1. Biology of B cells
In mammals, the early stages of B cell differentiation take place in the bone marrow and throughout the life of an individual. Different CD molecules are expressed at different stages of B cell development.
The earliest recognizable cell in the B cell lineage in the pro-B cell, in which the first stage of Ig H chain gene rearrangement takes place: A DH gene segment rearranges to a JH gene segment. Pro-B cells express CD19, it is expressed in all stages of B-cell development up to and including the mature B cell" but not plasma cells", pro B cells also express CD10

2. 3. The next stage is the pre-B cell, in which VH gene segment rearranges to the joined DJ segment to form a VDJ unit, putting the rearranged VDJ close to the C gene. The pre-B cell transcribes and translates the VDJC gene unit and thereby synthesizes a  chain. This  chain is expressed on the surface of the pre-B cell in association with surrogate light chains.
4. On the surface of the pre-B cell, the  chain and surrogate light chains are expressed with two closely associated transmembrane molecules: Ig (CD79a) and Ig(CD79b) is referred to as the pre-B cell receptor.'pre-BCR", Igα /Igβ are referred to as signal transduction molecules. Pre B cells express CD10 in addition to CD19, CD10 is not expressed by B cells at later stages of development, so it is a marker of early stages of B cell differentiation.
5. λ5 and VpreB are products of two nonrearranging genes which together function as surrogate light chains.

3. 6. Bruton,s tyrosine kinase "BtK" is an enzyme involved in intracellular signaling from the pre-BCR to the nucleus of pre-B cells. BtK plays a crucial role in the transition of pre-B cells to the next stage in B cell differentiation because boys with mutations in the BtK gene develop an immunodeficiency condition( X-linked agammaglobulinemia) in which B cell differentiation is arrested at the pre-B-cell stage.
7. In the next stage of differentiation, L chain genes start to rearrange; surrogate light-chain synthesis is shut down; and a  or  chains are formed, which associates with the cell's  chain. This results in the formation of an IgM molecule, which is expressed on the surface of the cell. This cell is referred to as an immature B cell which expresses CD20 ,it is also expressed in the next stage of B cell differentiation.

4. 8. If the immature B cell interacts with self antigen, it is generally inactivated. The interaction of immature cells with self-molecules__resulting in inactivation or deletion of cells with potential reactivity to self__is one of the important ways of maintaining self-tolerance (negative selection). Fig.7.3 shows that the immature B cell can respond to self Ags expressed on the surface of bone marrow cells. The interaction with self-Ag activates receptor editing in which the cell,s original IgH chain is paired with a new L chain. As a result the immature B cell synthesizes an Ig molecule with different Ag specificity. The recombination events that occur during receptor editing may generate an Ig specific for either self" where B cells are deleted via apoptosis and self tolerance- negative selection- develops in 1ry lymphoid organs" OR nonself molecule" immature B cell is rescued from deletion and leaves the bone marrow and becomes part of B cell responsive to nonself Ags". Fig.7.3 also shows that if the self Ag is soluble, the immature B cell may become anergic" inactivation for long period",these cells leave bone marrow.

8. 9. In the next phase of B cell differentiation, the mature B cell expresses IgM and IgD__with identical antigenic specificity__on the cell surface.
10. Further development of the mature B cell occurs predominantly outside the bone marrow and as a result of exposure to antigen. Activation of the B cell leads to proliferation and differentiation into a plasma cell, the cells that synthesize and secrete antibody. In the primary response to antigen predominantly IgM is synthesized. IgG and IgA- secreting plasma cells produced in the germinal centers of lymph nodes and spleen migrate primarily to the bone marrow where they may live for years. These long lived plasma cells synthesize high levels of IgG and monomeric IgA that provide protection in blood against 2nd exposure to viruses and bacteria.
Plasma cells that synthesize dimeric IgA that protects mucosal surfaces in GIT,RT, salivary and tear glands,and lactating mammary glands develop in MALT.
Memory B cells
They are long-lived, they can be activated for a subsequent"2ry" with more response to Ag. They express IgG,IgA or IgE on their surface but not IgM or IgD. Human memory cells can be identified by their expression of CD27.

9. 11. B cells that interact with T cells and their products__cytokines__undergo isotype (class) switching, i.e., produce antibody of different isotypes__IgG, IgA, or IgE. Isotype switching involves a rearrangement mechanism unique to B cells: the VDJ heavy-chain unit that was joined to the C and C genes rearranges to join another C-region gene, such as C, C, or C. the B cell that was synthesizing IgM and IgD can now synthesize antibody of a different isotype (IgG, IgA, or IgE) but with the same antigenic specificity.
12. Somatic hypermutation of genes coding for antibody V regions takes place in the germinal centres of secondary lymphoid organs. This results in the selection of B cells with mutations in their Ig V genes that code for antibodies with higher affinity for the antigen than the original B cell ("affinity maturation"). These selected B cells can develop into memory B cells or plasma cells.
13. In a single B cell, the H chain is coded for by the H chain gene segments found on either the maternally derived or the paternally derived chromosome; the L chain is also coded for by the L chain gene segments found on one or other chromosome. This phenomenon, the use of genes on only one chromosome to synthesize and Ig chain, is known as allelic exclusion and ensures that an individual B cell produces an Ig of only one antigenic specificity.

12. B- lymphocyte traffic Naïve B cells circulate throughout the blood to 2ry lymphoid organs, primarily lymph nodes and GALT such as Peyer,s patches of the intestine. The circulation time of about 12 h brings B cells with the correct antigenic specificity in contact with Ag. If the B cell interacts with Ag and TH cells in the lymphoid organ, memory cells and plasma cells are generated in germinal centers. Memory B cells migrate into tissues, plasma cells migrate to bone marrow and continue to synthesize Abs for long period, plasma cells which secret IgA move to mucosal tissue.

13. The migration of naïve B cells into 2ry lymphoid organs and the "homing" of Ag-activated memory and plasma cell populations into tissues are governed by expression at B cell surface of adhesion molecules and chemokine receptors. Naïve B cells express the chemokine receptor CCR7 and the adhesion molecule L-selectin"CD62L"and alpha 4B7"integrin". Both selectin and integrin bind to glycoprotein molecules on endothelial cells of HEV. Thymus-dependent Ags"TD" They require TH cells in order for B cells to synthesize Abs. TD response generates high affinity Abs. Early response to TD Ags generates IgM Abs. Later other classes are synthesized"IgG, IgA or IgE". TD Ab responses develop long-lived memory B cells and plasma cells which provide long-lasting protection against reinfection by bacteria and viruses.

14. Thymus-Independent Ags"TI" In this case B cells do not require TH cells to synthesize Abs. Polysaccharides of bacterial capsules are one set of TI Ags. The response to TI Ags is rapid. It involves synthesis of IgM" agglutinates Ag and fixes complement". It provides early protection against many bacterial and viral infections. Immunological memory does not develop. B-1 Cells They are a subpopulation of B cells that predominate in the peritoneal and pleural Cavities of many species and are a minor population in spleen and lymph nodes. In adults, B-1 cells synthesize predominantly low affinity IgM polyspecific antibodies early in the TI primary response to many bacteria. B-1 cells are considered responsible for synthesizing most natural(IgM) antibody that are detected in the blood in absence of antigen priming. Thus , B-1 cells are thought to play a role as the first line of defense against systemic bacterial and viral infections.

15. Most B-1 cells are characterized by the surface expression of CD5
Most B-1 cells are characterized by the surface expression of CD5. CD5+ B-1 cells
are the predominant cell type in chronic lymphocytic leukemia.
The interaction of T and B cells takes place predominantly in the germinal centers of
2ry lymphoid organs. The germinal center reactions involves:
Somatic hypermutation of genes coding for Ab V regions, resulting in affinity maturation.
Class switch recombination, in which a B cell that was synthesizing IgM and IgD switches to synthesizing Ab of a different isotype "IgG, IgA or IgE" with the same antigenic specificity.
Cytokines synthesized by T cells influence the isotype of Ab synthesized by the B cell.
Ab synthesis in Mucosal Tissue "fig.7.6"
In mucosa- associated lymphoid tissue, IgA –committed B cells develop at an inductive state, migrate out of the lymphoid tissue and home back via the blood to a different mucosal effector site, where they complete their differentiation to IgA –secreting plasma cells.

17. B-Cell Membrane proteins"fig.7.7"
Stage-specific markers i.e expression of molecules at different stages of B-cell development; CD10,CD19, CD20 and CD27.
Membrane Igs "bind Ags, identify B cells, separate B cells from other lymphocytes and mononuclear cells".
Signal transduction molecules associated with membrane Igs"Ig α and Igβ "
Their cytoplasmic regions contain sequences of amino acids known as immune-receptor tyrosine- based activation motifs(ITAMs).
These sequences are referred to as motifs because they are found in other signal transduction molecules expressed on the cells of immune system(such as those associated with TCR), after Ag binds to the BCR tyrosine residues are phosphorylated by tyrosine kinases.

18. B- Cell coreceptor: CD 19, CD81, CD21 are noncovalently associated in a complex known as B-cell coreceptor, the coreceptor reduces the threshold of B-cell activation in response to an Ag. The amount of Ag needed to stimulate Ab response is times less if the coreceptor is activated with BCR compared to BCR activation alone(fig.7.8) Binding of bacteria to both the coreceptor and Ig enhances the signal to the B cell. CD 21 is the receptor for complement component C3dg that is generated in plasma in response to microbial pathogens. Binding C3dg to CD21 of the coreceptor enhances the activation signal delivered through the BCR.

20. Negative regulation of B-cell signaling

21. Molecules involved in T cell-B cell Interactions In addition to Ig synthesis, B cells can act as APC and activate the helper CD4+ T cell. Activated B cells share several characteristics with APC that present Ag to CD4+ T cells; B cells express MHC class II molecules which bind peptides derived from protein Ags and present them to CD4+ T cells. Activated B cells express high levels of costimulatory molecules "they are required along with Ag to activate naïve T cells". B7 is a key costimulatory molecule expressed by B cells. CD40 is another costimulatory molecule expressed by B cells. CD40 interacts with CD40L or CD154 expressed on activated T cells.This interaction activates B cells and plays a critical role in isotype switching.

22. Inducible costimulatory (ICOS) ligand (ICOSL) is another important costimulatory molecule expressed by B cells. The interaction of ICOSL with ICOS expressed by activated T cells appear critical for the formation of germinal center. People who lack functional ICOSL or ICOS make very low levels of IgG, IgA and IgE.