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Immunology > The Life of a B-Cell: Surveillance and Warfare > Flashcards

The Life of a B-Cell: Surveillance and Warfare Flashcards

1
Q

What is the chance of a B-cell sensing its specific antigen in the periphery?
How long does it take for a B-cell to circulate through the body?

A

1/10^6

The total circuit time varies between 12 and 24 hours

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2
Q

What is a B-cell that has not seen an antigen called?

A

Naive or virgin mature B-cell

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3
Q

What is the path of the B cell when it enters the spleen or LN?

A

It transverses the T-cell zone toward the B-cell follicles

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4
Q

How long can a B-cells live while they are recirculating?

A

several weeks to a couple months

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5
Q

What type of pathogens does the spleen monitor for?

A

blood-borne pathogens

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6
Q

What type of pathogens does the lymph nodes monitor for?

A

tissue-derived pathogens (from liver, skin, brain, etC)

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7
Q

What type of pathogens does the MALT monitor for?

A

Pathogens entering via the mucosal portal

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8
Q

What type of pathogens does the GALT monitor for?

A

Enteric pathogens (including those in Peyer’s patches)

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9
Q

How many WBCs are there per microliter of blood?

A

4000-11,000

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10
Q

How many lymphocytes are there per microliter of blood?

A

1000-4000

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11
Q

What percent of all WBCs in blood are lymphocytes?

A

15-40%

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12
Q

What is the ratio of T to B cells in most secondary lymphoid organs?

A

2:1

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13
Q

What types of cells are found in the thoracic duct lymph?

A
  1. effector T cells
  2. memory B cells
  3. plasma cells

(very few naive lymphocytes)

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14
Q

What structure rejoins the lymph to the blood?

A

thoracic duct lymph rejoins blood circulation in the subclavian vein

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15
Q

How do naive lymphocytes gain access to the LN?

A

L-selectin on the lymphocyte binds to GlyCAM or CD34 on the HEV

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16
Q

After lymphocytes are activated in the LN or spleen, what happens to their cell surface molecules?

A

L-selectin is downregulated so the effector lymphocyte won’t reenter the LN or spleen.
VLA4 and LFA1 are upregulated to direct the lymphocyte to inflamed tissue

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17
Q

What homing receptor pair is most important for extravasation of lymphocytes from the LN to the target tissue?

What are the ancillary pairs?

A

VLA4/VCAM1 is most important

LFA1/ICAM and CD2/LFA3 are ancillary

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18
Q

What ligand/addressin is crucial for delivery of lymphocytes to the skin?

A

CLA

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19
Q

What ligand/addressin is crucial for delivery to the GALT (gut)

A

a4b7 integrin

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20
Q

What splenic structure serves the same function as the subcapsular sinus of the LN?

A

the marginal sinus

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21
Q

Where are primary B follicles located in the LN?

Where are they located in the spleen?

A

LN- cortex

Spleen- white pulp

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22
Q

Through what structure do naive lymphocytes enter the LN?

The spleen?

A

LN- through HEV in the paracortex

Spleen- through central arterioles in the PALS

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23
Q

Where are T cells located in the LN?

In the spleen?

A

LN- paracortex

Spleen- periarteriolar lymphoid sheath (PALS)

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24
Q

Where are plasma cells and macrophages located in the LN?

The spleen?

A

LN- medulla

Spleen- red pulp

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25
Q

What is the difference between a primary and secondary B-cell follicle?

A

Primary- no germinal center

Secondary- germinal centers with proliferating B cells

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26
Q

What constitutes the White pulp of the spleen?

A

B and T cell zones (follicles and PALS)

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27
Q

What cells localize primarily to marginal sinus and subcapsular sinus? What is the function of these cells?

A
  1. Marginal zone macrophages and B-cells which are important for T-independent immune responses
  2. Memory B-cells to sense pathogens entering via afferent lymph
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28
Q

What are the two ways the body protects from potentially cross-reactive B-cells that attack self-antigens?

A
  1. Central B-cell tolerance testing in the bone marrow

2. Two trigger activation of B-cells in the periphery (antigen trigger on BCR and Helper-T trigger via CD40)

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29
Q

What are the two signals needed to fully activate a B-cell?

A
  1. Antigen triggers BCR

2. Helper T-Cells trigger B-cell via CD40

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30
Q

Autoimmunity can only occur under what conditions?

A

If self-tolerance is breached in BOTH B and T cell compartments

Both atuoreactive B cells and autoreactive T cells must be specific for the same antigen and both must be present to elicit an autoimmune response

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31
Q

What does the CD40L molecule bind to? What is the function?

A

It binds to CD40 on the B cell and it sends the second activation signal to the B-cell.

(signal 3 is cytokines just like T-cells)

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32
Q

How do B and T cells specific for the same antigen rendezvous to activate each other?

A

DC presenting the antigen arrest the recirculating naive lymphocytes in the T-cell zone RIGHT at the exit from the HEV or central arteriole

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33
Q

What are the four key events that must occur for B and T cells to co-activate?

A
  1. Interdigitating DCs that picked up the pathogen position themselves in the T-cell zone (PALS or paracortex) at the exit from HEV or central arteriole
  2. Naive T cells exiting the HEV sense the cognate antigen and slow down dramatically to sample the antigenic peptides
  3. Naive B cells zipping out of the HEV toward the follicle ALSO slow down dramatically to sample in the paracortex
  4. LINKED RECOGNITION- B and T cells specific for the same antigen activate each other
34
Q

Do the B-cell and T-cell epitopes need to be the same for Linked Recognition to occur?

A

They don’t need to be the same or even overlap as long as the antigen has BOTH the B and T cell epitopes somewhere on them

35
Q

After the BCR recognizes an antigen, signal 1 is triggered. What three key events ensue?

A
  1. The antigen is endocytosed, processed and presented as MHC II
  2. CD40 is up-regulated
  3. CD80/CD86 are upregulated
36
Q

Why does the B-cell upregulate MHCII when it binds to an antigen?

A

The MHCII/peptide complex allows T-cells specific for the same antigen to bind aand the B-Cell is able to deliver “signal 1” to the T-cell

37
Q

What does the B-cell upregulate CD80/86 when it binds an antigen?

A

CD80/CD86 (B71-B72) binds to and activates CD28 which is the second signal for activating a T-cell

38
Q

When the B-cell delivers signal 1 (MHCII/peptide) and signal 2 (CD28 activation), the T cell becomes fully activated. What is the next step of linked recognition?

A

Since the T cell is activated, it upregulates CD40L, which binds to the CD40 upregulated on the B cell delivering signal 2 to the B-cell.

39
Q

What cells are T-cells in the T-cell zone most likely to receive their signals 1,2, and 3 from?

A

Dendritic cells although B-cells reactive to the same antigen can do the same

40
Q

What are the two fates that B-cells activated in the T-cell zone have?

A
  1. undergo cell division and mature into plasma cells in the primary focus to release Ab
  2. Move toward the B-cell follicle in the cortex to form a germinal center
41
Q

What are the two main regions of the germinal center? What events occur in each?

A 
Dark Zone:
1. B-cell enters from the T-cell zone
2. Clonal expansion
3. Somatic mutation
Light Zone:
1. FDCs determine the "fittest"::B-cells (the rest die..in fact the majority die)
2. Class-switching occurs
42
Q

What is somatic mutation?
Where does it occur?
When?

A

Somatic mutation is when mutations are randomly inserted into the hypervariable regions to increase avidity of the B-cell for the antigen
It occurs in the dark zone of the germinal center in the cortex of the LN or spleen
It occurs AFTER antigen recognition

43
Q

What is the key enzyme for somatic mutation of the B-cell hypervariable region?

A

AID (activation-induced cytidine deaminase)

44
Q

What is a follicular dendritic cell? Where is it located and what function does it serve?

A

FDC is a dendritic cell loaded with antigen in the germinal center of a follicle of the LN or spleen.
B-cells compete to bind to the antigen on the FDC and those with the highest avidity survive, the rest die in the light zone of the follicle

45
Q

What are the 2 events that occur in affinity maturation?

Which is antigen independent?

A
  1. random somatic mutation to increase affinity for the antigen- antigen independent
  2. positive selection for the B-cell clones with the highest avidity via FDCs
46
Q

What cells help the B-cells class-switch their Ig heavy chain isotope?
What surface molecule and cytokine mediate the process?
What enzyme is required?

A

Tfh mediated by CD40L and IL-21 cytokine.

AID (activation induced cytidine deaminase) is the enzyme that assists

47
Q

What are the two products of the germinal center reactions?

A
  1. plasma cells

2. memory cells

48
Q

Where do plasma cells reside?

A

Splenic red pulp, LN medulla, and long lived plasma cells reside in the bone marrow

49
Q

How long do plasma cells in the medulla of the LN and splenic red pulp live?

A

several months to a year

50
Q

Ig from what plasma cell source account for the majority of serum Ab?

A

Long-lived plasma cells in the bone marrow

51
Q

What are the three major distinguishing features of a memory B-cell?

A
  1. Class-switched and lack IgD
  2. higher affinity for antigen because of somatic mutation and positive selection by FDCs
  3. reduced threshold for activation
52
Q

Where are memory B-cells located?

A
  1. Subcapsular and marginal sinuses to readily encounter antigens as they enter the LN or spleen
  2. B-cell follicles
53
Q

What stage of the cell cycle are memory B-cells in?

A

G0 but can be quickly activated to cycle

54
Q

What two surface molecules are upregulated in memory B-cells?

A

MHC II and CD80/86

55
Q

What is class-switching?

Does it occur prior to or after antigen recognition?

A

Any constant region can be associated with the VDJ region that was selected for (recognized the specific antigen).

It occurs after Ag recognition and is T-cell regulated

56
Q

What is the purpose of class-switching?

A

It maintains specificity for a foreign antigen but changes the effector function

57
Q

Which Ig chain does class switching occur in?

A

It happens in the Fc region so it only affects the Ig heavy chain

58
Q

What features of the DNA allow class-switching to occur?

A

There are switch sequences at the 5’ end of each constant region (Cmu, Cgamma,Cdelta,Cepsilon, Calpha)

59
Q

At what level (DNA or RNA) does class switching occur? How does it happen?

A

It occurs at the level of DNA and there is Ch recombination with deletion of the intervening DNA sequences.
Allelic exclusion ensures that only 1 heavy chain is recombined

60
Q

In what direction does class-switching occur?

What enzyme mediates class-switching?

A

5’ to 3’ on one chromosome (NEVER reverse)

AID enzyme and cytokines like IL-21

61
Q

Where are “switch sequences” located on the DNA? (3’ to what and 5’ to what)
What do they allow to happen?

A

3’ to the VDJ region and 5’ to the Ch region (gamma, alpha, epsilon etc)
The switch sequences juxtapose the same VDJ to different constant regions allowing class-switching of the Ab.

62
Q

Is class-switching reversible?

A

No because one the switch sequences interact to bring the VDJ in proximity to the constant region, the intervening DNA is deleted

63
Q

What determines which switch sequences will be rearranged?

A

cytokines

64
Q

What cytokine is crucial for the transition from Pro-B to Pre-B?

A

IL-7

65
Q

What cytokines are crucial for growth and differentiation of immature T cells into mature T-cells?

A

IL-2 and IL-4

66
Q

What cytokine is crucial for the differentiation and survival of plasma cells?

A

IL-6

67
Q

What cytokine would allow Treg to influence plasma cells to secrete IgA?

A

TGF-b

68
Q

What cytokine does Th2 release to allow plasma cells to release IgA?

A

IL-5

69
Q

What two T-cell subsets help in the secretion of IgA from plasma cells?
Using what cytokines?

A

Treg- TGF-B

Th2- IL-5

70
Q

What T-cell subset influences plasma cells to release IgG4? Using what cytokine?

A

Th2- IL-4

71
Q

What T-cell subset influences plasma cells to release IgE? Using what cytokine?

A

Th2–> IL-13

72
Q

What T-cell subset influences plasma cells to release IgG1? Using what cytokine?

A

Th1–> IFN-gamma

73
Q

What are major targets in clinical trials for autoimmune diseases?
What two major interactions are scientists trying to disrupt?

A

Co-stimulatory molecules that deliver signal 2 to B and T cells
(Tcells- CD28, B-cells- CD40)

CD40/40L interaction and CD80/CD86- CD28 interaction

74
Q

What is CTLA4-Ig and how does it work?

What is the major disease it is used for?

A

It is an analog that blocks the CD28-CD80/86 interaction between T cells and APCs/B-cells.
It is used for autoimmune disorders like Rheumatoid Arthritis

75
Q

Patients with Hyper-IgM syndrome have a defect in what?
How are they treated?
What other mutation could present in a similar manner?

A

CD40-40L interaction because this disrupts T-cell and B-cell interaction. The B cell is not able to class switch or do somatic mutation.

They are treated with IVIG.

AID mutations present in the same manner (because AID is an enzyme necessary for somatic mutation and class switching)

76
Q

What is the major difference you would see in the secondary lymphoid organ between a Hyper-IgM patient and an AID deficient patient?

A 
The Hyper-IgM patient would not have germinal centers because the B-cells would not be activated at all (they require CD40-40L interaction in the T cell zone to activate)
The AID deficient patient would still have germinal cente with activated B-cells, but no somatic mutation or class switching would occur
77
Q

Patients with CVID (common variable immunodeficiency) lack what molecule? How do they present?

A

They lack ICOS (on T-cells) which disrupts interactions with ICOSL on B cells. The antibodies in this situation are not able to class switch

78
Q

What tumor is associated with Pre-B cell tumors?

A

Acute Lymphoblastic Leukemia

79
Q

What tumor is associated with the mature B-cell stage?

A

Chronic lymphocytic Leukemia (CD5+)

80
Q

What tumors are associated with germinal centers?

A

Burkitt’s Lymphoma and diffuse large B-cell lymphoma where there is extreme proliferation of germinal centers in B-cell follicles

81
Q

What tumor is associated with plasma cells?

A

Multiple mylenoma- lesions in bone (from long-living plasma cells in bone marrow), electophoretic spikes of a particular antibody type

Immunology (25 decks)

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