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Flashcards in Immunology Deck (134)
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1

What is an appropriate immune response?

Occurs to foreign harmful agents such as viruses, bacteria, fungi and parasites
- Required to eliminate pathogens
- Maybe concomitant tissue damage as a side effect, but as long as pathogen is eliminated quickly it will be minimal and repaired easily
Involves antigen recognition by cells of the immune system and antibody production

2

What is appropriate immune tolerance?

Occurs to self, and to foreign harmless proteins:
- Food, pollens, other plant proteins, animal proteins, commensal bacteria
Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production
- Antigen recognition in context of "danger" signals leads to immune reactivity, absence of "danger" to tolerance

3

What is a hypersensitivity reaction?

Occur when immune responses are mounted against:
- Harmless foreign antigens (allergy, contact hypersensitivity)
- Autoantigens (autoimmune diseases)
- Alloantigens (serum sickness, transfusion reactions, graft rejection)

4

What are the different types of hypersensitivity reaction?

Type I: Immediate hypersensitivity
Type II: Antibody-dependent cytotoxicity
Type III: Immune complex mediated
Type IV: Delayed cell mediated (Delayed-type hypersensitivity)

Types I, II and III depend upon the interaction of antigen with antibody
Type IV involves T cell recognition

5

Give examples of type I hypersensitivity

Immediate:
- Anaphylaxis
- Asthma
- Rhinitis
- Seasonal
- Perennial
- Food allergy

6

How does antigen exposure contribute to type I hypersensitivity?

1° antigen exposure
- Sensitisation not tolerance
- IgE antibody production
- IgE binds to mast cells and basophils
2° antigen exposure
- More IgE antibody production
- Antigen cross-links IgE on mast cells/basophils
- Degranulation

7

What is the clinical presentation of type II antibody-dependent hypersensitivity?

Depends on target tissue
1. Organ-specific autoimmune diseases
- Myasthenia gravis (Anti-acetylcholine R Ab)
- Glomerulonephritis (Anti-glomerular basement membrane Ab)
- Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
- Pernicious anaemia (Intrinsic factor blocking Ab)
2. Autoimmune cytopenias (Ab mediated blood cell destruction)
- Haemolytic anaemia
- Thrombocytopenia
- Neutropenia

8

What tests can you do for specific autoantibodies in type II hypersensitivity?

- Immunofluorescence
- ELISA e.g. anti-CCP (Cyclic Citrullinated Peptide Abs for rheumatoid arthritis)

9

What is type III immune complex mediated hypersensitivity?

- Formation of antigen-antibody complexes in blood
- Deposition of complexes in a tissue
- Complement and cell recruitment/activation
- Activation of other cascades e.g. clotting
- Tissue damage (vasculitis)
• Systemic lupus erythematosus (SLE)
• Vasculitides (Poly Arteritis Nodosum, many different types

10

Where do the immune complexes deposit and cause vasculitis in type III hypersensitivity?

- Renal (glomerulonephritis)
- Skin
- Joints
- Lung

11

Give examples of conditions associated with type IV hypersensitivity.

- Chronic graft rejection
- CVHD
- Coeliac disease
- Contact hypersensitivity

12

What are the varieties and mechanisms of type IV hypersensitivity?

Three main varieties:
- Th1
- Cytotoxic
- Th2
Mechanisms
- Transient
- T cell activation of macrophages, CTLs
- Much of tissue damage dependent upon TNF

13

What is the common cause of type IV contact hypersensitivities?

Nickel

14

What is the immune reactant in hypersensitivity reactions?

Type I: IgE
Type II: IgG
Type III: IgG
Type IV: Th1, Th2 and CTL

15

What is the effector mechanism in hypersensitivity reactions?

Type I: Mast-cell activation
Type II: Complement, FcR cells (phagocytes, NK cells); antibody alters signalling
Type III: Complement phagocytes
Type IV: Macrophage activation; eosinophil activation; cytotoxicity

16

What are the features of inflammation?

- Vasodilation, increased blood flow
- Increased vascular permeability
- Inflammatory mediators and cytokines
- Inflammatory cells and tissue damage

17

What are the signs of inflammation?

- Redness
- Heat
- Swelling
- Pain
- Loss of function

18

What causes increased vascular permeability in inflammation?

- C3a
- C5a
- Histamine
- Leukotreines

19

What cytokines are involved in inflammation?

- IL-1
- IL-6
- IL-2
- TNF
- IFN-γ

20

What chemokines are involved in inflammation?

- IL-8 / CXCL8
- IP-10 / CXCL10

21

What is the prevalence of atopy in young adults in the UK?

50%

22

What are the different severities of atopy?

- Mild occasional symptoms
- Severe chronic asthma
- Life threatening anaphylaxis

23

What are the risk factors for atopy?

Genetic
- ~80%
- Polygenic
• 50-100 genes linked to asthma/atopy
• Genes of IL-4 gene cluster (chromosome 5) linked to raised IgE, asthma, atopy
• Genes on chromosome 11q (IgE receptor)
linked to atopy and asthma
• Genes linked to structural cells linked to eczema (filaggrin) and asthma (IL-33, ORMDL3)

Environmental
- Age (increases from infancy, peaks in teens, reduces in adulthood)
- Gender (more common in males in childhood, females in adulthood)
- Family size (More common in small families)
- Infections (Early exposures protect)
- Diet (breast-feeding, anti-oxidants and fatty acids protect)

24

What are the types of inflammation in allergy?

Anaphylaxis, urticaria, angioedema
- Type I hypersensitivity (IgE mediated)
Idiopathic/chronic urticaria
- Type II hypersensitivity (IgG mediated)
Asthma, rhinitis, eczema:
- Mixed inflammation
•Type I hypersensitivity (IgE mediated)
Type IV hypersensitivity (chronic inflammation)

25

What is required for expression of disease?

- Development of sensitisation to allergens to sensitise instead of tolerance (primary response - usually in early life)
- Exposure to produce disease (memory response- any time after sensitisation

26

What is the process of sensitisation and subsequent exposure in atopic airway disease?

Sensitisation
1. Processed allergen presented to CD4⁺ cell
2. CD4⁺ activates Th2 cell but Treg and Th1 is inactive
3. Th2 secrete IL-4 and IL-13 which activates B cells
4. B cells proliferate and differentiate into plasma cells
- IgE synthesis and release

Subsequent exposure
1. Allergen presented to Th2 (memory)
2. Th2 produce IL-5 which activates eosinophils which produce inflammatory mediators
3. Th2 produce IL-4 and IL-13 which causes B cell differentiation to plasma cells
4. Plasma cells produce IgE which binds to mast cells and causes degranulation

27

What are eosinophils?

- 2-5% of blood leukocytes
- Present in blood but most reside in tissues
- Recruited during allergic inflammation
- Generated from bone marrow
- Polymorphous nucleus - two lobes
- Contains large granules (toxic proteins)
- Lead to tissue damage

28

What are mast cells (allergy)?

- Tissue resident cells
- IgE receptors on cell surface
- Crosslinking of IgEs leads to:
• Mediator release of preformed
- histamine
- cytokines
- toxic proteins
and newly synthesised
- leukotreines
- prostaglandins

29

What are neutrophils role in allergy?

Important in:
- virus induced asthma
- severe asthma
- atopic eczema
55-70% of blood leukocytes
- Nucleus contains several lobes
- Granules contain digestive enzymes
- Also synthesise:
• oxidant radicals
• cytokines
• leukotreines

30

What is the immunopathogenesis of acute asthma?

Acute inflammation of the airways
- Mast cell activation and degranulation
• pre-stored mediators (histamine)
• newly synthesised mediators (prostaglandins, leukotreines)
- Acute airway narrowing
• Vascular leakage (airway wall oedema, mucus secretion)
• Smooth muscle contraction

31

What is the response to a single allergen challenge in asthma?

- Early response (~30 mins)
- Late response (5 hours)

32

What is the immunopathogenesis of chronic asthma?

Chronic inflammation of the airways:
- Cellular infiltrate (Th2 lymphocytes, eosinophils)
- Smooth muscle hypertrophy
- Mucus plugging
- Epithelial shedding
- Sub-epithelial fibrosis

33

What is asthma? What are the symptoms?

Reversible generalised airway obstruction
- Chronic episodic wheeze
- Broncial hyperresponsiveness
- Bronchial irritability
Cough
Mucus production
Breathlessness
Chest tightness

Response to treatment
Spontaneous variation
Reduced and variable peak flow (PEF)

34

What are the types of allergic rhinitis?

- Seasonal: hayfever- grass, tree pollens
- Perennial: perennial allergic rhinitis
• HDM, animal

35

What are the symptoms of allergic rhinitis?

- Sneezing
- Rhinorrhoea
- Itchy nose, eyes
- Nasal blockage, sinunsitis, loss of smell/taste

36

What is allergic eczema?

- Chronic itchy skin rash
- Flexures of arms and legs
- HDM sensitisation and dry cracked skin
- Complicated by bacterial and (rarely) viral infections (herpes simplex)
- 50% clears by 7 years
- 90% by adulthood

37

What are common food allergies among infants (<3 years)?

Egg
Cows milk

38

What are common food allergies among children and adults?

Peanuts
Shellfish
Nuts
Fruits
Cereals
Soya

39

What are the symptoms of mild and severe allergies?

Mild
- Itchy lips
- Itchy mouth
- Angioedema
- Urticaria
Severe
- Nausea
- Abdominal pain
- Diarrhoea
- Anaphylaxis

40

What is anaphylaxis?

Severe, generalised allergic reaction
- Uncommon, potentially fatal
- Generalised degranulation of IgE sensitised mast cells

41

What are the symptoms of anaphylaxis?

- Itchiness around mouth, pharynx, lips
- Swelling of the lips, throat and other parts of the body
- Wheeze, chest tightness, dyspnoea
- Faintness, collapse
- Diarrhoea and vomiting
- Death is severe and untreated

42

What systems are involved in anaphylaxis?

Cardiovascular:
- vasodilation
- cardiovascular collapse
Respiratory:
- bronchospasm,
- laryngeal oedema
Skin:
- vasodilation
- erythema
- urticaria
- angioedema
GI
- vomiting
- diarrhoea

43

What investigations are conducted into anaphylaxis to make a diagnosis?

- Careful history essential
- Skin prick testing
- RAST (blood specific IgE)
- Total IgE
- Lung function (asthma)

44

What is the treatment of anaphylaxis?

Emergency treatment
- EpiPen and Anaphylaxis kit
• antihistamine, steroid, adrenaline
• Seek immediate medical aid
Prevention
- Avoidance of the known allergy
- Always carry a kit and EpiPen
- Inform immediate family and caregivers
- Wear a MedicAlert bracelet

45

What is the treatment for allergic rhinitis?

- Antihistamines (sneezing, itching, rhinorrhoea)
- Nasal steroid spray (nasal blockage)
- Cromoglycate (children, eyes)

46

What is the treatment for eczema?

- Emollients
- Topical steroid cream

47

What is the treatment for SEVERE rhinitis and eczema?

- Anti-IgE mAb
- Anti-IL4/13 mAb
- Anti-IL-5 mAb

48

What is the treatment for asthma?

Step 1:
Use short acting β₂ agonist drugs as required by inhalation
- Salbutamol

Step 2:
Inhaled steroid low-moderate dose
- Beclomethasone/Budesonide (50-800μg/day)
- Fluticasone (50-400μg/day)

Step 3:
Add further therapy
- Add long acting β₂ agonist, leukotreine antagonise
- High dose inhaled steroids - up to 2mg/day via a spacer

Step 4:
Add a course of oral steroids
- Prednisolone 30mg/day for 7-14 days
- Anti-IgE, anti-IL4/13, anti-IL-5 mAbs

49

What are the uses of immunotherapy?

Effective for single antigen hypersensitivities
- Venom allergy (bee or wasp stings)
- Pollens
- HDM
- Antigen used is purified

50

What are the different types of immunotherapy? Describe them.

1. Subcutaneous immunotherapy (SCIT)
- 3 years needed
- Weekly/monthly 2 hour clinic visit
2. Sublingual immunotherapy (SLIT)
- Can be taken at home
- 2-3 years is enough

51

Why do corneas "fail"?

- Degenerative disease
- Infections
- Trauma

52

Why does skin "fail"?

- Burns
- Trauma
- Infection
- Tumours

53

Why does bone marrow "fail"?

- Tumours
- Hereditary disease

54

Why do kidneys "fail"?

- Diabetes
- Hypertension
- Glomerulonephritis
- Hereditary conditions

55

Why does the liver "fail"?

- Cirrhosis (viral hepatits, alcohol, auto-immune hereditary conditions)
- Acute liver failure (paracetamol)

56

Why does the heart "fail"?

- Coronary artery or valve disease
- Cardiomyopathy (viral, alcohol)
- Congenital defects

57

Why do the lungs "fail"?

- Chronic obstructive pulmonary disease (COPD)/emphysema (smoking, environmental)
- Interstitial fibrosis / interstitial lung disease (idiopathic, autoimmune, environmental)
- Cystic fibrosis (hereditary)
- Pulmonary hypertension

58

Why does the pancreas "fail"?

- Type 1 diabetes

59

Why does the small bowel "fail"?

- Mainly children ("short gut")
- Hereditary conditions or related to prematurity (in adults - Crohn's, vascular disease)

60

What are the difference types of transplantation?

Autografts
- within the same individual
Isografts
- between genetically identical individuals of the same species
Allografts
- between different individuals of the same species
Xenografts
- between individuals of different species
Prosthetic graft
- plastic, metal

61

What is an allograft? Give examples.

A transplant between different individuals of the same species
- Solid organs (kidney, liver, heart, lung, pancreas)
- Small bowel
- Free cells (bone marrow, pancreas islets)
- Temporary: blood, skin (burns)
- Privileged sited: cornea
- Framework: bone, cartilage, tendons, nerves
- Composite: hands, face, larynx

62

What are the different types of allograft donor?

- Deceased donor
- Living donor
- bone marrow, kidney, liver
- genetically related or unrelated (spouse; altruistic)

63

What are the different types of deceased donor who can donate organs?

- DBD: donor after brain death (brain dead, heart beating)
(minimises ischaemic damage)
- DCD- donor after cardiac arrest (non-heart beating donors)
(longer period of warm ischaemia time)

64

What are the criteria for DBD donors?

Irremediable structural brain damage of known cause
Apnoeic coma not due to
- depressant drugs
- metabolic or endocrine disturbance
- hypothermia
- neuromuscular blockers
Demonstrate lack of brain stem function

65

How do you test 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>50mmHg)

66

What donors are excluded from organ donation?

- Viral infection (HIV, HBV, HCV)
- Malignancy
- Drug abuse, overdose or poison
- Disease of the transplanted organ (USS potential donor)

67

What is the absolute maximum cold ischaemia time for kidneys? How does this compare to other organs?

60 hours (ideal is <24)

Much shorter for other organs
(except cornea 96h- longer with cryopreservation)

68

What is the process of organ allocation? (kidney)

5 tiers of patients depending on:
- paediatric or adult
- highly sensitive or not
7 elements:
- Waiting time
- HLA match and age combined
- Donor-recipient age difference
- Location of patient relative to donor
- HLA-DR homozygosity
- HLA-B homozygosity
- Blood group match

69

In England, what proportion of potential donors after brain death without any medical contraindication to donation go on to donate organs?

50%

70

What is the main reason that potential DBD donors so not donate?

Family approached but declined consent to donation

71

What are the strategies to increase transplantation activity?

1. Decrease donation
- Marginal donors: DCD, elderly, sick
2. Living donation
- Transplantation across tissue compatibility barriers
- Exchange programmes: organ swaps for better tissue matching
3. The future?
- Xenotransplanation
- Stem cell research

72

What is the average half-life of a kidney transplant?

10 years

73

What are the most relevant protein variations in clinical transplantation?

1. ABO blood group
2. HLA (human leukocyte antigens) coded on chromosome 6 by MHC (major histocompatibility complex)

74

What does antibody activate?

- Complement
- Macrophages

75

What is the process and outcome of an ABO-incompatible transplantation?

- Remove the antibodies in the recipient (plasma exchange)
- Good outcomes (even if the antibody comes back)
- Kidney, heart, liver

76

What proteins make up MHC class I?

α₁
α₂
α₃
β₂ microglobulin

77

What proteins make up MHC class II?

α₁
α₂
β₁
β₂

78

What is the importance of correct HLA matching in transplantation?

Exposure to foreign HLA molecules results in an immune reaction to the foreign epitopes
The immune reaction can cause immune graft damage and failure (rejection)

79

How is rejection diagnosed and treated? What are the different types?

The most common cause of graft failure.
Diagnosis: histological examination of a graft biopsy
Treatment: Immunosuppressive drugs
- hyperacute rejection
- acute rejection
- chronic rejection
- T cell mediated rejection
- antibody-mediated rejection

80

What is the process of graft rejection?

1. Host-graft adaptation (stabilized by immunosuppressive drugs
2. Host and donor APCs move to lymphoid organs
3. APCs meet T cells in secondary lymphoid organs
4. Effectors T cells home to graft

81

What cells are involved in T cell mediated graft rejection?

Graft infiltration by alloreactive CD4+ cells
Cytotoxic T cells:
- Release of toxins to kill target (granzyme B)
- Punch holes in target cells (Perforin)
- Apoptotic cell death (Fas-ligand)
Macrophages:
- Phagocytosis
- Release of proteolytic enzymes
- Production of cytokines
- Production of oxygen radicals and nitrogen radicals

82

What is antibody-mediated rejection?

Antibody against graft HLA and AB antigen
Antibodies arise:
- Pre-transplantation ("sensitised")
- Post-transplantation ("de novo")

83

How are transplants monitored for rejection?

Deteriorating graft function:
- Kidney transplant: Rise in creatinine, fluid retention, hypertension
- Liver transplant: Rise in LFTs, coagulopathy
- Lung transplant: breathlessness, pulmonary infiltrate

Subclinical:
- Kidney
- Heart (no good test for dysfunction, regular biopsies)

84

What is the role of immunosuppressive drugs in organ transplantation?

- Targeting T cell activation and proliferation
- Targeting B cell activation and proliferation, and antibody production

Drugs have been developed to target all of the signalling pathways

85

What is the standard immunosuppressive regime for organ transplantation?

Pre-transplantation: Induction agent (T-cell depletion or cytokine blockade)

From time of implnatation: Base-line immunosuppression
- Signal transduction blockade, usually a CNI inhibitor: Tacrolimus or Cyclosporin; sometimes mTOR inhibitor (Rapamycin)
- Antiproliferative agent: MMF or Azathioprine
- Corticosteroids

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

86

What infections are transplant patients at risk of?

Increased risk for conventional infections
- Bacterial, viral, fungal
Opportunistic infections- normally relatively harmless infectious agents give severe infections because of immune compromise
- Cytomegalovirus
- BK virus
- Pneumocytis carinii

87

What malignancies have increased risk in patients post transplant

- Skin cancer
- Post transplant lymphoproliferative disorer- Epstein Barr virus driven
- Others

88

What is autoimmunity?

Adaptive immune responses with specificity for self "antigens" (autoantigens)
- Lymphocytes

89

What genetic and environmental factors contribute to autoimmunity?

1. Genes: twin and family studies
2. Sex: women more susceptible (e.g. 9:1 in SLE)
3. Infections: inflammatory environment
4. Diet: obesity, high fat, effects on gut microbiome, diet modification may relieve autoimmune symptoms
5. Stress: physical and psychological, stress-related hormones
6. Microbiome: gut/oral microbiome helps shape immunity, perturbation may help trigger autoimmune disease. Known to play a role in development of the immune system (from mice model)

90

What is the mechanism of autoimmunity?

- Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)
- Autoimmune diseases involve breaking T-cell tolerance
- Becuase self tissue is always present, autoimmune diseases are chronic conditions
- Effector mehanisms resemble those of hypersensitivity reactions (type II, III and IV) directed against self-antigen

91

What percentage of individuals are affected by autoimmune dusrase? What percentage are women?

8% of people are effected

80% of affected individuals are women

92

List some examples of important autoimmune diseases

- Rheumatoid arthritis
- Type I diabetes
- Multiple sclerosis
- Systemic Lupus Erythematosus
- Autoimmune thyroid disease

93

What immune reactions play a direct role in the pathology of autoimmune disease?

- Antibody response to cellular or extracellular matrix antigen (type II)
- Immune complex formed by antibody against soluble antigen (type III)
- T-cell mediated disease (delayed type hypersensitivity reaction, type IV)

94

What autoimmune diseases have a type II mediated pathology?

- Autoimmune haemolytic anaemia
- Autoimmune thrombocytopenia purpura
- Goodpasture's syndrome (Ab against type IV collagen)
- Pemphigus vulgaris
- Acute rheumatic fever
- Grave's disease (Ab binds TSH receptor and causes constant T3/4 release)
- Myasthesia gravis

95

What autoimmune disease have a type III mediated pathology?

Systemic lupus erythamatosus
(Soluble immune complexes circulated around the body and are deposited in various tissues)

96

What autoimmune diseases have a type IV mediated pathology?

- Insulin-dependent diabetes mellitus
- Rheumatoid arthritis
- Multiple sclerosis
(Cytotoxic (CD*) and helper (CD4) T cell responses can be involved

97

What MHC is recognised CD4 and CD8 T cells?

CD4 - MHC class II
CD8 - MHC class I

98

What is the dominant genetic factor affecting susceptibility to autoimmune disease?

MHC class II
Particular alleles have been linked to specific diseases

99

What is tolerance?

The acquired inability to respond to an antigenic stimulus
The 3 A's
- Acquired - involves cells of the acquired immune system and is 'learned'
- Antigen specific
- Active process in neonates, the effects of which are maintained throughout life

100

How does self tolerance work and how does it fail?

- Central tolerance
- Peripheral tolerance
- anergy
- active suppression (regulatory T cells)
(immune privilege, ignorance of antigen)

Failure in one or more of these mechanisms may result in autoimmune disease

101

What is central tolerance?

T-cells recognise peptides presented on MHC in the thymus- if a T cell binds very strongly they will be deleted
- Useless (can't see MHC): die by apoptosis
- Useful (see MHC weakly): receive signal to survive. "Positive selection"
- Dangerous (see self strongly): receive signal to die by apoptosis. "Negative selection"

Only 5% of thymocytes survive selection

102

What causes APECED?

Results from a failure to delete T-cells in the thymus
- Caused by mutations in the transcription factor AIRE (Autoimmune regulator) gene
- AIRE is important for the expression of "tissue-specific" genes in the thymus (e.g. production of insulin in the thymus)
- Involved in the negative selection of self reactive T-cells in the thymus

103

How does SLE have a failure of tolerance?

Genes affecting multiple pathways may lead to a failure of tolerance
- Induction of tolerance (B lymphocyte activation: CD22, SHP-1): autoantibody production
- Apoptosis (Fas, Fas-ligand): failure in cell death
- Clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence or autoantigen

104

What is the mechanism for peripheral tolerance?

Some antigens may not be expressed in the thymus or bone marrow, and may be expressed only after the immune system has matured
Mechanisms are requires to prevent mature lymphocytes becoming auto-reactive and causing disease
- Anergy
- Suppression by regulatory T cells
- (Ignorance of antigen)

105

What is anergy?

- Naive T-cells require costimulation for full activation: by CD80, CD86 or CD40- on APC
- These are absent on most cells in the body
- Without costimulation the cell proliferation and/or factor production does not proceed
- Subsequent stimulation leads to a refractory state: Anergy

106

What is immunological ignorance?

- Occurs when antigen concentration is too low in the periphery
- Occurs when relevant antigen presenting molecules are absent: most cells in the periphery are MHC class II negative
- Occur at immunologically privileged sites where immune cells cannot normally penetrate: e.g. in the eye, central and peripheral nervous system and testes. In this case, cells have never been tolerised against the auto-antigens

107

What is sympathetic ophthalmia?

Failure of ignorance
- Trauma to one eye results in the release of sequestered intraocular protein antigens
- Released intraocular antigens are carried to lymph nodes and activate T cells
- Effector T cells return via bloodstream and attack antigen in both eyes

108

What are the different components and functions of regulatory T cells?

CD4⁺CD25⁺CTLA-4⁺FOXP3⁺
CD25 is the IL-2 receptor
CTLA-4 binds to B7 and sends a negative signal
FOX P3 is a transcription factor requires for regulatory T-cell development

109

What is IPEX? What are the symptoms?

Fatal recessive disorder presenting in early childhood. Mutation in the FOXP3 gene which encodes a transcription factor critical for the development of regulatory T-cells. Causes accumulation of autoreactive T cells
Symptoms:
- early onset insulin dependent diabetes mellitus
- severe enteropathy
- eczema
- variable autoimmune phenomena
- severe infections

110

Give examples of autoimmune conditions that are linked to infection?

Multiple sclerosis: EBV, measles virus
Type I diabetes: Coxsackie virus B4, rubella virus, CMV, mumps
SLE: EBV
Rheumatic fever/myocarditis: Streptococci
Myasthenia gravis: HSV, HCV

111

What are the possible ways in which an infection could cause autoimmune disease?

- Molecular mimicry of self molecules
- Induce changes in the expression and recognition of self proteins
- Induction of co-stimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment
- Failure in regulation: effects on regulatory T-cells
- Immune deviation: shift in type of immune response (e.g. Th1-Th2)
- Tissue damage at immunologically privileged sited

112

What is PCD?

Paraneoplastic cerebellar degeneration
CDR2 = cerebellum degeneration-related antigen 2 is present in the serum
Present in a patient with breast cancer
-Immune response against the tumour affects neurones in the brain leading to elimination of Purkinje cells (autoimmune)

Some tumours can generate antibody responses against them

113

What is the role of the immune system in control of tumours?

- Adults can have microscopic colonies of cancer cells, with no symptoms of the disease. Immune control?
- Melanoma patients who have been treated and recovered, and then donated organs. Recipient of organ then got melanoma. Donor must have developed some sort of immunity to melanoma
- Immunosuppression increases risk of malignancy
- Men have twice the chance of dying from malignant cancer than women do; women mount stronger immune responses

114

What is tumour 'immunesurveillance'?

Concept that malignant cells are generally controlled by the action of the immune system
Can get T cell and antibody responses to tumours

115

What is the cancer-immunity cycle?

1. Cell death and release of antigens from tumour cells
2. Taken up by APCs and drained to lymph nodes, then presented to T cells
3. Priming and activation of APCs and T cells
4. Trafficking of T cells to tumours (CTLs)
5. Infiltration of T cells into tumours (CTLs, endothelial cells)
6. Recognitions of cancer cells by T cells (CTLs, cancer cells)
7. Killing of cancer cells (immune and cancer cells)
If cancer cells evolve without MHC receptors they will evade immune response. Giving cells a selective advantage
Tumours get to a certain size before they produce inflammation
- Then recruit the innate immunity
- Then recruits the adaptive, antigen-specific immunity

116

What are the requirements of a tumour to activate an adaptive anti-tumour immune response?

- Local inflammation in the tumour
- Expression and recognition of tumour antigens

117

What are the problems associated with immune surveillance in cancer?

- It takes the tumour a while to cause local inflammation
- Antigenic differenced between normal and tumour cells can be very subtle

118

What is the function of MHC class I and II molecules?

'Display' contents of cell for surveillance by T cells: infection, carcinogenesis

119

Give examples of tumour-specific antigens.

Viral proteins
- Epstein Barr Virus (EBV)
- Human Papillomavirus (HPV)

Mutated cellular proteins
- TGF-β receptor III
- Bcr-Abl

120

Give examples of opportunistic malignancies of viral origin.

- EBV-positive lymphoma: Post-transplant immunosuppression
- HHV8-positive Kaposi sarcoma: HIV

121

Give examples of cancers in immunocompetent individuals with viral origins.

- HTLV1- associated leukaemia/lymphoma
- HepB virus- and HepC virus-associated hepatocellular carcinoma
- Human papilloma virus-positive genital tumours

122

What are the oncoproteins of HPV?

E6 and E7

123

What proteins are targeted by the HPV vaccine?

Surface glycoproteins which are incorporated into VLPs

124

What is the use of the HPV vaccine?

Minority of people who have immune failure (no immunity to HPV) who acquire an infection will result in cervical neoplasia
- 50%: no immunity
- 50%: non-functional immunity

Preventative vaccination
OR
Therapeutic vaccination (to help control the tumour)

125

What are tumour-associated antigens? What is the problem with targeting these antigens?

Derived from normal cellular proteins which are aberrantly expressed (timing, location or quantity)
They are normal self proteins, for an immune response to occur tolerance may need to be overcome

126

Give examples of tumour-associated antigens.

- Cancer-testes antigens (developmental antigens): Silent in normal adult tissues except male germ cells (some expressed in placenta
e.g. MAGE family: Melanoma associated antigens. Identified in melanoma also expressed in other tumours
- 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: prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP)

127

What is the target of immunotherapy that treats melanoma?

Tyrosinase (poor self tolerance)
Results in localised skin depigmentation

128

What are the main problems of targeting tumour-associated auto-antigens for T-cell mediated immunotherapy of cancer?

1. Auto-immune responses against normal tissues
2. Immunological tolerance
- Normal tolerance to auto-antigens
- Tumour-induced tolerance

129

What are the different approaches for tumour immunotherapy?

1. Antibody-based therapy
2. Therapeutic vaccination
3. Immune checkpoint blockade
4. Adoptive transfer of immune cells
5. Combinations of 1-4 above

130

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

- Naked antibody
- Conjugates (e.g. to radioactive isotope or cytotoxic drug)
- Bi-specific antibodies (genetically engineered to combine 2 specificities- can target B cell tumour with T cells)

131

What is the only approved therapeutic cancer vaccination?

Provenge (sipuleucel-T) for advanced prostate cancer
- Patient's own WBC are treated with a fusion protein between protastatic acid phosphatase (PAP) and the cytokine GM-CSF
- Stimulates DC maturation and enhances PAP-specific T cell immune responses

132

What is immune checkpoint blockade cancer treatment? Give examples of drugs

Rather than directly stimulate new responses, this approach seeks to reduce/remove negative regulatory controls of existing T cell responses
Targets CTLA-4 and PD-1 pathways:
- CTLA-4 is expressed on activated and regulatory T cells, binds to CD80/86 (costimulatory molecules on APC)
- PD-1 is expressed on activated T cells, binds to PD-L1/L2 (complex expression patterns, may be upregulated on tumours)
e.g.
- Ipilimumab (anti CTLA-4)
- Nivolumab (anti PD-1)

133

How does adoptive transfer of cells treat cancer?

- Had tumour removed during surgery or take peripheral blood, and extract tumour infiltrating lymphocytes
- Culture in vitro
- Expand them by stimulating them with tumour antigen or cytokines
- Infuse them back into the patient

134

What are chimaeric antigen receptors?

CARs
T cells have TCR (which binds MHC) which is linked to the ζ (zeta) chain of CD3 that signals
- Can take variable bits of an antibody and link it on to CD3 ζ cytoplasmic domain that signals to T cells so that scFv (single chain of an antibody) will bind its antigen and activate the T cell to respond against the tumour cell
(These T cells are harvested, cultured and then infused back in to the patient)