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Immunology I > B cells and antibodies > Flashcards

B cells and antibodies Flashcards

1
Q

Does a PAx5 KO mouse still have pro-B cells?

A

Yes

Pax5 needed to get from pro to pre

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2
Q

Is monospecificity guaranteed with allelic exclusion?

A

Yes

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3
Q

Which cells are B cell IgM(low)IgD(+)

and which IgM(high)IgD(low)?

A

mature

immature

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4
Q

Name at least 4 characteristics of plasma cells.

A
  • produce high amounts of high affinity antibodies
  • relocate to BM after leaving GC (specialized niche for long term survival; except if produced in mucosa)
  • there are 2 types: short lived (red pulp) and long lived (BM)
  • have abundant rER, well developed Golgi
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5
Q

Name at least 4 characteristics of memory B cells.

A
  • generated during GC reaction
  • long lived
  • express surface BCR, but do not secrete antibodies
  • are in a resting state and recirculate in the body
  • are activated directly after Ag encounter (can differentiate rapidly into Ab producing cells)
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6
Q

Describe 6 phases of B cell development. Which are they, what is happening in relation to gene rearrangement, which molecules are expressed on the cell surface?

A
  1. early pro-B cell
    - DJ rearrangement of the heavy chain
    - germline light chain
    - nothing on the surface
  2. late pro-B cell
    - VDJ rearrangement of the heavy chain
    - germline light chain
    - nothing on the surface
  3. large pre-B cell
    - VDJ rearranged = heavy chain finished
    - germline light chain
    - pre-B receptor (= mi heavy chain + VpreB + lambda5 instead of light chain) –> signal for successful rearrangement of heavy chain upon clustering of the receptors via ligh chain substitutes dimerization
  4. small pre-B cell
    - heavy chain finished
    - VJ recombination of kappa chain first (if unsuccessful, lambda rearrangement)
    - nothing on the surface (mi heavy chain is internalized)
  5. immature B cell
    - heavy chain rearranged
    - light chain rearranged
    - IgM expressed on the cell surface
  6. mature B cell
    - alternative H-chain splicing leading to IgD expression on the surface too (besides IgM)
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7
Q

Ž - Where are B cells generated in birds and what is equivalent of that in mammals?

A

bursa of Fabricious

bone marrow and fetal liver

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8
Q

Ž - What were Max Cooper’s observations regarding levels of antibodies compared to severity of Herpes lesions in Wiscott-Aldrich syndrome vs X-linked agammaglobulinemia?

A

noticed, that despite higher levels of ABs in WAS, Herpes lesions were more severe and vice versa
meaning that AB alone cannot be responsible for viral protection

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9
Q

Ž - Which steps of B cell development happen in bone marrow and which in periphery?

A

BM: generation of BCR and negative selection of cells (self-reactive are removed), AB secretion, memory cells reside in BM too

periphery: migration to lymph nodes and activation by recognizing Ag (positive selection), partly AB secretion

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10
Q

Ž - BCR - Describe the structure of BCR - crystal structure AND the complex of coreceptors associated with it.

A

2 x heavy chain, 2 x light
variable domain at the N-end of each, the other 3 are constant
connections by disulphide bonds in the hinge region

membrane bound while BCR
Igalpha and Igbeta for transfer of signal into the cell (ITAMs)
co-receptors next to it: CD19, CD21, CD81

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11
Q

Ž - BCR - Which chain contains D segments in the genome in which does not? How many genes for heavy and how many for light chain do we have?

A 
heavy = VDJ
light = VJ only
heavy = 1
light = 2 (kappa and lambda)
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12
Q

Ž - BCR - How do BCR genes that will undergo rearrangement get close enough to each other so that Rag can connect 2 RSSs?

A

whole locus contraction happens

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13
Q

Ž - Antibodies can recognize virually any structure. How is this diversity achieved?

A
  • a lot of different V/D/J segments for both heavy and light chain
  • 2 alternative light chains
    = 2,6 x 10^6 combinations from that alone
  • additionally, random nucleotides are inserted during VDJ recombination
  • somatic hypermutation afterwards to increase affintiy
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14
Q

Ž - Which transcription factor leads to B cell development from common lymphoid precursor and what are the alternatives?
Which genes are expressed that lead to B cell fate?

A

B cell development = E2A (and EBF)
Notch = T cells
Id2 = NK cells

E2A and EBF target genes:

  • Pax5
  • Igalpha and Igbeta
  • Rag
  • VpreB, lambda5
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15
Q

Ž - Some BCRs recognize self-molecules. What happens with them in bone marrow and what in the spleen?

A

a) if they do not recognize Ag in the BM:
mature normally, go in the periphery and have IgM and IgD on the surface

b) if they recognize multivalent self-molecules:
in BM, they undergo receptor editing or cell death
in spleen, receptor editing is not an option anymore, so they die

c) if they bind soluble self-antigens that x-link the BCR:
become anergic, end up having IgD»IgM, migrate to periphery, fail to recieve survival signs because they do not recognize Ags, die

d) if they bind self-Ag, but it is either unaccessible to them or they bind it with very low affinity:
mature normally, but are clonally ignorant because even if the Ag is present, it is unable to activate them because its concentration is too low

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16
Q

Ž - What are transitional B cells?

A

transitional B cells are IgM+ immature B cells that migrated to the spleen (cca 10-20% of all immature B cells generated) and survived negative selection there, but have not undergone positive selection yet

17
Q

Ž - Which types of transitional B cells exist and what are their main characteristics?

A

T1: IgM > IgD, CD21 and CD23 negative, present in T cell zone in the spleen (PALS); recent immigrants from the bone marrow
T2: IgM & IgD
T3: IgM < IgD

18
Q

Ž - Besides transitional B cells, 2 other major types exist. Where do we find them?

A

marginal zone B cells in spleen only

follicular B cells in spleen and lymph nodes

19
Q

Ž - What are marginal B cells?

A

long lived B cells in the spleen, do not recirculate
are the first ones to come in contact with blood-borne pathogens -> differentiate in IgM-secreting plasma cells (fast) = increased reactivity, but have restricted antigen specificity
can be activated by thymus-dependent AND independent antigens

20
Q

Ž - What are follicular B cells?

A 
B cells located in the primary follicle (spleen and lymph nodes)
need to be activated by T cells upon Ag recognition -> form GCs and differentiate into Ab secreting plasma cells and memory cells
undergo affinity maturation and class switching
21
Q

Ž - In which 3 classes (subsets) do we sort B cells? Name a couple of characteristics of each.

A

B-1: in fetus, very limited recombination and somatic hypermutation, found in body cavities

B-2: 
a) conventional (follicular) ones - extensive gene rearrangement, undergo class switching (mostly IgG), need T cell help for activation, can become memory cells

b) marginal zone B cells: found in spleen only, long-lived, mainly IgM on the surface, can be activated by TI and TD antigens

22
Q

Ž - How is B cell tolerance against self-tissue maintained?

A

B cell encounter Ag during development in the secondary lymphoid organs
if they recongize self-antigens, they do not undergo deletion as T cells, but rather receptor editing and anergy
= consequence of the BCR signaling strength
= more signaling leads to downregulation of BCRs
= autoreactive B cells persist in the mature repertoir, but are anergic

23
Q

Ž - BCR - Which interactions (bonds) are formed between receptor and Ag?

A

noncovalent (electrostatic, hydrogen, VdW, hydrophobic)

24
Q

Ž - BCR - In which regions (V/D/J) are hypervariable sequences located? Where are they found in the final structure of the receptor?

A

in V region
3 in light, 3 in heavy chain
form antigen binding site

25
Q

Ž - How are V(D)J recombination and allelic exclusion linked?

A

successful expression of a rearranged chain shuts down expression of Rag = another allele cannot be rearranged

26
Q

Ž - BCR - Posttranslational modifications play an important role in BCR expression. How do we get IgM vs IgD and how do we get BCR vs AB?

A

IgM vs IgD = alternative splicing

BCR vs AB = alternative polyadenylation

27
Q

Ž - BCR - Which protein plays a crucial role in somatic hypermutation and class switching? What does it do?

A

activation-induced cytidine deaminase = AID

deaminates C to U -> repair mechanisms (UDG removes it and creates abasic spot) lead to introducing mutations

UDG… uracil-DNA glycosylase

28
Q

Ž - BCR - How does class switch happen?

A

different switch sequences downstream of VDJ-recombined genes
AID and UDG recognize and bind them
leads to loop formation and excision of unnecessary DNA

29
Q

Ž - BCR - There are 5 isotyp classes of antibodies. What is the structural difference between them?

A

Fc part

30
Q

Ž - BCR - There are 5 isotyp classes of antibodies. Describe IgM.

A

the first one to be expressed on B cell surface
predominant in the plasma (with IgG)
also predominant in the extracellular liquid of the body (with IgG and monomeric IgA)

forms pentameres

31
Q

Ž - BCR - There are 5 isotyp classes of antibodies. Describe IgG.

A 
predominates in the plasma and in the extracellular fluid of the body
fetus is provided with maternal IgGs via transplacental transport
4 subclasses (IgG1-4) that differ in hinge region
32
Q

Ž - BCR - There are 5 isotyp classes of antibodies. Describe IgE.

A

mainly found as a mast cell-associated Ab in the tissue underneath epithelial surfaces
prominent role in allergies:
- first exposure to e.g. pollen Ag drives B cells to produce IgE (IL-4 signal), that binds to mast cells
- second exposure = IgE recognition of Ag leads to release of mast cell contents -> allergic rhinitis

33
Q

Ž - BCR - There are 5 isotyp classes of antibodies. Describe IgA.

A

secreted form = dimer with J chain
secreted into the gut lumen through epithelial cells at the base of the crypts
bind to the mucus overlaying the gut epithelium
neutralize pathogens and toxins

also: main AB type in the secretory fluids of epithels (including milk)

34
Q

Ž - BCR - What are the functions of antibodies?

A
  1. recognition and neutralization of antigens
  2. mobilization of effector molecules and cells:
    - complement activation
    - opsonization -> phagocytosis
    - antibody-dependent cellular toxicity
    - mast cell activation
35
Q

Ž - How do you create monoclonal antibodies in the lab?

A

challenge mouse with an antigen
isolate spleen cells
fuse them with myeloma cells (keep dividing eternally) to create hybridomas that express antibodies
select for cells that recognize Ag with highest affinity
harvest monoclonal ABs

36
Q

Ž - There is a B cell stage between resting B cells and plasma cells. What is it? Properties?

A

plasmablast

has a lot of surface Ig, but also secretes ABs (high rate)
is not terminally differentiated, so it still grows
can undergo class switch

37
Q

E - Describe the initial steps of BCR signal transduction.

A

ITAMs are not on BCR directly, but:

  • Ig(alpha) and Ig(beta)
  • CD19 from the BCR coreceptor complex

upon Ag recognition with the receptor (and coreceptor; that makes signaling significantly stonger):
1. Src kinase phosphorylates ITAMs
2. recruitment of Syk kinase and PI3K
3. PI3K causes PIP3 localization in the membrane which leads to:
3a) PLCgamma recruitment:
- generation of PIP2
- cleavage of PIP2 into
— DAG -> PKC (-> IKK-beta inhibition -> NFkB activation) and Ras recruitment (-> Ras/MAPK pathway -> AP-1)
— IP3 -> Ca release in the cytosol from ER and external -> NFAT
= IL-2 generation

3b) Akt activation
- increasing cell survival by inhibiting Bad and activating Bcl-2
- increasing cell metabolism (lipid production, ribosome synthesis, mRNA synthesis, protein translation) by Rheb activation (-> mTOR)

  1. besides that:
    4a) LFA-1 adopts high-affinity conformation -> increased cell adhesion
    4b) PIP3 is bound by Vav -> increased actin polymerisation

Immunology I (8 decks)

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