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Molecular Immunology > Adaptive Immunity > Flashcards

Adaptive Immunity Flashcards

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1
Q

Adaptive immune responses are initially slower to develop than innate responses. What can it do that innate can’t?

A

Shows specificity and memory

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2
Q

Where do B and T lymphocytes acquire antigen receptors?

A

B lymphocytes acquire them in the bone marrow
T lymphocytes acquire them in the thymus

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3
Q

What happens to antibody when stimulated by presence of antigen?

A

Cells release antibodies (receptors) which bind the toxin so it can be eliminated

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4
Q

Difference between integral membrane proteins on B lymphocytes and soluble proteins secreted by plasma cells?

A

Integral membrane proteins on B lymphocytes – Antigen receptors
Soluble proteins secreted by plasma cells – Antigen eliminators

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5
Q

Explain the 4 chain structure of antibody?

A

Arms (N termini) recognise antigen and bind
Tail (C termini) initiates elimination of antigen

Arms and tail joined by disulphide bonds, as well as a hinge allowing them to move relative to eachother

2 arms each consisting of 2 domain light chain and 2 domains of heavy chain
Tail consisting of 2 domains from both heavy chains; These connect to arm heavy chains

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6
Q

What did cleavage of antibodies with papain uncover? (hint - 2 fragments)

A

One of the fragments bound to antigen – Fragment Antigen Binding (Fab)
- When the antibody is cleaved by pepsin, the F(ab’)2 fragment can bind antigen divalently, like it would in the intact molecule

The other fragment was found to be crystallised in solution – Fragment Crystallisable (Fc)
- Interacts with elements of the innate immune system (antigen elimination)

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7
Q

What are the 5 immunoglobulin classes that differ in the amino acid sequence of the heavy chain? (hint - one has unknown traits)
Give traits for each

A

IgG – γ
- Main classes in serum and tissues
- Important in secondary responses

IgM – μ
- Important in primary responses

IgA – α
- IN serum and secretions
- Protects musical surfaces

IgD – δ
- ?

IgE – Epsilon
- Present at very low levels in serum
- Involved in protection against parasites and allergy

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8
Q

What are the 2 light chain types?
Are they class restricted?

A

Kappa
Lambda

These are not class restricted; Can have IgG-Kappa or IgG-Lambda antibodies

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9
Q

What do the variable and constant regions do? Different specificities?
Where are they?

A

V region - Bind antigen; Differ between antibodies with different specificities
- Domains at N terminus

C region - Same for antibodies of a given H chain class or L chain type
- 6 domains

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9
Q

Describe the homologous nature of antibodies? (hint - domain names)

A

Hypothesised to form a series of globular domains, each stabilised by an intra-chain disulphide bond
- V-H, V-L
- CH1, CH2, CH3; On each chain
- CL1; On each chain

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10
Q

What is the immunoglobulin fold?

A

Specific folding pattern of antibody domains
C domain has 7 beta strands
V domain has 9 beta strands

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11
Q

What is the immunoglobulin gene superfamily involved in?

A

Recognition, binding, adhesion

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12
Q

What are the hypervariable regions? (hint - CDRs)

A

Loops on the end of V domains in Fab
3 complementary determining regions (CDRs) on the end of both light and heavy chains
- CDR1-3

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13
Q

What interactions are involved in antibody-antigen binding?
Strength? Specificity and affinity?

A

Non-covalent e.g. electrostatic, H-bonds

Individually weak but if many form simultaneously due to high complementary between epitope and antibody, the interaction is specific and high affinity

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14
Q

What immunoglobulins do B cells use as a receptor and how do they initiate signalling? (hint - ITAM)

A

IgM and/or IgD used as B-cell receptors
These recognise and bind antigen but can’t generate a signal

Membrane immunoglobulins are associated with 2 other proteins, Igα and Igβ
These contain ITAM (Immunoreceptor Tyrosine Activation Motif) in their tail to initiate signalling when antigen binds

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15
Q

What are the main determinants of antibody diversity? (hint - CDRs)
Where does most variability come from?

A

Variations in the sequence and length of CDRs are the main determinants

CDR3 tends to be most variable
Heavy chain contributes more to antigen binding and is more variable than the light chain

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16
Q

What are the 3 big things that drive antibody diversity?
What do they give rise to? (hint - V regions)

A

Multiple genes
Somatic Mutation
Somatic Recombination

Somatic recombination and mutation gives rise to a limited number of inherited gene segments, which make up the V regions

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17
Q

How many sets of immunoglobulin genes are there and what/where are they?
How is variability achieved? (hint - V and C region genes)

A

Heavy (H) chains - Chromosome 14
Kappa (κ) chains - Chromosome 2
Lambda (λ) chains - Chromosome 22

Each locus has multiple V region genes and one, or a few, C region genes
Somatic recombination of V region genes generates variation

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18
Q

How many DNA segments encode light chain V regions?
What segments?

A

2 segments of DNA

V and J (joining) regions

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19
Q

How many DNA segments encode heavy chain?
What segments?

A

3 segments of DNA

V, J and D (diversity) regions

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20
Q

How and when does rearrangement of light and heavy chains genes occur?

A

Somatic recombination with V gene being spliced to a J gene; Intervening DNA is excised
New V gene is transcribed with intervening sequences removed by RNA sequencing

Occur during B cell differentiation, leading to permanent changes in the DNA

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21
Q

What gene segments does CDR3 correspond to and why?

A

VDJ

CDR3 is on heavy chain and these are the heavy chain gene segments

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22
Q

Somatic recombination involves lymphocyte specific recombinases and conserved recognition signal sequences (RSSs). What are RSSs and where are they found?

A

Conserved sequence that consists of heptamer (7bp) + nonamer (9bp); These are separated by 12 or 23 random nucleotides

Found directly adjacent to the coding sequence of V, D or J gene segments

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23
Q

What do RSSs do?
What is the 12-23 base pair rule?

A

Guide rearrangements of the V, D and J segments

12-23 base pair rule – Gene segment with a 12bp spacer only joins with a gene segment with a 23bp spacer; Ensures correct V-D-J joining

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24
What enzymes are in the V (D) J recombinase complex? (3 key enzymes)
Normal DNA cleavage/repair enzymes RAG1-RAG2 protein complex (encoded by Recombination Activation Genes) Specialised endonucleases e.g. Terminal deoxynucleotide transferase (TdT)
25
What does the RAG1-RAG2 complex do during somatic recombination?
Recognises and aligns the RSSs adjacent to the gene segments to be joined Complex has endonuclease activity and cleaves the DNA Cleaved DNA is repaired to form the coding joint (V and J segments now next to one another) and the signal joint (intervening DNA excised into loop)
26
How is diversity in immune repertoire achieved via antigen independent mechanisms? (3 things) (hint - -combination)
Multiple copies of each V region gene segments - [Vn x Jn] - [Vn x Dn x Jn] Heavy and Light chain combination - [Vκ x Jκ] + [Vλ x Jλ] x [VH x DH x J] Recombination is imprecise which leads to junctional diversity - Nucleotides may be lost or added; Variable addition of nucleotides at junctions massively contribute to CDR3 diversity
27
How is diversity in immune repertoire achieved via antigen dependent mechanisms? (1 thing)
Somatic mutation of V regions following antigen activation - Point mutations - Base changes tend to be clustered in CDRs
28
Steps 1-3 in process of somatic recombination End result? (hint - signal)
1. RAG-1-RAG-2 complex recognises and aligns the RSSs adjacent to the gene segments to be joined 2. Two ssDNA breaks are made close to the RSSs 3. Free 3’-OH attacks phosphodiester bond on other strand of DNA to create a hairpin at the segments to be joined and a flush ds break at RSS boundary (The blunt ends formed at Stage 3 are ligated to form the “signal joint” and this DNA is typically excised)
29
Steps 4-8 in process of somatic recombination (just formed hairpins) (hint - imprecise)
4. DNA hairpins are cleaved at random, symmetrically 5. Or asymmetrically 6. For V-D-J joining of the H chain, nucleotides can be added by terminal deoxynucleotide transferase (TdT) 7. Unpaired overhangs are filled in by DNA polymerase or may be excised by an exonuclease 8. DNA ligase joins the nicked and repaired hairpins to form the “coding joint”
30
What is somatic hypermutation? How does it occur? (hint - AID) Where are mutations clustered in mature B cells?
Point mutations introduced in rearranged V regions Activation-induced cytidine deaminase (AID), an enzyme expressed by B cells in lymphoid tissue responding to antigen Clustered in CDRs
31
Somatic hypermutation can add diversity, but what is its main function?
Affinity maturation – Higher affinity receptors selected as immune response proceeds – “Survival of the Fittest”
32
What is class switching? What are its effects? (hint - flexible response)
Same recombined V region associates with different C region genes, changing antibody heavy chain e.g. IgM --> IgG, IgA etc. Antigen specificity retained, different localisation/effector functions induced - Flexible response to pathogens
33
How can class switching occur? - Reversible? How is the mechanism different to V-D-J joining? (hint - AID)
DNA recombination between switch regions - Intervening DNA lost - Irreversible Different mechanism to V-D-J joining; Initiated by AID acting at switch regions
34
What is mechanism of AID activation for class switching and somatic hypermutation?
AID deaminates cytidine to form uracil Activity triggers DNA repair pathways Repair pathways in B cells are error-prone, leading to different mutational outcomes: - Mismatch repair, base excision repair – Somatic hypermutation - Single strand nicks --> Double strand nicks (common in G-rich tandem repeat switch regions) – Class switching
35
Why must AID be tightly regulated?
AID mutation causes immunodeficiency – Hyper-IgM Syndrome Type 2
36
How are T lymphocyte receptor different to B cell?
Acquired in the thymus Receptors are only expressed on membranes, not as soluble proteins
37
What are the 2 major subpopulations of T cells? Give CD_ +ve for both What do they do?
T helper cells (CD4 +ve) - Augment immune responses T cytotoxic cells (CD8 +ve) - Specifically kill infected host cells
38
How are T lymphocyte receptors (TCRs) similar to immunoglobulins? Which parts of which chains are most variable?
Extracellular domains of the TCR are homologous to variable and constant regions of immunoglobulins - Each V region contains 3 CDRs CDR3 regions of α and β chains are the most variable
39
What chromosomes are T cell receptor α and β chains on? CD3 subunits are a part of the TCR complex. What do they contain?
α - Chromosome 14 β - Chromosome 7 Contains ITAMs (Immunoreceptor Tyrosine Activation Motifs) in their cytoplasmic regions
40
How does somatic recombination occur in TCR V region?
Same way as in B cells
41
How is diversity achieved in TCR genes? (3 ways) (hint - similar to B cell) What do V regions of TCRs not undergo?
1. Multiple copies of V region gene segment [Vn x Jn/Vn x Dn x Jn] 2. α and β chain combination [Vα x Jα] x [Vβ x Dβ x Jβ] = ~ 6 x 106 3. Junctional diversity - Concentrated in the CDR3s of TCR α and β chains - TdT active throughout T cell receptor gene rearrangement V regions of TCRs do not undergo somatic mutation; Why?
42
Why is B cell immunity important in defence against extracellular pathogens? (hint - native)
B cells recognise free "native" antigens
43
How do T cells recognise intracellular antigens? (hint - processing)
Major Histocompatibility proteins (MHC) which presents processed antigen at cell surface for T cell recognition
44
What context can T lymphocytes ONLY recognise antigen in? Why is this?
Context of self-MHC molecules TCR recognises complex of peptide + self-MHC - CDR1 and CDR2 bind self-MHC - CDR3 binds peptide (antigen) that is bound to MHC
45
What are the 2 classes of MHC proteins involved in antigen recognition? What cells express them?
MHC Class I - Expressed by all nucleated cells - Present peptides derived from ENDOgenous proteins to CD8 +ve T cells MHC Class II - Expressed by certain leukocytes e/g/ dendritic cells, macrophages, B cells - Presents peptides derived from EXOgenous proteins to CD4 +ve T cells
45
What are the traits of the 2 domain types in MHCs, membrane-proximal and -distal?
Proximal - Ig like Distal - Bind peptide via peptide binding cleft
46
Membrane distal domains in MHC are polymorphic, are inherited and don't rearrange. What does this mean in general and for diversity and specificity?
Polymorphic so take many forms; Very broad specificity, binding a wide range of peptides Lower diversity than B and T cell receptors
47
Size of peptides bound by MHCI and MHCII?
MHCI - Binds peptides 8-10 a.a. long MHCII - Binds peptides 13-18 a.a. long
48
Process of antigen presentation by MHCI (4 steps) (hint - TAP) Endogenous meaning?
Endogenous - Antigen is made within host cell that is infected Intracellular antigen transported to proteasome to break down misfolded proteins Then transported to ER by TAP (Transporter Associated with antigen Presentation) Peptides loaded onto MHCI in ER MHCI-peptide transported to cell surface for recognition by cytotoxic T cell
49
Process of antigen presentation by MHCII Exogenous meaning?
Exogenous - Antigen is taken up from outside the host cell Antigen taken up by phagocytosis/endocytosis Acidification in vesicles promotes unfolding and proteolysis Peptides associate with MHCII in the endocytic compartment MHCII-peptide transported to cell surface for recognition by helper T cell
50
What is cross-presentation? What does this allow and when is it important? (hint - avoid infection)
Some dendritic cells present exogenous antigen associated with MHCI to cytotoxic T cells Allows antigen presentation to cytotoxic T cells without the dendritic cells themselves being infected Important in cytotoxic T cell responses to many tumours
51
Where does most allelic variation occur in MHC genes?
Predominantly in the peptide-binding regions
52
Consequences of MHC polymorphism?
Graft rejection Ensures wide recognition of foreign peptides but variability of MHC molecules is small compared to that of TCR T cell responses determined by an individual’s MHC type Association with certain autoimmune disease
53
CD4 and CD8 both contain Ig like domains, allowing them to act as what for the TCR complex? (hint - co-) What 2 things require this function?
Allows them to act as co-receptors Required to stabilise interactions and facilitate signalling
54
What does engagement of CD4/CD8 co-receptors with TCR complex enhance? (hint - ITAMs)
Enhances phosphorylation of the ITAMs, promoting T cell activation
55
What is Thymic selection? (hint - +ve and -ve selection)
Process to select T cells which correctly identify self-MHC and MHC + peptide +ve selection - TCR doesn't bind self-MHC so it is rejected -ve selection - TCR doesn't bind self-MHC + peptide so it is strongly rejected
56
IgM traits - Structure - Location - Hinge? - Affinity and avidity (strength of the antibody-antigen interaction)
Pentamer (5 antibody monomers + J chain) Usually serum-restricted No defined hinge region Low affinity but high avidity
57
IgM monomer traits - Valency (number of binding sites) - Complement - Primary response - Hinge?
- High valency (deca- /pentavalent) --> Good agglutinator of particulate antigen - Can activate complement very efficiently - Important in primary antibody responses Has functional hinge
58
IgA secretory form - Structure - Valency - Complement - Monomer binding
IgA dimer + J chain + Secretory component High valency Doesn't activate complement Monomer binds Fc receptors on phagocytes
59
How does secretory IgA transport bacteria that has penetrated mucosa back into lumen? What is IgA's passive role?
IgA secreted in submucosa and binds pathogen Transport system then takes complex through epithelia into lumen IgA has passive role in preventing adhesion/infection
60
Where is IgG D presented, along with IgM? Where is it produced and what does it interact with?
Present as antigen receptor on many B lymphocytes, together with IgM Produced by B cells/plasma cells in upper respiratory tract Interacts with receptors on basophils, inducing antimicrobial, inflammatory and B cell stimulatory factors
61
IgE traits - Hinge? - FcR - Affinity - Allergy and parasites
No defined hinge Binds with high affinity to FcR on mast cells and basophils Important in allergy and defence against large extracellular parasites
62
What are the biological roles of immunoglobulins? (7 roles)
Label pathogens for elimination/destruction Specific binding/multivalency: - Antibodies are at least divalent; Avidity vs affinity Immobilise pathogens – IgM Agglutinate particles e.g. bacteria – IgM, IgA Form “immune complexes” with soluble antigen Block binding of pathogens to host cells – IgG, IgA - E.g. antibodies to bacterial adhesins or viral receptors Neutralise toxins (e.g. tetanus, diphtheria, cholera) – IgG, IgA
63
What are the Fc Effector functions? (3 functions) What do these mechanisms depend on?
Invoke destruction of labelled pathogens Activate complement Bind Fc receptors on leukocyte surfaces Depend on: - Site and type of infection Stage of the immune response; Primary or secondary
64
What does C1 consist of? What is produced from C1 when complement is activated? How does classical complement activation occur? (hint - IgG)
C1 = C1q + C1r + C1s C1r is a serine protease that cleaves and activates C1s, another serine protease C1q must interact with 2 Fc regions for activation to occur; Cross-linking
65
Which antibody is a more potent complement activator than IgG and why?
IgM as C1q can bound to one IgM with its pentameric structure as opposed to 2 for IgG
66
How do IgG and IgA act as opsonins?
Bind bacteria with Fab regions Fc regions bind Fc receptors (FcRs) on phagocytes, inducing phagocytosis
67
What do FcRs do for pathogens too big to phagocytose? Which antibodies are involved?
Release lysosomal contents IgG and IgA
68
What does IgG binding to FcRs on NK cells facilitate? (hint - ADCC) How?
Antibody-dependent cell-mediated cytotoxicity (ADCC) Binding of IgG-coated targets cells to FcRs on NK cells Cross-linking of FcRs causes degranulation of enzymes and perforin to kill pathogen
69
What is mediated and what happens when IgE binds FcRs on mast cells and basophils? What form of antigen is needed and why? (hint - multi-)
Mediate allergy/defence against large parasites Mast cells secrete inflammatory mediators and cytokines Multivalent antigen to cross-link antibody
70
B cell response to certain antigen doesn't require T cell help. What is this called and how does it work?
Thymus independent antigens Multiple cross-linking of B cell receptor by antigen induces a rapid response and production of IgM antibodies
71
B cell response to certain antigen requires T cell help. What is this called and how does it work?
Thymus dependent antigens Require T cells for differentiation of B cells into plasma cells Long-lived memory B cells may also be generated Responses can involve somatic hypermutation and class switching

Molecular Immunology (5 decks)

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