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Antibodies: structure and function Flashcards

1
Q

What are the 2 main type of cell involved in the adaptive immune system?

A

T lymphocytes: cellular immunity

B lymphocyte: humoral immunity via antibodies

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2
Q

What are antibodies?

A

= immunoglobulins = gammaglobulins

produced in response to foreign antigens, specific to a particular epitope.
Antibodies are highly specific to their antigens

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3
Q

What are the physical properties of antibodies?

A

heavy chain
light chain
migrate in the gamma-fraction in serum electrophoresis

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4
Q

What is the main function of antibodies?

A

to recognise and neutralise their specific antigen, aiding in the elimination of that pathogen

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5
Q

What are the 2 main forms of antibodies?

A

membrane-bound
- on surface of B cells (= Ag receptor)
Secreted
- present in circulation, tissues and mucosa)

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6
Q

What is the function of membrane-bound antibodies?

A

this is the first Ab form to be synthesised
They recognise Ag which results in B cell activation and thus plasma cell proliferation
IgM Ab are usually these membrane-bound Ab on B cells

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7
Q

What is the function of secreted antibodies?

A

circulate in the blood

NEUTRALISATION
- microbes this present prevent further release of toxins or colonisation of adjacent host tissues

OPSONISATION
- enhances phagocytosis

ACTIVATION
- of complement system (pathogen killing)

ADCC

  • antibody dependent cell-meditated cytotoxicity
  • NK cells driven
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8
Q

What is the structure of most antibodies?

A

TETRAMERIC proteins
= 2 identical heavy chains + 2 identical light chains

disulphide bonds

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9
Q

What are the main types of heavy chain?

A 
IgM = mu
IgG = gamma
IgA = alpha
IgD = delta
IgE = epsilon
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10
Q

What are the 2 types of light chain?

A

lambda

kappa

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11
Q

What is the clinical relevance of heavy/light chain in multiple myeloma?

A

Medication prescribed for MM is decided by looking at the types of heavy and light chains present in the tumour cells

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12
Q

What are the main classes of antibody? How are they classified?

A 
Distinguished by types of heavy chain
IgM
IgA
IgD
IgG
IgE
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13
Q

Some antibodies have subclasses, which ones are they? What are they?

A

IgG (IgG1-4)

IgA (IgA1-2)

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14
Q

Which antibody types are most abundant?

A

IgG - most abundant in serum
IgA - most readily synthesised, present in mucosal tracts
Note that atopic individuals will have elevated levels of IgE

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15
Q

What is the gross structure of a IgG antibody?

A

antigen binding site: comprised of both light and heavy chain
2 heavy chains
2 light chains
only light chain can be renally excreted (due to MW)

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16
Q

What is the heavy chain of an Ab made up of?

A

2-4 constant domains

1 variable domain

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17
Q

What is the light chain of an Ab made up of?

A

1 constant domain

1 variable domain

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18
Q

What are the variable domains made up of? How can they differ so much between Ab?

A

AA sequence varies massively between different Ab

Also post-translational modifications

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19
Q

What is the antigen binding site of an Ab determined by?

A

Variable domains
V(L) and V(H)
(@ light and heavy chains)

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20
Q

What is the structure of a membrane bound IgM Ab?

A

Ag binding: V(L) and V(H)
2 Ag can bind to each IgM as 2 Ab binding sites on each arm of Ab
Cter is intracellular/cytosolic as it anchors into the PM of B cells
4 constant domains, 1 variable domain (per arm)

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21
Q

What is the structure of a secreted IgM Ab?

A

3 constant domains
1 variable domain - 2 Ag binding sites V(L) and V(H) - one on each arm
Cter is not intracellular but is free
Her the Cter is important for complement activation, opsonisation and ADCC
will bind Fc receptor via the Cter

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22
Q

What is the FAb site?

A

FAb = fragment Ag binding

FAb is the antigen binding site at the Nter of Ab molecule

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23
Q

What are the 2 types of epitopes?

A

linear epitopes

  • 6aa at most
  • linear arrangment in peptide

Conformational epitopes

  • epitope is part of a 3D structure of AA arrangement
  • not necessarily adjacent in linear/primary structure
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24
Q

What are the generic binding sites in an Ab?

A

F-Ab (@ Nter): binds Ag at site between variable domains on heavy and light chains

F-c (@ Cter) binds complement, receptors or anchored into PM of B cells

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25
What are the 2 main functions of Ab?
- recognition of an infinite number of Ag | - Effector functions via Fc (multiple mechanisms)
26
Which innate immune cells have Fc receptors? How does this binding help their function?
Macrophages Eosinophils Enhances phagocytes via opsonisation
27
What functions are mediated through the F-Ab site?
neutralisation of microbes and toxins
28
What functions are mediated through the F-c site?
opsonisation and phagocytosis of microbes ADCC Phagocytosis via complement-mediated opsonisation inflammation complement activation microbial lysis
29
How do Ab achieve recognition of an infinite number of Ag?
F-Ab made up of V(H) and V(L) domains | These domains contain 3 HYPERVARIABLE regions
30
What are hypervariable regions in the Ab?
correspond to the protruding loops that have direct contact with the Ag (form the Ag-binding surface)
31
What are the main types of hypervariable regions? Which as highest variability?
Complementary Types: - CDR1, CDR2, CDR3 CDR3 has greatest variability due to genetic mechanisms that ensure Ab diversity
32
Why does CDR3 have the highest variability of the 3 hypervariable regions?
The is located in the area where the V-DJ joining occurs | Thus it is associated with greater gene recombination than the other hypervariable regions
33
What kind of AA patterns are observed between variable and hypervariable regions?
AAs in variable regions tend to be more conserved that those found in hypervariable regions => latter is at junction of VDJ region (post-recombination), inherently more variable
34
How are CDRs (hypervariable) placed in the tertiary structure of Ab?
in the tertiary structure, CDRs are adjacent to each other | this is not the case in the primary structure of the polypeptide
35
How does the diversity in AA sequence in hypervariable regions translate to infinite Ag recognition?
AA in CDRs make contact with AA in Ag epitope these mediate bond/interactions There are infinite combinations on both sides
36
What is the function of the remainder of the Variable regions (aside from the CDRs)?
they provide structure support and ensure CDRs are kept in place
37
What are the main tissue depots that B cells go through in their life cycle?
Bone marrow: made here and develop | Spleen and LNs/spleen: Naive B cells reside here and 'wait' for Ag
38
What is education for Adaptive cells?
lymphocytes must go through education process where cells are screened for any indication of reacting to self-antigens e.g remove B cells producing auto-antibody
39
How many Ig genes are inherited? How does this match to antibody diversity?
Ab diversity = 10^7 - 10^9 there are not even thousand genes, just gene segments => combos of gene segments allow generation of high number of Ig (VDJ class switching)
40
In which segments are V(H) domains encoded?
encoded in 3 segments V, D, J 2 joining steps: 1) D-J (DJ must occur first) 2) V-DJ
41
In which segments are V(L) domains encoded?
encoded in 2 segments V, J 1 joining step 1) V-J
42
What do the different segments mean?
``` V = variable D = diversity J = joining ```
43
How may of each segment are available for the different domains of the heavy chain?
Variable domain - 45x (V) - 23x (D) - 6x (J) Constant domain - 9x (C) (different types of heavy chain)
44
What gene segments encode the kappa light chain?
Variable domain - 35x(V) - 5x(J) Constant domain - 1x C
45
What gene segments encode the lambda light chain?
variable domain - 30x (V) - 4x (J) Constant domain - 4x(C)
46
What are the main steps in VDJ class switching at genomic level?
- Germline DNA - somatic recombination of VDJ segments + joining - RNA processing in 3 B cell clones (varieties of recombined VDJ combos) - Translation of these 3 clones
47
How are the 3 B cell clones generated during RNA processing?
endonuclease cuts randomly - after one D and before a J AND - after one V and before DJ Free ends then ligated together to form continuous/functional gene
48
In what order does the Ig gene recombination occur for heavy and light chains?
Heavy chain: D-J joining and then V-DJ joining Light chain: V-J joining Then the heavy and light chains are combined to form complete Ab
49
What kind of variation does gene segment recombination generate?
= combinatorial - 270 different light chain options - 20, 000 heavy chain options JUNCTIONAL diversity also increase the types of Ab recognition possible
50
What is junctional diversity?
= functions to increase the number of different Ab generates Created by TdT enzyme, which adds random bases to the empty spaces of free ends before joining CDR3 is located at the D-J (heavy) or V-J (light) sites these are also the sites where random nucleotides are added Therefore both create maximum variation in the Ig sequence - site of CDR3 is most hypervariable region
51
What is allelic exclusion?
B cells are diploid and so there are 2 alleles governing heavy chain expression Meaning that one Ab could have 2 different heavy chains BUT to stop this from happening, as soon as one allele rearranges and successfully transcribes a heavy chain the rearrangement process is switched off
52
What is light chain restriction?
POLYCLONAL B CELLS = a mixture of cells making kappa or lambda chains This can apparently be an indicator of lymphoma or other neoplasm ??
53
Can one B cell clone produce more than one type light chain?
No. Each clone will make either kappa or lambda light chains Otherwise, it is abnormal and may be associated with neoplasm
54
How is clonal selection important for lymphocyte production?
Ag-specific clones of lymphocyte develop before and after exposure When Ag exposure occurs, that Ag-specific clone is selected/activated Leads to expansion of that clone and generation of the Ag-specific Ab only
55
What kind of clonal response are natural immune responses?
POLYCLONAL = more than one clone of B cell is activated remember than a microbe is likely to have multiple Ag, and that one B cell clone will be specific for one Ag only so to get good immunity and coverage, multiple clones need to be activated
56
How to B cell Ab forms change during the activation?
B cells have membrane-bound IgM Ab Binding of Ag to this causes activation of B cell This promotes switch from membrane-bound IgM to secreted IgM Switch is mediated through differential splicing of exons
57
How does differential RNA splicing dictate whether an Ab is membrane bound or secreted?
After the VDJ exons segments at the 5' region of RNA, there is a section called C-mu (at 3') Here, there is a TMEM domain inserted for a membrane-bound Ab OR a secretion coding sequence (signal peptide?) for a secreted Ab
58
What are the specific functions of Ab classes?
work at specific locations and against specific pathogens e.g. IgG (blood), IgA (mucosa) IgE (parasites) First Ab produced will always be IgM as it is critical to B cell activation Then other Ab types (IgM, then IgA etc) will be synthesised to combat infection
59
What is isotype swithcing?
``` = during an immune response, B cells can switch the class of Ab they making, but all Ab for a given B cell clone will have specificity for one Ag e.g IgM -> IgG, IgA, IgE ```
60
Why does isotype switching occur during an immune response?
- Allows ability to perform different effector functions | - Can deal better with pathogens
61
What are 3 important factors to remember for isotype switching?
- requires signals from T helper cells to occur - it does not alter specify for the Ag of that B cell clone - will not alter the light chain (just the type of heavy chain)
62
How do T helper cells mediate 'isotype switching' in B cells?
T cell: - CD40L interacts with CD40 on B cells Specific cytokines mediate a specific isotype transition: - IFN-g: switch to IgG1, IgG3 - IL-4: switch to IgE TGF-b*: switch to IgA * also: APRIL, BAFF etc
63
What are the main effector functions of the different Ab classes?
IgM: complement activation and B cell activation IgG: Fc-dependent opsonisation/phagocytosis, complement activation, neonatal immunity (placental transfer) IgE: helminth immunity, mast cell degranulation (immediate hypersensitivity) IgA: mucosal immunity (transport via epithelia)
64
What is the mechanism behind isotype switching at the genomic level?
DNA rearrangement process Ab retain the already rearranged variable region => Constant regions are exchanged to mediate switch
65
What are the structural properties of membrane-bound IgM?
monomeric structure Cter contains TMEM domain which allows insertion into PM of B cells Low affinity Ag binding at F-Ab sites (2 per molecule)
66
What are the structural properties of secreted IgM?
``` Pentameric IgM 5x Y-shaped Ab polypeptides in a ring 10 binding sites (2 per molecule) High Ag affinity at F-Ab J chain present between 2 molecules of Ab in ring ``` J chain is present in ALL polymeric Ab
67
What are the main functional properties of secreted IgM Ab?
- secreted - present in blood - [serum] = 0.5-2g/L - 1st Ab produced in primary immune response - very efficient @ complement activation - promotes opsonisation and lysis
68
What are the main functional properties of secreted IgG Ab?
``` - most abundant in serum [serum] = 5-16 g/L - monomeric - complement activation - promotes opsonisation and lysis - neutralises microbes and toxins ``` IgG is ONLY Ab to cross placenta (neonatal protection)
69
What are the main functional properties of IgA Ab?
- mostly monomeric - in circulation, [serum] = 0.8-5g/L - major Ab in mucosal secretions where it is dimeric (contains J chain) - Dimeric structure extends half life as its less likely to be enzymatically degraded - prevents adherence and entry of pathogens int epithelial cells
70
How do dimeric IgA Ab get into the mucosal lumen?
produced by IgA-producing plasma cell in lamina propria - released as dimeric IgA - Binds to Poly-Ig receptor and then endocytosed into mucosal epithelial cell - proteolytic cleavage of Poly-Ig receptor and then dimeric IgA is released (exocytosed) into lumen of mucosal tract
71
What are the main functional properties of IgE Ab?
``` v. low levels in healthy individuals higher in atopic individual [serum] = 0.0001-0.0002g/L monomeric Fc receptors on eosinophils + mast cells (=> degradation) defence against parasites allergy/hypersensitivity reactions ```
72
What are the main functional properties of IgD Ab?
monomer Mainly B cell receptor together with membrane-bound IgM (co-expressed) Thought to aid Ag recognition
73
How does the splicing pf IgD differ from that of IgM?
differential splicing at gDNA level exons for C(mu) and C(delta) are transcribed as part of one precursor RNA ``` splicing can remove either C(mu) or C(delta) exons Depending on which type of C remains is what class of Ab is produced ``` IgM and IgD have the same VDJ arrangement
74
Which cells are responsible for mediating hyper-acute organ rejection following transplant?
B cells | will act as an antigen presenting cell

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