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hCMB2004 Flashcards

1
Q

what are the sources of infection

A
  • pathogens - organisms that cause disease
  • bacteria
  • viruses
  • fungi
  • parasites e.g. worms and protozoa
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2
Q

what are the characteristics of an effective immune system

A
  • be able to recognise and respond to any invading organism
  • not over react to benign or self
  • be able to direct different effector mechanisms against different pathogens
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3
Q

what is specific/adaptive immunity

A
  • is induced by exposure to a particular infection
  • shows a high degree of specificity
  • exhibits memory
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4
Q

what are the features of specific immunity

A
  • mediated by lymphocytes (B/T cells)
  • clonal distributed receptors
  • large repertoire:low frequency of cells specific for antigen
  • response takes time to develop
  • memory cells produced
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5
Q

what is the clonal selection theory

A
  • removal of potentially reactive immature lymphocytes by clonal deletions
  • pool of mature naive lymphocytes
  • proliferation and differentiation of activated specific lymphocytes to form a clone of effector cells
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6
Q

what are the different types of lymphocyte receptors for antigen

A
  • BCR expressed by B lymphocytes
  • TCR expressed by T lymphocytes
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7
Q

what are BCRs

A
  • membrane form of Ig binds free antigen
  • is subsequently secreted when B cell is activated now known as antibody
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8
Q

what are TCRs

A
  • membrane form only
  • recognises peptide fragments of antigen bound to MHC expressed by APC
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9
Q

what is the function of antibodies

A
  • importance shown in cases where absent
  • infection with encapsulated bacteria
  • activation of complement
  • activation of effect cells
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10
Q

consequences of activation of complement

A
  • opsonisation
  • classical pathway activation and MAC
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11
Q

consequences of activation of effector cells

A
  • cells that express FcR (receptor that binds Fc region of antibody)
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12
Q

what is the structure of antibodies

A
  • paired variable regions (from heavy and light chains) from 2 identical antigen- binding sites
  • constant regions are responsible for antibody structure and interacting with other molecules and cells of innate system –> antibody effector functions
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13
Q

basic structure of antibodies

A
  • immunologlobin
  • basic 4-chain structure
  • 2 identical heavy and light chains, held together by covalent/non-covalent bonds
  • 2 types of L chain (gamma and kappa)
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14
Q

what makes up antigen binding sites

A
  • Vh
    Vl
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15
Q

what are the 5 classes of antibodies

A
  • IgM
  • D
  • A
  • G
  • E
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16
Q

what makes up the different isotopes

A
  • different isotopes are determined by the heavy chain
  • isotopes differ in their structure and functions
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17
Q

what are antibody domains

A
  • analysis of amino acid sequences of H and L chains reveals homology regions
  • L chain - 2 domains
  • H chain - 4 or 5 domains
  • each domain comprises two beta sheets
  • linked by a disulphide bridge
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18
Q

what’s included in the immunoglobulin superfamily

A
  • TCR
  • MHC class I and II
  • CD4, CD8, CD80, CD96, CTLA-4, KIR, IL-6R
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19
Q

how to antigens interact with antibodies

A
  • hypervariable regions (3 in Vh and Vl
  • HV1-3
  • 6 hypervariable loops - antigen binding site
  • complementary-determining regions
  • antigen binds to aa in CDRs
  • size/shape of antigen affects binding
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20
Q

how are antigens recognised

A
  • epitopes recognised by antibodies may be continuous or conformations
  • antibody and antigen form non-covalent interactions
  • CDRs present in antibody V regions determine the specificity and the affinity of an antibody for antigen
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21
Q

what are the functions of TCR

A
  • doesn’t bind free antigen
  • binds/recognises processed antigen
  • presented in the cleft/binding groove of MHC class I or class II molecules
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22
Q

what are MHCs

A
  • major histocompatibility complex
  • different expression patterns
  • present peptides for different sources
  • first identified fur to role in transplant rejection
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23
Q

what are MHC class i

A
  • expressed on all nucleated cells
  • heterodimer - alpha and beta2 chains
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24
Q

what are the 3 different MHC class I molecules

A
  • HLA-A
  • HLA-B
  • HLA-C
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25
Q

what forms the peptide binding site in MHC class i

A
  • the alpha 1 and alpha 2 domains forms to form beta-sheets structure
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26
Q

key points of MHC class II

A
  • expression limited to APC
  • heterodimers, alpha and beta chains similar size and both transmembrane
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27
Q

what are the 3 different types of MHC class ii

A
  • HLA-DP
  • HLA-DQ
  • HLA-DR
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28
Q

what forms peptide binding sites in MHC class II

A
  • polymorphic alpha 1 and beta 1 domains
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29
Q

what makes up H chains in TCR beta

A
  • V region encoded by 3 gene segments
  • V,D J (V is the biggest)
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30
Q

what makes up L chain in TCR alpha

A
  • V regions encoded by 2 gene segments - V and J
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31
Q

what causes the rearrangement of Ig genes

A
  • in B cells the DNA containing the Ig gene segments is deliberately broken and the gene segments are rearranged to form function Ig genes
  • non-homologous end joining recombination
  • each individual B cell will perform both the breakage and rearrangement randomly
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32
Q

how are functional immunoglobulin genes produced

A
  • after DNA breaks, a single V and a single J gene segment are joined together to encode the v region of the light chain
  • this process is random
  • a random V, D and a J gene segment are joined together in single B cell to encode the V region of the heavy chains
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33
Q

what is the specific order of Ig rearrangement in B cell development

A
  • H chain gene segments rearrange (D-J then V-DJ)
    greater variability of H chains
  • then the light chain gene segments rearrange (kappa first)
  • if kappa rearrangement is unsuccessful, then gamma gene segments rearrange
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34
Q

which chromosome are the different loci present

A
  • H chain locus - chromosome 14
  • kappa chain locus - chromosome 2
  • lambda chain locus - chromosome 22
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35
Q

what are the stages in the recombination process

A
  • Ig gene segment rearrangement is guided by special sequences flanking each of the V,D and J gene segments = recombination signal sequences
  • rearrangement involves a complex of enzymes - V(D)J recombinase
  • recombination activating gene
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36
Q

what are recombination activating genes

A
  • RAG1 and RAG2 genes encode lymphoid specific components of the recombinase
  • mutations in RAG genes results in immunodeficiency
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37
Q

what is allelic exclusion

A
  • in each individual B cell, only one rearranged H chain gene from one chromosome is expressed
  • only one rearranged L chain from one chromosome is expressed by each individual B cells
  • light chain isotope exclusion
  • these mechanisms ensure that each individual B cell produces just one randomly generated BCR that is different from the BCR made but every B cell
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38
Q

what is light chain isotope exclusion

A
  • each B cell expresses either a rearranged kappa an lambda
  • light chain; never both
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39
Q

what is combinatorial diversity

A
  • different V,D, J segments recombine to produce different seuqneces
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40
Q

what are the mechanisms for generation of antibody diversity

A
  • there are multiple gene segments for each chain
  • combinatorial diversity
  • combinations of heavy and light chains
  • junctional diversity increases further
  • somatic hypermutations
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41
Q

how is junctional diversity increased further

A
  • imprecise joining (small differences in sequences where V-D and D-J segments join)
  • N regions (random addition of nucleotides at junctions of V-D and D-J by terminal transferase
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42
Q

what are somatic hypermutations

A
  • mutation frequency in antibody V genes is orders of magnitude higher than seen in all other areas of the genome
  • SHM occurs in germinal centres as B cells recognises antigen and proliferate
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43
Q

how do SHM occur

A
  • performed by the enzymes, activation-induced deaminase
  • AID acts on DNA to de-aminate cytosine to uracil
  • uracil is then recognised by error prone DNA repair pathways leading to mutations
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44
Q

membrane vs secreted antibody

A
  • following Ag recognition as each B cell differentiates, it will start to secrete its unique BCR as an antibodd
  • the secreted form made by each B cell has an alternative constant region that lacks transmembrane regions. as the original re-arranged VDJ regions are not altered, the secreted antibody has the same antigen specificity as the membrane BCR
  • the membrane and secreted forms are produced by alternative RNA processing
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45
Q

what is class switching

A
  • at the heavy chain locus, the Cmuw segment is physically closest to the V, D and J gene segments and so IgM is the first class expressed by each developing b cell
  • Cdelrta is next to Cmuw - hence IgD can be co-expressed with IgM by differential processing of the RNA from the two C region genes
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46
Q

what is required for switching to other classes

A
  • requires further DNA recombination - guided by switch regions
  • this process also involves the enzyme AID pathogen –> cytokine –> switch
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47
Q

why does class switching occur

A
  • as a result of the cytokine that may be present in this environment
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48
Q

where are T cells developed

A
  • thymus
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49
Q

TCR VS BCR

A
  • TCR is never secreted
  • no SHM occurs in TCR genes
  • TCR generation is very similar to the DNA rearrangement process seen in BCR generation
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50
Q

where are MHC class I expressed

A
  • all nucleated cells
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51
Q

where are MHC class ii expressed

A
  • on particular cell types e.g. B cells, macrophages, dendritic cells (antigen presenting cells)
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52
Q

how are MHC molecules polymorphic

A
  • many alleles
  • a single individual will have up to 12 different MHC molecules (if there are heterozygous for all 6 MHC loci
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53
Q

what is co-dominant expression of MHC molecules

A
  • 3 MHC class I molecules
  • of heterozygous at each loci, one person can express six different class I molecules
    similarly for class II
  • polymorphism and polygeny
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54
Q

what is the importance of high levels of MHC polymorphism

A
  • allows the binding of a vast range of peptides that can be presented to T cells, provides a clear evolutionary advantage to the population as can respond to almost unlimited number of different pathogens
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55
Q

what are the downsides of high polymorphic MHC

A
  • increases risk of immune mediated disease e.g. autoimmune diseases
  • also reduced pool of available donor organs for transplantation - as MHC alleles should match for best outcome
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56
Q

how do peptides end up on the surface of cells bound to MHC molecules

A
  • peptides derived from protein antigens synthesised inside a cell are usually presented by class I MHC molecules
  • peptides derived from protein antigen taken up from the outside of the cell are usually presented by class II MHC molecules
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57
Q

how are antigens presented by MHC class I molecules

A
  • intracellular antigen
  • antigen processing to peptide in proteasome
  • peptide transport into endoplasmic reticulum
    peptide binding by MHC class I
  • MHC class I present peptide at cell surface
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58
Q

how are antigens processed by MHC class I

A
  • antigen synthesised in cytoplasm
  • protein cleaved to peptides by proteasome
  • peptides transported to endoplasmic reticulum by TAP transporters
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59
Q

what are proteasome

A
  • proteasome functions in all cells - cytoplasmic protein turnover
  • proteasome in cells receiving inflammatory cytokines signals are modified to produce altered peptides
  • TAP is a component of a multi-protein assembly, the peptide loading complex - also induces tapas in and calreticulin
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60
Q

function of proteasome

A
  • cytosolic proteins are degraded to peptide fragments by the proteasome a large multicatalytic proteases
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61
Q

how are antigens processed by MHC class II molecules

A
  • antigen endocytosed into intracellular vesicles inside the cell
  • protein cleaved to peptides by acid proteases in vesicles
  • vesicles fuse with vesicles containing MHC class II molecules
  • peptides bind MHC class II molecules
  • MHC II then transported inside vesicles to cell surface
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62
Q

how is CLIP created

A
  • invariant chain forms a complex with MHC class II molecules, blocking the binding of peptides and misfiled proteins
  • II is cleaved in an acidified endoscope, leaving a short peptide fragment, CLIP, still bound to MHC class II
  • endocytosed antigens are degraded to peptides in endoscopes, but the CLIP peptide blocks the binding of peptides to MHC class II molecules
  • HLA-DM binds to the MHC class II molecules, releasing CLIP and allowing other peptides to bind. the MHC class II molecule then travels to the cell surface
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63
Q

what happens to CLIP at the cell surface

A
  • MHC class II molecules bind to invariant chain in the ER
  • this prevents peptides binding in the groove
  • in endocytic pathway lysosomal enzymes degrade this leaving CLIP peptide associated with binding groove
  • peptides from antigen displace CLIP when they bind
  • HLA-DM a class II like molecule, is required for loading of peptides into the groove
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64
Q

what happens to MHC class I and II in normal healthy cells

A
  • MHC I and II will bind and present peptides from self protein
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65
Q

what accessory molecules are involved in antigen processing and presentation

A
  • TAP and LMP ( class I pathway)
  • HLA-DM (class II pathway)
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66
Q

what are antigen presenting cells

A
  • specialised cell types that express MHC class II molecules
  • take up and present extracellular Ag to activate helper CD4+ T cells
  • e.g. macrophages, dendritic cells, B cells
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67
Q

what happens to viruses in MHC class I

A
  • as all nucleated cells express MHC class I molecules, any cell infected by a virus can present viral peptides on MHC class I molecules and be recognised and killed by cytotoxic CD8+ T cells
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68
Q

how are B cells developed

A
  • develop from haematopoietic stem cells in bone marrow that express PAX5 transcription factor
  • involves rearrangement and expression og ig genes
  • expression of lymphocyte, and the B cell specific markers e.g. CD45 then CD19
  • removal of self-reactive cells
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69
Q

how doB cell precurors rearrange its immunoglobulin genes

A
  • generation of B cell receptors in the bone marrow
  • adhesion molecules, close relationship between storm cells, negative selection of those that are auto reactive
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70
Q

how are immature B cells produced

A
  • H chain genes rearrange first moves to cell surface with Igalpha and Igbeta and expressed with surrogate light chain
  • then light chains rearrange, and displace V preB and lambda5 chains –> IgM BCR
  • immature B cells
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71
Q

how are pre B cell receptors formed

A
  • early pro B cell - Vh to DJh rearrangements occur
  • large pre B cell - stop heavy chain gene rearrangement
  • immature B cells - stop light chain gene rearrangement
  • mature B cells
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72
Q

how are Ig genes rearranged during B cell development

A
  • stem cell
  • early pro B cell
  • late pro B cell
  • large pre B cell
  • small pre b cell
  • immature B cell
  • mature B cells
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73
Q

what is the function of pre-BCR

A
  • delivers signal to pre B cell that H chain looks functional
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74
Q

how is a signal from pre-BCR produced

A
  • turns off RAG 1 RAG2 genes
  • cell division
  • surrogate light chain expression stops
  • RAG1 and RAG2 turned on again
  • L chain rearrangement starts
  • RAG genes needed for gene rearrangement
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75
Q

what rearrangement happens in early pro B cells

A
  • H chain gene rearrangement
  • D-J rearrangements on both chromosomes
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76
Q

what rearrangements happen on late pro B cell

A
  • H chain gene rearrangement
  • V-DJ rearrangement on first chromosome
  • V-DJ rearranagement on second chromosome
  • cell loss
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77
Q

what rearrangements happen in immature B cells

A
  • rearranagement ceases
  • cell expresses muw:kappa
  • cell expresses muw:lambda
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78
Q

which type of light chain will B cells express more of

A
  • as kappa light chain genes rearrange before lambda genes, more B cells will express kappa and lambda light chains
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79
Q

how are repeated rearrangements possible at the light chain loci

A
  • importance of signalling of pre B cell BTK involved, if not present GT no mature B cells being produced
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80
Q

how are immature B cells tolerant

A
  • bind multivalent self antigen undergo clonal deletion or receptor editing
  • bind soluble self-antigen –> cell becomes unresponsive
  • binding of self-antigen by immature B cells leads to death or inactivation
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81
Q

how are T cells developed

A
  • originate from bone marrow stem cells
  • rearrange receptor genes (once in thymus)
  • express pre T receptor
  • elimination of self-reactive T cells by negative selection
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82
Q

how are alpha/beta T cells developed

A
  • in the thymocytes:
  • rearrange TCR genes and express TCR
  • acquire other markers e.g CD3, CD4, CD8
  • undergo positive and negative selection
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83
Q

what is the thymus

A
  • bi-lobed organ in anterior mediastinum
  • each lobe divided into many lobules
  • each lobule has outer cortex and inner medulla
  • cells e.g. lymphoid cells, epithelial cells, macrophages and dendritic cells
84
Q

how do T cells mature in the thymus

A
  • pro-thymocytes enter cortex via blood vessels from bone marrow
  • firstly, they rearranged TCR beta genes
  • expressed along with pre T cell receptors
  • cells proliferate and then re-arrange TCR alpha genes
85
Q

what is the TCR complex

A
  • TCR expression requires the CD3 complex
  • CD3 transmits signal to T cell nucleus following TCR recognition of p/MHC
86
Q

what are lambda-delta TCR

A
  • lambda-delta T cells do not express CD4 or CD8 markers
  • recognise different antigens from alpha-beta T cells
87
Q

importance of alpha/beta TCRs

A
  • recognise self MHC and peptide from foreign ag
  • recognise self MHC and peptide from self ag
  • not able to recognise self MHC
88
Q

what is positive selection of T cells

A
  • positive selection of cells which recognise self MHC
  • positive selection of alpha:beta T cells by cortical epithelial cells in the thymus
89
Q

what is negative selection of T cels

A
  • TCR binding to MHC with high affinity causes T cell to die apoptosis
  • negative selection of alpha:beta T cells by dendritic cells, macrophages, and other cells in the thymus
90
Q

why is TCR affinity for p/MHC the basis for selection

A
  • all T cells recognising self MHC/self peptide are positively selected
  • those with the highest affinity TCR are then negatively selected
91
Q

how are the different types of cells related to MHC

A
  • a die due to insufficient affinity for self MHC
  • b and c are positively selected, but b are then negatively selected due to high affinity for self MHC
  • c intermediate affinity and survive
92
Q

what happens to cells that survive thymus selection

A
  • express TCR capable of binding self mic
  • are depleted of self-reactive cells
  • exit the thymus as mature, single positive T cells
93
Q

what type of T cells do naive T cells turn into

A
  • cytotoxic effector T cells (CD8+) - kill infected cells
  • helper effector T cells (CD4+) - secrete cytokines
94
Q

what happens to naive T cells

A
  • must encounter antigens for survival
  • enter lymph node from blood via high endothelial venules
  • move into T cell are which is rich in dendritic cells and macrophages
  • T cells enter lymph node cortex from the blood via high endothelial venues
95
Q

what are cell adhesion molecules

A
  • molecules expressed on surface of T cells, bind ligands expressed/released by other cells
  • once close to other cells different molecular sets of CAMs mediate cell/cell interactions
96
Q

how do T cells contact APC

A
  • using CAMs
  • T cells initially bind APC through low affinity LFA-1:ICAM1 interaction
  • subsequent binding of T cell receptors signals LFA-1
  • conformation change in LFA1 increases affinity and prolongs cell-cell contact
97
Q

what are the 3 types of signals APCs deliver to naive T cells

A
  • activation
  • survival
  • differentiation
98
Q

how is co-stimulation negative feedback

A
  • once activated T cells now proliferate and express ICOS and CTLA-4
99
Q

what is the role of ICOS

A
  • binds ICOSL on APC to induce cytokine secretion by T cells
100
Q

what is the role of CTLA-4

A
  • is highly related to CD28, and shows stronger binding to B7.1/2 than CD28
  • CD28 delivers inhibitor signals to activated T cells
101
Q

what is the importance of CTLA-4

A
  • CTLA-4 mutations associated with several autoimmune diseases
102
Q

what is the function of signal 3 (cytokines)

A
  • dictate the differentiation of activated CD4 cells into different sub-sets of effector cells
  • delivered by antigen presenting cells
  • TGF beta –> Treg cells
  • IL-6 –> TFH cells
  • TGF beta IL-6 –> Th17 cells
  • IL12 IFN-lambda –> TH1 cells
  • IL4 –> Th2 cells
103
Q

what are the two types of DC

A
  • myeloid
  • plasmacytoid
104
Q

what is the function of Myeloid

A
  • kep APC that initiate T cell responses
  • bone marrow derived
  • immature form found in epithelia
  • do not express co-stimulatory molecules *B7) until activated
  • released upon danger signal
105
Q

what is the function of DC

A
  • mature DC are found in T cell areas of lymphoid tissues
  • DC MHC I and ii will be loaded with peptides from pathogens they encountered in peripheral tissues
  • their levels of co-stimulatory molecules will be very high
  • they will express high levels of adhesion molecules
  • efficient activators of naive T cells
106
Q

how do DC activate naive T cells

A
  • immature dendritic cells in peripheral tissues encounter pathogens and are activated by PAMPs
  • TLR signalling induces CCR7 and enhances processing of pathogen derived antigen
  • CCR7 directs migration into lymphoid tissues and augments expression of co-stimulatory molecules and MHC molecules
  • mature dendritic cell in T cell some primes naive T cells
107
Q

what is cross presentation

A
  • some specialised DC take up and process exogenous antigen and present it via MHC I molecules
  • this allows these DC to activate naive CD8+ T cells. this means these CD8 effector cells can kill infected cells that are not APC so not expressing co stimulatory
108
Q

what are macrophages

A
  • function as killers of pathogens but also important APC for extracellular pathogens
  • highly phagocytic
  • express MHC class II and B7 which increases following T cell help
  • once activated by T cells secrete many inflammatory cytokines
109
Q

how can B cells act as antigen specific APC

A
  • antigen binding to BCR up regulates B7
  • specific antigen efficiently internalised by receptor mediated endocytosis
110
Q

what is the role of interleukin 2

A
  • IL2 is a potent autocrine T cell growth factor
  • IL2 binding to IL-2R on activated T cells results in T cell proliferation
111
Q

how are CD8+ T cells activated

A
  • requires high levels of co-stimulator activity
  • CD8+ T cells can be activated directly by infected or cross presenting APCa
112
Q

what is the role of a progenitor

A
  • gives rise to a large number of lymphocytes, each with a different specificity
113
Q

how do B cells become activated

A
  • mature B cells bound to foreign antigen is activated
  • activated B cells give rise to plasma cells and memory cells
114
Q

what is the molecular basis of ag/BCR signal 1

A
  • BCR-associated polypeptides involved in signalling
  • crosslinking BCR activated intracellular kinase
115
Q

how can signal 1 be increased

A
  • if antigen has activated complement cascade
  • lots of c3b
  • complement receptor 2 on B cell surface (cd21)
  • CR2/CD19/CD81 form the BCR co-receptor complex
  • augments the signal
116
Q

what provides signal 2

A
  • antigen itself
  • extensive cross linking of BCR
117
Q

what is the role of thymus independent antigen 1

A
  • TI-1 Ag bind to other receptors on all B cells providing signal 2
  • in high concentrations the antigens acts as polyclonal activators for B cells
  • the 2 signal lead to B cell activation proliferation and antibody secretion
118
Q

what is the role of TI-2 Ag

A
  • contain repeated epitopes
  • will therefore cross link many BCR molecules on same B cell surface
  • TI-2 antigens alone can signal B cells to produce IgM antibody
  • activated dendritic cells release a cytokine, BAFF, that augments production of antibody against TI2 antigens and induce class switching
119
Q

what are thymus dependent antigens

A
  • antibodies to TD Ag, requires presence of CD4+ T cells
  • antibody responses seen to TD Ag are much better than those of TI Ag
120
Q

how do B cells process and present Ag

A
  • CD4+ T cells –> receive signal 2
  • via CD40/CD40-L interaction
  • cytokines secreted by T cells (help B cell to class switch)
121
Q

how are thymus independent and thymus dependent antigens converted

A
  • B cell binds bacterial polysaccharide epitopes linked to tetanus toxoid protein
  • antigen is internalised and processed
  • peptides from protein component are present to the T cell
  • activated B cell produces antibody against polysaccharide antigen on the surface of the bacterium
  • way of improving the efficiency of a vaccine against pathogens that have T1 antigens
122
Q

what is an example of a conjugate vaccine

A
  • haemophilus influenza type B
  • TI Ag is coupled to a protein such as tetanus toxoid which then converts it to a TD Ag
123
Q

what is the role of CD40

A
  • CD40 signal also induces activation induced deaminase which is required for class switching and somatic hypermutation
124
Q

how are B cells activated with TD Ag

A
  • conjugates of B lymphoblasts and T cells mode to primary follicles
  • form germline centres within a B cell follicle in secondary lymphoid tissues
  • B cells divide rapidly to become centroblasts and undergo SHM and switching
  • differentiate into non-dividing centrocytes
125
Q

what happens to B cells in GC

A
  • differentiate into plasma cells
  • form long lived memory cells
  • die within lymphoid tissues
126
Q

where are GC found

A
  • in follicular dendritic cells
127
Q

what is the role of CD40

A
  • CD40 signal via CD40 L-expressed on Tfh (protects centrocytes from apoptosis
  • induces isotope switching (different cytokines induce different isotopes to be produced
128
Q

what are the different isotypes

A
  • polysaccharides - IgM
  • proteins - IgG1 and IgG3
  • IgA - antigens at mucosal surface
  • IgE
  • IL4 important for IgE switch
129
Q

why do we need immunological tolerance

A
  • random generation of repertoire of BCR and TCR
  • many self-reactive specificities will be produced
130
Q

what are the consequences of random TCR gene rearrangement

A
  • fail to recognise self MHC
  • recognise self MHC + peptide generated from Ag present in the thymus
  • recognise self MHC and any other peptide not present in the thymus
131
Q

what are AIRE

A
  • autoimmune regulator proteins
  • transcription factor
  • allows the expression of many tissue-specific Ag in the thymus
132
Q

what is Ig gene rearrangement

A
  • re-arrange another light chain
133
Q

what are the mechanisms of tolerance

A
  • anergy - leaving bone marrow as unresponsive
  • immunological ignorance - insufficient levels to activate T cells
  • privileged site - suppressive cytokines
  • many B cell responses are T cell dependent - no antibody response
134
Q

what is the mechanism of tolerance regulatory B cells

A
  • B cells recently described that secrete IL-10 are crucial in preventing autoimmunity
135
Q

why is it important to regulate immune responses

A
  • to ensure responses continue only for as long as they are needed
  • to minimize collateral damage
  • to ensure responses are qualitatively appropriate
136
Q

what are the different effector T cells

A
  • Th1
  • Th2
  • Th18
  • Treg/Breg
  • Tfh
137
Q

what is the role of Th1

A

activation of macrophages, NK cells and cytotoxic T cells
express CD40L

138
Q

what is the role of Th2

A

promote responses mediated by eosinophils and mast cells; role in antibody responses, especially IgE
secrete IL-4

139
Q

what is the role of Th17

A

promote responses against fungi
secrete IL-17

140
Q

what is the role of treg/breg

A

suppress unwanted responses
contain CD4+ CD25+ CD8+
Secrete IL10 and TGF beta

141
Q

what is the role of Tfh

A

specialised Th found in GC to help B cells

142
Q

what is inhibited by Th1 cytokines

A
  • development of Th2 and Th17
143
Q

what is inhibited by Th2

A
  • development of Th1 and Th17
144
Q

what is inhibited by Th17

A
  • development of Treg
145
Q

what is inhibited by Treg

A
  • Th1, Th2, Th17
146
Q

what is the importance of polarised responses

A
  • ensures correct responses for different types of pathogens
  • can go wrong may lead to allergy (excessive Th2)
  • control of auto reactivity/pregnancy
147
Q

what are the organisms that may cause disease

A
  • bacteria e.g. salmonella, streptococci
  • viruses e.g. HIV flu
  • fungi e.g. candida, pneumocystis carinii
  • parasites e.g. schistosome, trypanosome
148
Q

what do the different effector mechanisms depend on

A
  • type of pathogen
  • localisation
  • challenge
  • stage on infection
149
Q

what are the two types of host defence mechanisms

A
  • innate defence mechanisms
  • acquire/adaptive defence mechanisms
150
Q

two examples of gram positive bacteria

A
  • staphylococcus aureus
  • streptococcus app.
151
Q

what are the examples of gram negative bacteria

A
  • campylobacter
  • salmonella
  • shigella
  • haemophilus neisseria
152
Q

what are the features of the gram positive cell wall

A
  • thick layer of peptidoglycan cell wall
153
Q

what are the features of the gram negative cell wall

A
  • much thinner
  • has an outer membrane containing LPS
154
Q

how do the components of cell walls induce innate responses

A
  • bind to toll-like receptors on macrophages
  • 10 TLR in humans - recognise distinct patterns on microbes
  • nucleotide binding oligomerisation domains
155
Q

what can binding of toll like receptor induce

A
  • promote inflammation
  • promote dendritic cell maturation
  • influence differentiation of T cells
  • activate B cells
156
Q

what is the role of antibodies in bacterial infections

A
  • opsonisation
  • complement activation
  • bind to and neutralise toxins
  • bind to surface structures to prevent mucosal adherence
157
Q

what are the stages of complement activation

A
  • promote inflammation via c3a, c5a
  • opsonise by binding c3b receptor on phagocytes
  • lysis of gram negative organisms
158
Q

what is needed for protection against bacterial infection

A
  • antibodies important in protecting against extracellular pathoegns
  • T cell effector mechansims protect against intracellular organisms
159
Q

what are the 2 possible outcomes of leprosy

A
  • tuberculoid - strong Th1 response
  • lepromatous - strong Th2 and antibody response
160
Q

what are type 1interferons

A
  • synthesis of IFNalpha and IFNbeta induces in virus-infected cells
161
Q

Which type of bacterial infections can the MAC be particularly useful in killing the
pathogen

A
  • gram negative bacteria can be killed by complement lysis
162
Q

what are type 2 interferons

A
  • IFNlambda secreted by activated T cells and NK cells
  • inhibits Th2 response and promotes Th1
163
Q

what are natural killer cells

A
  • types of innate lymphoid cells
  • larger granular lymphocytes
  • can recognise stressed cells in absence of Igs and MHC
164
Q

what are the two types of NK cell receptors

A
  • activating receptors - recognise carbohydrate ligands, trigger killing
  • inhibitory receptors - recognises MHC class I molecules
165
Q

what are the two mechanisms cytotoxic T cells use to kill cells

A
  • secretion of cytotoxic granules
  • FAS ligand on T cells interact with Fas on target
166
Q

what are CTLs

A
  • CTL recognises and binds virus infected cells
  • CTL programs targets for death including DNA fragmentation
  • CTL migrates a new target
167
Q

what is the role of IFNlambda

A
  • inhibits viral replication
  • up regulates MHC class I and II expression and antigen presentation
  • increases macrophage phagocytosis of dead cells
  • promotes NK cell killing activity
168
Q

what is the role of antibodies in specific immunity

A
  • neutralise free virus
  • opsonise to increase phagocytosis
  • activate complement leading to lysis
169
Q

stages of HIV infection

A
  • attacks specific immune systems
  • target CD4 T cell, macrophages and dendritic cells
  • progressive development of AIDS leads to opportunistic infections
170
Q

what is the role of antibodies in acquired immunity

A
  • antibody and cell mediated immunity in influenza
  • infection induces antibody and cytotoxic T cell response
  • antibody recognises haemagglutinin and neuraminidase
  • high levels of CTL activity correlates within reduced viral shedding
171
Q

importance of CTLs in HIV

A
  • patients with higher levels of CTL activity show slower disease progression
  • virus mutations that escape CTL recognition may lead to progression of AID
172
Q

what is the immune response

A
  • dampens anti viral type 1 interferon –> aids viral replication
  • viral proteins can inhibit RIG1
  • viral proteins can stimulate NFkB activation –> pro inflammatory
  • antibodies protective and role of cytotoxic T cells
173
Q

what are the mechanisms used by antibodies

A
  • opsonisation
  • complement lysis
  • antibody dependent cell mediated cytotoxicity
174
Q

effector mechanisms induced by malaria

A
  • sporozoite and merozite may be susceptible to antibody
  • antibody may also kill infected red blood cells
  • cytotoxic T cells active against liver cells
175
Q

what are evasion mechanisms

A
  • concealment of antigens
  • antigenic variability
  • immunosuppression
  • interference with effector mechanisms
176
Q

what is concealment of antigens

A
  • some viruses inhibit antigen presentation by MHC class I
  • privileged sites
  • uptake of host molecules
177
Q

what is antigenic variability

A
  • large number of antigenic types
  • mutations
  • recombination
  • gene switching
178
Q

what is streptococcus pneumonia

A
  • leading cause of serious bacterial infections
  • gram positive
179
Q

what are the two streptococcus pneumoniae vaccine

A
  • pneumovax
  • Prevnar 13
180
Q

what is the correlation between antigenic variability and the influenza virus

A
  • the influenza virus can undergo antigenic drift and antigenic shift
181
Q

what is the relation between trypanosome and gene switching

A
  • changes in the major surface antigen of the trypanosome, brought about by genetic rearrangement
  • variant specific glycoprotein
182
Q

what causes immunosuppression

A
  • infection of immune cells
  • induction of regulatory T cells
183
Q

what biomarkers do regulatory T cells express

A

CD4 and CD25 on the surface and foxp3

184
Q

how do regulatory T cells leishmania induce immunosuppression

A
  • can hide and survive in macrophages
  • can increase expression of Treg cells
  • decrease immune response
185
Q

what are dendritic cells

A
  • antigen presenting cells
  • act as messengers between the innate and adaptive immune system
186
Q

what are the interference with effector mechanisms

A
  • molecules interfering with antibody function
  • molecules interfering with complement
  • molecules binding cytokines
  • subvert responses by producing molecules with cytokine activity
  • inhibition of phagocytic killing
187
Q

what are the pathological consequences of immune responses

A
  • innate - LPS induce macrophage cytokine secretion
  • specific - antibodies and/or T cell reactions may contribute to pathology
  • microbes play a role in initiating autoimmune responses
188
Q

what are the requirements of an effective vaccine

A
  • safe
  • high level of protection
  • long lasting protection
  • right type of response
  • low cost
  • stable
  • easy to administer
  • minimal side effects
189
Q

what are the 5 main types of vaccines

A
  • inactivated organisms
  • attenuated organisms
  • subunit vaccines
  • toxoid
  • conjugate something with low antigenic property covalently bound to something with high
190
Q

what are adjuvants

A
  • a substance administered with an antigen to promote the immune response
  • pure antigens often elicit weak immune responses
  • adjuvants enhance immune responses
191
Q

what are the various ways adjuvants act

A
  • activate dendritic cells via TLRs or NLRs
  • cause release of endogenous danger signals
  • promote antigen uptake by dendritic cells
  • stimulate release of chemokine/cytokines
  • promote cross-presentation of exogenous antigens by class I
192
Q

what are the adjuvants used in clinical practice

A
  • MF59
  • AS03
  • AS04
193
Q

what is an antiserum

A
  • contains antibodies that bind the antigen, along with other soluble blood components but doesn’t contain cells or clotting proteins
194
Q

how do we purify different antibodies

A
  • gel filtration chromatography
  • affinity chromatography
195
Q

what are the limitations of using antisera

A
  • once the antiserum has been used, then another individual will need immunising and the antibodies generated with never be exactly the same
196
Q

what are the uses of antibodies

A
  • antiserum
  • purified polyclonal antibodies
  • generation of monoclonal antibody producing hybridoma
197
Q

how are secondary antibodies produced

A
  • collect mouse sera
  • contains many different mouse antibodies
  • purify mouse antibodies
  • collect rat anti-mouse antiserum
  • purify ran anti-mouse polyclonal antibodies
198
Q

what are the uses of antibodies

A
  • in research
  • in diagnostic
199
Q

what is enzyme linked immunosorbent assay

A
  • detection of linear/non linear epitopes
  • very sensitive - detect the presence of a specific biological material
  • very reproducible
200
Q

what are the the different classes of ELISA

A
  • direct ELISA
  • indirect ELISA
  • sandwich ELISA
201
Q

what are the steps of direct ELISA

A
  • antigen added to plastic plate
  • labelled antibody added
  • substrate added
  • measure substrate conversion
202
Q

what are the steps of indirect ELISA

A
  • antigen added to plastic plate
  • unlabelled primary antibody added
  • labelled secondary added
  • substrate added
  • measure substrate enzyme label
203
Q

what are the steps of sandwich ELISA

A
  • unlabelled antibody added to plate
  • sample added
  • add labelled secondary
  • add substrate
  • measure substrate conversion
204
Q

what can antibodies identify

A
  • the presence of a protein
  • the location of a protein
  • characterising cells based on the presence of a marker protein
205
Q

what is flow cytometry

A
  • measures how single cells in a population affect a laser beam as they pass through it
206
Q
A

CM2001 (13 decks)

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