Block A - Pathogen Recognition

Question 1

What are the 3R’s (3 marks)

Answer 1

-recognition
-reaction
-resolution

Question 2

Are PAMPs and PRRs part of the adaptive or innate immune system?

Answer 2

Innate immune system

Question 3

By which process do antigen-specific receptors acquire their uniqueness

Answer 3

gene segment recombination

Question 4

What’s the role of Mucins?

Answer 4

prevents adhesion to the epithelium by microorganisms

Question 5

What’s the role of Lysozymes?

Answer 5

attacks peptidoglycan in bacterial cell wall

Question 6

What’s the role of Defensins?

Answer 6

disrupts cell membranes of bacteria and fungi via pore formation

Question 7

What’s the role of Cathelicidins?

Answer 7

disrupts cell membrane of a wide range of microorganisms

Question 8

What’s the role of Histatins?

Answer 8

active against pathogenic fungi

Question 9

What’s the role of RegIII family?

Answer 9

contain C-type lectins, which target peptidoglycans which promote pore formation

Question 10

What’s IL-1R’s role in the inflammatory response

Answer 10

binds to the cytokine IL-1

Question 11

What’s TLR’s role in the inflammatory response

Answer 11

recognizes pathogen-associated molecular patterns (PAMPs)

Question 12

Both TLRs and IL-1R possess a _______

Answer 12

conserved intracellular signalling domain (TIR domain)

Question 13

Name the purpose of the TIR domain and the proteins it recruits/activates

Answer 13

-TIR domain is critical for activating signalling pathways in innate immune receptors
-activates signalling cascades such as MAPK and NFkB
-recruits adaptor proteins such as MyD88

Question 14

Where in the cell are TLRs usually found

Answer 14

in the extracellular structure of the cell

Question 15

How do 2 TLRs become a heterodimer?

Answer 15

2 different proteins, such as TLR-1 and TLR-2 bring their Toll-IL-1 receptor (TIR) domains together to initiate cell signalling

Question 16

How does a TLR form a homodimer?

Answer 16

2 of the same proteins, such as 2 TLR-4 proteins recognise LPS and after exposure to LPS, binds to both TLR’s stabilising them together

Question 17

Describe the process of the MyD88 dependant pathway in relation to TLR4 after LPS binding to MD-2 has occurred. (3 marks)

Answer 17

-TLR binds to the TIR domain.
-which contains the adaptor protein TIRAP which activates MyD88, forming an active TLR4/MyD88 complex
-this activates NF-kB which leads to the production of pro-inflammatory cytokines like IL-6

Question 18

Describe the process of the TRIF dependant pathway in relation to TLR4 after LPS binding to MD-2 has occurred. (3 marks)

Answer 18

-the adaptor proteins TRIF and TRAM are recruited which activates TRAF3
-which activates TBK1
-which phosphorylates IRF3
-IRF3 induces the expression of genes that encode interferons (type 1)

Question 19

What are the 4 key outcomes of TLR4 signalling?

Answer 19

-pro-inflammatory cytokines
-type 1 interferons
-activation of MAPK pathways which contribute to inflammation, cell survival and apoptosis
-antimicrobial defence

Question 20

What purpose do Nod like receptors have?

Answer 20

they are intracellular sensors of bacterial invasion and cellular damage

Question 21

Whats the name of the domain for NLRs

Answer 21

CARD domain (caspase recruitment domain)

Question 22

Describe the inflammasome and its activation?

Answer 22

-multi-protein complex that detects harmful stimuli and triggers inflammation via activation of caspase-1 which activates inflammatory cytokines like IL-1B and IL-18
-PAMPs and DAMPs are detected by sensor proteins like NLRP3
-sensor proteins interact with ASC, which has a domain that binds to caspase-1
-pyrin domains are structurally related to CARD and TIR domains

Question 23

What are the potential consequences of the inflammasome?

Answer 23

recently been linked to the pathogenesis of several inflammatory diseases

Question 24

Describe what 3 molecules help activate the NLRP3 inflammasome?

Answer 24

NLRP3, ASC and pro-caspase

Question 25

Antibodies can only attach to their ______ ______

Answer 25

specific antigen

Question 26

antibodies are produced by?

Answer 26

B lymphocytes

Question 27

What’s the most variable parts of the V region?

Answer 27

HV1, HV2 and HV3 (CDRs)

Question 28

What are the framework regions (3 marks)

Answer 28

-these are the 4 regions between the CDRs
-FRs show less variability
-forms the beta sheets that provide the structural framework of the variable domain and holds the CDRs in position to contact the antigen

Question 29

Describe how V(D)J recombination generates antibody diversity

Answer 29

-V, D and J segments recombine in heavy chains while only D and J recombine in light chains
-the process shuffles the segments to create different combinations, creating a variety of antibodies
-this process is mediated by RAG1/2

Question 30

Describe how junctional diversity generates antibody diversity

Answer 30

-during V(D)J recombination, enzymes like RAG1/2 and TdT add or remove nucleotides at the junction between V, D and J segments

Question 31

Describe how somatic hypermutation generates antibody diversity

Answer 31

-this introduces point mutations to the DNA at a high rate particularly in the CDR regions
-B cell producing antibodies, that have a higher affinity for the antigen that original B cell receptors are chosen to mature into antibody producing B cells

Question 32

Describe how class switch recombination generates antibody diversity

Answer 32

-B cells can change the constant region of the antibody heavy chain, which determines the antibody class
-this allows the same antigen specificity (variable region) to be linked to different effector functions

Question 33

What’s the role of CD8+ cytotoxic cells

Answer 33

kill infected or cancerous cells

Question 34

What’s the role of CD4+ helper cells

Answer 34

activates other immune cells through cytokine release

Question 35

What’s the process of the TCR recognition mechanism

Answer 35

TCR recognises the peptide fragments bound to MHC molecules on antigen-presenting cells (APCs)

Question 36

What’s the function of a TCR

Answer 36

to signal to the T cell that it has bound its antigen

Question 37

Describe 2 differences between TCR and antibodies (5 marks)

Answer 37

-TCRs are membrane bound and do not have soluble forms (unlike antibodies)
-antibodies have effector functions (such as opsonisation, neutralisation) via their constant region (Fc), TCRs are solely involved in antigen recognition

Question 38

Describe the structure of a TCR (3 marks)

Answer 38

-is a heterodimer composed of αβ chains, or less commonly γδ chains.
-The variable regions bind peptide-MHC complexes
-It includes a transmembrane domain that anchors it to the cell membrane and a short cytoplasmic tail.

Question 39

How do TCR’s generate a wide range of diversity?

Answer 39

-diversity is achieved through a process of random and imprecise rearrangement of gene segments in the thymus
-the TCR alpha’s V and J segments are rearranged
-the TCR beta’s V, D and J segments are rearranged
-mediated by RAG1/2 (same as antibodies)

Question 40

EQ-What are the structural components of a T cell receptor (TCR), and how do these components contribute to its function in recognizing antigens? (7 marks)

Answer 40

-TCR is a heterodimer made up of two glycoprotein chains, alpha and beta chains
-these two chains are highly polymorphic, which allows the TCR to recognize a wide variety of peptides
-in each chain the extracellular part consists of 2 domains, resembling the antibody V and C domains
-in each varible domain there are regions specifically high in amino acid sequence variability which are critical in antigen recognition and the specificity of antigen binding
-these are called CDRs, each variable domain contains 3 CDRs
-CDR1 and CDR2 are created from V gene segments while CDR3 is created from a combination of V, D and J segments
-this makes CDR3 the most diverse region and critical for antigen binding

Question 41

EQ-Why is the third hypervariable region (CDR3) of the TCR particularly important for its diversity and antigen recognition? (3 marks)

Answer 41

-CDR3 is the most polymorphic and interacts with antigen in a specific way
-it located in the centre of the antigen-binding site and makes more contact with the antigen than any other CDR
-while on the other hand the CDR1 and CDR2 loops form the periphery and mainly come in contact with the MHC component, which is less varible than the peptide component

Question 42

EQ-How does the diversity of TCRs contribute to immune tolerance, and what mechanisms are involved in preventing autoreactivity? (5 marks)

Answer 42

-a diverse TCR repertoire is essential for mainatining self-tolerance
-it increases the likelihood that T cells will recognize and eliminate autoreactive clones during the selection process
-when TCR diversity is reduced, either due to genetic or environmental reasons, there is a higher risk of self-reactive T cells escaping selection in the thymus possibly leading to the development of autoimmune diseases
-mechanisms that prevent autoreactivity include negative selection, where T cells that bind strongly to self-antigens are deleted, reducing the risk of autoimmunity
-another mechanism is clonal deletion which removes self-reactive clones from the repertoire

Question 43

Why does the CDR3 region vary most in length than the other CDR’s? (1 mark)

Answer 43

-it’s constructed from several components (V, D and J segments) while CDR1 and CDR2 are made up of V segments

Question 44

What can compromise immune tolerance?

Answer 44

TCR signalling defects can compromise immune tolerance by affecting the development and function of reguartory T cells, or by hyperactivating autoreactive T cells