123
What are the adnexal structures and where are they found?
- pilosebaceous unit - hair follicle, sebaceous gland and arrector pili muscle
- eccrine sweat glands - all over the body
- apocrine sweat glands - in the axillae and groin -\> make a more viscous sweat
o the dermis
124
Describe the epidermis.
- melanocytes sit on the basement membrane -\> produce melanin and protect keratinocyte nuclei
- Langerhans cells are APCs within the epidermis
- Merkel cells are thought to be involved in sensation
- keratinocytes begin at the bottom in the stratum basale -\> as they proliferate they move up the epidermis -\> go on to form keratin, which makes up the bulk of the stratum corneum -\> once cells have reached the corneum, they lose their nuclei and form a dead layer = BARRIER
125
What is the differentiation of keratinocytes?
- basal cell -\> prickle cell -\> granular cell -\> keratin
126
What is filagrin?
- one of the elements of the "cement" which seals cells together in the stratum coreneum
- mutation in the filagrin gene is common in eczema patients
127
What is meant by 'atopic march'?
- atopic diseases come about at different times in an individual’s life
- first disease to come on is eczema, then food allergies, then asthma, and then rhinitis
128
What happens in atopic eczema?
o barrier of the skin is defective (e.g. due to a filagrin gene mutation) which leads to dryness -\> allergens (such as pollen, house dust mites or food products) can penetrate -\> sensitisation
- irritants and pathogens can also penetrate (e.g. soap, detergents), drying out the skin further and make the barrier function even more defective
o immune response is activated via the Langerhans cells -\> acute atopic dermatitis, with activation of CD4 lymphocytes (Th2 response)
- if this is left to go on for weeks/months, this can turn into a chronic atopic eczema, which shows more of a Th1 immune response
129
Name a common/obvious sign of filagrin mutation.
- palmar hyperlinearity
130
What areas are most commonly affected in infantile atopic eczema?
- face, arms, elbows and knees -\> anywhere that they rub
131
How does the common sites for eczema outbreaks change throughout life?
- as the child grows up, the pattern of the eczema often changes
- remains on the face, but as the child gets older, it particularly affects the antecubital fossa, the popliteal fossa, hands, face and neck -\> flexural areas, and areas where there is build up of sweat
132
What changes will occur as eczema moves towards a more chronic state?
- acute eczema is very red and may be slightly blistery (often colonised with bacteria)
- chronic eczema will change its appearance to look less red -\> will appear excoriated and lichenified (skin looks thickened and there is accentuation of the skin lines)
133
What is the name for eczema which is affecting 90% or more of the body surface?
- erythrodermic
134
What pathogens often colonise the skin and can take advantage due to eczema?
- staphylococcus aureus -\> acts as a super antigen -\> activates the eczema -\> worsening of eczema
- treated with antibiotics (colonisation), emollients, topical and oral steroids
- eczema herpeticum = herpes simplex virus has proliferated on the surface of the skin -\> patients with this can become very unwell -\> can progress to encephalitis -\> brain damage and death
135
What are the 4 main types of eczema?
- atopic
- seborrhoeic eczema
- allergic contact dermatitis
- discoid
136
What is seborrhoeic eczema?
- same as dandruff but is affecting the face or other areas which isn't the scalp
- is an overgrowth of yeast and dermatitis occuring at the same time
137
What are the symptoms of seborrhoeic eczema?
- poorly defined areas of redness with greasy, scaly skin -\> is not generally itchy
- main affected areas are the nasolabial folds, eyebrows, forehead, within the beard area, the chest and back
138
How is seborrhoeic eczema treated?
- anti-dandruff/anti-fungal shampoo, antifungal cream and topical steroid
- gets worse in times of stress, staying up late or drinking too much alcohol -\> improves when the patient is not stressed, sleeps well, is exposed to sun and goes on holiday -\> lifestyle factors are important in the treatment
- seborrhoeic eczema is worse in people with other health conditions (immunodeficiency) -\> management of these condition is vital
139
What is allergic contact dermatitis?
- patients are very allergic to certain allergens when they come into contact with the skin
- if the eyelids are affected, it may be due to makeup, preservatives in contact lens fluid and eye drops another common sensitiser is PPD (black pigment in henna and hair dye)
- more liekly to be acquired if patient has atopic eczema
140
What is discoid eczema?
- occurs in discoid areas (often on the legs, but can be anywhere)
- each individual disc looks like eczema but the intervening skin may look normal
- cause of this is often just dry skin with secondary dermatitis – can be due to over washing of the skin with cleaning products
- treatment is emollient use, topical steroids and avoidance of soap/shower gel
141
What is psoriasis?
- an inflammatory dermatoses characterised by salmon pink plaques with a silvery scale
142
What are the risk factors for psoriasis?
- a genetic predisposition -\> is polygenetic
- is then triggered by an environmental trigger which may include infections, stress, alcohol, smoking or certain drugs
143
Describe the histology of psoriasis.
- epidermis becomes thicker -\> acanthosis
- stratum corneum also becomes thicker -\> hyperkeratosis
individual cells are not losing their nuclei -\> parakeratosis
- is an influx of neutrophils within the epidermis (this can form pustules) -\> inflammation
- dilatation of blood vessels in the dermis -\> red colour
144
What drives psoriasis?
lymphocytes within the dermis and excess cytokines/TNF-alpha
145
What are the common sites of psoriasis?
- scalp, elbows, knees, and genital areas, around the umbilicus, hands, feets and at the natal cleft of the buttocks
- plaques are very well defined
146
Describe guttate psoriasis.
- lots of little, raindrop like lesions on the skin
- generally affects young people (teenagers), and can occur after a streptococcal sore throat
- rash can persist for weeks or months
- can treat the patient with antibiotics and topical steroids to clear the psoriasis
- patients have a genetic susceptibility -\> are more likely to develop chronic plaque psoriasis
147
Describe palmoplantar pustulosis.
- plaques form on the body, pustules form on the palms of the hands and soles of the feet -\> patients are otherwise well, however this can be itchy and sore
- must be driven by a different genetic susceptibility
- patients are often smokers, but cessation of smoking doesn’t seem to make it better
148
Describe generalised pustular psoriasis.
- condition makes patients very unwell -\> are febrile and toxic -\> require hospital admission
- have a high HR, and low BP
- treated with immunosuppressants as well as emollients and topical steroid treatment
- condition is rare, but without treatment, mortality rate is high
149
What is acne?
- a disease of the pilosebaceous unit which can occur at any age, but normally occurs at the onset of puberty, teenagers and young adults
- is driven by hormones - androgenic stimulation causes hypertrophy of sebaceous glands -\> excess production of sebum
- causes a build up of dead cells, and hyperkeratinisation (thickening of the infundibulum of the hair follicle) -\> forms a blackhead (whitehead is the same as a blackhead, but it is covered with skin, so it can’t be seen)
150
What are the clinical features of acne?
- blackheads (open comedones) -\> built up of keratin in the hair follicle pore
- whiteheads (closed comedones) -\> the same as blackheads, but covered with skin
- inflammatory lesions -\> papules, pustules and nodules
- lesions do heal but can heal with scarring
- areas affected are the areas where sebaceous glands predominant (face, neck, upper chest)
151
Where is the basement membrane zone in skin?
- between the epidermis and dermis
152
What is bullous pemphigoid?
- an autoimmune disease in which you get tense blisters
- usually an elderly patient in their 70s/80s/90s
- condition begins with a rash (looks like eczema), followed by the development of blisters -\> blisters progress, and without treatment, they become infected -\> patients can then die from sepsis
153
What is the pathology of bullous pemphigoid?
- two proteins are involved (BPAg 1 and BPAg 2) -\> are the targets of autoantibodies
- BPAg proteins are located on the basement membrane -\> disease causes inflammation at the BM zone, and splitting of the epidermis from the dermis -\> forms deep blisters, where the deep blister split is at the location of the basement membrane
154
What is the treatment for bullous pemphigoid?
- high dose oral steroids, and other immunosuppressant drugs (methotrexate)
- treatment must be maintained for a number of years, before the illness burns out
155
What is epidermolysis bullosa?
- in bullous pemphigoid and pemphigus, there is an auto-antibody attacking the bp protein -\> if someone has a mutation in one of the genes for these protiens, they get a genetic blistering condition, called epidermolysis bullosa
156
What is pemphigus vulgaris?
- an autoimmune disease in which superfiical blisters form
- is an auto-antibody, but this time it is directed at a component of the hemidesmosomes, called desmoglein, within the epidermis -\> causes blisters, but these are much more superficial -\> break down and flake off -\> erosions of skin
157
What is the treatment for pemphigus vulgaris?
- oral steroids, immunosuppressants -\> gets much better and patients live a very normal life afterwards
Y2 MCD
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