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Year 2: MCD > Immunology > Flashcards

Immunology Flashcards

1
Q

What are appropriate immune responses?

A

Occur to foreign harmful agents such as viruses, bacteria, fungi, parasites

  • Required to eliminate pathogens
  • May be concomitant tissue damage as a side effects, but as long as pathogen is eliminated quickly, it will minimal and repaired easily
  • Involves antigen recognition by cells of the immune system and antibody production
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2
Q

What can appropriate immune tolerance occur to?

A
  • Self
  • Food
  • Pollens
  • Other plant proteins
  • Animal proteins
  • Commensal bacteria
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3
Q

What causes appropriate immune tolerance?

A
  • Antigen recognition and regulatory T cells and regulatory antibody (IgG4) production
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4
Q

What are hypersensitivity reactions?

A
  • Occur when immune responses are mounted against
  • Harmless foreign antigens (allergy, contact, hypersensitivity)
  • Autoantigens (autoimmune diseases)
  • Alloantigens (serum sickness, transfusion reactions, graft rejection)
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5
Q

How are hypersensitivity reactions classified?

A

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

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6
Q

Give examples of type I hypersensitivity reactions

A
  • Anaphylaxis
  • Asthma
  • Rhinitis (seasonal, perennial)
  • Food allergy
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7
Q

What happens during Type I immediate hypersensitivity?

A

Primary antigen exposure:
- The immune system is sensitised to the specific antigen
- IgE antibody production
- IgE binds to Mast cells & Basophils
Secondary antigen exposure:
- More IgE antibodies are produced
- Antigen cross-links IgE on mast cells/basophils
- Degranulation

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8
Q

What is the clinical presentation of Type II Antibody-dependent hypersensitivity in organ-specific autoimmune diseases?

A

1) Myasthenia gravis- antibodies act on Ach receptors in muscle
2) Glomerulonephritis- antibodies act of glomerular basement membrane
3) Pemphigus vulgaris- act on epithelial cell cement proteins
4) Pernicious anaemia- intrinsic factor blocking antibodies

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9
Q

What is the clinical presentation of Type II antibody-dependent hypersensitivity in Autoimmune cytopenias?

A

Antibody destruction of blood cells leads to cell shortage
- Haemolytic anaemia (RBC)
Thrombocytopenia (platelets
Neutropenia (neutrophila)

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10
Q

How is type II antibody-dependent hypersensitivity tested for?

A

Test for specific antibodies

  • Immunofluorescence
  • ELISA
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11
Q

What is involved in Type III immune complex mediated hypersensitivity?

A
  • Formation of antigen-antibody complexes in the blood
  • Deposition of complexes in a tissue
  • Complement and cell recruitment/activation
  • Activation of other cascade e.g. clotting
  • Tissue damage (vasculitis) such as systemic lupus erythematosus (SLE) and vasculitides
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12
Q

Give examples of Type IV delayed hypersensitivity responses

A 
Th1 mediated:
- Chronic graft injection 
- GVHD 
- Coeliac disease 
- Contact hypersensitivity
Th2 mediated
- Asthma 
- Rhinitis 
- Eczema
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13
Q

What are the three main varieties of type IV delayed hypersensitivity responses and the mechanisms?

A

Th1, Cytotoxic, Th2
Transient/persistent antigen is processed and presented by APC, which causes T cell activation of macrophages and CTLs
- Th1 mediated reactions involve the release of IFN-gamma and IL-2 from Th1 cells.
IFN-gamma leads to macrophage activation and pro-inflammatory TNF-alpha release
IL-2 activates cytotoxic T lymphocyte activation which leads to cell destruction
- Much of tissue damage is dependent upon TNF

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14
Q

What are the signs of inflammation?

A
  • Redness
  • Heat
  • Swelling
  • Pain
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15
Q

What are the features of inflammation?

A
  • Vasodilation, increased blood flow
  • Increased vascular permeability
  • Inflammatory mediators and cytokines
  • Inflammatory cells and tissue damage
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16
Q

What causes increased vascular permeability in inflammation?

A

C3a
C5a
Histamine
Leukotrienes

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17
Q

What cytokines are involved in inflammation?

A 
IL-1
Il-6
IL-2 
TNF 
IFN-gamma
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18
Q

What chemokines are involved in inflammation?

A

IL-8/CXCL8

IP-10/CXCL10

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19
Q

What des the inflammatory cell infiltrate involve?

A
  • Cell trafficking: chemotaxis
  • Neutrophils, macrophages, lymphocytes, mast cells
  • Cell activation
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20
Q

What are the genetic risk factors of allergy?

A

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 links to eczema (filaggrin) and asthma (IL-33, ORMDL3)
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21
Q

What are the environmental risk factors of allergy?

A

1) Age- increases from infancy, peaks in teens and reduces in adulthood
2) Gender- asthma more common in males in childhood, females in adults
3) Family size- more common in small families
4) Infections- early life infections protect
6) Animals- early exposure protects
7) Diet- breast feeding, anti-oxidants, fatty acids protect

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22
Q

What are the types of inflammation in allergy?

A

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

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23
Q

What des expression of allergic disease require?

A
  • 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)
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24
Q

What happens during subsequent exposure in atopic airway disease?

A
  • Subsequent exposure to the allergen causes memory T cells to rapidly differentiate to Th2 cells leading to IgE secretion from plasma cells
  • IgE then binds to IgE receptors on mast cells, cross-linking the receptors causing mast cell degranulation and release of inflammatory mediators
  • Th2 also releases IL-5 which causes eosinophils to release inflammatory mediators
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25
Q

What happens during primary sensitisation in atopic airway disease?

A
  • Antigen is inhaled
  • Allergen in picked up in airway lumen. It is processed and presented in naive T cells by dendritic cells
  • Naive T cell differentiates to form either Th1, Th2 or T-reg cell.
  • T-reg cells secrete IL-10, Th1 secreted IFN-gamma. Both inhibit differentiation of naive T cells into Th2 cells
  • Th2 cells then secrete IL-4 and IL13, which stimulate the proliferation and differentiation of B cells into plasma cells, which in turn synthesise and release IgE
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26
Q

What are eosinophils?

A
  • 2-5% of blood leukocytes
  • Present in blood but most reside in tissues
  • Recruited during allergic inflammation
  • Generated from bone marrow
  • Polymorphous nucleus- 2 lobes
  • Contains large granules with toxic proteins
  • Can lead to tissue damage
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27
Q

What are mast cells?

A
  • Tissue resident cells
  • IgE receptors on the cell surface
  • Crosslinking of IgEs leads to degranulation and mediator release.
  • Mediators may be preformed (histamine, cytokines and toxic proteins) or newly synthesised (leukotrienes and prostaglandins)
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28
Q

What are neutrophils?

A
  • Important in virus induced asthma, severe asthma and atopic eczema
  • 55-70% of blood leukocytes
  • Nucleus contains several loves
  • Granules contain digestive enzymes
  • Synthesise oxidant radicals, cytokines and leukotrienes
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29
Q

What causes acute inflammation of the airways in asthma?

A
  • Mast cell activation and degranulation
  • The pre- stored mediator involved is histamine
  • The newly synthesised mediators involved are prostaglandins and leukotrienes
  • Results in acute airway narrowing
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30
Q

What causes chronic inflammation of the airways in asthma?

A
  • Cellular infiltrate of Th2 lymphocytes and eosinophils
  • Smooth muscle hypertrophy
  • Mucous plugging
  • Epithelial shedding
  • Sub-epithelial fibrosis
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31
Q

What are the clinical features of asthma?

A
  • Reversible generalised airway obstruction: chronic episodic wheeze
  • Bronchial hyper-responsiveness: bronchial irritability
  • Cough
  • Mucous production
  • Breathlessness
  • Chest tightness
  • Response to treatment
  • Spontaneous variation
  • Reduced and variable peak flow
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32
Q

What is allergic rhinitis?

A

May be
Seasonal: hay fever- grass, tree pollens
Perennial- House dust mites or animal proteins

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33
Q

What are the symptoms of allergic rhinitis?

A
  • Sneezing
  • Rhinorrhoea
  • Itchy nose, eyes
  • Nasal blockage, sinusitis, loss of smell/taste
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34
Q

What is allergic eczema?

A
  • Chronic itchy skin rash
  • Flexures of arms and legs
  • House dust mite sensitisation and dry cracked skin
  • Complicated by bacterial and viral infections (herpes simplex)
  • 50% clears by 7 years
  • 90% by adulthood
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35
Q

What food allergies are seen in infants and children/adults?

A

Infancy- 3 years: Egg, cows milk

Children/adults- Peanut, shell fish, nuts, fruits, cereals, soya

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36
Q

What are the mild and severe symptoms of food allergies?

A 
Mild: 
Itchy lips, mouth, angioedema, urticaria
Severe: 
Nausea, abdominal pain, diarrhoea 
Anaphylaxis
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37
Q

What is anaphylaxis?

A
  • Severe generalised allergic reaction
  • Uncommon, potentially fatal
  • Generalised degranulation of IgE sensitised mast cells
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38
Q

What are the symptoms of anaphylaxis?

A
  • Itchiness around the mouth, pharynx, lips
  • Swelling of the lips, throat and other parts of the body
  • Wheeze, chest tightness, dyspnoea
  • Faintness, collapse
  • Diarrhoea and vomiting
  • Death if severe and untreated
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39
Q

What systems are affected in anaphylaxis?

A
  • Cardiovascular: vasodilation, cardiovascular collapse
  • Respiratory: bronchospasm, laryngeal oedema
  • Skin: vasodilation, erythema, urticaria, angioedema
  • GI: vomiting, diarrhoea
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40
Q

How are allergies investigated and diagnosed?

A
  • Careful history essential
  • Skin prick testing
  • RAST (blood specific IgE)
  • Total IgE
  • Lung function (asthma)
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41
Q

How is anaphylaxis treated?

A

Epipen and anaphylaxis kit

- Includes antihistamine, steroid and adrenaline

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42
Q

How is allergic rhinitis treated?

A
  • Antihistamines: sneezing, itching rhinorrhoea
  • Nasal steroid spray: nasal blockage
  • Cromoglycate: children, eyes
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43
Q

How is eczema treated?

A
  • Emollients
  • Topical steroid cream
    If severe: anti- IgE, anti-IL4/13, anti IL-5 mAb
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44
Q

What are the steps in asthma treatment?

A

Step 1: Use short acting Beta-2 agonist drugs as required by inhalation
- Salbutamol
Step 2: Inhaled steroid low-moderate dose
- Beclomethasone/Budenesonide
- Fluticasone
Step 3: add further therapy
- Add long acting beta-2 agonist, leukotriene antagonist
- High dose inhaled steroids
Step 4: Add courses of oral steroids
- Prednisolone
- Anti-IgE, anti-IL4/13, anti-IL-5 mAbs

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45
Q

What is immunotherapy used for?

A

Effective for single antigen hypersensitivies: venom allergy, pollens, house dust mite, antigen used is purified

  • Subcutaneous immunotherapy (SCIT): 3 years needed, weekly/monthly clinic visits
  • Sublingual immunotherapy (SLIT): 2-3 years, can be taken at home
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46
Q

What is autoimmunity?

A

Adaptive immune responses with specificity for self ‘antigens’ (autoantigens)

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47
Q

What are the mechanisms of autoimmunity?

A
  • Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens
  • Autoimmune diseases involve breaking T-cell tolerance
  • Because self tissue is always present, autoimmune disease are chronic conditions
  • Effector mechanisms resemble those of hypersensitivity reactions, types II, III and IV
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48
Q

Give examples of major autoimmune diseases

A
  • Rheumatoid arthritis
  • Type I diabetes
  • Multiple sclerosis
  • Systemic lupus erythematosus (SLE)
  • Autoimmune thyroid disease
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49
Q

What gender are autoimmune diseases more common in?

A

Women

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50
Q

Give examples of organ-specific autoimmune diseases and their targets

A 
Graves disease- Thyroid 
Hashimoto's thyroiditis- Thyroid 
Type I diabetes- Pancreas 
Goodpasture's syndrome- Kidney 
Pernicious anaemia- Stomach 
Primary biliary cirrhosis- Liver, bile 
Myasthenia gravis- Muscles
Dermatomyositis- Skin/Muscles 
Vasculitis- Blood vessels 
Rheumatoid arthritis- Joints 
SLE- Multiple targets
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51
Q

How do autoantigens show a play a direct role in immunopathogenesis?

A
  • Result in the clearance or complement-mediated lysis of autologous erythrocytes
  • Direct link between autoantibodies and disease (also antibody transfer experiments)
52
Q

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

A
  • 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)
53
Q

Give examples of Type II autoimmune diseases where the antibody works against cell-surface or matrix antigens

A
  • Autoimmune haemolytic anaemia
  • Autoimmune thrombocytopenia purpura
  • Goodpasture’s syndrome
  • Pemphigus vulgaris
  • Acute rheumatic fever
  • Grave’s disease
  • Myasthenia gravis
54
Q

What is the autoantigen and consequences in Goodpasture’s syndrome?

A

Autoantigen: Non-collagenous domain of basement membrane collagen type IV
Consequence: Glomerulonephritis, pulmonary haemorrhage

55
Q

What is the autoantigen and consequence of Grave’s disease?

A

Autoantigen: Thyroid- stimulating hormone receptor
The receptor is activated with no negative feedback
Consequence: Hyperthyroidism

56
Q

What happens in SLE?

A
  • Autoimmune disease of the nuclei of immune cells. IgG binds to double stranded DNA, forming complexes
  • Autoantigens: DNA, histones, ribosomes, snRNP, scRNP
  • Symptoms are caused by the deposition of complexes in the glomerulus (affecting kidney), vessels (vasculitis) and joints (arthritis)
57
Q

Give examples of Type IV- T-cell mediated diseases

A
  • Insuline dependent diabetes mellitus
  • Rheumatoid arthritis
  • Multiple sclerosis
  • Cytotoxic (CD9+) and helper (CD4+) T cell responses can be involved
58
Q

What is the autoantigen and pathology in insulin dependent diabetes mellitus?

A

Autoantigen: Pancreatic Beta cell antigen
Pathology: Beta cell destruction

59
Q

What is the autoantigen and pathology in rheumatoid arthritis?

A

Antigen: Unknown synovial joint antigen
Pathology: Joint inflammation and destruction

60
Q

What is the autoantigen and pathology in multiple sclerosis?

A

Autoantigen: Myelin basic protein, proteolipid protein

Multiple sclerosis: Brain degeneration (demyelination), weakness/paralysis)

61
Q

What happens in normal T-cell responses to antigens?

A
  • T cells recognise processed antigens which are presented by MHC molecules in APC
  • CD4+ cells recognise class II MHV
  • CD8+ cells recognise class I MHC
62
Q

What is HLA?

A

Human leukocyte antigen

  • Human MHC genes code for HLA molecules, the dominant genetic factor which affects susceptibility to autoimmune disease
  • Significant polymorphism within population of HLA type, different allotypes affect the relative risk of different autoimmune diseases
63
Q

What is tolerance?

A

The acquired inability to respond to an antigenic stimulus
‘3 A’s’
- Acquired involved cell of the acquired immune system and is ‘learned’
- Antigen- specific
- Active- process occurs actively in neonates, the effects of which are maintained throughout life

64
Q

What mechanisms underly self tolerance?

A
  • Central tolerance
  • Peripheral tolerance
  • Failure in one or more of these mechanisms may result in autoimmune disease
65
Q

How does central tolerance for T cells occur?

A
  • Takes place in Thymus
  • Here, T cells are excluded or retained according to the affinity of their receptors for peptide antigen and the abundance of antigen
66
Q

How are T cells selected in the thymus for central tolerance?

A
  • Useless (can’t see MHC): die my apoptosis
  • Useful (see MHC weakly): receives signal to survive. Positive selection
  • Dangerous (sees self strongly): receives signal to die by apoptosis
  • Only 5% of thymocytes survive selection
67
Q

How does central tolerance for B cells occur?

A
  • Occurs in bone marrow
  • Cross linking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells aid in deletion
  • Some immature autoreactive B cells still manage to go into the periphery
68
Q

What is a consequence of a failure of central tolerance?

A

APECED (Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy)

  • 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
  • Involved in the negative selective of self reactive T cells in the thymus
  • Results in persistence of the autoreactive cells
69
Q

Which biological pathways are SLE genes involved in that may lead to a failure of tolerance?

A
  • Induction of tolerance- B lymphocyte activation (CD22, SHP-1): leads to autoantibody production
  • Apoptosis (Fas, Fas-ligand): failure in cell death
  • Clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence of autoantigen
70
Q

What is peripheral tolerance?

A
  • Some antigens may not be expressed in the thymus or bone marrow, may be expressed only after the immune system has matured
  • Mechanisms are required to prevent mature lymphocytes becoming auto-reactive and causing disease:
  • Anergy
  • Ignorance of antigen
  • Suppression by regulatory T cells
71
Q

What is anergy and its role in peripheral tolerance?

A
  • Absence of costimulation
  • Naive T-cells require costimulation for full activation (CD80,CD86,CD40)
  • These are absent on most cells of the body
  • Without costimulation then cell proliferation and/or factor production does not proceed
  • Subsequent stimulation, even in the presence of costimulatory molecules leads to a refractory state named ‘ANERGY’
72
Q

When does immunological ignorance occur?

A
  • Occurs when antigen concentration is too low in the periphery
  • Occurs when relevant antigen present molecule in absent: most cells in the periphery are MHC class II negative
  • Occurs at immunologically privileged sites where immune cells cannot normally penetrate (eye, CNS, PNS and testes). The cells in this case have never been tolerised against the auto-antigens
73
Q

What can a failure of immunological ignorance result in?

A

Sympathetic opthalmia

  • Trauma to one eye results in the release of sequestered intraocular protein antigens
  • These released antigens are carried to the lymph nodes and activate T cells
  • Effector T cells then return via the bloodstream and attach antigens in BOTH eyes
74
Q

What is suppression by regulatory T cells in peripheral tolerance?

A
  • The active mechanism to suppress peripheral responses.
    Prevents autoreactive T cells from responding to the autoantigen.
    Controlled by other cell types:
  • CD25- Interleukin-2 receptor
  • CTLA-4 binds to B7 on T cells and send a negative signal
  • FOX P3- transcription factor required for regulatory T-cell development. The most important
75
Q

What is a consequence of a failure in the regulation of peripheral tolerance?

A

IPEX- Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome

  • Fatal recessive disorder presenting early in childhood.
  • Caused by a mutation in the FOXP3 gene which encodes a transcription factor critical for the development of regulatory T-cells
  • Only defective T regulatory cells present so there will be an accumulation of autoreactive T cells
76
Q

What are the symptoms of IPEX?

A
  • Early onset insulin dependent diabetes mellitus
  • Severe enteropathy
  • Eczema
  • Variable autoimmune phenomena
  • Severe infections
77
Q

By which mechanisms can infections affect the tolerance state?

A
  • Molecular mimicry of self molecules
  • Induce changes in the expression and recognition of self proteins
  • Induction of co-stimulatory molecules or inappropriate MHC class I 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 sites
78
Q

How can the immune system interact with tumours?

A
  • Certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues
  • The immune system can, in principle, detect such abnormally expressed antigens and, as a result, launch an attack against the tumour
  • In certain cases, this may result in auto-immune destruction of normal somatic tissues
79
Q

What is the concept of tumour ‘immunosurveilllance’?

A

Malignant cells are generally controlled by the action of the immune system

80
Q

How is the immune response to tumours elicited by the adaptive immune response?

A

T cells recognise MHC Class 1 and Class 2 molecules on the surface of cells

  • Alpha-bT cell receptors recognise small peptides which sit in the MHC molecules
  • Therefore T cells can recognise material inside of the cell, as peptides that are presented on the surface of the cell, come from proteins inside the cell. B cells cannot do this
  • This acts as an advantage in the recognition of tumours
81
Q

Describe the cancer immunity cycle

A

1) Release of cancer cell antigens
2) Cancer antigen presentation (dendritic cells/APCs)
3) Priming and activation (APCs & T cells)
4) Trafficking of T cells to tumours (CTLs)
5) Infiltrations of T cells into tumours (CTLs, endothelial cells)
6) Recognition of cancer cells by T cells (CTLs, cancer cells)

82
Q

What factors induce mutations in cellular DNA leading to cancer?

A
  • Irradiation
  • Chemical mutagens
  • Spontaneous errors during DNA replication
  • Tumour virus-induced changes in genome
83
Q

How does a tumour activate the innate immune system?

A
  • When the tumour has reached a certain size (already established) it induces inflammatory signals
  • Activates immune system leading to recruitment of dendritic cells, macrophages and NK cells
  • Innate immune cells recruit and active B and T cell. (Dendritic cells move to draining lymph node to engage with naive T cells)
  • Antibodies and T cells elicit their effector function but tumour rarely disappears
84
Q

What are the requirements for activation of an adaptive anti-tumour immune response?

A

1) Local inflammation in the tumour

2) Expression and recognition of tumour antigens

85
Q

What are the problems in immune surveillance of cancer?

A

1) Takes the tumour a while to cause local inflammation. Therefore, takes a long time before tumour is even recognised by innate immune system
2) Antigenic differences between normal and tumour cells can be very subtle. Therefore they are difficult to distinguish by the immune system

86
Q

What is the aim of cancer immunotherapy?

A

To teach the adaptive immune system to selectively detect and destroy tumour cells

87
Q

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

A

Display the contents of the cell for surveillance by T cells : infection, carcinogenesis

88
Q

Give examples of tumour-specific antigens

A 
Can be 
Viral proteins:
- Epstein Barr Virus (EBV) 
- Human Papillomavirus (HPV) 
Mutated cellular proteins:
- TGF- Beta receptor III
Bcr-Abl
89
Q

What cancers have viral origins?

A

1) Opportunistic malignancies: immunosuppression
- EBV-positive lymphoma; post-transplant immunosuppression
- HHV8-positive Kaposi sarcoma; HIV
2) Immunocompetent
- HTLV1- associated leukaemia/lymphoma
- HepB virus- and HepC virus associated hepatocellular carcinoma
- Human papilloma virus-positive genital tumours

90
Q

How is cervical cancer induced and maintained?

A

E6 and E7 oncoproteins of HPV

  • E6 and E7 are intracellular antigens
  • Their role is to help the virus evade the immune system in order to allow the virus to expand
91
Q

What are the target antigens for preventive HPV vaccinations?

A
  • Targets late genes (L1 and L2) which are expressed by the HPV virus and are responsible for forming the viral particle.
    Therefore the virus is unable to infect
92
Q

What are tumour-associated antigens?

A

They derive from normal cellular protein to which the immune system is not tolerance and which become immunogenic when expressed by the tumour

93
Q

What are ectopically expressed auto-antigens?

A

Tumour-associated antigens

  • Cancer-testes antigens: silent in adult tissue except male germ cells and some are expressed in the placenta.
  • One family of these antigens is MAGE
  • MAGE- melanoma associated antigens. Identified in melanoma and also expressed in other tumours
94
Q

What is the relevance of p53 in cancers?

A
  • Frequently mutated and overexpressed in human cancer
  • Involved in cell cycle control
  • Often accumulates in tumours, tumours often express much high levels of p53 than normal cells, and the protein itself s often mutated
95
Q

What type of antigens can mutated p53 be regarded as?

A
  • Tumour-associated antigen (over-expressed in tumours)

- Tumour-specific antigen (mutated form in unique to the tumour)

96
Q

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

A

1) Autoimmune responses against normal tissues
2) Immunological tolerance
- Normal tolerance to auto-antigens
- Tumour induced tolerance

97
Q

What are the different approaches for tumour immunotherapy?

A

1) Cancer ‘vaccination’- immunisation to stimulate natural anti-tumour responses
2) Genetic modification of a patient’s own T cells to express a receptor capable of recognising the tumour
3) Blockade of molecules that inhibit T cell responses e.g. PD-1/PD1L1 (e.g. nivolumab)

98
Q

Why is immunotherapy against melanoma accompanies by auto-immune skin depigmentation (vitiligo)?

A

Many of the antigens targeted in melanoma are also found on normal skin melanocytes
- Induction of auto-immune CTLs for therapy of melanoma also normal melanocytes and cause auto-immune skin depigmentation

99
Q

Why do organs fail?

A

1) Cornea: degenerative disease, infections, trauma
2) Skin/composite: burns, trauma, infections, tumours
3) Bone marrow: tumours, hereditary diseases
4) Kidney: diabetes, hypertension, glomerulonephrititis, hereditary conditions
5) Liver: cirrhosis (viral heptaitis, alcohol, auto-immune hereditary conditions), acute liver failure (paracetamol)
6) Heart: coronary artery or valve disease, cardiomyopathy (viral, alcohol) congenital defects
7) Lungs: COPD/emphysema, intersitial fibrosis/lung disease, cystic fibrosis, pulmonary hypertension
8) Pancreas: Type I diabetes
9) Small bowel: mainly children, hereditary conditions

100
Q

What is an autograft transplantation?

A

Within the same individual

101
Q

What is an isograft transplantation?

A

Between genetically identical individuals of the same species

102
Q

What is an allograft transplantation?

A

Between different individuals of the same species

103
Q

What is a xenograft transplantation?

A

Between individuals of a different species

  • Heart valves (pig/cow)
  • Skin
104
Q

What is a prosthetic graft transplantation?

A

Plastic, metal

105
Q

Give examples of allografts

A
  • Solid organs (kidney, liver, heart, lung, pancreas)
  • Small bowel
  • Free cells (bone marrow, pancreas islets)
  • Temporary: blood, skin (burns)
  • Framework- bone, cartilage tendons, nerves
  • Composite: hands, face, larynx
106
Q

What are the types of donor used for allografts?

A

1) Deceased donor
2) Living donor
- Bone marrow, kidney, liver
- Genetically related or unrelated (spouse; altruistic)

107
Q

How are deceased donors classified?

A

1) DBD: donor after brain death (brain dead, heart-beating)
- Road traffic accident, massive cerebral haemorrhage
- Confirm brain death
- Harvest organs and cool to minimise ischaemic damage
2) DCD- Donor after cardiac death (non-heart beating donors)
- Heart stopped before organ harvest
- Longer period of warm ischaemia time
- Suitable for kidney

108
Q

What is required of DBD deceased donors?

A

1) Irremediable structural brain damage of KNOWN cause
2) Apnoeic coma NOT due to
- depressant drugs
- metabolic or endocrine disturbance
- hypothermia
- neuromuscular blockers
3) Demonstrate 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 (PaC02 >50mmHg)

109
Q

What is the exclusion criteria for deceased donors?

A
  • Viral infection (HIV, HBV, HCV)
  • Malignancy
  • Drug abuse, overdose or poison
  • Disease of the transplanted organ

Organs must be removed rapidly, cooled and perfused.
- Absolute maximum cold ischaemia time for kidney 60h (ideally

110
Q

What are the risks of live donation (kidney donation)?

A
  • Risk of preoperative mortality
  • Preoperative morbidity
  • Late mortality
  • Associated with asymptomatic, non-progressive proteinuria
111
Q

For what reasons might a transplant be required?

A
  • Life saving: when other life-supportive methods are not fully developed or have reached the end of their possible use
  • Life enhancing: when other life-supportive methods are less good e.g. dialysis vs kidney transplant
112
Q

What are the most relevant protein variation sin clinical transplantation?

A

1) ABO blood group

2) HLA coded on chromosome 6 by MHC

113
Q

Where are A and B proteins present?

A

On red blood cells and the endothelial lining of blood vessels

114
Q

What is hyperacute rejection? Use a patient with blood group A and a blood group B donor as an example

A
  • Patient serum contains naturally occurring anti-B antibodies
  • Donor cells express blood group B
  • Circulating, pre-formed, recipient anti-B antibody binds to B blood group antigens on donor endothelium
  • Activates complement leading to complement mediated lysis and increased permeability
  • Other cells like phagocytes are rapidly recruited
  • Results in disruption of endothelium as platelets are activated. There is inflammation and thrombosis.
    This is hyperacute rejection
115
Q

What is ABO-incompatible transplantation?

A
  • Recently is has become possibly to remove the antibodies in the organ recipient with good outcomes
  • Used for kidney, heart and liver
116
Q

What are Human Leukocyte Antigens (HLA)?

A
  • Cell surface proteins with highly variable portion that is important in defence against infection and neoplasia.
  • HLA molecules are recognised as self therefore no immune response is mounted.
  • HLA molecules present foreign antigens to T cells therefore enabling the immune response
  • Highly polymorphic: lots of alleles for each locus
117
Q

What are the classes of HLA antigens?

A
  • Class I (A,B,C): expressed on all cells

- Class II (DR,DQ,DP): expressed on immune cells but can also be upregulated on other cells

118
Q

Why is HLA matching important in transplantation?

A
  • 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
  • T cell mediated rejection
  • Antibody mediated rejection (B cells)
119
Q

What is the most common cause of graft failure and how is it treated?

A
  • Rejection is the most common cause
  • Diagnosed by histological examination of a graft biopsy
  • Treated by immunosuppressive drugs
120
Q

What is acute antibody-mediated rejection?

A

Antibody production and complex formation with graft HLA and AB antigens

  • Antigens may arise pre-transplanation (sensitised)
  • Antigens may arise post-transplantation (‘de novo’
  • Antibody complexes activate complement and macrophages
121
Q

How is rejection diagnosed?

A

1) Deteriorating graft function
- Kidney transplant: rise in creatinine, fluid retention, hypertension
- Liver transplant: Rise in LFTs, coagulopathy
- Lung transplant: breathlessness, pulmonary infiltrate
2) Pain and tenderness over graft
3) Fever

122
Q

How is rejection prevented?

A
  • Maximise HLA compatibility

- Life long immunosuppressive drugs

123
Q

What do immunosuppressive drugs target?

A
  • T cell activation and proliferation

- B cell activation and proliferation and antibody production

124
Q

What is the standard transplant immunosuppressive regim?

A

1) Induction agent: T cell depletion or cytokine blockade
2) Base-line immunosuppression
- Signal transduction blockade, usually a CNI inhibitor
- Antiproliferative agent: MMF or Azathoprine
- Corticosteroids
3) Treatment of episodes of acute rejection
- T cell mediated: steroids, anti-T cell agents
- Antibody mediated: IVIG, plasma exchange, anti-CD20, anti-complement

125
Q

What infections arise post-transplantation?

A
  • 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
126
Q

What post transplantation malignancies can occur?

A
  • Skin cancer

- Post transplant lymphoproliferative disorder- Epstein Barr virus driven

Year 2: MCD (4 decks)

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