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Infection and Immunity > Ab interaction w/ Ag > Flashcards

Ab interaction w/ Ag Flashcards

1
Q

What is an Ag?

A

A molecule on pathogen which triggers an Ab response

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2
Q

What do Ab recognise?

A

Recognise conformational Ags composed several sequentially discontinuous segments brought together by folding of molecule

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3
Q

What is different between Ab and TCR?

A

TCR can recognise linear Ag (sequentially linear segment of continuous residues) when presented by APC

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4
Q

What is an epitope?

A

Part of Ag recognised by Ab

Large Ag can have many different epitopes that are recognised by different Ab

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5
Q

What is a paratope?

A

Complementary part of Ab

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6
Q

What is the relationship between paratope and epitope?

A

They are confirmationally complementary - so they can bind together

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7
Q

Describe the structure of an Ab

A

Ab has heavy chain and light chain
Fc region responsible for effector function - comprised only heavy chain constant domains
Fab fragment - 1 constant + 1 variable region

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8
Q

What forms the Ag binding domain?

A

Variable region - heavy + light chain

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9
Q

How many segments of variability does each variable region have?

A

Each variable region has 3 segments of variability = hyper-variable region
Can identify hyper-variable region on heavy and light chain on H+L chain
Each Ab binding site have 6 hyper-variable regions = complementarity determining regions

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10
Q

What are hyper-variable regions?

A

They corresponds to 3 loops @ outer edge beta sheets of Ig domain

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11
Q

Describe the Ag binding site

A

When CDR loops from heavy chain and light chain bought together, creates single hyper-variable site @ top each arm Ab molecule

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12
Q

What is combinatorial diversity?

A

Different combination heavy and light variable regions will generate different Ag specificities

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13
Q

What is significant about the framework regions?

A

Have less variability at any given amino acid position - more stable sequence

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14
Q

How is variability limited to the hyper-variable regions Ab?

A

Have much higher ratio of different amino acid at any given position relative to the most common amino acid
hence, variability limited to hyper-variable region

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15
Q

What is the Ab-Ag interaction like?

A

Neither Ab or Ag is changed by binding
During interaction between Ab+Ag - 1 Ab binding site binds to 1 epitope on Ag

Binding is non-covalent and is reversible

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16
Q

What bonds are involved in the Ab-Ag interaction?

A

Ionic bonds - occurs between oppositely charged amino acid side chains

H-bonds - H shared between electronegative O2/N atom

Hydrophobic bonds - groups interact together to exclude water w/ tyr, phe, leu, ile etc

Van der waals forces - occur when fluctuations in electron clouds surround molecules are oppositely polarised neighbouring atoms between transient poles (short range)

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17
Q

What is the interaction between Ab and Ag determined by?

A

Dependent on Ab+Ag involved and distance between molecules

Total contribution of forces determine overall strength interaction

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18
Q

What is affinity?

A

Strength of interaction

Each force acts over short distance - 1x10^-7 mm or less

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19
Q

How can Ab affinity be calculated?

A

Can calculate because Ab-Ag reaction is reversible so can get dynamic eqm

K = [AbAg] conc. Ab/Ag complex
———- = ——————————–
[Ab][Ag] conc. unoccupied binding site on Ab
+ conc. unoccupied binding site Ag

K = affinity = eqm. constant
Can calculate how much AbAg complex present @ eqm

Typically higher affinity Ab will bind greater amount Ag in shorter period of time than lower affinity Ab

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20
Q

What is avidity?

A

Measurement of overall strength of Ab-Ag complex

Dependent on how many binding sites are occupied

21
Q

What is valency?

A

Number of Ag binding sites available

All Ab are multivalent

22
Q

Describe the different levels of valency

A

Monovalent - can occur when low level Ag and not enough Ag present to occupy both Ag binding sites on Ab
Low avidity

Bivalent - Occurs when sufficient Ag so both Ag binding sites are occupied eg. IgG
High avidity

Polyvalent - IgM as can form pentameric structure of 5 IgM molecules - 10 possible Ab binding sites
Very high avidity

23
Q

When is binding defined by affinity?

A

Intrinsic affinity

Fab fragment:
Only 1 Ag binding site occupied
Valence = 1
Low eqm constant - 10^4 L/mol

IgG w/ insufficient Ag
Valency = 1, low eqm constant

24
Q

When is binding defined by avidity?

A

Functional affinity

IgG with sufficient Ag for both binding site to be occupied
Valency = 2
Higher eqm constant - 10^7 L/mol

IgM - up to 10

25
Q

What is more important for functionality? (avidity or affinity)

A

Avidity likely to be more important than affinity

26
Q

What else is used to strengthen an Ab-Ag interaction?

A

Additional signals such as Ig alpha and beta, once BCR ligated (accessory molecules)
T cell help in form of T cells
Additional co-stimulation required from co-stimulatory receptors eg. CD-19

All signals come together to induce proliferation 1000-10,000 times differentiation into plasma cells + Ab prod

27
Q

When does the first humoral response?

A

When B cell encounters an Ag, produces Ab to make up humoral response

28
Q

What occurs during the primary immune response?

A

1st infection
Where naive B cells activated
Begin to proliferate and differentiate into Ab producing plasma cells
Maximal Ab production typically reached w/in 5-10 days
Predominant Ab production is IgM
Ab binds to Ag to eliminate pathogens encountered

29
Q

What occurs when the primary infection is cleared?

A

Small proportion B cells remain as memory B cells - these activated quickly when same pathogen encountered

30
Q

What occurs in the secondary immune response?

A

Get a much higher level Ab production reached w/in shorter time frame
Maximal Ab secretion occurs 0-5days
IgG Ab most predominant

31
Q

What occurs after the secondary infection is clear?

A

Following clearance, memory B cells generated at much higher number than following primary response

Hence, why secondary vaccination important because increase pool memory cells able to respond to infection

32
Q

What are the functional consequences of Ab binding?

A
  1. Neutralisation microbes and toxins
  2. Opsonisation and phagocytosis microbes because Ab binding pathogen and subsequent binding to Fc receptor on immune cells
  3. Ab dependent cellular cytotoxicity
  4. Complement pathway - coating Ab-Ag complex w/ C1q
33
Q

What can activation of the complement pathway cause?

A
  1. lysis microbes
  2. phagocytosis microbes opsonised with complement fragment eg. C3b
  3. Cleavage products - causes inflammation
34
Q

Describe the neutralisation of viruses

A

Depends on type of virus, target cell and class Ab

Limit viral infectivity - may inhibit virus-cell interaction
Prevent endocytosis virus
Prevent uncoating inside virus

All above methods more effective with complement

35
Q

How is vaccine efficacy measured?

A

Assessed by measuring circulating levels of neutralising Ab

36
Q

Describe neutralisation of toxins

A

Ab can bind bacterial endotoxins
Prevents binding to surface receptors immune cells
eg. binding cholera toxin to ganglioside GM1

Stimulates toxin clearance in Fc receptor mediated manner
IgG+IgA - important neutralising Ab

37
Q

Describe opsonisation

A

Coat particles by either Ab, complement, acute phase proteins (APP) - CRP

Ab bind micro-organism via Fab fragment and binds to cell via Fc
Does on phagocytes eg. macrophages to cause phagocytosis

Increases efficiency of phagocytic process - organism cleared more effectively

38
Q

Describe complement

A

Ag-Ab complex can activate complement system
Part of innate immune response - classical and alternative pathway

Functional pathways:
Chemotaxis
Opsonisation
Lysis of target cells
Priming adaptive immune response
39
Q

What are Fc receptors?

A 
How Ab interact with immune cells 
Several classes of Fc receptor based on Ab class they recognise
40
Q

What is the g-chain responsible for?

A

Signalling molecule

Some Fc receptors associate with a g-chain

41
Q

What occurs following Ab binding to the Fc receptor?

A

Aggregation occurs as aggregation receptors generate downstream signalling via ITAMa in associated chains

ITAMS - immunoreceptor Tyrosine based activation/inhibitory motifs

42
Q

What are the effector functions induced by the Fc receptor?

A 
Ab dependent cell cytotoxicity
phagocytosis 
Apoptosis
Mediator release
Enhancement of Ag presentation
43
Q

Describe the CD64 (FcYR1)

A

Binds monomeric IgG1 + IgG3 w/ high affinity
IgG4 w/ low affinity
No binding to IgG2

3 extracellular domains allows binding to sole IgG monomer
intracellular portion associates with Y chain for ITAM signalling

Expressed on mononuclear phagocytes

44
Q

Describe the CD32 (FcYR2)

A

Comes in 2 forms:
FcR2a - wide cellular distribution
moderate affinity for monomeric IgG1 + IgG3
high affinity for complexed IgGs
Has ITAM intracellular portion - binding to receptor is activatory

FcR2b - same specificity for IgG
BUT instead has ITIM = binding is inhibitory

45
Q

What does binding to FcYR2b cause?

A

Ab conc reaches threshold level, Ab-Ag complex binds to inhibitory receptors eg. Fc2b simultaneously w/ BCR
Causes negative feedback which blocks BCR signalling and ultimately inhibiting B cell responses

46
Q

Describe CD16 (FcYR3)

A

2 forms - A = transmembrane molecule and B = GPI linked molecule

FCY3a - moderate affinity for monomeric IgG
Associated w/ Y, Beta and zeta chains - CD3 complex
expressed monocytes, macrophages, NKC, some T cells
Responsible for ADCC

FCY3b - GPI linked w/ low affinity for IgG
Expressed neutrophils and basophils
activated by lipid raft formation and associates with other membrane signalling molecules

47
Q

Describe the FCalphaR1 (CD89)

A 
Associated gamma signalling chain 
Found on myeloid cells
Composed 2 extracellular Ig-like domains
Can bind to both IgA + IgA2 Ab
Can trigger phagocytosis, cell lysis + release inflammatory mediators
48
Q

Describe the FcER1

A

High affinity for IgE
2 Ig-like domains - associate w/ gamma and beta chains
Expresses mast cells and basophils
X-linking Ab molecules bound to R1 -> mediator release histamines
IgE always bound FcER1 .˙. always saturate (low serum IgE) - allergic response is quick

49
Q

Describe the CD23 (FcER2)

A

Low affinity receptor for IgE
Not member Ig-superfamily similar to c-type lectins
eg. mannose binding lectin

Expressed on leukocytes and lymphocytes in 2 forms:
CD23a - B cells, involved IgE prod
CD23b - expressed on lots of cell types and induced by IL-4

Infection and Immunity (8 decks)

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