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Semester 4 > Defence > Flashcards

Defence Flashcards

1
Q

What is the definition of innate immunity

A
  • Born with it
    • Natural / native
  • Ancient
    • Plants, insects and all animals have it
  • Developed by evolution
  • Was in place before infection
  • Responds in the same way to repeated infections
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2
Q

What are the functions of the innate immune system

A
  • Reacts to microbes + injured cells
  • 1st line of defence
    • Initial response
  • Rapid
    • Immediate to maximal response in hours
  • Prevents, controls and sometimes can even eliminate infections
  • Many pathogens are evolved to resist + escape the innate immune system
  • Eliminated by adaptive immune system
  • Innate Immune System keeps the infection in check = immune activation
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3
Q

What are the components of the Innate immune system
- Cells
(Effector cells)

A
  • Phagocytes
    • PMN
    • M
  • NK cells
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4
Q

What are the components of the Innate immune system

- Soluble Molecules

A
  • Effector proteins
    • Complmenet
  • Mediators of inflammation
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5
Q

Barriers of the innate immune system :

1 - The epithelial surface

A
  1. The epithelial surfaces
    • Skin
    • Mucosa of gastrointestinal tract
    • Mucosa of the respiratory tract
    • Prevents the entry of microbes
    • Therefore it’s a physical barrier
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6
Q

Epithelial barrier prevent entry of microbes

A

Mucus = will coat microorganisms
Mucus = prevents adherence to epithelium
Pathogen gets expelled by the movements of cilia

- Pathogen will get expelled 
- Due to the movements of the cilia
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7
Q

Barriers of the innate immune system :

2 - Chemical Barriers

A
  • Chemical barriers
  • Antibacterial enzymes
    • Lysozyme - tears and saliva
  • Antimicrobial peptides
  • Defensins and cathelicidins
  • Will kill bacteria, by damaging the bacterial cell membrane
- Produced by epithelial cells 
	• PMN
		○ Neutrophils
	• NK cells 
		○ Natural Killer Cells
	• CTLs 
		○ Cytotoxic T lymphocytes
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8
Q

Barriers of the innate immune system :

3 - Chemical Barriers

A
  • Chemical barriers
  • Antibacterial enzymes
    • Lysozyme - tears and saliva
  • Antimicrobial peptides
  • Defensins and cathelicidins
  • Will kill bacteria, by damaging the bacterial cell membrane
- Produced by epithelial cells 
	• PMN
		○ Neutrophils
	• NK cells 
		○ Natural Killer Cells
	• CTLs 
		○ Cytotoxic T lymphocytes
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9
Q

Barriers of the innate immune system :

3 - Chemical (Microbiological) Barriers

A 
- Microbiological barriers 
	• Normal flora non-pathogenic bacteria 
	• Competition 
- Clinical note - this is an antibiotic treatment 
- Kills normal flora 
- Replaced with pathogenic organisms
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10
Q

Innate immune system and disease

A
  1. Loss of the integrity will predispose to infection
    • Wounds
    • Burns
  2. Genetic defects: cystic fibrosis
    • Defective mucus production
    • Inhibition of ciliary movements
      ○ Frequent lung infections
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11
Q

What are the characteristics of the effector cells within the innate immune system

A 
- Cells (phagocytes )
	• Myeloid lineage 
		○ PMN, Mo, Dendritic cells 
		○ Identify, ingest, destroy 
- Other cells 
	• Lymphoid lineage 
		○ NK cells
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12
Q

What are the characteristics of NK Natural Killer Cells

A
  • Kill virus infected cells
    • Kill malignantly transformed cells
      ○ Tumour cells
    • Express cytotoxic enzyme
      ○ Lyse target cells
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13
Q

Give more characteristics of the Natural Killer Cells

- Kill malignant tumour cells without prior activation

A
  • CD8+ T cells
  • Need to be activated and differentiate into CTL
    • Cytotoxic T lymphocytes
    • To kill target cells
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14
Q

Give more characteristics of the Natural Killer Cells

- Contain perforin

A
  • There are in target cells
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15
Q

Give more characteristics of the Natural Killer Cells

- Contain cytolytic enzymes

A
  • Granzymes A, B
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16
Q

NK cells: how do they recognise the target cells

- The inhibitory receptors

A 
- KIRs
	• Killer inhibitory receptors 
- NKG2A
	• C type lectin receptors 
- Lecocyte Ig like receptors 
	• LIRs
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17
Q

NK cells: how do they recognise the target cells

- The activating receptors

A
  • NKG2D
  • KIRs
  • CD16
  • Adaptor proteins: which are:
    • DAP10
    • DAP 12
  • Activating receptor recognise infected, or injured cells
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18
Q

NK cells - recognition of target cells

A
  • NK cells have inhibitory and activating receptors
  • Outcome of NK cell interaction with other cells is determined by integration of signals from inhibitory and activating receptors
  • All healthy autologous nucleated cells have MHC 1
  • Inhibitory receptors recognise MHC class
  • There is a blockade of signals from activating receptors
  • NK cells do not attack healthy autologous cells
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19
Q

NK cells - recognition of target cells

A
  • The virus infected cells
    ○ These will downregulate MHC 1
  • Malignant (tumour) cells
    ○ Downregulate MHC 1
  • Inhibitory receptors are NOT litigated by MHC class 1
  • Signals from activating receptors are not blocked
  • NK cells attack, and kill the virus infected / tumour cells
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20
Q

Describe the NK cells receptors

A
  • Cytoplasmic tails of inhibitory receptors contain ITIM motif
  • ITIM engage molecules phosphatases that block the signalling pathways
    • (triggered by activating receptors)
  • Activating receptors contain ITAM motif
  • ITAMs engage in signalling events that promote target cell killing and cytokine secretion by NK cells
  • ITAMs are often located not in activating receptors, but in cytosolic portion of adaptor molecule (e.g. DAP 12)
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21
Q

Describe the NK cells killing of target cells : Perforin

A
  • Forms pores

- Delivery of granzymes

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22
Q

Describe the NK cells killing of target cells : Granzymes

A
  • A B C

- Initate apoptosis

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23
Q

NK cells killing of target cells

A
  • Granzymes
  • Will activates caspases
  • This will lead to apoptosis
  • Granzyme B
  • Can trigger mitochondrial apoptotic pathway
  • Killing of infected cells by NKs
  • Eliminates reservoirs of infections
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24
Q

Defects in NK cells and disease

A
  • Human NK cell deficiencies
    • As part of broader immuno deeficiencies
    ○ e.g. Chediak Highashi
    • Complete absence of circulating NK cells
    • Functional NK cells deficiencies (normal numbers)
  • Patient have fatal viral infections
    • Hepesviruses
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25
Q

Phagocytes characteristics

A 
- Specialised cells 
	• Identify 
	• Ingest 
	• Destroy pathogens 
	• Neutrophils 
	• Mo
	• Dendritic cells 
	• Belong to the innate immune system
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26
Q

What is the definition of phagocytosis

A 
- Cell eating 
	• Microorganisms 
	• Other cells 
	• Nutrients 
- Mechanisms of innate immune system
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27
Q

What are the roles of phagocytosis

A
  1. Protection from pathogens
  2. Disposal of damaged and dying apoptotic cells
  3. Processing and presentation of the antigens (Ag)
    • Activation of adaptive immune system
    • Links innate and adaptive immunity
    • Main phagocytes
    • PMN
    • Mo
    • DCs
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28
Q

Steps of phagocytosis

A
  1. Phagocyte mobilisation
    • Chemotaxis
  2. Recognition and attachment
  3. Engulfment
  4. Digestion
    • Pathogen destruction
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29
Q

Phagocyte defects and disease

A
  • Can be quantitative or qualitative
  • Quantitative = fall in number
  • Qualitative = fall in function

Examples

1. Chronic granulomatous disease 
2. Chediak Higashi syndrome 
3. Leucocyte adhesion defects (LADs)
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30
Q

Defects in phagocytosis and disease

A
  • Chronic granulomatous disase
    • Mutation in NADPH component
    • Defect in oxidation
  • Phagocytosed microbes cannot be killed
  • Get recurrent infections
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31
Q

Describe characteristics of chediak higashi syndrome

A
  • Defect in phagosome lysosome fusion
  • Phagocytosed microbes cannot be killed
  • Recurrent infections occur
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32
Q

Give the characteristics of Chediak Higashi syndrome

A
  • Rare genetic disease
  • Defective gene
    • LYSosomal Trafficking Regulatory (LYST)
    • Defect in lysosome function
  • Neutrophils have defective phagocytosis
  • Repetitive, severe infections
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33
Q

Leucocyte adhesion defects

A
  • Defect in the beta chain integrins

- Defective neutrophil chemotaxis

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34
Q

Defects in pathogen recognition

A
  • TLRs = recognise pathogens
  • Present on:
    • Phagocytes
    • Mucosal epithelial cells
    • Endothelial cells
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35
Q

Defects in pathogen recognition

- cell surface

A
  • TLR1, TLR2, TLR4, TLR5

- Detect extracellular pathogens

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36
Q

Defects in pathogen recognition

- inside cell

A
  • TLR3, TLR7, TLR8, TL9

- Microbial nucleic acids

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37
Q

Defects in TLRs and disease

A
  • Humans lacking TLRs have not been identified
  • Polymorphism in TLR genes will presdispose to:
    • Bacterial infections
    • Asthma
    • Autoimmunity (lupus)
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38
Q

Response to infection from the innate immune system

A
  • Rapid response
  • Non-specific (generic anti-bacterial, or anti-viral mechanism)
  • Most often fails to completely eliminative the infection
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39
Q

What are the characteristics of the innate immune system

A
  • Born with (natural + native immunity)
  • In place before the infection gets there - 1st line of defence
  • Rapid response (immediate and then is maximal in hours)
  • Limited recognition capacity ~ 1000 structures
  • Responds in the same way to repeated infections
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40
Q

What are the characteristics of the adaptive immune system

A
  • Triggered by exposure to microbes, so is acquired
  • There is a lag time - exposure to maximum response can take days
  • Combats pathogens that evade or overwhelm innate system
  • More efficient @ eliminative infections
  • Exquisitce specificty, > 107 structures
  • Has memory + remembers pathogens
  • Better / faster with each repeated exposure
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41
Q

What are the components of the adaptive immune system

A
  • T & B lymphocytes
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42
Q

What are the characteristics of humoral immunity

A
  • Humor = fluid

- Serum contains substances that will neutralise the infectious agent - “Antibody Ab”

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43
Q

What is the definition of antibodies

A
  • Antibodies (Ab) = immunoglobulins (Ig)
  • Produced in response to foreign structures, (antigens Ag)
  • The part of an antigen that is recognised by the antibody is the epitope
  • Antibodies have exquisite specificity for their antigens
  • Antibodies are very diverse (>107 specificites)
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44
Q

What is the definition + action of antibodies

A
  • They are immunoglobulins
  • The migrate in Y globulin fraction of serum
  • Fraction of serum that has immune properties

Serum protein electrophoresis

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45
Q

What can antibodies be used for

A 
- As tools for diagnostic assays 
	Ø ELISA 
	Ø Western Blotting 
	Ø Flow Cyotmetry 
	Ø + research
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46
Q

Describe the structure of antibodies

A
  • Tetrameric proteins
  • 2X identical heavy chains and 2X identical light chains, which are held together by disulfide bonds
  • There are 5 types of heavy chains
    • m, g, a, d, e
  • There are 2 types of light chains
    • k, l
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47
Q

Describe the structures of antibodies

A
  • The light chains = 24kDA

- Heavy chain = 50-70kDa

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48
Q

Antibody heavy chain characteristics

A
  • 3-4 constant © domains and 1 variable (V) domain
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49
Q

Antibody light chain characteristics

A
  • 1 constant domain, 1 variable domain
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50
Q

Describe the antibodies structure + function relationship: what are the 2 main roles of antibodies
= Recognition of an infinite number of antigens

A
  • Antigen binding site (Fab)
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51
Q

Describe the antibodies structure + function relationship: what are the 2 main roles of
antibodies
Effector functions of antibodies

A
  • Via Fab
  • Bind + neutralise / block entry of antigens
  • Other effector functions - mainly mediated by Fc portion
  • Interaction with other cells, complement activation
    Ø Macrophages
    Ø Eosinophils
    Ø Both have Fc receptors (FcR)
    ○ Binding of microbes opsonised by Ab
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52
Q

How to achieve this recognition of infinite antigens

A
  • Antigen binding site = Fab
  • VH and VL domains, have 3 hypervariable regions
  • These hypervariable regions correspond with protruding loops
  • These protruding loops make contact with the antigen
  • Hypervariable regions of heavy and light chain, form the antigen binding surface
  • Hypervariable regions = complementarity-determining regions
    Ø CDR1
    Ø CDR2
    Ø CDR3
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53
Q

What is special about CDR3

A
  • Has the highest variability

- Due to genetic mechanisms, that ensure Ab diversity

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54
Q

Describe hypervariable regions and Ag binding

A
  • Ig Primary structure = CDRs are separated

- Ig Tertiary (3D) structure= CDRs become adjacent to each other

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55
Q

Describe what happens in hypervariable regions & Ag binding

A
  • Amino acid residues in hypervariable regions, will make contact with the aa residues in Ag
  • Biding of diverse antigens by antibodies, is mainly due to hypervariable regions of VH and VL
  • The rest of the variable region forms a framework
  • This keeps the hypervariable regions in position to interact with Ag
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56
Q

Describe the generation of antibody diversity

A
  • Over 107-109 different types of B cells generated randomly
  • Each of these B cells makes different antibody,
  • B cells are generated in bone marrow, where they go through different developmental stages
  • Naïve B cells populate lymph nodes / spleen. Wait for antigens
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57
Q

Describe the process of clonal selection

A
  • Antigen specific clones of lymphocytes will develop before, and in the absence of the antigens in central (generative) lymphoid organs
  • Lymphocyte clones specific for >107 antigens
  • Present BEFORE exposure to antigen
  • When antigen enters (infection), it activates (selects) the specific lymphocyte clone
    • Expansion of antigen specific clone
    • Generation of Abs specific for that Ag only
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58
Q

Natural immune responses are polyclonal - describe how

A
  • More than 1 clone of B cells is generated
  • More than one Ig is synthesised
  • Because there are:
    Ø Multiple antigens on organism
    Ø Multiple epitopes on each antigen
    Ø More than one Ig may recognise the same epitope
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59
Q

How many Ig genes are inherited?

A
  • No complete Ig gene is inherited
  • Only bits of genes, gene segments
  • Combinations of gene segments allow generation of a high number of different immunoglobulins
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60
Q

Antibodies - generation of diversity:

Describe immunoglobulin gene locus

A
  • Rearrangement of Ig genes during B cell development

- Gene segment recombination = Ab diversity

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61
Q

Antibodies - generation of diversity:

Gene segments for variable & constant domains

A
  • VH encoded in 3 gene segments (V,D,J)
  • VL encoded in 2 gene segments (V,J)
  • Gene segment recombination = Ab diversity
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62
Q

Describe the heavy chain gene locus - Variable region

A

Ø 45V (variable)
Ø 23D (diversity)
Ø 6J (joining)

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63
Q

Describe the heavy chain gene locus - Constant region

A

Ø 9C (different types of heavy chain

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64
Q

Describe the light chain gene locus

A
  • K chain segments
    Variable region
    Ø 35V (variable)
    Ø 5J (joining)

Constant region
Ø 1C

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65
Q

Describe the generation of diversity in antibodies

A
  • There is somatic recombination (V-D-J) joining, addition of N and P nucelotides
    • Transcription and RNA processing the 3 cell clones
    • Endonuclease cuts randomly after 1 D + before one J and then after 1 V and before DJ
    • The free ends are ligated together, to form a functional gene
    • This is DNA joining and NOT RNA splicing
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66
Q

What increases the number of antibodies

A

Ø Junctional diversity and other mechanisms

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67
Q

What is junctional diversity?

A
  • Increases the number of Ab generated
  • The enzyme terminal deoxynucelotidyl transferase (TdT)
  • Adds random nucleotides (N nucelotides) to the free ends, before joining
    • Leads to differences in the sequences of Antibodies that are produced

Ø CDR3 – the most variable portion of the Ig molecule is located at the site of D-J (heavy chain) or V-J joining (light chain)
Ø D-J or V-J joining are the sites of N nucleotide addition => maximum variation of Ig sequence corresponds to CDR3

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68
Q

Why is TdT important

A
  1. Generates Ig + TCR gene diversity
  2. Leukaemia marker
  3. Useful enzyme in genetic engineering and recombinant DNA work
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69
Q

What is alleic exclusion

A
  • B cells = diploid => 2 alleles of all Ig genes
  • Heavy chain
    Ø 2 allels
    Ø In theory could make 2 different heavy chains
  • This never happens because of allelic exclusion
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70
Q

What is the mechanism of alleic exclusion (heavy chain)

A
  • As soon as one allele rearranges successfully and heavy chain product is produced
  • This will turn off the heavy chain rearrangement
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71
Q

Describe allelic exclusion in light chains

A
  • 2 allels for K chain, and 2 alleles for (upside downY) CHAIN
  • In theory they could make 4 different light chains!
  • This never happens because of allelic exclusion
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72
Q

What is the mechanism of allelic exclusion (light chain)

A
  • As soon as one allele rearranges successfully and the light chain protein is produced
  • Will switch off light chain rearrangement
  • Each B cell or B cell clone makes either K or λ chains, never both
  • Polyclonal B cells are a mixture of cells making K or λ chains ==> light chain restriction
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73
Q

Describe Ig Expression during B cell maturation?

A

Ø Functional Ig is expressed as membrane (cell surface) IgM
Ø Membrane IgM acts as B cell receptor (together with IgD)
Ø Antigen recognition by membrane IgM => activation of signalling pathways => B cell activation

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74
Q

Membrane vs. Secreted Abs

A

Ø B cells have membrane bound Antibody (the antigen receptor)
Ø Upon activation => switch to secreted form of Ab
Ø Generated by differential splicing of exons

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75
Q

Describe the characteristics of Antibodies (Abs)

A
  • There are 2 forms
    1. Membrane bound on B cell surface => Ag receptor
    2. Secreted (circulation, tissues, mucosa)
  • Membrane bound Igs
    => Ag recognition => B cell activation => Humoral IR
    -
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76
Q

With antibodies, what are the characteristics of secreted Igs?

A

Ø Circulate in the blood
Ø Access various sites to deal with pathogens
Ø They have effector function
1. Neutralisation of microbes + toxins
2. Opsonisation of microbes, to enhance phagocytosis
3. Complement activation (pathogen killing)

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77
Q

How do antibodies work?

A

Ø There are different classes of Abs. They work best at certain sites
• IgM
• IgG - Blood
• IgA - Mucosa
Ø Different classes of Abs work best against certain pathogens
• IgE - Parasites
Ø Bind to extracellular microbes & toxins
• Neutralise (block adherence and entry)
• Elimination
Ø Opsonisation is the increase of phagocytosis
Ø Lysis

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78
Q

Describe the isotype switching in Antibodies

A
  • During an immune response, the B cells will become capable to produce antibodies of different classes, but without changing specificity
    • Respond to the same Ag.
  • IgM, switch to => IgG, IgA, IgE
  • IgG, switch to => IgA, IgE
  • Ability to perform different effector functions
  • Can therefore deal better with pathogens
  • Isotype switch needs signals from the helper T cells
  • Isotype switching does NOT alter specificity for the Ag.
  • Isotype switching does NOT alter the light chain.
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79
Q

Describe T cell help and the Ab isotype switch

A
  1. CD4 0L on the T cell will interact with CD40 on B cells
  2. Cytokines are produced by the T cell

IFN y => Switch to IgG1, IgG3
IL4 => switcch to IgE
TGF b (& other cytokines) => switch to IgA

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80
Q

Antibodies - isotype switching

A
  • This is the DNA rearrangement process

- Antibodies retain already rearranged variable regions, whilst exchanging constant regions

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81
Q

Describe the Co-expression of IgM and IgD

A
  • IgD is coexpressed, with IgM (works as antigen receptor)
    Ø IgM is 1st immunoglobulin to be produced
    Ø IgD is produced at the same time with IgM
    ○ The mechanism for this is differential splicing
  • Exons for Cμ and Cδ are transcribed as part of a single precursor RNA
  • Differential splicing, can remove Cμ exons => now Cδ exons are used => IgD (same VDJ as IgM joined to the Cδ)
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82
Q

What can differential splicing remove

A
  • IgD is coexpressed, with IgM (works as antigen receptor)
    Ø IgM is 1st immunoglobulin to be produced
    Ø IgD is produced at the same time with IgM
    ○ The mechanism for this is differential splicing
  • Differential splicing, can remove Cμ exons => now Cδ exons are used => IgD (same VDJ as IgM joined to the Cδ)
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83
Q

What is affinity maturation?

A

Ø Antibodies that are produced early during the immune response have lower affinity for antigen
Ø Later on during the immune response, & in secondary immune responses => production of high affinity antibodies
Ø This process will lead to increased affinity of Antibodies = affinity maturation
Ø MECHANISM: Somatic mutation of Immunoglobulin genes are followed by a selection of B cells, that produce antibodies with the highest affinities
• This needs signals from helper T cells

Ø The activated B cells, have a high rate of point mutations targeted by the Ig genes = somatic hypermutation
Ø Somatic hypermutation is localised in rearranged VDJ or VJ (corresponding to the variable region)
Ø Some mutations decrease affinity for binding to Ag
Ø Some mutations increase affinity for binding to Ag
Ø The next step is selection of B cells with high affinity for Ag.

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84
Q

What is the mechanism of affinity maturation?

A

Ø Antibodies that are produced early during the immune response have lower affinity for antigen
Ø Later on during the immune response, & in secondary immune responses => production of high affinity antibodies
Ø This process will lead to increased affinity of Antibodies = affinity maturation
Ø MECHANISM: Somatic mutation of Immunoglobulin genes are followed by a selection of B cells, that produce antibodies with the highest affinities
• This needs signals from helper T cells

Ø The activated B cells, have a high rate of point mutations targeted by the Ig genes = somatic hypermutation
Ø Somatic hypermutation is localised in rearranged VDJ or VJ (corresponding to the variable region)
Ø Some mutations decrease affinity for binding to Ag
Ø Some mutations increase affinity for binding to Ag
Ø The next step is selection of B cells with high affinity for Ag.

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85
Q

What is the mechanism of affinity maturation?

A

Ø Somatic mutation of Immunoglobulin genes are followed by a selection of B cells, that produce antibodies with the highest affinities
Ø Affinity maturation needs signals from helper T cells

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86
Q

Characteristics of affinity maturation in B cells

A

Ø B cells, that have high affinity Ag receptors are selected to survive
Ø B cells with low affinity Ag receptors might fail to survive (competiton for antigen recognition on follilcular dendritic cells, in the germinal centres)
Ø There is preferential selection of B cells, that have high affinity Ag receptors during immune responses

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87
Q

Describe B cell selection in Germinal Centres

A
  1. B cell activation by protein antigen & helper T cells
  2. B cells with somatically mutated Ig V genes and Igs with varying affinities for the antigens
  3. B cells encounter antigen on follicular dendritic cells (FDC) & present antigen to the TFH cell
  4. B cells with high affinity antigen receptors will preferentially recognise the antigen on FDCs, interact with TFH cells and are selected to survive
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88
Q

B cell antigen presentation to helper T cells

A
  1. There is exit of high affinity antibody secreting memory and B cells
  2. Somatic mutation and affinity maturation, isotype switching
  3. B cell proliferation
  4. Activation of B cells and migration into the germinal centre
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89
Q

Class switching summary

A
  • Occurs by DNA rearrangement

- The arranged VDJ (codes for Ag specificity) is not altered in class switching

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90
Q

Somatic hypermutation

A
  • Ig genes in activated B cells, undergo somatic hypermutation
  • B cells which gain higher affinity for antigen are selected to survive
  • The result is affinity maturation (increased Ab affinity for Ag)
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91
Q

What is complement?

A

Ø Means - “to make complete”
Ø Complements / adds to the action of antibodies, e.g. bacterial killing
Ø Originally described as: “Heat sensitive component of serum that could augment the ability of antibodies to inactive antigen”

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92
Q

Definition of complement

A
  1. Group of plasma proteins, normally inactive
    Ø More than 30 plasma & cell surface proteins
    Ø 9 central components of the complement cascade
    Ø Complement component 1 (C1) to C9
  2. Triggers => activation of complement pathways
    Ø Part of both innate immunity and humoral immunity
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93
Q

What is the purpose of complement activation

A

Ø The generation of products that mediate effector functions of complement

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94
Q

What does complement activation involve

A

Ø Cascade of enzymatic cleavage of complment proteins (proteolytic cascade) [amplification]
Ø Products of complement proteolysis attach covalently to microbial surfaces, or antibodies that are bound to microbes, or other antigens [stabilisation]
Ø Regulatory proteins will inhibit complement activation on the healthy host cells, absent from microbes [specificity]

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95
Q

What is amplification in the complement cascade

A
  • When each activated protease can generate multiple activated proteases in the following step
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96
Q

What is stabilisation in in the complement cascade

A
  • Complement proteins are inactive/transciently active when in the fluid form
  • Stable activation when deposited on the microbes
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97
Q

What is specificity in relation to complement

A
  • Complement activation on the microbial surfaces, whilst minimising complement mediated damage to the host cells
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98
Q

What are the roles of complement

- 1. To eliminate microbes

A
  1. Pathogen opsonisation - facilitates phagocytosis
  2. Inflammation - recruitment + activation of leucocytes
  3. Microbe lysis
    MAC: Membrane Attack Complex

(2. Eliminate apoptotic cells + debris
3. Promote clearance of Ag:Ab (immune) complexes
4. Promote B cell activation )

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99
Q

Complement activation pathway: describe the classical pathway

A
  • C1 interacts with antibodies (IgM, IgG), bound to microbes
  • Effector mechanism of humoral (adaptive) immunity
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100
Q

Complement activation pathway: describe the alternative pathway

A
  • Direct recognition of microbial structures (innate immunity )
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101
Q

Complement activation pathway: describe the Lectin pathway

A
  • MBL (mannose binding lectin) will recognise terminal mannose residues on microbes (innate immunity)
  • Ficolin recognises residues on microbes (innate)
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102
Q

Characteristics of the complement activation pathways

A
  • There are different triggers for initiation of each pathway, but there are similar consequences:
    Ø Generation of proteolytic enzymatic complexes
    Ø C3 convertase
    ○ Cleaves C3 in C3a and C3b
    Ø C5 convertase
    ○ Cleaves C5 in C5a and C5b
  • Proteolytic products of complement proteins identified by lowercase letters afterwards
    Ø “a” for smaller product, “b” for larger product
  • C3 cleavage is crucial for all complement functions
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103
Q

Explain the alternative complement activation pathway

A

Ø Spontaneous cleavage of C3 in plasma (C3 tickover)
Ø C3 contains a reactive thioester bond (which is hidden)
Ø C3 cleavage induces conformational change in C3b, which exposes this thioester bond
Ø This exposed thioester bond will react with an amino, or hydroxyl group on the surface of microbes to form ester bonds => covalent attachement of the C3b to the surface of microbes/cells
Ø When there is an absence of covalent attachement, C3b remains in fluid phase, rapidly inactivated by hydrolysis => further complement activation is stopped.

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104
Q

Steps of the alternative pathway

A
  1. Covalently tethered C3b will bind factor B
  2. This bound factor B is cleaved by Factor D (plasma protease)
  3. Generates Bb (large) and Ba (small) fragments
  4. Bb will remain attached to the C3b
  5. C3bCb complex, is the alternative pathway C3 convertase
  6. C3 convertase has main function, to cleave more C3 molecules => amplification of complement activation
  7. Newly generated C3b deposits of microbial surface
  8. C3a is a soluble fragment; mediates biological activities
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105
Q

What is the alternative pathway to C3 covertase

A
  • C3bCb complex
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106
Q

Role of C5 convertase in the alternative pathway

A
  • Some C3b molecules will bind to C3 convertase (C3bBbC3b)
  • C3bBbC3b is alternative pathway for C5 convertase
  • C5 convertase cleaves C5 & initiates late steps of complement activation
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107
Q

Steps of the alternative pathway (late steps )

A
  1. C5 convertase will cleave C5 in C5b (large) and C5a (small)
  2. C5a = soluble fragment, has several biological activities
  3. C5b remains bound to C5 convertase
  4. C5b recruits C6 and C7
  5. C7 = hydrophobic ==> inserts into lipid membranes
  6. C7 recruits C8
    Ø 3 chains, one will insert into the membrane
  7. C5b-C8 complex will recruit C9 ==> C9 polymerises ==> pores
  8. C5b - C9 is called MAC (Membrane Attack Complex)
  9. Lysis of microbe by MAC; entry of H20 via C9 pores
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108
Q

Describe the classical pathway

A
  • Initated by binding of C1 to antigen bound IgG or IgM
    Ø C1 = multimeric protein complex of C1q, C1r, C1s
    Ø C1q binds to antibodies (IgM, IgG1, IgG3)
    Ø C1r & C1s = proteases
    Ø C1 does not bind to soluble (free) antibody molecules
    Ø C1 binds only to antibodies, that are bound to Ag.
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109
Q

Characteristics of C1 complement component

A

Ø C1q hexamer = 6 globular heads, which are connected via collagen like arms, to a central stalk (“bunch of tulips”)
Ø C1r (x2) & C1a (X2) form a tetramer

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110
Q

The classical pathway steps - what actually happens

A
  • The globular heads to C1q will bind specifically to the Fc regions
  • Each Fc region has only 1 C1q binding site
  • C1q must bind at least 2 Ig Fc regions, to be activated
  • Only antibodies bound to Ag fulfil this requirement
  • Multiple IgGs are brought together, only when bound to Ag
  • Free (circulating) IgM is pentameric, and in planar configuration
  • C1q cannot access the Fc regions of the free IgM
  • When the IgM binds to Ag => “staple” configuration
    • Unmasks the C1q binding site of the Fc regions => binds to C1q
  • Binding of 2+ globular heads of C1q to Ag- bound antibodies => activates C1r
  • C1r cleaves + activates C1s
  • C1s cleaves C4 => C4b (large) + C4a (small + soluble)
  • C4 has similar structure to C3 (internal thioester bond)
  • C4b binds covalently to the antigen surface
  • Recruitment of C2
  • C2 is cleaved by C1s into C2a (larger) and C2b (smaller; no biological function)
  • C4bC2a complex is classical pathway C3 convertase
111
Q

What is classical pathway C3 convertase

A

C4bC2a complex

112
Q

Steps of the classical pathway

A
  1. C3 convertase cleaves more C3 molecules
  2. Newly generated C3b deposits on microbial surface
  3. C3a = soluble fragment - mediates biological activities
  4. Some C3b binds to C3 convertase complex => C4b2a3b
  5. C4b2a3b is the classical pathway of C5 convertase
  6. C5 convertase cleaves C5 and initiates the late steps of complement activation
113
Q

Lectin pathway = complement activation

A
  • This is initated in the absence of antibodies
  • Triggered by microbial carbohydrate recognition by PRRs
  • PRRs involved:
    • MBL (mannose/mannan binding lectin)
    • Ficolins
    • Similar structure to C1q
  • MBL binds to mannose residues on microorganisms
  • Ficolin = binds to N-acetylglucosamine residue on microbes
114
Q

Complement activation - lectin pathway

A
  • Binding of MBL to mannose residues on microorganisms
  • Binding of ficolin to N-acetylglucosamine residues on microbes
  • Activates of MBL - Associated Serine Proteases (MASP1 & MASP2)
  • MASPs will cleave C4 and then C2
  • Then proceeds similarly to the classical pathway
115
Q

Functions of complement

A

Ø C3a, C4a, C5a all trigger acute inflammation
Ø Bind to mast cells => degranulation => histamine release
Ø Also known as anaphylatoxins (mast cell degranulation similar to anaphylaxis)
Ø C5a also acts on neutrophils => chemotaxis + ROS
Ø C5a increases permeability of endothelial cells + neutrophil adhesion to the endothelium

116
Q

Regulation of the complement activation

A
  • Prevents complement activation on healthy cells

- Limits the duration of complement activation on microbes or Ag: Ab complexes

117
Q

Mechanisms of complement regulation?

A
  1. Inhibits formation of C3 convertase
  2. Break down/ inactivate C3/C5 convertase
  3. Inhibits MAC formation
118
Q

What are the fluid phase regulators of complement

A

Ø Present in plasma, body fluids
Ø Factor H, properdin (activator) => alternative pathway
Ø C1 inhibitor (C1INH), C4 Binding Protein (C4BP)

119
Q

Membrane bound regulators of complement?

A

Ø CD46 (MCP = Membrane Cofactor Protein)
Ø CD55 (DAF, complement Decay Accelerating Factor)
Ø CD59 (protectin)
Ø Complement Receptor 1 (CR1)

120
Q

Complement regulators - C1 INH

A
  • Inhibits formation of C3 convertase
    Ø C1INH dissociates C1r and C1a from C1q
    Ø C1INH blocks proteolytic activity of C1r and C1s
121
Q

Where are DAF, MCP, CR1 found?

A
  • Present on surface of healthy cells
122
Q

Where are factor H and C4BP found

A
  • Present in plasma
123
Q

DAF, CR1 actions?

A
  • Displace C2a from C4b2a C3 convertase

- Displaces Bb from alternative pathway C3 convertase

124
Q

C4BP actions?

A
  • Binds C4b + displaces C2a from C4B2a C3 convertase
125
Q

Factor H actions?

A
  • Binds C3b & displaces Bb from alternative pathway C3 convertase
126
Q

MCP actions?

A
  • Binds C3b, C4B => Co-factor for Factor 1 degradation of C3b + C4b
127
Q

Complement regulation - C3b degradation

A
  • Covalently bound C3b is degraded by plasma factor 1
  • ## MCP, factor H, C4BP, CR1 are cofactors for Factor 1
128
Q

Complement regulators - CD59 (protectin)-

A

Ø Present on surface of healthy cells
Ø Binds to C5-C8
Ø Inhibits the recruitment + polymerisation of C9
Ø Inhibits MAC formation

129
Q

Complement regulators:

Ø DAF, MCP, CR1, CD59

A
  • On healthy cell and absent on microbes
  • Selective inhibition of complement activation on host cells
  • Preferential activation of complement on microbes
  • Healthy host cell surface = rich in sialic acid residues
  • Favours binding of factor H over factor B
  • Selective inhibition of complement activation on host cells
  • Preferential activation of complement on microbes
130
Q 
Complement deficiencies (regulatory proteins)
- what happens in C2, C4, C1q deficiency
A
  • SLE like syndrome
131
Q 
Complement deficiencies (regulatory proteins)
- what happens in C3 deficiency
A
  • Frequent serious infections with pyogenic bacteria
132
Q 
Complement deficiencies (regulatory proteins)
- what happens in Properdin, Factor D deficiency
A
  • Infections pyogenic bacteria
133
Q 
Complement deficiencies (regulatory proteins)
- what happens in C5-C9 (MAC) deficiency
A
  • Disseminated infections

- With Neisseria (N.Meningitis, N gonorrhoea)

134
Q 
Complement deficiencies (regulatory proteins) - C1 INH deficiency
	Ø Increased cleavage C4, C2
	Ø Oedema in the skin + mucosa
	Ø Abdo pain, D&V
	Ø Airway obstruction
A
  • Hereditary angioedema
135
Q

Complement deficiencies (regulatory proteins) - DAF, CD59 deficiency

A
  • Paroxysmal nocturnal haemoglobinuria

- Recurrent intravasuclar haemolysis (RBC lysis)

136
Q

Complement deficiencies (regulatory proteins) - Factor I deficiency

A
  • Uncontrolled cleavage of C3 => C3 depletion

- Increased infections with pyogenic bacteria

137
Q

What is the definition of a vaccine?

A

Ø Material from an organism that will actively enhance adaptive immunity
Ø Produces an immunologically “primed” state that allows for a rapid secondary immune response on exposure to antigen
Ø Disease prevention, but not infection prevention
Ø Long lasting
Ø Requires immunological memory
Ø Antibodies and or T cells
Ø There is humoral and cell mediated immunity

138
Q

What is the rationale behind vaccines

A
  • Decreases the rate and severity of disease
  • Protection of the individual and the population
  • Disease eradication (e.g. smallpox and poli)

Ø Rubella = mild disease. The aim is to prevent congenital damage, not protecting the population

139
Q

What is the vaccine paradox?

A
  • Herd immunity: memory is boosted by:
    1. Period outbreaks of disease in the community
    2. Vaccines
  • As the disease states decline, there is no natural boosting
  • This increases the important of vaccination take up rates.
140
Q

What are the types of immunity? - Active immunity

A
  • Natural exposure (carriage)
  • Infection
  • Vaccination
  • Innate
  • Adaptive (CMI, antibodies)
  • LONG effect
141
Q

What are the types of immunity? - Passive immunity

A
  • Prophylaxis and or treatment
  • Antibody from another source: serum
  • SHORT effect
    • e.g. pooled human immune sera with high titre vs. VZV (VZIG)
    • Horse anti-tetanus sera in WW1 decreased mortality X30
    • Post exposure protection in rabies + vaccine (long incubation period, so vaccine works)
  • Hypogammaglobulinaemia: kept infection free with pooled normal human IgG
142
Q

Describe the human responses to antigen - Primary exposure

A
  • 5-7 days => antibody response
  • 2 weeks => full response
  • IgM => IgG switching
  • Memory T and B cells
143
Q

Describe the human responses to antigen - Secondary exposure

A 
(prior exposure) 
	- 2 days for full protective response
	- Post exposure immunoprotection because of response vs specific antigens 
		○ Surface proteins 
		○ Polysaccharides 
		○ Toxins 
		○ Good targets for vaccine candidates
144
Q

What are the general principles of vaccines

A
  1. They induce the correct type of response
    Antibodies => polio virus
    Cell mediated immunity => Tuberculosis
  2. Induce responses in the right place
    Mucosal - sIgA => flu, polio
    Systemic- Yellow feverØ Parenteral vaccines = poor mucosal immunity
    Ø Oral vaccines = processed by MALT, good IgA.
3. Duration of protection 
	Short term (travel) - antibody is sufficient 
	Long term = memory is essential!
	Boosters = can be natural (seasonal epidemics, carriage), vaccines 
	Infection type:
	Ø Long incubation time = systemic (measles)
	Ø Short incubation time = surface (cholera)
	- It is difficult to induce long lasting immunity @ mucosal surfaces
145
Q

Describe the haemophilus influenzae in Bacterial meningitis

A
  • Paeditric disesae
    1. Nasopharynigitis intially (starts with a viral infection)
    2. Spreads to otitis media, sinusitis, bronchitis, pneumonia or sometimes the epiglottis which will require a tracheotomy - croup
      Ø Bacteraemia
      Ø Septic arthritis
      Ø Meningitis (60% cases)
      Ø Neurological disorders (33%)
      Ø Death (5% if not vigorously treated)
146
Q

What are the advantages of oral vaccine administration?

A 
Ø Avoids the use of needles (HIV, HepB)
Ø Mimicry of natural route of infection 
Ø Ensures exposure to "large immune surface"
Ø There is a good sIgA response 
Ø Humoral immunity via lymphocyte trafficking to other mucosal sufaces 
Ø But was it swallowed?
	The new vaccines on this basis:
	- Experimental typhoid Ty21a
	- Cholera B subunit
	- Rotavirus
147
Q

Describe the nature of antigens?

- Monotypic antigens

A
  • Measles
  • Get once

There is antigen variation + genetic diversity
- Post exposure immunoprotection due to response vs. specific antigens
○ e.g. surface proteins, polysaccharides, toxins = good targets for vaccine candidates
- Most antigens = immunogenic. But NOT immunoprotective.
- Serology = can differentiate exposure from vaccination, e.g. Hep B surface Antigen.

148
Q

Describe the nature of antigens?

- polytypic antigens

A
  • Flu, gonorrhoea
  • Multiple
  • There is antigen variation + genetic diversity
  • Post exposure immunoprotection due to response vs. specific antigens
    ○ e.g. surface proteins, polysaccharides, toxins = good targets for vaccine candidates
  • Most antigens = immunogenic. But NOT immunoprotective.
  • Serology = can differentiate exposure from vaccination, e.g. Hep B surface Antigen.
149
Q

Describe Types of Vaccines that are live, attenuated organisms

A
  • BCG, polio (Sabin), MMR, yellow fever, VSV
  • By serial passage
  • Low temperature adaptation
  • Recombinant genetics (S. typhi Ty21a; galE + aroA/B/C mutant)
  • Selection of natural attenuated strains.
  • There are 3 different doses. This prevents strain antagonism & ensures that there is adequate immune response against each type.
150
Q

Polio (sabin) characteristics

A
  • Type 1 has 57 mutations
  • But type 2& 3 only have a few mutations
  • Possible to revert
151
Q

Describe the characteristics of sub-unit vaccines (individual components)

A
  • Proteins
  • Toxoids (diptheria, tetanus)
  • Peptides (synthetic)
  • Polysaccharide
    • Poor antigens
    • Conjugated to toxoid + outer membrane protein - e.g. MenC; Hib
  • Recombinant proteins
  • Sub cellular fractions
  • Surface antigens
    • Hepatitis B, influenza haemagglutinins
  • Virulence determinant
    • aP-pertissis:- adhesin + toxoid + OMP
  • DNA vaccines (encoding antigen)
    • i/m => expression => MHC => Ig + T cells
  • Transgenic food
152
Q

Describe the use of Bacterial Capsular Polysaccharides as vaccines

A

Ø Poor antigens
Ø Short term memory
Ø No T cell immunity
Ø Less immunogenic in children (that are less than 2 years)
• The poor IgG2 responses - IgG2 promotes opsonisation
Ø Enhances immunogenicity by protein conjugation
Ø Toxoids D/T + outer membrane proteins => leads to long lasting immunity + response in children
• e.g. Neisseria Meningitidis Group C (Men C vaccine)
• Haemophilus influenzae Type B (Hib vaccine)

153
Q

Describe the process of conjugation

A

Ø Conjugation links polysaccharide antigen to protein carrier, e.g. diphteria or tetanus, that the infants immune system already recognises in order to provoke an immune response

154
Q

What can vaccine adjuvants + delivery systems do?

A
  1. Enhance the immune response to the antigen
  2. Promotes uptake + antigen presentation
  3. Stimulates the correct cytokine profiles
    e.g. aluminium salts (ALUM)
    Ø Form trapped particles (depot)
    Ø Slow release of Ag
    Ø Large number of Mps exposed
155
Q

Describe the characteristics of Oposthotonus

A
  • Gram positive rods
  • Terminal drumstick spores anaerobe
  • Soil dweller
156
Q

Characteristics of bacterial meningitis - haemophilus influenzae

A
  • Peadiatric disease
  • Usually 6 months to 3 years old
  • Nasopharygnitis (often starting with viral infection) => spreads to otitis media =>sinusitis, bronchitis, penumonia, or sometimes epiglottis (which would need a teracheoctomy) - croup
  • Spreads:
    • Bacteraemia
    • Septic arthritis
    • Meningitis (60% cases)
  • Neurological disorders (33%)
  • Death (5%) if not vigourously treated!
157
Q

Describe the treatment and prevention of Hib meningitis

A
  • Antibiotic therapy (ampicillin) immediately if diagnosis is suspected
  • Or Gram negative pleomorphic rods are seen in the CSF
  • Vaccine effective (99% cases = Type B)
  • Type B Capsule polysaccharide linked to conjugate
    • Diphteria / tetanus toxoids
    • + outer membrane proteins
158
Q

Give examples of vaccines where development is problematic - Neisseria Meningitis Group B

A
  • Capsular polysaccharide - poorly antigenic - sialic acid
  • Non capsular vaccines
    • Outer membrane vesicles of epidemic strains
    • Which antigen induces protective immunity
    ○ porA, adhesins & surface proteins
    • Antigenic variation of many surface components
159
Q

Describe the new MenB vaccine

A
  • Outer membrane vesicles (OMV), from the Neisseria meningitidis group B strain - MenZB (called Bexsero in the UK)
  • Surface proteins (non-variant) of the bacterial - recombinant
    Ø Factor H binding protein (fHbp)
    Ø Neisseria Heparin Binding Antigen (NHBA)
    Ø Neisserial Adhesin A (NadA)
  • 88% efficacy & strain coverage
  • Duration of protection = 10 years
  • 30% reduction in carriage rates
160
Q

Whooping cough - pertussis; describe the Dtap Vaccine

A
  • The DT a P vaccine is used for whooping cough (Pertussis)
  • Whole cell vaccine - killed organisms
  • New low risk acellular vaccine
    Ø Adhesin + pertussis toxoids + outer membrane proteins
  • Blocks adhesion + neutralises toxins - antibody
  • Very effective
161
Q

Describe the influenza virus vaccine that has been introduced

A
  • Trivalent flu vaccine - 70% protection for 1 year
  • 2A + 1B surface antigens
    What will the vaccine contain:
    1. A/New Caledonia/20/99(H1N1)-like virus
    2. A/Fujian/411/2002(H3N2)-like virus
    3. B/Shanghai/361/2002-like virus
162
Q

Describe how you could do skin testing with PPD

A
  • PPD is a purified protein derivative of M. Tuberculosis
  • The Mantoux test does not measure immunity to TB.
    • It measures the degree of hypersensitivity to tuberculin
163
Q

What are the characteristics of cholera and ETEC

A
  • Gives one acute water diarrhoea / travellers diarrhoea

- Vibrio cholera gives a Gram negative curved rod.

164
Q

What are the characteristics of cholera and ETEC vaccine DuKoral

A
  • Cross species protection
  • Similarity of organisms & toxin LT-E.coli & cholera toxin
  • Oral, inactivated (heat and formalin)
  • 4 strains (serotypes e.g. EI Tor) of whole V. cholera
  • Recombinant cholera toxin B subunit
  • The protective immunity is based on antigenicity of toxin B & organism
165
Q

What is the pneumococcal vaccine, streptococcus pneumoniae:

Ø The pneumococcal polysaccharide vaccine PPV23

A

Ø 23 valent pneumococcal polysaccharide vaccine (PPV), for at risk adults + children over age of 2
Ø Children under 2 => not able to make long lasting protective immune response to polysaccharide vaccinse
Ø These 23 types of bacteria = cause ~96% of all pneumococcal disease cases in the UK

166
Q

What is the pneumococcal vaccine, streptococcus pneumoniae:

Ø The pneumococcal conjugate vaccine PCV-13V

A

Ø Polysaccharide from the 13 most common capsule types conjugated to T/D toxoids + OMP as for Hib and MenC

167
Q

HPV vaccination: Gardasil

A
  • Protects against HPV 6,11,16,18
168
Q

HPV vaccination: cervariz

A
  • Protects against HPV 16, 18
169
Q

What is herd immunity?

A
  • The level of immunity in a population against a specific disease
  • Adequate herd immunity is needed to prevent outbreaks of infectious diseases
  • High level of herd immunity particularly will protect vulnerable + unprotected groups
  • When vaccination rates are low = herd immunity will fall + epidemics can occur
170
Q

Immunisation needs of high risk groups: patients with immunodeficiency

A
  • Primary
  • Secondary
    • Acquired through illness e.g. HIV / leukaemia
    • Through treatment like steroids, chemo, radiotherapy
  • Particularly susceptible to lots of infections
  • May not be able to mount normal immune response to live vaccines
  • Could suffer severe manifestations (like disseminated infection with BCG or paralytic poliomyelitis from oral vaccine virus)
  • In general, live vaccines = avoided, inactivated vaccines are safe + indicated. But they might have reduced efficacy.
171
Q

Immunisation needs of high risk groups: patients with hyposplenism

A
  • People with no spleen. Or with “functional hyposplenism” = @ increased risk from bacterial infections
  • Most commonly caused by encapsulated organisms
  • Recommend the following:
    Ø Penumococcal
    Ø Hib
    Ø Influenza
    Ø Meningococcal A & C
172
Q

What are the contraindications to immunisation

A
  • Acute illness = but minor infections without systemic upset NOT reasons to postpone
  • Live vaccines => contraindicated in individuals with immunodeficiency + in pregnancy
  • Anaphylactic reaction to previous dose
  • Specific contraindications for individual vaccines
    • Like hypersensitivity to egg will contraindicate influenza vaccine
173
Q

Contraindications to immunisation - pertussis vaccine

A
  • There are very few individuals who cannot receive pertussis
    Ø Anaphylactic reaction to previous dose
    Ø Anaphylactic reaction to neomycin, streptomycin, polymyxin B (present in trace amounts)
174
Q

Which groups is pertussis recommended for?

A
  • Children w/ history of epilepsy / febrile convulsions
  • Give advice on prevention of pyrexia to minimise the risk of febrile convulsions occuring
  • Children with stable neurological conditions such as cerebral palsy or spina bifida.
    • Neurological complications = more common after whooping cough infection than after pertussis vaccination
175
Q

What are the possible test types that we could do to identify different viruses?

A

What are the possible test types that we could do to identify different viruses?

176
Q

Describe the use of electron microscopy in relation to viruses

A
  • Viruses can be visualised with electron microscope
  • There are lots of different viruses
  • Can be visualised, but this now rarely performed
  • This is still possibly a useful means for faeces and vesicle specimens
  • Replaced by molecular techniques of looking @ the viruses
177
Q

Describe the isolation of viruses within cell culture

A
  • Viruses need host cells
  • To be able to replicate
  • They might cause a cytopathic effect (CPE) of cells
  • When a patient sample that contains a virus incubated with a cell layer
  • Old method = now replaced by molecular techniques
  • But still needed for research, or for rare viruses
  • We can use different cell lines in test tubes, or plates
  • Slow but occasionally useful in antiviral sensitivity testing
178
Q

Describe the CPE= cytopathic effect

A
  • Different viruses can give different appearances
  • Different cell lines might support the growth of different viruses
  • Identify the virus by using antigen detection techniques or neutralisation of growth
179
Q

What are the most common methods of antigen detection

A
  1. Direct immunofluorescence
  2. Immuno-chromatographic methods
  3. Enzyme immunoassay (Enzyme Linked ImmunoSorbent Assay)
180
Q

What are the characteristics of immunofluorescence as a method of antigen detection?

A
  • Antigen from the infected host cells - are bound to the slide
  • Specific antibody (either polyclonal or monoclonal)
  • To that antigen, is tagged to a fluorochromes
    • And then in mixed to the sample
  • Viewed using a microscope equipped to provide ultraviolet illumination
181
Q

Describe the use of ELISA to detect antigens on a virus

A

Ø ELISA = Enzyme Linked Immunosorbent Assay
• A component of the reaction is adhered to a solid surface
• Can be indirect, direct, or sandwich

182
Q

Describe the process of antigen detection via ELISA method

A
  1. Plate gets coated with capture antibody (“to capture” and hold down any antigens that we particularly want to look at)
  2. Sample gets added & any antigen that is present will bind to the capture antibody
  3. Enzyme conjugated primary antibody is added and this binds to the detecting antibody
  4. Substrate is added and is converted by the enzyme to detectable form
183
Q

Describe the immunochromatographic methods that can be used to detect antigens

A
  • Can be in cassette form
  • e.g. diagnosis of dengue
  • Flavivirus
  • Arthropod vector
  • Common infection in returning travellers
184
Q

Describe the diagnosis that can be carried out via antibody detection

A
  • When infected with a virus the humoral immune response will occur
  • This results in production of immunoglobulins
  • IgM antibodies specific to the I virus are produced 1sst
  • IgM present for a variable period, usually between 1-3 months
  • As the IgM declines, IgG is produced
  • Quantity of IgG increases
185
Q

HOW can diagnosis be done by antibody detection

A
  • Detection of IgM
  • Or by the demonstration of seroconversion
    • Negative antibody at first
    • Then presence of antibody
186
Q

Describe the process of serology

A
  • There is indirect detection of the pathogen

- Diagnostic mode of choice for the organism which are refractory to culture

187
Q

What can serology be used to do?

A
  • Detect antibody response, in symptomatic patients
  • Determine if the vaccination has been successful
  • Directly look for the antigen that is produced by the pathogens
  • Serological tests are not limited to blood and serum
    • They can also be performed on other body fluids
    • Such as semen and saliva
188
Q

What are the characteristics of the serum

A
  • Produced from processing blood
    • Blood gets coagulated with micronized silica particles
    • Gel is used to traps cellular components
  • Tubes = centrifuged
  • Supernatant (serum) gets removed and then stored - 4 degrees short term and then -40 degrees Celsius long term
  • Routinely, serum tubes are centrigued fror 10 min @ 1000xg
  • Serum contains
    Ø Proteins
    Ø Antigens
    Ø Antibodies
    Ø Drugs
    Ø Electrolytes
189
Q

Describe the modern lab detection of antibodies & antigens that are in the blood

A
  • Serology
    • This is study of the antigen antibody interactions
  • Can be used to detect antibody and or antigens
  • Usually by ELISA (enzyme immunoassays) or related technology
    • e.g. microparticle immuno chemi luminescence
190
Q

Describe how the antigens and antibodies are actually detected and where this is used?

A
  • Useful for Hep B, Hep C and HIV
  • Allows us to establish if acute or chronic infection
  • This might have therapeutic implications
191
Q

Describe the use of the molecular diagnostic tests

A
  • Nucleic acid amplification (NAAT)
  • e.g. PCR although there are other examples
  • Can detect RNA or DNA
  • Ability to multiplex using fluorescence probes
    • Can look for several targets in 1 sample
  • Might be qualitative or quantitative
  • Requires nucleic acid extraction, prior to the amplification
192
Q

Describe the process of organism sequencing

A

Ø DNA or RNA viruses
Ø Used to predict the response to anti virals
• e.g. for HIV in Rx naïve patients
• Or if clinical suggestion of resistance in drug experienced patients
Ø Consensus sequence based on clinical observation of resistance or in vitro evidence
Ø Minority species sequencing
• Might be selected by treatment
Ø Useful for outbreak investigation = by showing identical sequences in suspected source and recipient

193
Q

Describe the combination of methods e.g. HIV

A
  • Antibody & antigen detection, for initial diagnosis
    • Screening test = EIA
    • Confirmatory test = EIA
  • Viral load (NAAT) @ baseline and to monitor treatment response
    • Quantification of virus in the blood
  • Resistance testing (sequencing)
    • Look for mutations known to confer resistance before and during treatment
194
Q

Give examples of type 1 hypersensitivity

A
  • Pollen. Animal hair, house dust mite, moulds, insect bites, food - peanuts, latex, medicine (penicillin)

Ø 1st exposure to pollen = the sensitisation phase
Ø B lymphocytes will recognise the antigen
Ø They will internalise the antigen, and then present the antigen to the Th2 cells
Ø The Th2 cells will secrete IL4
• This is important in inducing the B cells to switch class ====> IgE producing cells
• And to become IgE producing cells

195
Q

Describe sensitization (1st exposure to pollen) in Type 1 hypersensitivity

A

Ø 1st exposure to pollen = the sensitisation phase
Ø B lymphocytes will recognise the antigen
Ø They will internalise the antigen, and then present the antigen to the Th2 cells
Ø The Th2 cells will secrete IL4
• This is important in inducing the B cells to switch class
• And to become IgE producing cells

196
Q

Describe the effector phase, which is the 2nd step in Type 1 hypersensitivity

A
  • IgE that has been produced from the previous contact with the allergen
  • Will diffuse throughout the body
  • The IgE will come into contact with the mast cells
  • IgE will bind to the MAST CELLS via its tial end, the Fc region
  • This is because the mast cells have receptors for binding to the Fc part of IgE
197
Q

What happens in the second exposure to pollen

A
  • There are mast cells with attached antibodies
  • Pollen enters & binds to antibody Fab region.
  • Mast cells have granules of histamine inside
  • Pollen binds antibodies mast cell surface.
  • Sometimes pollen can LINK 2 antibodies together (cross linking)
    ↓
  • And histamine is released
  • The cross linking happens triggers the histamine release
  • = How allergy is being generated
198
Q

What is the LATE phase reaction of Type 1 hypersensitivity

A
  • Mast cells generating other cytokines
  • They will encourage T helper cells to be able to produce cytokines
  • They encourage T helper cells - to produce cytokines as well
  • Allergic reaction is prolonged
  • This will make the allergy reaction longer
199
Q

IgE mediated allergic diseases characteristics

A
  • 15% population have them, asthma is another e.g.
  • In asthma, the allergic inflammatory response to the allergen
  • Will sensitise the airways
  • Non-specific agents, will then cause the allergic response
200
Q 
Hypersensitivity characteristics 
(Type 2 and 3)
A
  • Type 2 & 3 are initiated by antigen and antibody interaction, IgM and IgG mediated
  • Examples of type 2
    Ø Myasthenia Gravis
    Ø Rhesus isoimmunisation
    Ø Haemolytic disease of the newborn
    Ø Graves’ disease
    Ø Myasthenia gravis and graves’ disease
    ○ In some reports = classified as Type V
201
Q
  • Examples of type 2 Hypersensitivity
A
  • Examples of type 2
    Ø Myasthenia Gravis
    Ø Rhesus isoimmunisation
    Ø Haemolytic disease of the newborn
    Ø Graves’ disease
    Ø Myasthenia gravis and graves’ disease
    ○ In some reports = classified as Type V
202
Q

What are the characteristics of myasthenia gravis

A
  • In healthy people = normal stimulation of muscle contraction
    • The nerve impulses will trigger release of Ach from the nerve endings
    • This will bind to Ach receptors on the muscle cells triggering contraction

What happens in people with myasthenia gravis
• AUTOANTIBODIES
• To the Ach receptors are produced
• These will block Ach receptors @ then post synaptic neuromuscular junction = muscle contraction cannot happen
• Muscle contraction is thus diminished
○ Antibodies binding to the receptors = transmission of the signals cannot happen anymore.

  • Muscle weakness :( = e.g. drooping eyelids
203
Q

What are the characteristics of Rhesus isoimmunisation?

A
  • RhD antigen (rhesus)
  • Is carried on the RBCs
  • Mother = RHD negative
  • Father = RHD positive
  • First pregnancy = mother is sensitised, and often sensitisation will occur at the birth of the first child
  • Mother will make ANTIBODIES against RHD.
  • @ 2nd pregnancy, the fetus again is RHD +
  • There are small amounts of erythrocytes passing across the placenta, which stimulate the memory cells
  • More anti -RHD antibodies are produced
  • And these anti RHD antibodies will cross the placenta
  • Haemolytic disease of the newborn
  • Encourages the memory cells to start producing more antibodies
204
Q

Characteristics of Graves’ disease

A
  • Autoimmune thyroid disease
  • Healthy people = pituitary will make thyroid stimulating hormone (TSH)
  • TSH binds TSH receptors on the cells of the thyroid follicle
  • Triggers them to produce thyroid hormones
  • Thyroid hormones engage in an inhibitory feedback loop, and they stop more TSH being produced

Summary of Graves’ disease
- Pituitary ==> TSH ==> binds to thyroid follicle ==> thyroid hormone is produced ==> negative feedback to stop TSH from being produced
• Autoantibodies continue to trigger the release of thyroid hormones

  • There are circulating autoantibodies to the TSH receptor
  • These will bind to the TSH receptors and trigger the cells to release thyroid hormones
  • The antibodies will STOP the pituitary from making TSH
  • But the autoantibodies are present
  • And will continue to trigger the release of thyroid hormones
  • So the control system is not working anymore
205
Q

What are the characteristics of type 3 hypersensitivity

A
  • Type 3 = target is the soluble circulating antigen
  • Antigen can be own tissue, or foreign material
  • e.g. in systemic lupus erythematosus
206
Q

Characteristics of systemic lupus erythematosus (SLE) autoimmune disease

A
  • Familial pattern, but we do not know how it arises definitely.
  • Patients will make autoantibody that is directed against several self-molecules
  • Such as DNA and nuclear ribonucleoproteins
  • Immune complexes are formed
  • The antibodies in these immune complexes can fix complement - tissue injury
  • Complexes are trapped in the kidney
  • Glomerulonephritis
  • B cell activation = abnormal in patients that have SLE
  • Higher number of B cells @ all stages of activation in SLE patients
207
Q

Problems in systemic lupus erythematosus (SLE) autoimmune disease

A
  • There is evidence that B cells in SLE patients = MORE sensitive to stimulatory cytokines
  • B cells can engage in polyclonal activation
    • If we try to activate a B cell = usually a specific antigen will activate it
    • But activation of B cells in patients will be by several signals which are less sensitive
    • Immune complexes = not cleared by phagocytes. And going into the kidneys and causing problems
  • Changes in cytokine levels
  • Changes in T cell function = Th1 response reduced
  • Problems with phagocytic cells
  • Immune complexes are NOT cleared by phagocytes
  • 9/10 = women, and higher in black population.
208
Q

Type IV hypersensitivity characteristics

A
  • This is delayed hypersensitivity
  • T cell mediated
    • Dendritic cells, macrophages & cytokines contribute to disease process
    • Mantoux test is an example.
  • Patient is injected with extract of mycobacterial antigen in the skin
  • Macrophages will present antigen
  • Th cells are activated
  • Th cells in response ==> release cytokines, which activate macrophages to release cytokines
  • = Firm red swelling of the skin
209
Q

Characteristics of endocrine autoimmune diseases

A
  • Insulin dependent diabetes = Type 1 diabetes
  • Beta cells in the islets of Langerhans
  • Will act as autoantigens
  • Presented by the antigen presenting cells, in the context of MHC class 2
  • Stimulate the CD4+ Th cells
  • Th1 cells release cytokines
  • Activate the T cytotoxic cells
  • Damage the Beta cells
210
Q

Characteristics of Gastrointestinal diseases

A
  • Coeliac disease, small intestine, intolerance for gluten
  • Patients genetics do matter. HLA type = important
  • Patients have:
    Ø IgA anti gliadin antibodies
    Ø Antiendomysium antibodies
    Ø Antireticulin antibodies
  • Antibodies could have originated from the intestinal mucosa
  • T cells present in the intestine
  • Villous atrophy
  • Malabsorption
  • Other examples of type IV hypersensitivity = inflammatory bowel diseases
    Ø Ulcerative colitis
    Ø Chrons disease
    ○ Any part of the GI tract might be involved
    Ø Psoriasis
211
Q

Characteristics of Ulcerative colitis

A
  • Colon

- The mucosal layer is affected

212
Q

Characteristics of GI diseases

A
  • ∆s in relative proportion of T and B lymphocytes
  • High # of B cells producing the antibody on site
  • Deposition of complement components in the intestinal mucosa
  • Possible presentation of autoantigens on MHC class 2
  • Increased interleukin levels
  • Ulcerative colitis Th2 might be involved
  • Chrons T helper 1 cells might be involved
213
Q

What is psoriasis?

A
  • Chronic skin disease
  • 2% of caucasians
  • Onset = usually puberty or menopause
  • Red plaque that covered by silvery skin scales
  • Relapsing and remitting
  • Genetic and environmental factors might also play a role
  • There are lots of CD4+ cells in the skin
    • CD4+ aka T helper cells
  • Immunosuppressive treatment = effective
    • This suggests that the cells involved in pathogenesis
  • Antigen specificity of cells = not known
214
Q

What is autoimmunity

A
  • Acquired immune reactivity
  • To self-antigens
    • Responds to self antigen epitopes in the same way that it would respond to something non-self.
215
Q

When does autoimmune disease occur

A
  • When autoimmune response leads to tissue damage

- 3.5% people have autoimmune disease

216
Q

Factors contributing to the development of autoimmune disease

A

Ø Age + gender could predispose
Ø Autoantibodies = more common in elderly
Ø SLE and Graves are more common in women

217
Q

Genetic predisposition of development of autoimmune disease

A
  • HLA genes (Human Leucocyte Antigen)

- Associated with certain autoimmune diseases

218
Q

Infectious predisposition - of development of autoimmune disease

A
  • There is an association between the infection with EPV and SLE
  • EPV = glandular fever
219
Q

Describe the specific autoantigens involved in development of autoimmune disease

A
  • Highly conserved proteins
  • Are often targets for autoimmune response
    • Antibodies to human heat shock proteins
    • Are seen in some autoimmune disease
    • Could be a cross reaction of antibodies, that were targetting microbial HSPs
    ○ Start making antibodies to that heatshock protein
    ○ They might be similar to the HSPs in our bodies
    ○ So accidentally target our own heat shock proteins
    § So it usually happens in regions that are common between ourselves AND the
220
Q

Drugs predisposition of development of autoimmune disease

A
  • Certain drugs can start autoimmune reaction
  • The mechanism is not known
  • Patients on ventricular arrhythmia’s treatment
  • Develop SLE
  • Stopping treatment will resolve the problem
  • Immunodeficiency will allow persistent infections or inflammation resulting in autoimmunity
221
Q

Disorders of the immune system - immunodeficiency

A

Primary/congenital/inherited

- Immunodeficiency = complement 
- Example is C1q inhibitor deficiency, hereditary angioedema - continuous complement activation
- C3 deficiency = infection
222
Q

Immunodeficiency - phagocytes role + example where this is deficient

A
  • For example Chediak Higashi syndrome

- This is the failure of phagolysosome formation and also lysosome degranulation

223
Q

What happens in B cells deficiencies

A

Severe combined immune deficiency (SCID)

  • Lack of development of the stem cells → T & B cells
  • Hyper IgM syndrome
  • Increased IgM - but little or no IgG

Common variable immunodeficiency (CVID)

  • IgG/IgA deficiency
  • Mainly, a consequence of B cells, being unable to mature into plasma cells
224
Q

T cell deficiency

A
  • Lack of thymus
  • DiGeorges syndrome = incomplete development of the thymus
    • & so cannot produce T cells properly
225
Q

What happens in secondary immunodeficiency

A
  • HIV infection = acquired immunodeficiency syndrome
  • Malnutrition
  • Tumours - cancerous cells that can release immunosuppressive factors
  • Therapy, using cytotoxic drugs + irradiation
226
Q

The capture and processing of antigen:

What is an antigen?

A
  • The word antigen = combination of “antibody” and “generate”… Antibody generators when they come into the system
  • Any molecule that can bind specifically, to an antibody
  • Antigen = usually refers to:
    • Proteins
    • Carbohydrates
    • Lipids
    ○ That are capable of binding to the B cell receptors, T cell receptors, and or innate immune receptors
    ○ And then producing a response
    • Grass pollen = can induce antibody responses in those who are allergic
    • HIV expresses gp120 protein on its surface, envelope protein, which is an ag itself
227
Q

Antigen vs epitope - describe and explain the relationship between the 2

A
  • Adaptive immune reactions occur to specific epitopes
    ○ Epitopes = portions of the antigen molecule
    § Which will specifically interact with antibody
    § Can have multiple epitopes
    § + refers to the portions of antigens that are seen by T cells
  • As opposed to the adaptive immune reactions occurring to the entire antigen itself
  • Infection and vaccination, will usually induce polyclonal T and B cell responses
228
Q

Explain how T cells do NOT recognise native antigens

A
  • B Cell = When there is cross linking of the surface membrane Ig, this will lead to proliferation and antibody production.
    Ø B cell has B cell receptors
    Ø These will be become antibodies when they are released
    Ø Begins to proliferate and multiply, and generate clones of the founder B cells, thus producing the B Cell response
  • T Cell = If there is NOT cross linking of the surface membrane Ig, then there will be no proliferation and no cytokine release
229
Q

Explain how antigens must be processed, in order to be recognised by the T cells

A
  • If a T cell encounters soluble antigens = no response
  • There is a T cell response when:
    ○ The cell surface peptides of the antigen
    ○ Get presented by the cells that express MHC antigens.
  • Have to be processed in a particular way and then presented on the cell in context of the MHC molecule
  • Needs another cell to induce activation
230
Q

Describe the uptake of exogenous antigens

A
  1. Membrane Immunoglobulin mediated uptake (B cell which expressed B CR can capture Ag)
    Ø Whole pathogen opsonised
  2. Complement receptor mediated phagocytosis
  3. Fc receptor mediated phagocytosis
  4. Uptake mechanisms direct the antigen into intracellular phagocytosis
  5. There is pinocytosis and phagocytosis
231
Q

What are “professional” antigen presenting cells (APCs)

A
  • These are immune cells that express high levels of the surface MHC class 2
  • And can therefore efficiently induce the T cell response
232
Q

Which cells recognise + process the antigen?

= macrophages

A
  • Better equipped to kill pathogens
    • Due to higher NO production
  • HIGHLY PHAGOCYTIC ESPECIALLY
233
Q

Which cells recognise + process the antigen?

= Dendritic Cells

A
  • Better at migrating to the lymph nodes
    • Via CCR7
  • And presenting the antigen to the T cells
  • Highly phagocytic
  • MOST efficient APCs in the body
234
Q

Which cells recognise + process the antigen?

= B Cells

A
  • They are highly abundant in the blood and the mucosal tissues
  • NOT properly phagocytic cells - can touch the antigens an internalise into endosomes
  • Receptor mediated internalisation of antigens
    • As opposed to phagocytosis
  • Primary function to make antibody - plasma cells, but still very good at antigen presentations
  • Possibly is the main inducer of T cell immune response to pathogens, such as Neisseria meningitidis
235
Q

What are the characteristics of the B-Cells

A
  • They are highly abundant in the blood and the mucosal tissues
  • Receptor mediated internalisation of antigens
    • As opposed to phagocytosis
  • Primary function to make antibody - plasma cells, but still very good at antigen presentations
  • Possibly is the main inducer of T cell immune response to pathogens, such as Neisseria meningitidis
236
Q

Explain whether exogenous antigen presentation is sufficient?

A
  • Only a few cells can take up bacteria endogenously
  • The macrophages have well developed lysosomal systems
  • These are specialised for:
    Ø Motility
    Ø Phagocytosis
    Ø Introduction of particles to the lysosomal system
  • Most cell types do not have lysosomal systems developed as well as macrophages
  • But viruses can infect most of the cell types
  • A non-lysosomal mechanism to process antigens for presentation to T cells is required
237
Q

Peptide antigens produced in the cytoplasm are physically separated from the newly formed MHC class 1

A
  • Peptides need access to the ER

- In order to be loaded into the MHC class 1 molecules

238
Q

Describe what happens in non lysosomal antigen processing

A
  • Inactive virus will raise a weak CTL response
  • The processing of antigens from inactive viruses:
    • Is sensitive to lysosomotrophic drugs

Ø Antigens from inactive viruses
Ø Are processed, via the EXOGENOUS pathway

  • Infectious virus raises a strong CTL response
  • The processing of antigens from infectious viruses is not sensitive to lyosomotrophic drugs
  • Most CTL recognise antigens that are generated via a non lysosomal pathway
  • protein synthesis is required for non lysosomal antigen processing

Ø Antigens that are from infectious viruses
Ø Are processed via the ENDOGENOUS pathway
• Do the 2 pathways generate the same type of T cell receptor ligand?

239
Q

Where are antigens from inactive viruses processed

A
  • Via the exogenous pathways
240
Q

Where are antigens from infectious viruses processed

A
  • Via the endogenous pathway
241
Q

Describe how an antigen is processed and presented in the Exogenous pathway

A
  • Requires a VIRUS to infect the cell
    • And produce proteins in the cytosol
  • It will have been partially degraded in the proteosome
  • The peptides are formed, which need to travel to the golgi apparatus
  • They load MHC1 molecules, and then will travel to the surface and present these endosomal peptides to the CD8 cells
  • Antigens come into the cell and then get processed
    • And they are loaded onto MHC2
242
Q

Describe how an antigen is processed and presented in the Endogenous pathway

A
  • Requires antigen presenting cells
  • The proteins will get proteolytically degraded into peptides
  • These peptides will then get loaded onto the MHC2 molecules
    • MHC2 molecules are made in the Golgi body
    • And then get transported into the phagolysosomes
  • Get transported to the MHC molecule
  • And then they get to the cell surface, and are expressed on the cell surface
  • They can engage a CD4 type cell
243
Q

Describe how antigens that are generated from endogenous and exogenous antigen processing will activate different effector functions

A
  • Antigens that are generated by endogenous and exogenous antigen processing, activate different effector functions
  • Antigens that are generated by the Endogenous pathway = are really important for elimination of many viruses
  • T cells will kill virally infected cells
  • These are cytotoxic T cells
Exogenous pathogens (on the left hand side)
- Generates cytokines
244
Q

Give the characteristics of the exogenous pathogens - how are they eliminated

A
  • They are eliminated by antibodies and phagocyte activation
  • By T helper cells
  • That use antigens generated by Exogenous processing
245
Q

Give the characteristics of the endogenous pathogens - how are they eliminated

A
  • Via the endogenous pathway, there is:
    Ø Killing of the infected cells by the CTL
  • That use antigens generated by endogenous processing
246
Q

MHC CLASS 1 molecules characteristics

A
  1. Expressed on ALL nucleated cells.
  2. Binds short peptides, (8-10 amino acids)
  3. Presents to CD8+ T-Cells
  4. Deal with antigens from the cytosol (+cross-presentation)
247
Q

MHC CLASS 2 molecules

characteristics

A
  1. Expressed on APCs and activated T cells
  2. Specific to longer peptides (15-24 amino acids)
  3. Presents to CD4+ T cells
  4. Deal with antigens from phagosomes and endosomes
248
Q

Describe the tissue expression of MHC molecules

A 
Ø MHC class 1 = Expressed on all cells apart from RBCs which have no nucleus and therefore no protein synthesis 
Ø MHC class 2 = Expressed only on certain cell types, like macrophages and dendritic cells
249
Q

Human MHC Class 1 Isotypes

A

HLA = human leukocyte antigen

250
Q

The TCR and immunological synapse:

What are the characteristics of the T Cell Receptor

A
  • The T cell receptor, will bind to the peptide-MHC (pMHC) complexes
  • Cannot recognise peptide alone
    Ø Huge diversity - potentially up to 1x10 to the 13 different TCRs specificites
    Ø Exists in a TCR complex, with accessory molecules such as CD3

TCR is the structure on the T cell, that engages this complex on APC
Ø Cannot recognise peptide alone
Ø Has to be in complex with MHC molecules

251
Q

What are the characteristics of the T cell receptor and B Cell receptor

There are crucial diffferences between the 2 = WHAT ARE THE SIMILARITIES

A 
1. The similarities to the B cell receptor / antibody 
Ø Belongs to Ig superfamily 
Ø Like Fab fragment of the antibody 
Ø Large diversity
Ø But single specificity
252
Q

What are the characteristics of the T cell receptor and B Cell receptor

There are crucial diffferences between the 2 = WHAT ARE THE DIFFERENCES

A

Ø Lower affinity - interaction of T cell receptors needs amny additional interactions to increase the strength of the 2 cells
Ø Cannot be released - no soluble T cell receptor
Ø No Fc fragment - therefore T cell receptor cannot activate complementlike antibodies can
○ So no cellular functions
Ø Single, rather than 2 binding sites
○ Therefore has half of the capacity to bind antigens as B cell receptors
Ø B cell receptor / Ab: 5 classes
Ø T cell receptor : 2 classes (alpha beta, and gamma beta)
○ Based on these structural units
○ Alpha beta = conventional receptor
○ Gamma delta = much less frequent

253
Q

Describe T cell receptor diversity generation

A
  • There are various mechanisms which generate B cell receptor diversity
  • Before antigen stimulation: somatic recombination
  • After antigen stimulation : somatic hypermutation = and therefore further diversity
  • Mechanisms which generate T cell receptor diversity
  • Before antigen stimulation: somatic recombination
  • After antigen stimulation: none
    • This is why T CELLS HAVE LOWER AFFINITY THAN B Cells

Ø Receptor gene rearrangement takes place during T cell development in the thymus

254
Q

Generation of diversity

A
  • Alpha and beta locus which has several sets of genes
    Ø Each derived from the germline DNA
  • Combined & get translated

Using many different combinations = can generate lots of diversity of how the molecule could turn out at the end

255
Q

Describe APC-T Cell interactions

What is the 3 signal model of T cell activation

A
  • 3 signal model of T cell activation - The 3 important steps that are involved
    1. Peptide-MHC (pMHC complex)
    2. Co stimulation
    3. Cytokines
  • Signals 1 and 2 alone = will activate a NAIIVE T cell
  • But signal 3 as well, is also important for a strong response and also determining T cell phenotype
  • The cytokines are from the APC and help the cell go the right way about it
256
Q

Describe APC-T-Cell interactions Signal ONE

A

Ø This is the main signal
Ø The signal gets delivered from the APC
Ø By a peptide MHC complex to the TCR
• The receptors have to be specific for that peptide in the MHC Complex
• Or interaction will not occur and none of the molecules will be engaged

257
Q

Describe APC-T-Cell interactions Signal TWO

A
  • Signal is delivered from the APC by germline-encoded accessory receptors
  • Such as the B7 family (CD80 and CD86)
  • Although many of these receptors are NOT fully characterised, or understood
258
Q

Describe APC-T-Cell interactions Signal THREE

A

Ø Signal 3 is formed of cytokines, that are secreted by the APC to determine the T-cell phenotype
• IL12 = promotes the TH1 cells
• IL4 = promotes the TH2 cells
• IL23 = promotes the TH17 cells - functional implications of what these cells can become

259
Q

Describe what happens @ the immunological synapse

A
  • Many interactions between a B cell and antigen presenting cells = peptide complex & the receptor will interact
  • For B cells to stay together long enough = there must be additional strengthening of interaction by integrins which help hold it together - all need to take place for the T cell to become productively activated, needs to be controlled so that the cell does NOT become needlessly activated
    • There is complex interaction of many molecules
  • Simplistically, Signals 1 and 2 are CENTRAL
  • And the surrounding integrins and accessory molecules will help to stabilise this interaction
260
Q

Describe the APC-T-Cell interactions

A
  • TCR engagement = activation of those signalling molecules (that do not need remembering )
  • Convey the message to the nucleus where transcription of genes will occur

These are the pathways that occur following engagement of the molecule

261
Q

T Cell co receptors - CD4 and CD8: CD4

A
  • Either Th1 or TH2
    • TH1 = will engage the macrophages
    • Macrophage might be infected by bacteria and it kills the bacteria
  • Activation of the macrophage and will become more bactericidal
  • Stimulates B cells by the production of TH2 cytokines = B cell activating better and secreting antibodies that count as pathogens
  • Do not kill target cells, they help other cells do their job better
262
Q

T Cell co receptors - CD4 and CD8: CD8

A

Ø Will engage virally infected cells and will kill it
Ø Will kill virus
Ø Cytotoxic T cells
Ø Primary function is to KILL virally infected cells
Ø Killing the cells that cannot be fixed or repaired

263
Q

NEGATIVE REGULATION

- Describe the characteristics of antigen presentation

A
  • Overly vigorous immune response, will be harmful to the host
    • Therefore there are negative regulatory of antigen presentation, will provide an immune checkpoint
      ○ Which will limit T cell activation ==> homeostasis
    • There are 2 important molecules:
      1. CTLA4 (Cytotoxic T Lymphocyte Associated Protein 4)
      2. PD-L1 (Programmed Death Ligand 1)
    • These are both crucial for dampening the T cell response
264
Q

What is the mechanism of PD-L1 and CTLA-4 inhibition of T cell function

A
  • Inhibits T cell activation by interacting with the standard pathway
  • Blockage = and there is competition for the main signalling pathway
  • Dampening by invasion of these molecules
265
Q

What are the characteristics of self-antigen?

A
  • T cells arise from the thymus
    Ø Any T cell that binds too weak or too strong will be deleted
  • Thymus = “a school for T cells”
  • T cells are exposed to self-antigens, and tested for reactivity
  • T cells that CANNOT bind the self antigen-MHC are deleted, in positive selection
    Ø Because these T cells are useless
    Ø As they cannot protect against pathogens
  • T cells that bind self antigen-MHC too strongly are also deleted, in negative selection
  • These T cells are dangerous because they are too self reactive :(
266
Q

Which T cells will be deleted?

A
  1. Those that cannot bind the self-antigen-MHC
    - This is positive selection
    - Because they cannot protect against pathogens
  2. T cells that bind self-antigen MHC too strongly
    - This is negative selection
    - Those T cells are dangerous because they are TOO self reactive
    • HUGE potential for autoimmunity = this is really dangerous
    - Most of these cell production hormones are eliminated
267
Q

Self antigen characteristics

A
  • In some models (STOCHASTIC MODEL)
  • FOX P3
  • A proportion of the T cells that are strongly reactive to self antigen will express the transcription factor FOXP3
  • This is the master controlled of the regulatory T cells (TREG)
268
Q

Describe how pathogens can impede antigen presentation - 1

1. Mycobacterium tuberculosis

A 
- Upregulates PD-L1 on the APCs
	• In order to shut down T cell activation 
- Blocks MHC class 2 expression
	• Via multiple mechanisms
269
Q

Describe how pathogens can impede antigen presentation - 1

Neisseria Gonorrhoeae

A
  • Expresses the OPA protein
  • Which binds to T cells
  • & induces tyrosine phosphatases
    • Which “switch off” key molecules involved in the TCR signalling
270
Q

Describe how pathogens can impede antigen presentation - 1

Neisseria Meningitidis

A
  • Blocks DC activation
    • Low CD40, CD86, and MHC Class I and II expression
  • Antigens (capsule) with homology to self antigen
  • Therefore anergic T cells
271
Q

Describe how pathogens can impede antigen presentation HIV

A
  • Upregulation of PD-1 on the T cells
    • This will antagonise the TCR signalling
  • Binds to DC-SIGN to suppress the DC activation
    • Via Rho GTPases
272
Q

Pathogens can impede antigen presentation - give examples of this
(1. Herpes Simplex Virus)

A
  • Produces protein
  • Which binds to and inhibits TAP
  • Prevents viral peptide transfer to the ER
273
Q

Pathogens can impede antigen presentation - give examples of this
(2. Adenovirus )

A
  • Produces protein which binds MHC class 1 molecule

- Prevents the MHC class 1 molecule from leaving the ER

Semester 4 (10 decks)

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