Thymus-dependent (TD) activation: B cell activation can occur one of two ways. The first way depends upon TH cells and is called Thymus-dependent (TD). The other way does not and is referred to as thymus-independent (TI).  Antigens which activate the TD route are usually soluble proteins whereas such antigens are usually bacterial cell wall components for the TI route. The vast majority of antigens activate the TD route. 

The types of antigens which activate the TI route come in 2 types. The first type includes some bacterial cell wall components like lipopolysaccharide (LPS) whereas the second type of antigens are highly repetitious molecules like bacterial cell wall polysaccharides with repeating polysaccaride units. Most of the type 1 antigens that are thymus independent are polyclonal B cell activators (mitogens) in that they are able to activate B cells regardless of their antigenic specificity. Studies involving haptenated polymers have shown that arrays of 20-30 haptens, spaced optimally by 5-10 nm, can activate B cells in the absence of T cell help. In general, these responses are thymus independent type 2 (TI-2) which means that they still depend on some T cell help. The response can become completely T cell independent (TI-1) if determinants are not arranged linearly on a flexible polymer but in a rigid, paracrystalline, two dimensional array. Many viruses examined for induction of TI B cell responses exhibit repetitive, identical neutralizing epitopes that can be defined as highly organized. This includes all nonenveloped viruses that exhibit a highly organized icosahedral structure. Also, many of the enveloped viruses have highly repetitive surface structures.

B-Cell Signalling: 

Transduction of activating signals actually involves the Ig-alpha/Ig-beta heterodimers of the BCR. Both cytoplasmic tails of the heterodimers contain several tyrosine residues that can be phosphorylated by 3 members of the src family of tyrosine kinases. When mIg is cross linked with an antigen, each of these protein kinases is activated and they then act to phosphorylate and activate a number of molecules involved in signal transduction.

Whereas binding of a thymus independent antigen to a B cell provides both signals for B cell activation, a thymus dependent antigen provides signal 1 by cross-linking mIg, but a separate interaction between CD40 on the B cell and CD40L on an activated TH cell is required to generate signal 2.

Thymus-dependent activation: The sequence of events for thymus-dependent antigen activation of a B cell is though to involve 1) crosslinking mIg which generates signal 1, which leads to increased expression of class II MHC and costimulatory B7. 2) A TH cell recognizes antigen-class II MHC on B cell membrane and this plus the co-stimulatory signal activates the TH cell. 3) THcell begins to express CD40L which interacts with the CD40 providing signal 2.

Germinal centers in lymph nodes arise after exposure to a thymus-dependent antigen. In these centers, B cell differentiation events occur which are 1) affinity maturation, 2) class switching and 3) formation of plasma cells and memory B cells.

Antigen-C3d complexes increase sensitivity to antigen: Antigen-C3d complexes cross-link BCR and CR2-CD19 complex which increases sensitivity of B cells to antigen.

What changes occur after B cell activation

• B cells increase in size and go from G0 to G1 of the cell cycle.

• There is upregulation of MHC classII

• upregulstion costimulatory molecules (B7-2)

• upregulationadhesion molecules (ICAM1)

• upregulationcytokine receptors (IL-2R).

• B cells become receptive to T cell help (protected from fas).

• B cells migrate to outer T zone (altered response to chemokines).

• B cells also enter mitosis if provided with submitogenic does of other stimuli (LPS, CD40L, IL-4)

Self-Tolerance: 

Many diseases are characterized by pathogenic autoantibodies such as hemolytic anemia (erythroctye surface antigen), graves’ disease (thyroid stimulating hormone R).

There are several ways to deal with autoreactive immature B cells in BM.

Clonal deletion: This involves deletion and editing in the bone marrow.

Receptor editing: change their receptor to become non-self reactive. If cell is successful in receptor editing, it can move to periphery. Otherwise cell dies. Receptor editing is a mechanism to eliminate self reactive B cells upon encounter with strong self antigen. About 1/4 of the cells of immature B cells undergo receptor editing.

Developing proginotr B cells with receptors specific for self antigens are normally induced to undergo secondary light chain VJ gene rearrangements, a process called receptor editing. When receptor editing still fails to remove the self reactivities, the autoreactive B cells are induced to under go apoptosis or anergy. It has been estimated that 25-75% of all developing B cells are lost per individual organism to these processes of self tolerance. (Wahl, US 10,813,346). 

Anergy: make the cells unresponsive to antigen and short lived. Chronically exposure to antigen results in reduced ability to signal. When a tolerant B cell encounters a CD4+ T cells, will not behave properly. It can trigger a TCR but not good at inducing other molecules. However, multivalent foreign antigen (stronger antigens) can still activate anergic B cells.

Competitive elimination: of autoreactive B cells in the periphery. Elimination is promoted by the pro-apoptotic BH3-only molecule Bim, a bcl-2 antagonist.