asilmi 07- b cells and antibodies today b cell development

Asilmi 07- B CELLS AND ANTIBODIES

TODAY

B CELL DEVELOPMENT


STAGES OF B CELL DEVELOPMENT GE

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S1. B Cells develop from pluripotent stem cells in the bone marrow.

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22. The stem cell develops into a mature IgM+ B cell.

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B Lymphocytes are predicted to generate approximately 1 X 1011 distinct antigen receptors.

However, the human genome only contains about 35,000 distinct genes.

How does such a limited genome enable the generation of an almost infinite number of antigen receptors?


Answer: Diversity is generated through somatic recombination of gene segments that code for the variable regions of the receptors.


Going from DNA (gene) to protein:the usual way.

Genomic DNA

Promoter Exon 1 Exon 2

Primary Transcript

Transcription

mRNA

Splicing

Protein

Translation


THE GERMLINE ORGANIZATION OF ANTIGEN RECEPTOR GENE LOCI.

The Ig Heavy chain locus contains up to a few hundred variable (V) region genes. The variable region gene segments are followed by diversity (D)

and joining (J) gene segments.

The Light chain loci displays a similar organization to the Heavy chain locus, except that it lacks any D gene segments. There are two light chain loci - and .


GENERATING DIVERSITY BY V(D)J SOMATIC RECOMBINATION

6. The resulting mRNA is translated to generate a unique IgM heavy chain.

5. The V-D-J gene segment is spliced to the first C region RNA ( Chain)

4. The new gene is then transcribed.

3. A V gene segment then recombines with the D-J segment, generating a recombined V-D-J gene.

2. In a single lymphocyte clone, one D gene segment randomly recombines with one J gene segment.

1. V, D and J gene segments are arranged in tandem.


V D J constant V D J constant

VDJ recombination #1

variable constant

VDJ recombination #2

variable constant

1. Each recombination generates a unique variable region - unique antigen specificity.

VARIABLE REGION

2. In contrast, the constant region does not change - conserved effector function.


SOURCES OF DIVERSITY



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3. The mature, naïve B cells circulates through the peripheral lymphoid organs.



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3. The mature, naïve B cells circulates through the peripheral lymphoid organs.

4. B cells that fail to encounter antigen die through apoptosis.

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STAGES OF B CELL DEVELOPMENT

5. B cells that encounter antigen are activated. PE

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1. Naïve B cell encounters antigen.

STAGES OF B CELL ACTIVATION

2. Helper T cells stimulate B cells.


PRESENTATION OF ANTIGENS TO T HELPER CELLS BY B CELLS

1. The naïve B cell receptor binds its cognate antigen.

2. The receptor triggers endocytosis of the antigen.

3. Antigen is processed and presented on a Class II MHC molecules. (B cell acts as classical APC)

4. B cell stimulates T cell activation.


HELPER T CELL ACTIVATION OF B CELLS

1. B Cells process and present antigens to helper T cells.

2. T cells commence production of molecules that activate B cells (CD40, cytokines).

3. The combination of CD40 (physical contact) and cytokines activates B cells.

4. T helper cell signals induce B cell activation (proliferation and differentiation).





3. Activated B cells begin clonal expansion.


CLONAL EXPANSION

Each B and T cell encodes a unique BCR or TCR with a unique specificity.

When a BCR or TCR encounters its cognate antigen the B cell or T cell is stimulated to undergo multiple rounds of cell division, thereby expanding. Each daughter is identical to the parent cell, i.e. a clone.






4. Some B cells differentiate into antibody secreting plasma cells.







5. Others become memory cells.


MEMORY LYMPHOCYTES

Active Lymphocyte

Memory Lymphocyte

Some active lymphocytes differentiate into memory lymphocytes.

MEMORY LYMPHOCYTES: Produced from naïve lymphocytes as a result of antigen exposure. Persist for years in a quiescent state. Rapidly reactivated by repeat exposure to antigen and mediate faster, more potent immune responses.


Secondary Versus Primary Antibody Responses.

THE SECONDARY RESPONSE IS…….

FASTER

STRONGER

MORE SPECIFIC







5. Others become memory cells.

6. Others switch class to produce a new Ig Isotype.


CLASS SWITCHING

A clone of B cells is not committed to make a single Ig isotype forever.

All mature B cells start out making IgM

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IgM mRNA

IgM


CLASS SWITCHING


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B cell activation triggers rearrangements at the Ig locus

DNA encoding some constant regions is deleted

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Exposed DNA ends are joined together

End result: New class of Ig

IgG


CLASS SWITCHING - AFFINITY


V

IgM mRNA

IgM

V

IgG

IgG mRNA

The Antibody retains Antigen specificity throughout.

Class switching does not affect the variable region.

UNCHANGED


CLASS SWITCHINGClass switching explains why IgM is not seen upon re-exposure to antigen.

2. Lymphocyte is activated by antigen and starts to secrete IgM

1. Mature B lymphocyte express IgM as BCRBCR

Ag

IgM

BCR

Ag

3. Activation induces class switching, so that repeat exposures induce IgG, IgA or IgE.

IgG BCR

Ag

asilmi 07- b cells and antibodies today b cell development

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nave b cells

antibodies b lymphocytes

mature igm b cell

pluripotent stem cells

d gene segments

j gene segments

peripheral lymphoid

v gene segment