A10 Mature of B-cells

Question 1

B-cell

Answer 1

• Progrenitor and immature B-cells are in the bone marrow (in bursa Fabricii)
• Native Atg recognition (conformation epitop)
• No MHC-restriction
• Secondary maturation: in folliculi
• Atg stimuli causefurther differentiation
• Secondary maturation results in plasma cell or memory cell
• Clonal B-cell receptor
• Cell-line marker: CD19+

Question 2

BM

Answer 2

The microenvironment for the production, maturation and differentiation of B-cells
• One kind of specificity • Elimination of autoreactive cells • Transfer of useful B-cells to the periphery • Place of memory cells

Question 3

Stages of development in the bone marrow

Answer 3

• Signal provided by the environment (bone marrow stroma cells)
• Progenitor B-cell (Pro-B-cell): earliest expression of CD19 (B-cell marker)
• Precursor B-cell (Pre-B-cell): expresses successfully rearranged heavy chain with Cµ-chain and surrogate light chain
• Immature B-cell: expresses successfully rearranged light chain (mainly κ) and membrane-bound IgM (mIgM

Question 4

Negative selection

Answer 4

• When the heavy and light chains bind, the cell is ready to recognise the Atg
• The cells with high autoreactivity BCR should not enter to the circulation
• In the bone marrow the autoreactive clones re-edit BCR with new recombination →receptor editing

Question 5

Maturation of B-cells

Answer 5

Immature 
-Periphery, spleen
Mature
-T cell independent Atg response
-Long life, recirculating B-cell
-T cell dependent Atg response

Question 6

BAFF and APRIL

Answer 6

BCMA • Plasma cell survival
TACI • T-cell independent response • Isotype switching
BR3 • Immature Bcell survival • Isotype switching

BAFF: B-cell Activating Factor
APRIL: proliferation-inducing faktor

Question 7

Lymph Nodes

Answer 7

B-cells prolipheration, somatic mutation, Few T-cells

B-cells Isotype switching, B memory-cells

Question 8

B-cells, as APCs

Answer 8

• 10^4-10^6 less Atg concentration is effective
• Receptor-mediated endocytosis
• 1-6 hours between the pathogen intake and presentation
• The cells reproduce BCR within 8-24 hours
• Conformation-specific BCR, MHCII present linear Atg
• Presentation depends on:
–CR2 (CD21) positive
–FcγRIIb1 negative

Question 9

Follicular Dendritic Cells (FDC)

Answer 9

• In the stratum germinativum of the secunder folliculi
• Myeloid (?) progenitor
• FcR and complement receptors
• Atg is held in a native form to B-memory cells
• No phagocytoticactivity
• No expression of MHCII

Question 10

Antigen Binding Receptors of B cell

Answer 10

C= Constans domain V= Variable domain H= Heavy chain L= Light chain Fab= Antigen binding sites Fc=Crystallized part

Question 11

The Response of B-cells

Answer 11

Atg recognition
-Naive IgM+, IgD+ B-cell

Th -cell and other stimuli=>Activated B-cell

Activation, Proliferation and Differentiation
Proliferation
1. plasma cell-Antibody secretion
2. IgG expressing B-cell- Isotype switching
3.High-affinity IgG, High-affinity Ig expressing B-cell
IgG expressing
Affinity maturation
Memory B-cell

Question 12

Intro

Answer 12

• Immature B cells are produced in the bone marrow of most mammals.
o Rabbits are an exception => B cells develop in appendix-sacculus rotundus.
• Like T cells, B cells are formed from multipotent hematopoietic stem cells (HSCs) in the BM and follow a pathway through lymphoid stem cell and lymphoblast.
• Unlike T cells, however, lymphoblasts destined to become B cells do not leave the bone marrow and continue to mature in the bone marrow.
• B-cell development occurs through several stages, each stage representing a change in the genome content at the antibody loci.
• When the B cell fails in any step of the maturation process, it will die by apoptosis, here called clonal deletion.

Question 13

A) Bone Marrow – (Antigen independent phase)

Answer 13

• 1) Signal from environment: BM Stromal Cell → HSC become Pro-B cell - With earliest expression of CD19+ (B-cell marker)
• 2) Pro-B cell becomes Pre-B cell: translated heavy chains organize and present on the surface of the cell, together with a protein complex called surrogate light chain → Pre-BCR (B cell receptor)
• 3) Pre-B cell becomes Immature B cell - Expression of surface IgM: Light chain and heavy chain present together on the surface of the cell → this is called IgM or BCR
• Immature B-cells: negative/positive selection and receptor editing: cells with high autoreactivity BCR should not enter the circulation → clonal deletion. The autoreactive clones re-edit BCR with new recombination → receptor editing
• After reaching the IgM+ immature stage in the bone marrow, these immature B-cells migrate to the spleen, where they are called transitional B-cells, and some of these cells differentiate into mature Blymphocytes.

Question 14

B) Spleen – further maturation to transitional B-cells (TR) – (Antigen dependent phase)

Answer 14

• 3 forms of maturation: T1, T2, T3
• Needed also for survival: BAFF (B-cell Activating Factor), APRIL (proliferation-inducing factor)
o Transitional B cells depend on BAFF for survival and differentiate into mature B cells in the spleen.
• Those transitional 1 and 2 (T1/T2) B cells with strong self-reactivity undergo clonal deletion or remain outside splenic follicles as hypo-responsive anergic B cells that can be rescued upon receiving T cell help to enter the mature B-cell pool.
• Mature B cells that are activated by foreign antigen and enter germinal center (GC) reactions give rise to isotype-switched memory B cells and plasma cells.
• During the process of somatic hypermutation (SHM), a few memory B cells acquire self-reactivity due to random immunoglobulin gene rearrangements and persist as IgG+ self-reactive clones in the periphery.

Question 15

C) Periphery

Answer 15

• FOI matured lymphocyte
• FOII matured lymphocyte (MZ and long-life recirculation B-cells)
• TACI: T-cell independent response