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Y2 MCD > Immunology > Flashcards

Immunology Flashcards

1
Q

What are involved in appropriate immune tolerance?

A
  • regulatory T cells
  • regulatory antiody production
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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
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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
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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
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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

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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

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7
Q

What tests can be ran to test for specificauto-antiboides?

A
  • immunofluorescence
  • ELISA -> e.g. anti-CCP
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8
Q

What is the mechanism of type 3 hypersensitivity?

A
  1. formation of antigen-antibody complexes in blood -> immune complexes
  2. immune complexes can’t fit through the small blood vessels -> complexes deposit in the vessels and tissues
  3. leads to complement activation and cell recruitment/activation and clotting cascade activation -> tissue damage (vasculitis-destruction of blood vessels by inflammation)
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9
Q

What are the common sites of vasculitis?

A
  • renal -> glomerulonephritis
  • skin
  • joints
  • lungs
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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
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11
Q

What are the features of inflammation?

A
  • vasodilatation
  • increased vascular permeability
  • inflammatory mediators & cytokines
  • inflammatory cells & tissue damage
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12
Q

What are the signs of inflammation?

A
  • redness
  • heat
  • swelling
  • pain
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13
Q

What cause increased vascular permeability in inflammation?

A
  • C3a, C5a, histamines, leukotrienes
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14
Q

What mediates allergic inflammation?

A
  • Th2 -> either by transient antigen presence or persistent antigen
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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
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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)
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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
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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)
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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
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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
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21
Q

Where are eosinophils found?

A
  • in blood (0-5% of blood leukocytes)
  • most reside in tissue
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22
Q

Briefly describe the appearance of eosinophils.

A
  • polymorphus nucleus -> two lobes
  • contains large granules full of toxic proteins
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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
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24
Q

Where are neutrophils found?

A
  • tissue resident cells
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25
Q

Describe the organisation of mast cells?

A

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
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26
Q

What is the consequence of mast cell activation?

A
  • acute inflammation
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27
Q

Describe the organisation of a neutrophil?

A
  • multi-lobed nucleus
  • granules contain digestive enzymes
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28
Q

What allergic diseases are neutrophils thought to be particularly important in?

A
  • virus induced asthma
  • severe asthma
  • atopic eczema
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29
Q

Where are neutrophils found?

A
  • predominantly in the blood -> 55-60% of blood leukocytes
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30
Q

What do neutrophils synthesise?

A
  • oxidant radicals
  • cytokines
  • leukotrienes
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31
Q

What are the three main processes leading to airway narrowing?

A
  • vascular leakage leading to airway wall oedema
  • mucus secretion fills up the lumen
  • smooth muscle contraction around the bronchi
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32
Q

Describe chronic asthma.

A

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

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33
Q

What are the important clinical features of asthma?

A
  • 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
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34
Q

What are the symptoms of allergic rhinitis?

A
  • sneezing
  • rhinorrhoea
  • itchy nose and eyes
  • nasal blockage, sinusitis, loss of small/taste
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35
Q

Where is allergic eczema most commonly found?

A
  • the flexures of the arms and legs
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36
Q

What is the most common cause of allergic eczema?

A
  • house dust mite sensitisation -> house dust mite proteins can get through the dry, cracked skin
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37
Q

What is the prognosis of allergic eczema?

A

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

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38
Q

What type of hypersenitivity is food allergy?

A
  • type 1 -> IgE mediated
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39
Q

What are the symptoms of food allergy?

A

o mild reaction

  • itchy lips and mouth
  • angioedema
  • urticaria

o severe reaction

  • nausea
  • abdominal pain
  • diarrhoea
  • anaphylaxis
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40
Q

What is anaphylaxis?

A

o severe generalised allergic reaction due to generalised degranulation of IgE sensitised mast cells

  • anaphylaxis is uncommon but potentially fatal
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41
Q

What are the symptoms of anaphylaxis?

A
  • 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
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42
Q

What is the emergency treatment of anaphylaxis?

A
  • EpiPen and anaphylaxis kit
  • if mild = antihistamine which can be backed up with a steroid injection
  • if SEVERE = ADRENALINE
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43
Q

What are the prevention/precautional steps to avoiding anaphylaxis?

A
  • avoidance of the known allergen
  • always carry an anaphylaxis kit and EpiPen
  • inform immediate family and caregivers
  • wear a MedicAlert bracelet
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44
Q

What are the techniques in investigation and diagnosis of an allergic reaction?

A

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)
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45
Q

What is the treatment for allergic rhinitis?

A
  • 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)
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46
Q

What is the treatment for eczema?

A
  • 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
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47
Q

What is the treatment for asthma?

A

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

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48
Q

Describe immunotherapy for allergy.

A
  • 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
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49
Q

What factors influence the chance of suffering from an autoimmune disease?

A

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
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50
Q

What are the mechanisms of autoimmunity?

A
  • 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
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51
Q

What immune reactions are knwon to play a direct role in the pathology of human autoimmune disease?

A
  • 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

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52
Q

Name some type II autoimmune diseases?

A
  • autoimmune haemolytic anaemia
  • Goodpasture’s syndrome
  • Grave’s disease
  • Myasthenia gravis
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53
Q

What is Goodpaster’s syndrome?

A
  • 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
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54
Q

What is Grave’s disease?

A
  • an autoimmune disease in which an antibodies that is agonistic to the TSH receptor is produced -> hyperthyroidism
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55
Q

Name a type III autoimmune disease.

A
  • SLE -> results in glomerulonephritis, vasculitis and arthritis
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56
Q

What is the difference between type II and III hypersensitivity?

A
  • 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
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57
Q

Name some type IV autoimmune diseases.

A
  • 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

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58
Q

Mutations in what genes increases your susceptibility to autoimmune diseases?

A
  • MHC class II
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59
Q

Define immunological tolerance.

A
  • the acquired inability to response to an antigenic stimulus
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60
Q

What are the 3 A’s of immune tolerance?

A
  • 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
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61
Q

What are the 2 main types of tolerance?

A
  • central
  • peripheral
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62
Q

Summarise central tolerance.

A

o ELIMINATION of self-reactive lymphocytes during lymphocyte development in the thymus and bone marrow

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63
Q

What are the 3 mechanisms of peripheral tolerance?

A
  • anergy
  • active suppression -> regulatory T cells
  • immune privilege (ignorance of antigen)
64
Q

How is central tolerance maintianed by the bone marrow?

A

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
Q

What is the selection process for T cells that provides central tolerance?

A
  • 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
Q

What is receptor editing, in the case of B cells?

A

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
Q

How does the bone marrow occasional produce antigen against self?

A
  • 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
Q

What is APECED?

A
  • 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
Q

What is co-stimulation?

A
  • 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
Q

Describe immunological ignorance.

A
  • 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
Q

What happens is immune ignorance is broken, such as in sympathetic opthalmia?

A
  • 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
Q

What is FOX P3?

A
  • encodes a transcription factor critical for the development of regulatory T-cells
73
Q

What is IPEX?

A

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
Q

What are the symptoms of IPEX?

A
  • early onset insulin dependent diabetes mellitus
  • severe enteropathy (disease of the intestines)
  • eczema
  • variable autoimmune phenomena
  • severe infections
75
Q

How can infections affect the tolerant state?

A
  • 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
Q

What are the 5 types of transplantation?

A
  • autografts
  • isografts
  • allografts
  • xenografts
  • prosthetic grafts
77
Q

What is autograft transplantation?

A
  • transplanting tissue from an individual from one area if the boody to another area of the body -> reconstruction etc
78
Q

What is isograft transplantation?

A
  • transplant between two genetically identical individuals of the same species
79
Q

What is allograft transplantation?

A
  • transplant between different individuals of the same species
80
Q

What is xenograft transplantation?

A
  • transplant between different species -> used for heart valves and surgical skin replacement -> has lots of ethical issues
81
Q

What is a prosthetic graft?

A
  • a graft made from plastic or metal
82
Q

What are the 2 types of deceased organ donation?

A

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
Q

How is a brain dead diagnose made?

A

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
Q

What are organs checked for before the transplantation procedure can take place?

A
  • viral infection (HIV, HBV, HCV)
  • malignancy
  • drug abuse/overdose
  • poison
  • disease of the transplanted organ
85
Q

WHat is tranplant allocation based on?

A

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
Q

Describe the chain of events that leads to organ rejection due to blood groups.

A
  • 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
Q

How can ABO-incompatible tranplants take place now?

A
  • 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
Q

How does HLA play a role in transplant rejection?

A
  • 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
Q

How many HLA mismatches are feasible with a potential donor? How is this displayed in the notes?

A
  • 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
Q

What is the most common type of graft failure?

A
  • rejection -> most commonly due to exposure to foreign HLA molecules
91
Q

What is the treatment for rejection?

A
  • if rejection is confirmed by histological examination of a biopsy IMMUNOSUPPRESIVE DRUGS are given as treatment
92
Q

What can rejection be due to?

A
  • T-cell mediated
  • antibody mediated
93
Q

How are rejections classified?

A
  • hyperacute -> immediate
  • acute -> days to weeks
  • chronic -> gradual build up over a number of years
94
Q

Explain the mechanism of T-cell mediated graft rejection.

A
  • 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
Q

Decribe antibody-mediated rejection.

A
  • 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
Q

What are the signs of kidney transplant rejection?

A
  • risee in creatinine
  • increased fluid retention
  • hypertension
97
Q

What are the signs of liver transplant rejection?

A
  • rise in LFTs
  • increased coagulopathy
98
Q

What are the signs of lung transplant rejection?

A
  • breathlessness
  • pulmonary infiltrate
99
Q

What organs often have subclinical signs of rejection?

A
  • kidney
  • heart -> no good test for dysfunction -> required regular biopsies
100
Q

What are the main target cells for immunosuppressive drugs?

A
  • T and B cells
  • also target antibody production
101
Q

What is the standard immunosuppressive regime?

A

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
Q

What are more likely to occur due to tranplantation?

A
  • as patients are on immunosuppressors
  • > infections
  • > tumours and malignant cancers -> partcularly vunerable to skin cancers and EBV driven cancers
  • > drug toxicity
103
Q

What evidence exists thats shows the immune system can mount a response to cancer?

A
  • 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
Q

Describe the cancer-immunity cycle.

A
  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
Q

What is required for activation of an adaptive anti-tumour immune response?

A

o co-stimulation must occur

  1. local inflammation in the tumour (“danger signal”)
  2. expression and recognition of tumour antigens
106
Q

What are the problems with immune survelliance of cancer?

A
  • 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
Q

What molecules make ideal molecules for cancer immunotherapy?

A

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
Q

Describe some cancers of viral origin.

A

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
Q

Describe the HPV vaccine.

A
  • 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
Q

What are tumour-associated antigens?

A
  • 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
Q

Name some tumour-associated antigens.

A
  • 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
Q

What are two major problems with targeting of tumour-associated auto-antigens for T cell-mediated immunotherapy of cancer?

A
  1. auto-immune responses against normal tissues
  2. immunological tolerance -> MUST be overcome
    - normal tolerance to auto-antigens
    - tumour-induced tolerance
113
Q

What approaches are being used/developed for tumour immunotherapy?

A
  • antibody-based therapy
  • therapeutic vaccination
  • immune checkpoint blockade
  • adoptive transfer of immune cells
  • combinations of all above
114
Q

What are the different types of monoclonal antibody-based therapy?

A
  • naked
  • conjugated
  • bi-specific antiboides
115
Q

What is ‘naked’ monoclonal antibody-based therapy?

A
  • antibody is administrated with nothing attached
  • e.g. trastuzumab (Herceptin) -> anti-HER2 antibody -> used in breast cancer
116
Q

What is ‘conjugated’ monoclonal antibody-based therapy?

A

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
Q

What is ‘bi-specific’ monoclonal antibody-based therapy?

A
  • 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
Q

Describe therapeutic cancer vaccination.

A
  • 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
Q

Describe personalised tumour specific cancer vaccines.

A
  • 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
Q

Describe immune checkpoint blockade therapy.

A
  • 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
Q

Describe adoptive transfer of cells as an anticancer treatment.

A

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
Q

Describe chimaeric antigen receptors (CARs).

A
  • 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
Q

What are the adnexal structures and where are they found?

A
  • 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
Q

Describe the epidermis.

A
  • 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
Q

What is the differentiation of keratinocytes?

A
  • basal cell -> prickle cell -> granular cell -> keratin
126
Q

What is filagrin?

A
  • 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
Q

What is meant by ‘atopic march’?

A
  • 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
Q

What happens in atopic eczema?

A

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
Q

Name a common/obvious sign of filagrin mutation.

A
  • palmar hyperlinearity
130
Q

What areas are most commonly affected in infantile atopic eczema?

A
  • face, arms, elbows and knees -> anywhere that they rub
131
Q

How does the common sites for eczema outbreaks change throughout life?

A
  • 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
Q

What changes will occur as eczema moves towards a more chronic state?

A
  • 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
Q

What is the name for eczema which is affecting 90% or more of the body surface?

A
  • erythrodermic
134
Q

What pathogens often colonise the skin and can take advantage due to eczema?

A
  • 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
Q

What are the 4 main types of eczema?

A
  • atopic
  • seborrhoeic eczema
  • allergic contact dermatitis
  • discoid
136
Q

What is seborrhoeic eczema?

A
  • 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
Q

What are the symptoms of seborrhoeic eczema?

A
  • 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
Q

How is seborrhoeic eczema treated?

A
  • 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
Q

What is allergic contact dermatitis?

A
  • 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
Q

What is discoid eczema?

A
  • 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
Q

What is psoriasis?

A
  • an inflammatory dermatoses characterised by salmon pink plaques with a silvery scale
142
Q

What are the risk factors for psoriasis?

A
  • a genetic predisposition -> is polygenetic
  • is then triggered by an environmental trigger which may include infections, stress, alcohol, smoking or certain drugs
143
Q

Describe the histology of psoriasis.

A
  • 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
Q

What drives psoriasis?

A

lymphocytes within the dermis and excess cytokines/TNF-alpha

145
Q

What are the common sites of psoriasis?

A
  • 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
Q

Describe guttate psoriasis.

A
  • 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
Q

Describe palmoplantar pustulosis.

A
  • 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
Q

Describe generalised pustular psoriasis.

A
  • 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
Q

What is acne?

A
  • 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
Q

What are the clinical features of acne?

A
  • 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
Q

Where is the basement membrane zone in skin?

A
  • between the epidermis and dermis
152
Q

What is bullous pemphigoid?

A
  • 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
Q

What is the pathology of bullous pemphigoid?

A
  • 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
Q

What is the treatment for bullous pemphigoid?

A
  • high dose oral steroids, and other immunosuppressant drugs (methotrexate)
  • treatment must be maintained for a number of years, before the illness burns out
155
Q

What is epidermolysis bullosa?

A
  • 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
Q

What is pemphigus vulgaris?

A
  • 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
Q

What is the treatment for pemphigus vulgaris?

A
  • oral steroids, immunosuppressants -> gets much better and patients live a very normal life afterwards

Y2 MCD (5 decks)

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