This document discusses the B cell receptor (BCR) and its role in chronic lymphocytic leukemia (CLL). The BCR is composed of immunoglobulin and Igα/Igβ proteins that transmit signals into cells. CLL results when too many B cells become abnormal lymphocytes. In CLL, tonic BCR signaling provides growth signals and plays a key role in disease progression. New drugs target proteins in the BCR pathway like Btk and Syk to block this signaling and stop cancer cell growth and division. Ibrutinib is an approved treatment that inhibits the BCR complex and brings hope to CLL patients.

1. realized by:
 Draoui Jihéne
 Saidi Nasreddine
BCR – B cell receptor
Faculté des Sciences de Tunis
Département de Biologie

2. Plan
Stucture
What is B cell receptor ?
What is chronic lymphocytic
leukemia?
BCR pathway
Adaptor molecules
Isotypes of Antibodies
Treatment
Biological effect

3. What is B cell receptor ?
BCR consists of an antigen-binding
transmembrane immunoglobulin (mIg) in
complex with two trans-membrane
polypeptides, namely Igα and Igβ, containing
immunoreceptor tyrosine activation motifs
(ITAMs), which enable the transmission of
intracellular signaling.

4. Stucture
• monomer of immunoglobulin
• light and heavy chains
• light –
• heavy –
• variable part – constant part

5.  IgM - B cell surface receptor for
antigen attachment; secreted
early in an immune response
where it is very effective in
killing bacteria.
 IgG - most abundant antibody; produced in
large numbers
 IgE - mediator for common
allergic responses (hay
fever, asthma, & hives)
 IgD - found on the surface of many B cells;
function is unknown (but may play a role in
activation of B cells)
 IgA -- a doublet -- concentrates in body
fluids such as tears, saliva, and the secretions
of the respiratory and gastrointestinal tracts.

7. Adaptor molecules
Adaptor molecules are involved in modulating signal transduction
the SRC-family protein-tyrosine kinase
(PTK)
LYN has one SH2 domain and one SH3
domain, as well as an enzymatic domain

8. Structure of adaptor molecules

9. Coreceptor complex of B lymphocyte
Complement
activation
recognition by
the B
lymphocyte
signals coming
from the Ig co
mplex and CR2

10. BCR pathway
The aggregation of the BCR by Ag
ITAM Tyrosyl residus Phosphorylation by Tyrosin Kinases
Activation of the Ras pathway
Phospholipase C activation :
*The SYK-phosphorylated forms a complex with the Phospholipase C and
phosphoryl it
**the activated PLC realizes the PIP2 hydrolysis by producing IP3 and DAG
***IP3 allows the ca 2 + mobilization
motives ITAM contact with Proteins Kinases of the family Src:
Fyn, Lyn, Blk
SYK translocation from the cytoplasm to the membrane

11. Biological effect
Antibody
production
Differentiation
Proliferation

12. The second phase involves the
formation of the memory B-cell pool
and seeding of long-lived plasma cells
to the bone marrow.
Short-lived plasma cells that make
mostly IgM (but some IgG) are
generated during the primary response
and occupy sites, such as lymph nodes.
Development of
memory B cells and
effector B cells (plasma
cells) occurs in two
phases.

13. What is chronic lymphocytic leukemia?
chronic lymphocytic Leukemia is a blood
cancer of the B cells manifesting when too
many stem cells become abnormal lymphocytes
Leukemia cells

14. B lymphocytes are the cells that most often develop into chronic lymphocytic
leukemia (CLL) cells.
Antigen engagement of BCR is followed by intracellular recruitment and activation of:
• BCR-associated kinases
• spleen tyrosine kinase (Syk),
• Bruton's tyrosine kinase (Btk)
• phosphatidylinositol 3-kinases (PI3K).
Normal B lymphocytes
receive signals from B-cell
antigen receptor (BCR) that
are triggered by binding of
the BCR to an external
antigen
Tonic signaling through the
BCR provides growth and
signals to chronic
lymphocytic leukemia (CLL)
cells, and plays an important
role in the pathogenesis and
progression of the disease

15. • There are now B cell receptor pathway inhibitors that interfere
with the proteins involve in the signaling pathways and affectively
block signals that tell CLL cells to grow and divide uncontrollably
• This therapy can help stop cancer progression while preserving
well healthy cells

16. • The compounds that are currently
investigated in patients with CLL include
ibrutinib –inhibitor of Btk
 fostamatinib-inhibitor of Syk
• Ibrutinib is a first in class oral therapy
and is new agent that inhibits the B cell
receptor signaling complex, then plays an
important role on the survival of
malignant B cells
• It is one of the first medicines to follow
Bringing new hope to many suffering
from CLL and other B cells malignancies.

17. Thanks for your attention

18. References
 http://people.eku.edu/ritchisong/301notes4b.html
 http://www.nature.com/nri/journal/v7/n12/fig_tab/nri2204_F3.html
 http://www.onclive.com/publications/obtn/2013/October-2013/Novel-B-Cell-Receptor-Signaling-
Inhibitors-Show-Promise
 http://www.biooncology.com/research-education/bcell/types/cll/options
 http://www.nature.com/nri/journal/v2/n5/fig_tab/nri801_F6.html
 http://lmt.projectsinknowledge.com/Activity/index.cfm?showfile=b&jn=2041&sj=2041.05&i=26&sc=20
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