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Immunology > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

somatic hypermutation

A

how entire V region is diversified after B cell activated by antigen, AID makes point mutations

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2
Q

AID

A

activation-induced cytidine deaminase: converts cytosine to uracil and only active during B cell proliferation

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3
Q

affinity maturation

A

when B cells that bind better to antigen are positively selected for

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4
Q

IgM

A

first isotype made in primary immune response, secreted as a circular pentamer held by J Chain, strongly binds to antigen but limited in effector mechanisms thus need isotype switching

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5
Q

switch regions

A

flanks the 5’ side of C genes

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6
Q

isotype switching

A

involves recombination within cluster of C genes that removes a previously expressed C gene and brings a different one into its place

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7
Q

Steps of Isotype Switching

A

1) initiation of transcription of C region
2) Targeting of AID of cytosines in switch region
3) Uracil is removed (abasic nucleotide)
4) endonuclease removes nucleotide and leaves a nick
5) nicks in both switch regions facilitate recombination
(takes place between u and any other C region or can happen sequentially)

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8
Q

Hyper IgM immunodeficiency

A

patients lacking AID cannot undergo somatic hypermutation or isotype switching making them susceptible to pyogenic bacteria infection in sinuses, ears, lungs.

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9
Q

Neutralizing antibodies

A

inactivate pathogen or toxin and prevent interaction with human cells

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10
Q

Opsonizing antibodies

A

act as opsonins or complement activators - phagocytes have receptors for Fc component of antibody

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11
Q

IgG

A

more flexible and can wave, rotate, wag, bend to increase chance of binding 2 antigens and effector molecules. Susceptible to proteolytic cleavage so there are subgroups that differ in hinge and heavy chain.

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12
Q

IgG1

A

most protein antigen

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13
Q

IgE

A

recruits effector functions of mast cells

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14
Q

IgA

A

present at mucosal sufaces as dimeric form held together by J Chain. important in protecting mucosal surfaces and in total is most abundant antibody

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15
Q

IgG2

A

repetitive carbohydrate antigens

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16
Q

IgG3

A

best at complement activation

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17
Q

IgG4

A

can exchange heavy-light chain dimer with another IgG4 (can only neutralize) - anti-inflammatory

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18
Q

T Cell Receptors

A

beta chain like the heavy chain with VDJ and alpha chain like the light chain with VJ

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19
Q

T Cell Receptor Function

A

only involved in antigen recognition, not effector function, mainly recognizes proteins.

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20
Q

T Cell similarities to immunoglobulins

A

undergo rearrangement as well as junction diversity

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21
Q

T Cell differences to immunoglobulins

A

there is only one C(alpha) and two functionally identical C(beta), never soluble

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22
Q

Severe Combined Immunodeficiency Disease

A

rare disease where genetic defects result in absence of RAG proteins leading to lack of B and T lymphocytes. Babies die very quickly without immediate bone marrow transplant.

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23
Q

Ommen Syndrome

A

missense mutation in RAG proteins that lowers activity

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24
Q

Rage Genes and Evolution

A

Because RAG is essential in T and B development and without them babies die, RAG genes might be important in the evolution of adaptive immune systems. RAG genes don’t have introns and resemble the transposase gene of a transposon (mobile genetic element) which cleaves dsDNA

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25
Q

Self vs Non Self

A

the power of adaptive immunity is from infinite possible binding sites on receptors but there is the potential to recognize self antigens

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26
Q

Immunological Tolerance

A

when cells realize how to not attack the self - happens during lymphocyte development

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27
Q

positive selection

A

T Cells are selected that have antigen receptors that work effectively with MHC class I and class II

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28
Q

negative selection

A

T Cells that bind too strongly to self-MHC molecules die by apoptosis

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29
Q

B Cell selection

A

B Cells are dependent of T cells for activation so negative selection still happens but isn’t as critical

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30
Q

Regulatory T Cells

A

provide additional tolerance in peripheral tissues by being autoreactive to determine if other T cells are autoreactive

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31
Q

Functional T-Cell Receptor

A

TCR must associate with four invariant proteins in order to make it to the cell surface (CD3 complex, zeta chain)

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32
Q

CD3 complex

A

CDgamma, CDdelta, CDepsilon

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33
Q

Invariant Protein Purpose

A

important in transmitting signal of antigen binding into the cells (similar to Igalpha and Igbeta in immunoglobulins)

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34
Q

T Cell Receptor Classes

A

cand have alpha:beta or gamma:delta where a/g are similar and b/d are also similar.

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35
Q

T Cell Receptor Classes Only One or Other

A

can have a:b T-cell receptors or g:d T-cell receptors, never both because the delta gene locus resides in the middle of the alpha chain locus so rearrangement of the alpha chain deletes the delta chain locus

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36
Q

The enzyme responsible for both somatic hypermutation and aiding in isotype switching is

A

Activation-induced cytidine deaminase

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37
Q

Antibodies that bind to a pathogen or toxin and inactivate the molecule preventing interaction with human cells are

A

neutralizing antibodies

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38
Q

Each variable region of each T-Cell receptor subunit has how many hypervariable regions?

A

3

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39
Q

Which of the following is not a component of the T Cell Receptor?

A

Ig(alpha)

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40
Q

Which of the following is mismatched?

a. affinity maturation: isotype switching
b. surface immunoglobulin: B-cell antigen receptor
c. constant regions of antibodies: binding to complement proteins
d. activation-induced cytidine deaminase: somatic hypermuation
e. switch sequences: class switching
A

a) affinity maturation: isotype switching

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41
Q

Which of the following is mismatched?

a. affinity maturation: isotype switching
b. surface immunoglobulin: B-cell antigen receptor
c. constant regions of antibodies: binding to complement proteins
d. activation-induced cytidine deaminase: somatic hypermuation
e. switch sequences: class switching
A

a)IgA

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42
Q

Identify which of the following is not associated with activation-induced cytidine deaminase activity?

a) synthesized in prolifeating B cells during active immune responses
b) diversification of the Vh domain but not the Vl domain
c. somatic hypermutation
d. isotype switching
e. cytosine conversion to uracil

A

b) diversification of Vh domain but not the Vl domain

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43
Q

In contrast to immunglobulins, T-cell receptors recognize epitopes present on antigens.

a. carbohydrate and protein
b. lipid
c. carbohydrate and lipid.
d. protein
e. carbohydrate

A

d. protain

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44
Q

Which of the following characteristics is common to both T-cell receptors and immunoglobulins?

a. The antigen receptor is composed of two identical heavy chains and two identical light chains.
b. . Somatic recombination of V, D, and J segments is responsible for the diversity of antigen-binding sites
c. . Somatic hypermutation changes the affinity of antigen-binding sites and contributes to further diversification.
d. class switching enables a change in effector function
e. carbohydrate, lipid, and protein antigens are recognzied and stimulate a response

A

b. somatic recombination of V, D, and J segments is responsible for the diversity of antigen-binding sites

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45
Q

How many hypervariable regions contribute to antigen-binding site in an intact T-cell receptor?

a. 12
b. 4
c. 6
d. 2
e. 3

A

c. 6

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46
Q

In B cells, transport of immunoglobulin to the membrane is dependent on association with two invariant proteins, Ig and Ig. Which of the following invariant proteins provide this function for the T-cell receptor in T cells?

a. All of the given answers are correct
b. CD3gamma
c. CD3delta
d. CD3epsilon
e. zeta

A

all of them

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47
Q

Antigen Processing and Presentation

A

TCR recognize peptide bound to MHC which requires antigen processing and antigen presentation

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48
Q

Antigen Processing General

A

degradation of pathogen-derived proteins into peptides

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49
Q

Antigen Presentation General

A

peptides are loaded onto MHC molecules and peptide:MHC complexes are displayed on cell surfaces where TCRs can recognize them

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50
Q

MHC stands for

A

major histocompatibility complex

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51
Q

MHC class 1 (general)

A

antigens from intracellular pathogens

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52
Q

MHC class II (general)

A

antigens from extracellular pathogens

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53
Q

Types of effector T cells

A

Cytotoxic T Cells and Helper T Cells

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54
Q

Cytotoxic T Cells

A

intracellular infections, express CD8

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55
Q

Helper T Cells

A

extracellular infections, express CD4

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56
Q

T-Cell Co-Receptors

A

CD8 and CD4 allow effector T cells to recognize the correct MHC class molecules so T Cells will express a co-receptor but never both

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57
Q

MHC class I cells

A

most cells express this because any cell can be infected

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58
Q

MHC class II cells

A

only dendritic cells, macrophages, and B cells express this because they are professional phagocytes that attack extracellular pathogens

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59
Q

CD8 on Cytotoxic T Cells

A

recognize MHC Class I presenting intracellular

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60
Q

CD4 on Helper T Cells

A

recognize MHC class II presenting extracellular

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61
Q

Cytotoxic T Cells funtion

A

main effector function is kill cells infected with pathogen

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62
Q

Helper T cells function

A

main effector function is to help other cells respond to extracellular sources of infection (B cells and macrophages)

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63
Q

MHC Class I Structure

A

transmembrane alpha chain, beta2-microglobulin (not encoded by gene in MHC)

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64
Q

MHC Class II Structure

A

transmembrane alpha chain, transmembrane beta chain

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65
Q

Peptide binding groove structure

A

peptide binding groove of both MHCs is formed by two immunoglobulin-like domains which are also important in co-receptor binding

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66
Q

Promiscuous binding specificity

A

the peptide-binding site in an MHC can bind many different peptides

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67
Q

MHC class 1 peptide binding groove constraints

A

MHC class I binds peptides of 8, 9, 10 amino acids and the last amino acid is usually hydrophobic or basic

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68
Q

MHC class 2 peptide binding groove constraints

A

binds peptides of 13-25 amino acids (or longer)

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69
Q

MHC class 1 Antigen Presentation General

A

1) intracellular pathogen produces proteins using cellular machinery
2) some proteins naturally degraded and transported to the ER where they can bind MHC class 1
3) MHC class 1 bearing peptide leaves the ER and moves to the cell surface
4) cytotoxic T cells that have the proper T cell receptor and CD8 can recognize the MHC class 1:peptide complex and kill the affected cell

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70
Q

MHC class 1 Peptide Generation

A

intracellular pathogen uses cytoplasmic ribosomes to make protein but cells also have the proteasome. peptides are transported across ER membrane thought the protein TAP

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71
Q

Proteasome

A

how normal cells break down cellular protein and if the cell is responding to INF-gamma, the proteasome will adopt a function of making MHC class 1 peptides

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72
Q

TAP

A

transporter associated with antigen processing - lets MHC class 1 peptides into the ER

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73
Q

MHC Class 1 Peptide Loading Complex

A

1) class I heavy chain is stabilized by calnexin until b2-microglobulin binds
2) calnexin is released. the heterodimer of class 1 heavy chain and b2m forms the peptide-loading complex with calreticulin, tapasin, TAP, and ERp57
3) a peptide delivered by TAP bind to the class 1 heavy chain forming the mature MHC class I molecule
4) the class I molecule dissociates from the peptide-loading complex, and is exported from the ER

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74
Q

Calnexin

A

keeps MHC in ER until it is properly folded

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75
Q

Peptide-loading complex

A

MHC class 1 binds b2m after calnexin and then incorporates with calreticulin, tapasin, TAP, and ERp57

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76
Q

MHC Class 1 Peptide Trimming

A

1) MHC class 1 is loaded with peptide that is too long at the N terminus (but usually has correct carbody terminus)
2) ERAP removes N-terminal aa to give a peptide of 8-10
3) MHC class 1 molecule moves to Golgi and then plasma membrane

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77
Q

ERAP

A

endoplasmic reticulum aminopeptidase

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78
Q

Bare Lymphocyte Syndrome

A

non-functional TAP protein so antigen cannot get into the ER and there is a very poor CD8 responses

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79
Q

Self-Peptides on MHC class I

A

These can also be presented but T Cell development prevents response

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80
Q

MHC class II Antiger Presentation General

A

1) macrophage (or dendritic) engulfs and degrades bacterium, producing peptides
2) bacterial peptides bound by MHC class II in vesicles (endosome)
3) bound peptides transported by MHC class II to the cell surface
4) helper T cell recognizes complex of peptide antigen with MHC class II and activates macrophages

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81
Q

Where MHC class II molecules are made

A

made in the secretory pathway, but they don’t meet antigen peptide until their vesicles from the Golgi fuse with endocytic vesicles

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82
Q

Do MHC Class II get loaded in the ER?

A

NO but the MHC Class II molecules enter the secretory patheway and ER but don’t get loaded. Work through the invariant chain

83
Q

MHC class II molecules meeting antigen

A

1) MHC class 2 molecules are in ER
2) MHC class II alpha and beta chains associate with the invariant chain
3) invariant chain blacks binding of peptides to MHC class II molecules in the ER
4) In vesicles, invariant chain in cleaved, leaving the CLIP fragment
5) CLIP blocks binding of peptides to MHC class II in vesicles
6) HLA-DM facilitates release of CLIP, allowing peptides to bind

84
Q

CLIP

A

class II associated invariant chain peptide - cleaved from the invariant chain once the MHC class II moves to an endocytic vesicle from the ER

85
Q

HLA-DM

A

exchanges CLIP with a pathogenic peptide

86
Q

Cross-Presentation of Peptides

A

exogenous antigens can be presented via MHC class I molecules via cross-presentation

87
Q

Exogenous antigens

A

a forgein antigen like in allergy, transplant protein, taken in by breathing or eating etc

88
Q

When does Cross-presentation happen?

A

occurs when phagocytic cells engulf and infected and apoptotic cell and generated peptides are transproted to the ER but the mechanism is unknown.

1) phagocyte engulfs infected cell
2) phagolysosome produces antigens that go to the ER
3) present at class 1 but the vesicle also binds somehow

89
Q

How T Cells recognize the antigen on MHC

A

TCR makes contact with BOTH peptide and MHC molecule. The third hypervariable region of the TCR alpha and beta chains (most variable) make peptide contact while the first two hypervariable regions contact the MHC molecule

90
Q

Differential Expression of MHC Class I and Class II Molecules

A

virtually all cells express MHC class I (intracellular pathogens) but MHC class II are seen on cells of the immune system specialized for uptake, processing, and presentation of antigen (extracellular pathogen)

91
Q

The protein responsible for transporting intracellular pathogen peptides into the endoplasmic reticulum is:

a. CLIP
b. TAP
c. HLA-DA
d. ERAP

A

b. TAP

92
Q

CLIP, which binds to MHC class II molecule is derived from:

a. Calnexin
b. proteasome
c. HLA-DA
d. Invariant Chain

A

d. Invariant Chain

93
Q

Tapasin

A

a bringing protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules

94
Q

The T-cell co-receptor CD4 interacts with bound to the surface of .

a. MHC Class II; antigen-presenting cells
b. MHC Class I; antigen-presenting cells
c. MHC Class I; T cells
d. MHC Class II; T cells
e. None of the answers given are correct
A

a. MHC Class II; antigen-presenting cells

95
Q

The degradation of pathogen proteins into smaller fragments called peptides is a process commonly referred to as:

a. antigen presentation
b. peptide loading
c. antigen processing
d. endocytosis
e. promiscuous processing

A

c. antigen processing

96
Q

Which of the following best describes the function of tapasin?

a. Tapasin is a bridging protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules
b. Tapasin is an antagonist of HLA-DM and causes more significant increases in MHC class I than MHC class II on the cell surface
c. Tapasin is a lectin that binds to sugar residues on MHC class I molecules, T-cell receptors, and immunoglobulins and retains them in the ER until their subunits have adopted the correct conformation
d. Tapasin is a thiol-reductase that protects the disulfide bonds of MHC class I molecules
e. Tapasin participates in peptide editing by trimming the amino terminus of peptides to ensure that the fit between peptide and MHC class II molecules is appropriate
A

a. tapasin is a bridging protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules

97
Q

Antigen processing involves the breakdown of protein antigens and the subsequent association of peptide fragments on the surface of antigen-presenting cells with

a. MHC class I or class II molecules
b. immunoglobulins
c. T-cell receptors
d. complement proteins
e. CD4
A

a. MHC class I or class II molecules

98
Q

Which of the following describes a ligand for an a:b T cell receptor?

a. peptide:MHC complex
b. carbohydrate:MHC complex
c. lipid:MHC complex
d. All of the complexes given are correct
e. None of the complexes given are correct
A

a. peptide:MHC complex

99
Q

MHC molecules have promiscuous binding specificity. This means that

a. a particular MHC molecule has the potential to bind to different peptides
b. when MHC molecules bind to peptides, they are degraded
c. peptides bind with low affinity to MHC molecules
d. None of the answers given describe promiscuous binding specificity
A

a. a particular MHC molecule has the potentail to bind to different peptides

100
Q

Which of the following removes CLIP from MHC class II molecules?

a. HLA-DM
b. HLA-DO
c. HLA-DP
d. HLA-DQ
e. HLA-DR
A

a. HLA-DM

101
Q

Human MHC

A

is called human leukocyte antigen complex (HLA) called HLA class I and HLA class II

102
Q

MHC Diversity Comes From?

A

Gene families and genetic polymorphism

103
Q

MHC gene families

A

multiple similar genes encoding the MHC chains

104
Q

MHC genetic polymorphisms

A

presence of multiple alternative forms of a gene in a population

105
Q

Isotype

A

product of different genes in MHC class I or II family

106
Q

Allele

A

different form of a gene

107
Q

Allotype

A

encoded protein from and allele

108
Q

MHC Class I Isotypes

A

HLA-A, HLA-B, HLA-C, HLA-E, HLA-G, HLA-F

109
Q

HLA-A, HLA-B, HLA-C

A

highly polymorphic, present antigen to CD8 T cells and are ligands for NK cells

110
Q

HLA-E and KLA-G

A

oligomorphic, ligands for NK cells

111
Q

HLA-F

A

unknown function but intracellular

112
Q

MHC Class II Isotypes

A

HLA-DP, HLA-DQ, HLA-DR, HLA-DM, HLA-DO

113
Q

HLA-DP, HLA-DQ, HLA-DR

A

highly polymorphic, present antigen to CD4 T Cells

114
Q

HLA-DM, HLA-DO

A

oligomorphic, involved in peptide loading of class II

115
Q

HLA Class II and I Gene Complex

A

Consists of about 4 million base paris on chromosome 6 with three regions in order Class II Region, Class III Region, Class I Region

116
Q

Class I Region

A

HLA class I genes and nonfunctional class I gene fragments

117
Q

Class II Region

A

HLA class II genes and nonfunctional class II gene fragments

118
Q

Class III Region

A

separates class I and Class II with other genes

119
Q

HLA Gene complex notation

A

Remember class II has and alpha and beta chain so genes are A and B (HLA-DMA or HLA-DMB). If there is more than one gene, and number is added to the end (HLA-DQA1 or HLA-DQA2)

120
Q

Haplotype

A

combination of HLA alleles - over human history HLA genes have been recombined to thousands of haplotypes - combination of different haplotypes through inheritance means that million of different HLA combinations are represented

121
Q

HLA-DR Subdivisions

A

There is one single HLA-DRA gene, but there are 4 different genes encoding the HLA-DR beta chains(DRB1, DRB3, DRB4, DRB5). So DRB1 is present on every chromosomes 6 and can be the only one expressed and there are 3 other types of chromosome 6 that carry either DRB3, DRB4, or DRB5 in addition in DRB1.

122
Q

HLA class II region genes

A

almost entirely dedicated to genes involved in antigen processing: HLA alpha and beta chains, TAP, subunits of proteasome that are induced by interferons

123
Q

Interferons

A

involved in coordinately regulating genes involved in antigen presentation and processing (HLA class I heavy chains, b2m, TAP, proteasome subunites)

124
Q

INF-gamma

A

coordinates expression of HLA class II genes and invariant chain genes through the action of the trascriptional acitvator C2TA

125
Q

C2TA

A

MHC class II transactivator

126
Q

Impaired C2TA

A

can lead to bare lymphocyte syndrome where class II molecules are not made and CD4 cells cannot function

127
Q

MHC Polymorphism

A

highly polymorphic can differ by 1-50 amino acids but substitutions are mainly in domains that bind peptide and interact with T cell receptor but not all contact residues are different

128
Q

Peptide binding groove variations

A

determines the type of peptide that can bind but certain positions, most have the same or similar amino acid (anchor residue)

129
Q

Peptide-binding motif

A

combinations of anchor residues that bind to a particular MHC isoform

130
Q

MHC Restriction

A

antigen-specific T Cell response is restricted by the MHC type. The most diverse aa in MHC molecules is located in the surfaces that the TCR bind. So both the MHC type and antigen have to match the TCR for binding to occur.

131
Q

MHC Diversity

A

driven by natural selection from pathogen infections. AA substitutions are concentrated at sites of peptide binding in a nonrandom way. Polymorphisms can provide different peptide-binding specificity

132
Q

Heterozygote advantage

A

high degree of polymorphism of HLA isotypes ensures that most of the population are heterozygotes since they can more pathogens

133
Q

balancing selection

A

processes that act to maintain a variety of MHC isoforms in a population where successive epidemics make homozygotes die

134
Q

directional selection

A

during a specific, epidemic disease exposure, certain MHC isoforms are selected for

135
Q

Generation of new MHC Alleles

A

quick rate of pathogen adaptation to MHC molecules, likely suggests rare MHC allels that have not been adapted for are selected for and new variants can form by point mutation, recombination, interallelic conversion

136
Q

Interallelic Conversion

A

recombination in which segment of one allele has been replaced by a homologus section of another

137
Q

HIV/AIDS

A

MHC heterozygosity has been shown to provide a selective advantage to AIDS progression in people infected with HIV

138
Q

Autologous

A

how self-MHC isoforms are described

139
Q

Allogenic

A

how foreign MHC isoforms are secribed

140
Q

Alloreactive T Cells

A

In every individual, these T cells can respond to peptide and allogeneic MHC molecules from cells of other healthy individuals which is a problem for transpants

141
Q

HLA Type

A

need to be similar or identical HLA alleles to avoid alloreaction

142
Q

Alloantibodies

A

made during pregnancy from natural alloreaction if the mother’s immune system is stimulated by the HLA molecules n the fetus from the father. Not a danger to fetus but cna be a problem is mom need transpalnt in future.

143
Q

The term used to describe the expressed protein of a certain gene is:

a. allele
b. allotype
c. haplotype
d. isotype

A

b. allotype

144
Q

Foreign MHC molecules are referred to as

a. autologous
b. interallelic
c. allogenic
d. haplotypes

A

c. allogenic

145
Q

Six Phases of B-Cell Development

A

Repertoire assembly (acquiring of functional immunoglobulins), negative selection, positive selection, circulation of mature B cells, B-Cell activation, B-Cell effector functions (stem cells make 60 billion new b cells a day)

146
Q

B-Cell Development in Bone Marrow

A

pluripotent hematopoitic stem cells have DC34, give rise to common lymphoid progenitor cell (CD34 and CD10), B-Cell Precursor (CD34, CD10, CD127), pro-b-cells are begining of B cell lineage (CD34, CD10, CD127, CD19)

147
Q

Pro-B-Cell Stage

A

rearrangement of the heavy-chains first occurs between D and J gene (early pro-b-cell stage) and then between V and the rearranged DJ (late pro-b-cell stage). Then transcription occurs through the u C-region gene making pre-b-cells

148
Q

Pre-B-Cell Stages

A

Large pre-b-cell (not yet rearranging light chain) and small pre-b-cell (rearranging of light chain has begun)

149
Q

Stromal Cells

A

stromal cells of the bone marrow provide a microenvironment for b-cell development by making specific contacts with developing B cells and produce growth factors that act on attached b cells (SCF and IL-7)

150
Q

Nonproductive Rearrangement

A

when rearrangment of the heavy chain in pro-b-cell is imprecise and ineffecience so the addition of N and P nucleotides can change the reading frame. If this happens from both heavy chain loci then the b cell will die.

151
Q

Productive Rearrangement

A

gives rise to function immunoglbulin chain from correct rearrangment of the heavy chain in pro-b-cells. Requires RAG1 and RAG2 which are activated by E2A and EBF trx factors

152
Q

surrogate light chain

A

VpreB and gamma5 produced by the b cell to act as a temporary light chain to test the functionality of the pro-b-cell u heavy chain

153
Q

Pre-B-Cell Receptor

A

in the ER the u heavy chain assembles with the surrogate light chain and Iga and Igb to make this. must be functional in order to transition to pre-b-cell stage

154
Q

Allelic Exclusion

A

ensure only one functional immunoglobulin in made for strong interactions with multivalent antigens. how pre-b-cell receptor prevent more than 1 u chain. once one is made RAG gene trx stops, RAG degrades, chromatin remodles to prevent gene rearragment

155
Q

Light Chain Rearrangment in Pre-B-Cells

A

large pre-b-cells divide into small pre-b-cells that don’t make b-cell receptor, RAG reactivate, rearragment of light happens one locus at a time between V and J, 4 loci (2 kappa 2 delta) 85% success, functional IgM shuts down further recombination.

156
Q

Checkpoints of B Cell Development

A

make sure functional heavy/light since recombo ineffective.
1) formation of pre-b-cell receptor
2) formation of functional b-cell receptor.
If no pass, apoptosis.

157
Q

What drives B Cell development?

A

Protein expression. RAG only active when rearrangement occurs. Tdt expressed during heavy chain rearrangment (why only 50% light chain genes have N nucleotide), Iga and Igb always expressed (important in allelic exclusion and functional IgM)

158
Q

How does protein expression change for B cell development?

A

Transcription factors! Required for rearrangement of RAGs, E2A EBF, Pax-5 (binds enhancer regions to begin trascription)

159
Q

B-Cell Tumors

A

Because there is lots of cutting, splicing, mutating DNA. Often from translocation of an immunoglobulin gene with a different chromosome

160
Q

Typical B-Cell Tumor Translocation

A

between immunoglobulin and proto-oncogene (MYC on chrom 8 and BCL2) Ig on Chrom 14

161
Q

CD5 Expression on B Cells

A

only on subset of B cells that arise during embryonic development and don’t go through these 6 phases of b cell development

162
Q

B Cells with CD5

A

B-1 cells or called CD5 B Cells (CD5 usually on T cells)

163
Q

Polyspecificty

A

allows antibodies produced by B-1 cells to be of lower affinity and thus binds multiple antigens that are typically specific to carbohydrate antigens

164
Q

Adult B-1

A

maintain population of B-1 cells through division as no new ones are made in bone marrow

165
Q

The surrogate light chain is made up of what two proteins?

a. VpreB and lambda5
b. CD34 and CD5
c. E2A and EBF
d. RAG-1 nad RAD-2

A

a. VpreB and lambda5

166
Q

What is the main function of pro-b cell development

a. expression of CD5
b. heavy chain rearrangement
c. isotype switching
d. light chain rearrangement

A

b. heavy chain rearragement

167
Q

Negative Selection of B Cells

A

repertoire assembly can make self reactive immunoglobulins that recognize self antigen and immature B cells are programmed to generate negative signals if bind to self antigen resulting in apoptosis or inactivation

168
Q

Beginning of Negative Selection

A

begins in bone marrow where multivalent self-antigens present on stromal cells, hematopoiteic cells, and blood plasma macromolecules prevent B cells from leaving the bone marrow

169
Q

B-Cell Receptor Editing

A

if immature B cell is multivalent self reactive IgM, IgM expression decreases while RAG continues to allow for further light chain rearrangment. If a new light chain occurs, it can assemble with the old heavy chain to hopefully make new, functional immunoglobulin. Then can leave bone.

170
Q

Clonal Detection

A

cell death by apoptosis if new light chains cannot rearrancge with nonfunctional heavy chains to make a good immunoglobulin in B cell

171
Q

B-Cell Anergy

A

inactivation of immature b cells with monovalent self-reactive IgM (doesn’t go through editing or apoptosis).

172
Q

Anergenic B Cells

A

make IgD and IgM but the IgM cannot assemble on cell surface and the IgD receptors don’t signal activation upon antigen binding. will circulate blood for 1-5 days (normal 40 day half life)

173
Q

Central Tolerance

A

Three ways B cells can become self-tolerant - receptor editig, death of multivalent self-reactive B cells by apoptosis, anergy of monovalent self-reactive B cells

174
Q

Peripheral Tolerance

A

Because not all self antigen is in bone marrow, b cells can also die by apoptosis or become anergic if they encounter self antigens in peripheral tissues

175
Q

Autoimmune Response

A

Caused by B cells that react to self antigens that are inaccessible to B cells (intracellular molecules)

176
Q

B Cell Maturation General

A

1) immature B cells produce high levels of IgM and low levels of IgD but that flops when mature
2) maturation requires immature b cells to migrate to secondary lypohid tissues
3) in lymphoid tissue, chemokines are secreted by stromal cells (CCL21) and dendritic cells (CCL19) to attract B cells
4) B cells migrate to primary lymphoid follicle that contains dendritic follicular cells (CXCL13)
5) in primary follicle, maturation of B cells occurs to produce naive B cells (not yet exposed to antigen)

177
Q

B Cell Differentiation

A

1) B cell encourters antigen keeps the b cell in the t-cell area of the lymphoid tissue to become activated by CD4 T Cells
2) B cell activation causes proliferation and some plasma cell differentiation (antibodies)
3) other activated b cells move to germinal cells to mature into centrocytes
4) centrocytes can migrate to other lymphoid tissue or marrow to become plasma cell (isotype switched antibodies)
5) come germinal center B cells will develop into memory b cells (isotype switch antibodies)

178
Q

centrocytes

A

dividing B cells that have undergone isotype switching and somatic hypermutation)

179
Q

B Cell Tumor Origin

A

every cell has an identical rearranged immunoglobulin so they divide from same ancestral cell, but tumors from different patients have different immunoglobulins

180
Q

B Cell Tumors and Development

A

Tumors corresponding to all stages of b cell development have been described and their location at defined sites in lymphoid tissue is maintained

181
Q

follicular center cell lymphoma

A

grow in follicles of lymph nodes

182
Q

myeloma

A

grow in bown marrow

183
Q

hodgkin’s disease

A

germinal center b cell origin

184
Q

The genetif recombination of immunoglobulins that produces a monovalent self-reactiv IgM causes what mechanism to be activated:

a. receptor editing
b. anergy
c. apoptosis
d. clonal deletion

A

b. anergy

185
Q

centrocytes are dividing B cells that:

a. immeduately produce soluble IgM and IgD antibodies
b. function as memory cells in a secondary immune response
c. are self-reactive and need to be inactivated through anergy
d. produce antibodies that have matured through isotype switching and somatic hypermutation

A

d

186
Q

T Cell Precursor

A

what a:b and g:d T cells develop from in the thymus

187
Q

Thymocytes

A

immature T cells - develop among epithelial cells known as the thymic stroma

188
Q

Thymus Development

A

Fully developed before birth and starts to degrade at 1 years old but this nor a thymectomy grossly affects T Cell immunity because repertoire of T cells is long lived and or self-renewing

189
Q

Thymocyte development

A

progenitor cells that enter thymus not yet committed, needs interaction with thymic stromal cells to cause division and differentiation. After 1 week prodenitors express CD2 and are committed thymocytes

190
Q

Double-negative (DN) thymocytes

A

thymocytes that express CD2 and are committed to becoming T cells, but do not express TCR or a co-receptor

191
Q

Notch 1

A

cell-surface receptor on thymocytes that interacts with thransmembrane ligands on thymic epithelial cells and keeps thymocytes on road to T cell

192
Q

Notch 1 Activity

A

it is inactive when bound to membrane, binding of the extracellular domain causes cleavage, release of intracellular domain, which acts as trascription factor in nucleus.

193
Q

T Cell Lineages

A

either a:b or g:d and happens through complex process where b,g,d all start to rearrange at the same time and there is a competition.

194
Q

Double-positive (DP) thymocytes

A

occurs when functional b is made first and incorporated into a pre-t-cell receptor and rearrangment stops so both co-receptors are expressed. Race between g, d, and a begins.

195
Q

pTalpha

A

The surrogate chain to test if productive or nonproductive rearrangment of b chain happened.

196
Q

if g:d t cell rearranges frist

A

the g:d dimer forms and assembles with CD3 to form a functional receptor and b chain rearrangement stops

197
Q

productive b chain in T-cell

A

if b can bind to pTalpha, it complexes with CD3 and zeta to form pre-t-cell-receptor which acts as superdimer)

198
Q

superdimer

A

both a receptor and ligand

199
Q

Pre-T Cell

A

thymocytes that make functional pre-t-cell receptor that is a superdimer that activates signals to move through checkpoint

200
Q

rearrangement of alpha chian gene

A

pre-T-cell receptor stops rearrangement by suppressing RAG, allelic exlusion at the b chain locus, pre-t cell proliferates and expressed CD4 and CD8 makeing DP Thymocytes, large DP proliferate into small DP, rearrangment reactivates to target a, g, d. alpha chain has multiple attmepts.

201
Q

Delta Locus

A

situated in the middle of the alpha locus, will be deleted after alpha chain rearrangement thus stopping g:d rearrangment

202
Q

Gene expression during T Cell Development

A

First part of a:b development includes CD4, CD8, T-cell receptor. RAGs only expressed during b and a rearrangments.

203
Q

ZAP-70 and Lck

A

important signaling molecules that are expressed for most of T cell development

204
Q

Trascription factors in T cell development

A

Ikaros and GATA-3 which are expressed through whole development. Th-POK is needed fo rCD4 T Cell development and is activated later.

Immunology (5 decks)

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