B cell Activation

CD4 Th CELLS ACTIVATE B-CELLS

• In general, B cell activation requires help from "activated" Th cells. This help comes mainly from Th2 cells, but Th1 cells can also activate synthesis of Ig. Those antigens that can activate B cells only if CD4 Th cells do provide the "help" are referred to as Thymus Dependent (TD) Antigens. Certain antigens that can activate B cells in the absence of Th cells, are referred to as Thymus Independent (TI) antigens.

• B cell activation requires Two signals.
  1)    The first is direct recognition of an antigen (bacteria X) by membrane bound Ig, on the surface of a naive B cell.
  2)    The second signal is provided by direct contact between this B cell and an "activated" Th cell. This contact provides two additional signals to the B cell.
         i.    One is the binding of the MHC II:Antigen complex on the surface of the B cell with TCR of the CD4 Th cell. Remember that B cells also have some APC function. Thus the surface Ig bound antigen on the naive B cell engulfs, processes, and presents the antigen.
         ii.   The second signal coming from Th cell contact comes from the binding of CD40 on the B cell with CD40 ligand  (CD40L) on the T cell.

Note:

• Only activated Th cells express CD40L, thus T cell activation in the Lymph node need to occur before B cell activation. 

• The Th cell and the B cell need to react against the same source of antigen. The Th cell has to be activated by peptides from the same bacteria X. The specificity of TCR:MHC II:antigen will ensure that activated Th cells only activate those B cells that have bound and engulfed that same antigen that has activated the Th cell in the first place. A Th cell is activated by peptides from bacteria X. If an adjacent B cell binds bacteria Y, ingests it, and presents its peptides within its MHC II. The original Th cell cannot activate the second B cell because its TCR is specific for bacteria X.    

• The Th cell need NOT be activated by the same peptide fragment as the B cell. The B cell ingests, processes and presents any linear peptide fragment with MHC II, from a whole bacteria. Different peptide fragments from that whole bacteria will be presented on the surface of this same B cell. A Th cell may be specific to any one of those peptides (ignore the other MHC II:antigens) and activate the B cell. But the original B cell Ig is specific for only one surface protein on that bacteria, independent from the linear peptide that is recognized by the Th cell.
  Note: B cell Ig must recognize a mature protein in its secondary and tertiary structure, but a T cell TCR can only bind peptides that the Ig may not recognize.

• An activated B cell produces high levels of CD40, which serves as an important Co-Stimulator for naive T cell activation. Of
  the three types of APC, B cells possess the most specific and efficient antigen binding receptor, namely surface Ig. Remember, the other APC's possess mostly non-specific receptors. Thus, once activated B cells express Co-stimulators, they become the main APC's in the recruitment of more naive CD4 T cells.
  

SEQUENCES OF B CELL ACTIVATION

(note: you have to differentiate between the following terms: primary foci vs. primary follicle.  Follicular Dendritic cell vs. Dendritic cell


-1- CLONAL EXPANSION: After the initial B cell activation by Th cells, B cells undergo Clonal Expansion. Within the Lymph Node (LN), they undergo several rounds of cell division, forming a cell cluster called a primary Foci.

-2- GERMINAL CENTER FORMATION (GC): GC is a highly organized arrangement of clusters of activated B cells, Th cells, and Follicular Dendritic cells (FDC).

• Important- FDC's are not the APC Dendritic cells. FDC's do not express MHC II, plus they do not have a hematopoietic origin. However, FDC's play a crucial role in further differentiation of B cells.

• The figure below shows the life cycle of a B cell. After activation, the B cell will differentiate into an Ig producing cell. The type of Ig that the B cell will secrete depend on its specific differentiation route, and anatomical environment (e.g. within the submucosa they will secrete IgA). The specific mechanism that determines the direction of differentiation is not know, but presumably involve Th cells and T cell derived cytokines. After a period of antibody differentiation, a sub-group of the B cells will differentiate into memory B cells, that will circulate throughout the body for a few more years. Whether the B cell lymphoblasts go through the intermediate stage of Ig secretion, or if a fraction directly differentiates into memory cells is not known. However, most of the plasma cells are terminally differentiated and die via Apoptosis after exhaustive Ig secretion.