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IHO Week 4 > Deibel- B cell and T cell maturation > Flashcards

Deibel- B cell and T cell maturation Flashcards

1
Q

Where does B cell development occur in adults? Does it require contact with an antigen?

A

Bone marrow

Does NOT require contact w/ an antigen

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2
Q

Describe B cell generation in the bone marrow.

A

B cells rearrange their genes for H or L chains and synthesize cell surface IgM which acts as their initial BCR.

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3
Q

What are the components of the BCR complex?

A

Membrane bound mIgM

Signaling chains Ig alpha and Ig beta (CD79a,b,)

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4
Q

Where do B cells go after development in the bone marrow?

A

Enter the periphery where they continue to mature in secondary lymphoid organs (spleen)

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5
Q

What happens to B cells that don’t encounter antigens in secondary lymphoid organs?

A

APOPTOSIS

they die w/in a few weeks

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6
Q

What happens to B cells if they DO find specific antigen in the secondary lymphoid organs?

A

Activation>
proliferation >
differentiation >
generation of plasma cells and memory B cells

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7
Q

What are progenitor B cells?

A

They are the earliest stage of antigen-independent B cell development

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8
Q

B cells can be divided into three groups based on expression of TdT and B220 (CD45R). What are they?

A

Early- Tdt alone

Intermediate- both TdT and B220

Late- B220 and have downregulated Tdt

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9
Q

What is B220 (CD45R receptor)?

A

Receptor for cell growth and differentiation that remains expressed on the cells surface throughout B cell ontogeny

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10
Q

The rearrangement of heavy chain genes in the pro-B cel stage leads to the expression of …..

A

CD43- leukosialin
CD 19
RAG 1 and 2

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11
Q

What is CD 19?

A

A BCR co receptor that works w/ CD21 and CD81

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12
Q

What is down regulated as late pro-B cells pass into the pre- B cell stage?

A

TdT
RAG 1 and 2
CD43

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13
Q

What is cKIT?

A

A molecule expressed by pro-B cells

It binds to stem cell factor expressed on bone marrow stromal cells and induces pro- B to prolif and differentiate into precursor B cells (pre-B)

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14
Q

What is on the surface of pre-B cells?

A

Igu heavy chains
a pre-B cell receptor complex
Surrogate light chain–holds complex stable while it’s going through recombination

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15
Q

What cytokine do Pre-B cells express and what does it do?

A

IL-7R

Stimulate to divide and differentiate using IL-7 (hematopoietic GF secreted by bone marrow stromal cells)

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16
Q

What are the 6 stages of B cells seen in B cell maturation?

A 
Stem cell
Pro B cell
Pre B cell
Immature B cell
Naive B cell
Mature B cell
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17
Q

What is the final stage of B cell development in the bone marrow?

A

Immature B cell stage

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18
Q

What is observed on the the surface of immature B cells?

A

IgM

They have successfully rearranged light chain genes

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19
Q

In immature B cells RAG 1 and 2 are….

A

downregulated

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20
Q

What happens to immature B cells as they develop into mature B cells?

A

They begin to express IgM and IgD on their surface.

This means they are free to exit the bone marrow and can enter the transition phase.

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21
Q

Several cytokines affect B-cell development. What does IL-7 do?

A

Promotes B lineage development

*Mice that don’t ahve IL-7 have an early arrest in the pro-B cell stage

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22
Q

What does Blys do?

A

It’s important for the survival of pre-immune B cell stages from transition stage onwards.

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23
Q

What cytokines are important in initiating the process of B cell differentiation?

A

IL-4, IL-3, L-BCGF

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24
Q

Transcription factors also help to regulate B cell generation. What do E2A and EBF do?

A

activate early B cell genes

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25
Q

What does Pax5 do?

A

Ensures development to B cell lineages

Restricts transcription of lineage inappropriate genes and activates expression of B lineage signaling molecules

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26
Q

What do Sox4 and LEFI do?

A

Promote the survival and proliferatoin of pro-B cells

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27
Q

What do IRF4 and IRF8 do?

A

terminate pre-BCR signaling by IRF4 and promote differentiation to small pre-B cells

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28
Q

Bcl-6 exp is req for….?

A

Germinal B cell differentiation and generation of memory B cells

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29
Q

What TF suppresses Bcl-6 expression and is required for development of Ig secreting cells and maintenance of long lived plasma cells?

A

Blimp 1

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30
Q

Immnodeficiency XLA in humans affects what stage of B cell development?

A

It leads to a block at the pro-B cell to large pre-B cell transition in the bone marrow

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31
Q

What enzyme is linked to XLA? What does it do?

A

Bruton’s tyrosine kinase (BTK)

Key enzyme involved in signal transduction downstream of the pre-BCR and

32
Q

XLA pts have_______circulating B cells and _______serum immunoglobin.

A

few

negligible

33
Q

Agammaglobulinemia is most often linked to what genetic defect?

A

XLA

34
Q

How does CVID differ from XLA?

A

CVID affects the later stages of B cell development while XLA affects the earlier stages.

35
Q

What are the characteristics of what CVID?

A

Reduced serum Ig
Reduced memory B cells
Reduced class switch recombination and B cell activation

36
Q

Mutations in:
CD40 ligand on T cells
B cell surface receptor CD19
Costimulatory molecules ICOS and TACI

are all identified in pts with what disease?

A

CVID

37
Q

Where does negative selection of self-reactive B cells occur and what does it do?

A

Bone marrow
(occasionally in periphery after somatic hypermutation)

Limits the development of antibody-mediated autoimmunity

38
Q

What are the two things that can happen if immature B cells expressing mIgM recognize self-antigen?

A
  1. undergo apoptosis

2. edit light chain genes to produce a different light chain that when combined w/ heavy doesn’t recognize self antigen

39
Q

What is a t-dependent antigen?

A

Immune response to most antigens depends on both T cells and B cells recognizing antigen in a linked fashion

40
Q

What are TI angiens?

A

A small number of antigens that can activate B cells w/out MCH II restricted T cell help

41
Q

What TI antigen are predominately bacterial cell wall components, like LPS from Gram - bacteria?

A

TI-1

42
Q

What TI antigens are predominantley large polysaccharide molecules w/ repeating antigenic determinants?

A

TI-2

ficoll, dextran, polymeric bacterial flagellin

43
Q

TI antigens can also be ________recognized by _______.

A

PAMPS

TLRs

44
Q

What do TI antigens activate?

A

B1 B cells w/ CD5 receptors

45
Q

How does a B1 B cell bind to LPS and what are the characteristics of these receptors?

A

TLR4- non specific–> stimulate both immature and mature B cells–> polyclonal activation

or BCR= specific–> clonal activation

46
Q

What is produced in response to TLR4 and BCR stimulation?

A

ONLY IgM

47
Q

How do B1 B cells bind to TI-2 antigens and what does this cause?

A

Cross-linking BCR–>
stimulates mature B cells ONLY–>
clonal activation

48
Q

What is produced by TI-2 activation?

A

Mostly IgM, but it can involve class switching w/ help of Th2 produced cytokines

49
Q

How do TI and TD relate to memory cells?

A

TI produces poor memory, antigens come a day sooner and you only get IgM

TD requires CD4 T cells, IgM early, IgG late, and can be rechallenged in the future

50
Q

Describe the intracellular process that leads to B cell activation.

A
  1. BCR receptor plus something is required.
  2. IgM or IgD bind.
  3. If cross linked, then CD79a/b activate signaling through ITAM repeats
  4. Activation of NFkB and G proteins that activate TFs Rho, Rac and Ras
51
Q

What IL’s does Th2 make? What do these IL’s do?

A

IL-2,4,5

Push B cell proliferation and differentiation.

52
Q

Describe the primary Ab response.

A 
Naive B cell
lag 4-7 days
Primarily IgM
Ab affinity low
Short lived cells
53
Q

Describe the secondary Ab response

A 
Memory B cell
Lag 1-3 days
Primarily IgG
Ab affinity high d/t somatic hypermutation
long lived cells
mag of response greater
54
Q

What is the main difference between the primary and secondary immune responses?

A

Secondary is
faster
better
bigger

55
Q

When do T cells mature and where do B cells mature?

A

B cells are mature when they leave the bone marrow, where as T cells require further education in the thymus.

56
Q

What is required to commit T cells to lineage differentiation?

A

Notch

57
Q

How many weeks does it take for T cells to pass through the thymus and what percent make it out?

A

3

2%

58
Q

Describe the progression of T cell maturation in the thymus:

A 
HSC
HPC
T cell precursor
DN1
DN2
DN3
DN4
Double positive (CD4,8)
Single positive (CD8 OR CD4)
59
Q

What is DN?

A

Double negative

NO CD4 or CD8

60
Q

What is DP?

A

Double positive

both CD4 and CD8

61
Q

What cellular markers are used to determine the stage of T cell development?

A

CD44
Ckit
CD25

62
Q

CD44 is required for…

A

relocalization to the thymus

63
Q

Ckit is required for…

A

replication

64
Q

CD25 is required for….

A

IL-2 driven replication

65
Q

What is positive selection?

A

Restriction

T cells must recognize self MHC molecules w/ intermediate binding affinity

66
Q

What is negative selection?

A

Self Tolerance

T cells CANNOT respond to self antigens.

67
Q

What happens to T cells once they enter circulation?

A
  1. Naive CD4 or CD 8 recognize MCHI/II presented by APC.
  2. Antigen binding leads to gene activation
  3. Activation
  4. Clonal expansion
  5. Differentiation
  6. Effector functions (activation of macrophages and B cells; killing of targeted cells)
68
Q

What genes are activated immediately upon antigen binding?

A

Fos, Myc, Jun, NFAT, NFkB

69
Q

What genes are activated early upon antigen binding?

A

IL2, IL2R, IL3, IL6, IFNy

70
Q

What genes are activated late upon antigen binding?

A

adhesion molecules

71
Q

What are the requirements for T cell activation?

A

TCR binds to MHC-ag of APC
Appropriate costimulatory molecules
cytokines

72
Q

Activation of T cells leads to the expression of what type of receptor on the T cell?

A

High affinity IL-2R

*IL-2 synthesis increases by 100x

73
Q

IL2 binding to IL-2R leads to

A

clonal expansion
generation of effector and memory cells

**after expansion most T cells die

74
Q

What is clonal anergy?

A

When APC MHC binds to a T cell but no CD28/B7 binding occurs–>
desensitized cell that can’t be activated–>
cell dies in a few days

75
Q

What is a superantigen?

A

Can bind both the MHC nad TCR outside of the antigen groove of the complexes. It initiates non-specific interactions to stimulate many T cells of different antigenic specifications. Activation of many T cells > over induction of IFNy and TNFalpha> toxic shock.

76
Q

What mediates the polarization of CD4 into Th1, TH17 and Th2?

A

Different cytokines released by APCs

**Different types of pathogens influence cytokines released so most appropriate T cell can be recruited to the site of injury

IHO Week 4 (15 decks)

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