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MB3008 > B cells & Antibodies > Flashcards

B cells & Antibodies Flashcards

1
Q

Molecules of the immune system

A
  • antibodies
  • TCRs
  • MHC
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2
Q

Types of epitopes

A
  1. Linear - formed by several (6) linear/adjacent AA residues - can be accessible to the ab as they are on external surface - if buried in protein (can only be accessible via denaturation)
  2. Conformational - formed by aa residues not in the linear sequence - become spatially juxtaposed in folder protein
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3
Q

Antibody Class-Switching

A

Switch from primary (IgM) to secondary (IgG, IgA, IgE)

*IgG present on ab in circulation

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4
Q

Immunological Memory

A
  • can respond to subsequent infection w/ the same pathogen with a response
    • much faster
    • greater magnitude ….. than initial exposure
  • can be very long lived (2009 Influenza A) or short lived (Covid-19)
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5
Q

Effective vs Sterilising immunity

A

Effective

  • if you encounter virus, you may get infected remain asymptomatic and transmit on the virus
  • infection but subsequent successful eradication of virus
  • vaccine induced immune response - unable to stop every virus from replicating

Sterilising

  • someone who’s vaccinated or naturally infected will not catch the virus or transmit it further
  • these abs neutralise and block virus entry into cells and prevent virus replication
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6
Q

Subclasses of ab

A

IgM, IgG, IgA, IgD

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7
Q

Clonal selection theory

A
  • B cells specific for different Ag develop before exposure to these Ags (Ag-independent)
  • Ag selects the appropriate B cell/Ab from pre-existing B cell pool
  • All surface ab on any one naive B cell is the same - clonal
  • Following Ag exposure - B cells expand, differentiate, proliferate and secrete ab (Ag-dependent)
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8
Q

IgM

A
  • monomer on surface of B lymphocyte
  • pentameric form is secreted
  • held together by J chains
  • found mainly in blood - does not penetrate tissues well
  • 1st ab made in response to a specific infection
  • efficient at complement activation
  • efficient at neutralisation of bacteria and viruses
  • not involved in opsonisation or ADCC
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9
Q

IgG

A
  • most abundant ab in serum
  • 4 subtypes - differ in hinge region
  • longer half life than IgM ( 23 vs 5 days)
  • All but IgG2 cross placenta - protection to fetus
  • efficient at complement activation
  • efficient at neutralisation of bacteria and viruses
  • promotes opsonisation or ADCC
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10
Q

IgA

A
  • most abundant ab in the body in terms of quantity (70%)
  • exists as monomeric but when secreted onto mucous surfaces - dimeric
  • synthesised in the gut
  • 2 types
    • IgA1 - longer hinge region - found in serum
    • IgA2 - found in secretions
  • has J chain
  • SIgA - secreted out of cell onto mucous surface
    • prevents pathogen adherence to mucous surfaces via neutralisation
    • promotes ADCC by interacting with FcR of NK cell
    • poor at complement fixation and opsonisation
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11
Q

IgE

A
  • present in trace amounts in serum
  • normal role - controlling worm infections
  • greatly increased in hypersensitivity (asthma, hay fever, allergies)
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12
Q

Ab structure

A
  • Light chain
  • Heavy chain
  • held together by sulphide bridges between cysteine
  • Fc region - receptors of phagocytes
  • highly variable regions: CDR1,2,3 on L and H chain
    • how these regions come together - dictates type of antigen will bind
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13
Q

Mechanisms generating ab diversity

A
  1. Multiple germ line V genes
  2. V-j and V-D-J recombinations
  3. N-nucleotide addition
  4. Recombinational inaccuracies
  5. Somatic hypermutation (SHM)
  6. Assorted H and L chains
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14
Q

V-D-J Junctional Diversity

A
  • NTs are randomly deleted and inserted at junctional joining sites
  • Mechanism to increase junctional diversity - increased complexity of abs
  • TDT enzyme
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15
Q

3 termination codons

A
  1. UGA
  2. UAA
  3. UAG
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16
Q

Allelic Exclusion

A
  • maintains law of clonal selection - each B cell is clonal and can only produce 1 ab
  • each B lymphocyte has 2 copies of each H and L chain - maternal and paternal
  • allelic exclusion prevents co-expression of both alleles
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17
Q

Ab Repertoire

A
  • junctional flexibility - N regions additions, deletions and somatic mutation - increases all possible combinations of B cells (~ 109 naive mature B cells circulating at one time)
  • Many B cells don’t reach circulation
  • naive B cells migrate to secondary lymphoid organs (LN and spleen)
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18
Q

How do naive B cells undergo differentiation into ab-secreting plasma cells?

A
  • binding of antigen to membrane anchored ab receptor leads to internalisation of the ab
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19
Q

Ab class switching

A
  • 1st ab made in response to particular infection is IgM (hl 4 days)
  • Ab class switch from primary to secondary (IgG, IgA, IgE)
  • Fab region - antigen binding region stays the same
  • Fc region is exchanged
20
Q

Ab class switching: Switch Recombination

A
  • rearranged VDJ combines with downstream C gene with removal by deletion of the intervening DNA
  • T helper cell dependant/driven
21
Q

Cytokines that play a roles in switch recombination

A
  • IL4: promotes switch to IgG4 and IgE
  • IFNᵧ: promotes switch to IgG2 - from Th lymphocytes
22
Q

Mode of Action of Abs

A

Direct effector:

  1. Neutralisation - prevention of virus/bacterial toxin from interacting with its receptor - prevent infection

Secondary effector:

  1. Opsonisation - promotes phagocytosis by macrophages/NFs - Fc receptor required for uptake
  2. ADCC - promoted by opsonisation by CTLs and NKs - activated by ab attaching to surface of pathogen cell

Activation of complement - membrane attack complex - lysis of bacteria in some viruses

23
Q

Ab producing B cells

A
  • plasmablasts
  • SLPCs
  • LLPCs
  • Memory B cells
24
Q

Plasmablasts

A
  • secrete low affinity abs but still receive sufficient stimulation signals to survive
  • supply earliest ab to pathogens - short-lived
  • most immature ab-producing B cell
  • affinity for antigen is 1/100 of that of germinal centre B cell
25
Q

Short-lived plasma cells (SLPCs)

A
  • following antigen encounter naive B cells proliferate and terminally differentiate into SLPCs
  • produces large amounts of antigen-specific ab of IgM and IgG - ab factory
  • optimum response seen after 2 weeks
  • following control of infection - undergo cell apoptosis
  • don’t play a role in long term memory
26
Q

Long-lived Plasma Cells (LLPCs)

A
  • B cells that have been successfully stimulated with antigen do not become SLPC - migrate further into the follicle and enter GC
  • B cells can initiate a new GC or enter existing GC
  • can live and produce ab for months-yrs
  • relocate into the bone marrow or GALT
27
Q

Memory B Cells

A
  • GC-derived where they are class switched and hypermutated
  • basis of long-term immunity
  • B cells not receiving sufficient signals - Fas mediated apoptosis
28
Q

T follicular helper (Tfh) cells

A
  • Contain surface markers: CD4+, Bcl-6, CXCR5
  • Interact with memory B cells at B-T cell junction
  • crucial for long-term survival of MBCs
  • Secrete cytokines: IL-4, IL-21, IFNᵧ
29
Q

Role of memory B cells in response to future re-exposure to antigen

A
  • MBCs are quiescent and require re-stimulation to stimulate memory response
  • re-exposure to antigen - rapid activation of MBCs in spleen and LNs - produce ab-secreting SLPCs
  • Some reactivated MBCs give rise to new LLPCs and others stay in GC
30
Q

GC features in severe COVID

A
  • Bcl-6+ GC B cells and Tfh cells are diminished
  • Low levels of somatic hypermutation in GC B cells
  • Plasmablasts accumulate in blood
  • Formation of dysfunctional B cells and plasmablasts
  • TNF-𝛼, IL-6, IL-8 production - damage of GC - lymphopenia
  • Loss of GCs compromises production of long-lived B cell memory and high-affinity abs
31
Q

Somatic Hypermutation of abs

A
  • somatic mutations in ab genes with selective survival of B cells - produce abs with highest affinities
  • takes place in GC in LN and spleen
  • Follicular DCs - sequester B cell antigen and stimulate B cell
  • crucial fro LLPC and memory B cell long term survival
  • turn on anti-apoptosis pathways
32
Q

Mechanism of Somatic Hypermutation

A
  • somatic point mutation in variable gene of H and L chain genes
  • more mutation seen after secondary and tertiary infection
  • causes deamination of cytosine to uracil in DNA by activation-indeuced cytidine deaminase (AID)
  • mismatch occurs (G:C becomes G:U)
33
Q

How is a somatic mismatch hypermutation resolved?

A
  • uracil not found in DNA but RNA
  • U bases removed via repair enzyme - uracil-DNA glycosylase
34
Q

Types of Immunity

A
  • Natural Active Immunity
  • Natural Passive Immunity
  • Artificial Vaccination
  • Artificial Passive
35
Q

Natural Immunity

A
  • Active Immunity - get disease, immune response (abs and T-cells) - develop lifelong or partial immunity (memory)
  • Passive Immunity - abs from mother across placenta to foetus
36
Q

Artificial Immunity

A
  • Vaccination - develop lifelong or partial immunity
  • Passive - direct injection of monoclonal abs - short lived, ab eventually degraded
37
Q

Types of Vaccines

A
  • mimic natural infection in the immune system - develops B and T cells immunity to vaccine

1st gen:

  • killed - inactivated
  • live - nonvirulent (attenuated)
38
Q

Limitations of vaccines

A
  • not all infections agents can be cultured
  • extensive safety precautions required
  • batch variation
  • reversion to virulence
  • limited shelf-life
39
Q

Subunit vaccines

A
  • derived from outer surface of pathogen
  • viral or bacterial surface protein

Advantages

  • no live components - no risk of inducing disease
  • chemically defined
  • safe and more stable than LAV (live)

Disadvantages

  • expensive
  • less immunogenic than LAV

E.g.

  • Hep B sag vaccine - recombivax HB
  • COVID-19 spike protein - Novavax
40
Q

Nucleic Acid Vaccines

A
  • mRNA viruses approved for COVID
    • moderna
    • Pfizer
41
Q

Virus Vector Vaccines

A
  • use virus vector to carry vaccinating agent
  • Adenoviruses - persist in cells as extra-chromosomal episomes

e.g

  • vaccinia virus - small pox
  • AstraZeneca - replication-deficient monkey adenoviral vector vaccine encoding SARS-CoV-2 spike gene
41
Q

Virus Vector Vaccines

A
  • use virus vector to carry vaccinating agent
  • Adenoviruses - persist in cells as extra-chromosomal episomes

e.g

  • vaccinia virus - small pox
  • AstraZeneca - replication-deficient monkey adenoviral vector vaccine encoding SARS-CoV-2 spike gene
42
Q

mAbs production

A
  • HAMA effect - person’e immune system sees murine mAb as a foreign protein - develops its own abs against the mAb
  • CDR grafting - replace as much of mouse gene regions with human gene regions

e.g. Trastuzumab (Herceptin) - HER2 Metastatic breast cancer

43
Q

Example of mAb application

A

Rheumatoid Arthritis

  • mAbs to inflamm cytokines (TNF-𝛼, IL-6, IL-1)
  • cell involved in RA - endothelial, synovial cell, leukocytes
44
Q

Ab-drug conjugate (ADC)

A

Kadcyla

  • consists of mAb trastuzumab (Herceptin) linked to cytotoxic agent mertansine (DM1) - Tubulin inhibitor

MB3008 (9 decks)

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