Lecture 3: Antigen Receptors

Front 1

BCR, TCR and MHC all do what?

Back 1

bind antigen

Front 2

what characteristics make an antigen provoke a strong immune reaction

Back 2

large, size, difference from self, stable, chemically complex, susceptible to fragmentation. Proteins better than lipids, carbohydrates, NA's.

Front 3

fundamental differences between BCR and TCR antigen recognition

Back 3

BCR - membrane bound Ig, can bind native antigen directly, confirmational epitopes, surface antigens only
TCR- only recognises antigen in association with bound MHC on APC, only processed antigens, can recognise processed intracellular antigens.

Front 4

A B cell that is actively secreting Ig it is called

Back 4

a Plasma cell

Front 5

what composes the heavy chains of Ig

Back 5

Vh, Ch1, Ch2 and Ch3

Front 6

what composes Ig light chains

Back 6

Vl and Cl

Front 7

what composes Ig Fc portion and what does it do

Back 7

Ch2 and Ch3 or 2 heavy chains. Binds Fc receptors to opsonise antigens, Ch2 also activates complement.

Front 8

Fab region ic made up of

Back 8

Vl, Cl, Vh, Ch1 x2

Front 9

5 isotypes of Ig

Back 9

MADGE, all different heavy chains

Front 10

types of light chain

Back 10

kappa and lambda

Front 11

how many types of each Ig type

Back 11

M1
A2
D1
G4
E1

Front 12

which Ig can cross the placenta

Back 12

IgG

Front 13

Which Ig is associated with allergy

Back 13

IgE

Front 14

most common Ig

Back 14

IgG (1,2,3 then 4, descending amounts) actually more IgM and IgA1 than IgG3 &4

Front 15

Functions of IgG

Back 15

Transplacental transfer
agglutination reactions with bacteria/viruses
complement activation (only IgG1 and 3)
Opsonising (esp IgG1 and 3)
Antibody dependent cell-mediated cytotoxicity (ADCC) (IgG1 and 3)
Neutralising toxins (eg viruses or tetanus)

Front 16

important aspects of foetal Ig transfer

Back 16

only IgG, FcRn active transporter across placenta, FcRn also expressed in newborn gut (maternal milk), haemolytic disease of the newborn

Front 17

how does ADCC occur

Back 17

IGg1 and IgG3 target cell and bind, exposed Fc regions recognised by NK receptors causing lysis.

Front 18

difference between IgG types

Back 18

length of hinge region (IgG4 hinge too short to allow complement activation by Ch2)

Front 19

IgM structure

Back 19

pentamer, no hinge regions, Fc portion has 3 constant domains, central binding J chain

Front 20

Primary response Ig

Back 20

M

Front 21

IgM functions

Back 21

foetal protection (only Ig produce by foetus), very effective agglutination, very effective complement activator, surface-bound B cell IgM monomer.

Front 22

Ig most associated with mucosal areas

Back 22

IgA (secretory IgA2 is a dimer)

Front 23

what inhibits IgA breakdown at mucosal surfaces

Back 23

secretory piece, glcosylation of H chains

Front 24

functions of IgA

Back 24

secretory protection, neonatal protection (colostrum) from enteric pathogens

Front 25

structure of IgE

Back 25

monomer with 3 constant portions in Fc region

Front 26

cells that bind IgE

Back 26

mast cells and basophils

Front 27

IgD

Back 27

not secreted by plasma cells found on B cell surface

Front 28

what are RAG 1 and RAG 2

Back 28

recombination activating gene's- manage gene rearrangement in the creation of the millions of potential combinations of Ig genes

Front 29

Light chain Fab region is composed of

Back 29

Vl (variable)30-40, Jl (joining)4-6 and Cl (constant)
all of either kappa or lambda

Front 30

heavy chain Fab region is composed of

Back 30

V(50), D diversity(25), J(6), C

Front 31

creation of gene rearrangement diversity

Back 31

VJC of light and VDJC of heavy are randomly recombined and sections excision circles cut out to create heavy chain then light chain. Transmembrane region is splced out at transcription so Ig produced can be secreted.

Front 32

process of B cell development

Back 32

H chain recombination, pairing, surrogate L chain binding, if functional this Pre BCR receives survival signal prompting allelic exclusion of H chain recombination, L chain rearangement, cecation of surrogate L chain expression.
once functional L chain bound goes to golgi and expressed as BCR- further survival signal

Front 33

what is allelic exclusion

Back 33

once functional H chain recombination has occurred (as tested by surrogate L chain binding) rearrangement at homologous chromosome is stopped. Also happens for L chain. Ensures that all Ig produced by one plasma cell is identical.

Front 34

what Ig's are expressed on the surface of a mature B cell

Back 34

M and D

Front 35

what associated molecules signal to the cell interior once surface Ig bind antigen

Back 35

CD79a and CD79b

Front 36

where are autoreactive B cells signaled for apoptosis

Back 36

in the bone marrow prior to release to the periphery

Front 37

what is somatic hypermutation

Back 37

when B cells improve their Ig specificity following first encounter with antigen

Front 38

MHC1 genes

Back 38

HLA- A, HLA-B, HLA-C

Front 39

MHC2 genes

Back 39

HLA-DP, HLA-DQ, HLA-DR
alpha and beta chains

Front 40

MHC1 function

Back 40

present antigen to CD8+ cytotoxic T cells, small peptides of intracellular pathogens

Front 41

MHC1 structure

Back 41

alpha chain (a1, 2,3), beta microglobulin
a3 binds CD8, a1 and 2 form peptide binding groove

Front 42

MHC 1 + cells

Back 42

all nucleate cells except neurones

Front 43

what are the variables that distinguish different MHC1 molecules

Back 43

AA residues in the peptide binding groove that give conformational change and so different binding afinities. Some positions are key 'anchor residues' 2or 3 required to bind to an MHC

Front 44

how many MHC1 molecules will an individual express on their cells

Back 44

6, 3 maternally inherited and 3 paternally. MHC are not exclusive like Ab's- each one can bind many (similar) peptides

Front 45

Do MHC discriminate between self/non-self

Back 45

No

Front 46

What is the name of the system by which antigens are prepared for presentation on MHC1

Back 46

the endogenous pathway

Front 47

normal cytosolic lysis of proteins is performed by

Back 47

proteasome

Front 48

antigenic peptides are prevented from being digested to AA's by

Back 48

HSP's, heat shock proteins

Front 49

where do HSP's deposit peptides

Back 49

the TAP (transporter of Antigen Presentation) ATP dependant pump on the endoplasmic reticulum

Front 50

where are MHC molecules formed

Back 50

transcribed on the ribosomes of the rough ER, transported into ER for folding and peptide binding

Front 51

what molecules chaperone MHC 1 folding and peptide binding

Back 51

Calnexin folds and associated beta microglobulin, then calreticulin displaces and transports to TAP, tapasin and ERp57 transfer on peptide (this complex is the peptide loading complex)

Front 52

what constitutes the peptide loading complex

Back 52

MHC1, calreticulin, ERp57, tapasin

Front 53

what happens to the formed peptide loading complex

Back 53

taken to cell surface by golgi complex

Front 54

what cells express MHC 2

Back 54

professional APC's (dendritic cells, macrophages, B cells)

Front 55

structure of MHC2

Back 55

alpha and beta domains, alpha 1 and beta 1 are distal to the cell membrane (form binding groove), alpha 2 and beta 2 are proximal

Front 56

that element of MHC2 binds CD4+ T cell

Back 56

beta 2 domain

Front 57

difference between MHC 1 & 2 binding grooves

Back 57

MHC2 is open ended, larger peptides

Front 58

antigen processing for MHC2 presentation is called

Back 58

the exogenous pathway

Front 59

How does MHC2 come to bind a peptide

Back 59

synthesised on ribosomes of ER, taken into ER and bind the invariate chain (blocks binding groove and has endosome targeting signal), taken in golgi to bind endosome containing ingested digested peptides to form MHC2 loading compartment MIIC, cathepsin S cleaves invariant chain (CLIP- class II associated invariant chain peptide remains in groove), HLA-DM catalyses swap of peptide for CLIP then taken to cell surface

Front 60

how is the invariant chain removed from MHCII

Back 60

cathepsin cleaves leaving CLIP, HLA_DM catalyses peptide/CLIP swap.

Front 61

what happens in the MIIC

Back 61

MHC II loading compartment- invariant chain cleaved to CLIP by cathepsin, peptides replace CLIP catalysed by HLA-DM

Front 62

cells that leave the bone marrow on the way to developing into T cells are called

Back 62

pro thymocytes

Front 63

where does T cell maturation occur (organ and region of organ)

Back 63

pro-thymocyte goes from bone marrow to thymus and proliferate in subcapsular cortex, with maturation and selection transit through cortex to medulla.

Front 64

TCR rearrangement is dependant on which enzymes

Back 64

Rag 1 and RAG 2

Front 65

what are the 2 TCR subtypes

Back 65

a/b (>95%) and g/d

Front 66

which CD do immature thymocytes express

Back 66

neither- double negative

Front 67

First stages of TCR production

Back 67

TCR gene rearangement, TCRb created, if functional it binds to pre-Ta, if not then TCRb on homologous chromosome rearranged, if it is also non-functional then apoptosis. Once functional TCRb binds to pre-Ta (becomes pre-TCR)

Front 68

A functional pre-TCR contains

Back 68

TCRb and pre-Ta

Front 69

a functional pre-TCR signals for what to happen (5 things)

Back 69

survival, prevent rearrangement at homologous chromosome (if 1st one yielded pre-TCR), induce TCRa rearangement, stop pre-Ta expression, cause CD4 and CD8 expression (double positve),

Front 70

what is a double positive thymocyte and when does it occur

Back 70

expresses both CD4 and 8, occurs once pre-TCR is formed (TCRb and pre-Ta)

Front 71

what composes a mature TCR

Back 71

a heterodimer of TCRa/b

Front 72

what surface feature is found associated to TCR (both CD4 and 8) and what doeas it do

Back 72

CD3, multimolecular complex that transmits signals into cell following TCR binding.

Front 73

which occurs first in TCR selection, +ve or -ve

Back 73

positive

Front 74

where does positive selection of TCR occur

Back 74

thymic cortex

Front 75

what cells are involved in judging TCR suitability in positive selection

Back 75

CEC, cortical epithelial cells

Front 76

describe positve selection of TCR

Back 76

double positive (DP) thymocyte interacts with cortical epithelial cell that expresses both CD4 and 8, apoptosed if does not bind to one type. DP then looses expression of non-binding CD type

Front 77

where does TCR negative selection occur

Back 77

corticomedullary junction of thymus

Front 78

describe TCR negative selection

Back 78

at thymic corticomedullary junction single positive thymocytes interact with medullary epithelial cells and dendritic cells (expressing AIRE protein allowing presentation of self peptides) if they bind too strongly they are marked for apoptosis.

Front 79

where do mature thymocytes go after positive then negative selection

Back 79

cortex to corticomedullary junction to secondary lymphoid tissue as mature T lymphocyte.