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B Cell Activation and Adaptive Immunity

The Importance of B Cells in Immune Defense

B lymphocytes, also called B cells, are white blood cells that carry out a vital process in human adaptive immunity. B cells create a type of protein called an antibody.  Antibodies bind to antigens associated with a particular pathogen and neutralize foreign substances (this is essential for humoral immunity). B Cells can also recruit other cells to help destroy an infected cell. B cell activation is integral for the pathogen-recognition abilities of the human immune system. When B cells encounter specific antigens and activate, they become plasma cells that produce antibodies that neutralize pathogens or mark them for destruction, triggering activation in other cell types.

B cells also differentiate into memory B cells, serving as long-term immunity that ensures a quick response in the event of a re-exposure to the same pathogen.

Overview of B Cell Activation

B cell activation occurs in the secondary lymphoid organs (eg, human lymph nodes and spleen). The spleen and lymph nodes provide an optimal environment for T and B cell interactions as B cell activation depends on the presence of helper T cells for stimulation.

B cells carry a unique B-cell antigen receptor (BCR) on their cell surface. The BCR has two roles in B-cell activation.  First, BCR will bind to its specific antigen. Second, it delivers the cellular message from the binding site through the cell to the nucleus and intracellular sites. The antigen is then engulfed and internalized by the cell through receptor-mediated endocytosis.

Within the cell, the antigen is degraded and returned to the B-cell surface as peptides bound to major histocompatibility complex class II molecules (MHC II).  MHC II can be displayed to neighboring T cells,  stimulating them to make proteins that, in turn, cause B cell activation.

T-Cell-Dependent (TD) B Cell Activation

B cells obtain help from helper T cells by acting as antigen-presenting cells for activation. In T-cell-dependent (TD)  B cell activation, B cells use their MHC II-antigen complex to activate T cells and stimulate cytokine release from helper or CD4 T cells. These cytokines serve as costimulatory molecules for B cell proliferation and differentiation.

The presence of helper T cells in an immune response increases the overall quality and effectiveness of the inflammatory attack. T cells promote the development of antibodies by providing high-affinity specificity. Helper T cells releasing cytokines stimulates a significant expansion of specialized B cells and memory cells and fuels a more robust inflammatory response.

T Cell-Independent (TI) B Cell Activation

Some antigens can stimulate B cells to proliferate and differentiate without the help of T Cells. These T cell-independent (TI) antigens are microbial polysaccharides, found on the surface of pathogen cell walls,  that do not activate helper T cells. Therefore, multipoint binding to B cell antigen receptors can generate a strong first signal to activate the B cell directly without costimulation. The binding of the TI antigen is sufficient to trigger activation and differentiation into plasma cells.

Plasma cells that are activated in this manner secrete antibodies tailored to the TI antigen. Because they do not activate helper T cells, they fail to induce B cell memory, class switching, or affinity maturation. Therefore, they tend to have a lower binding affinity (but high avidity) and limited antibody diversity when compared to antibodies from TD B cell activation. TI responses are less effective against complex pathogens and viruses due to their lack of immune response coordination, typically facilitated with T cells in TD B cell activation.

B Cell Activation Steps

B cell activation begins when the B cell recognizes an antigen that matches its specific BCR. This antigen can be any piece of a pathogen that can bind to BCR and initiate activation, like a protein or polysaccharide.

Once the antigen is bound to the BCR, it forms an antigen-BCR complex, which initializes the internalization of the antigen into the B cell. The process of engulfing an antigen through BCR is called receptor-mediated endocytosis.

This internalization is followed by antigen processing and presentation. The protein antigens are broken down into a series of peptide epitopes displayed on the B cell’s surface. These peptides bind to grooves in  MHC II molecules to form a complex ready to bind to T cells and communicate about the potential infection to the neighboring cells.

The complex formed by the epitopes of antigens and MHC II molecules is presented to helper T cells in the secondary lymphoid organs. TCR, or T-cell receptor, the unique surface immunoglobulin in T cells, binds to the MHC II complex and costimulatory molecules to activate the T cell.

The interaction between BCR, MHC II complex, and TCR activates the helper T cell and releases cytokines, such as interleukin-4 (IL-4), interleukin 5 (IL-5), interleukin-6 (IL-6), and interleukin-21 (IL-21). Cytokines stimulate and regulate cell activation and differentiation.

The cytokines released by the T cells provide the necessary components to activate the B cells. Once activated, the B cells undergo proliferation, differentiation, antibody production, and memory cell formation. Proliferation of B cells rapidly increases the number of B cells with antigen specificity against the infection. Activated B cells will transform into plasma cells that release antibodies, small molecules tailored to neutralize the pathogen.

Plasma cells are terminally differentiated B cells that provide protective immunity through the continuous secretion of antibodies. The plasma cells produce and secrete large quantities, up to 100 million molecules per hour, of antibody molecules. These antibodies readily circulate throughout the body as a means of surveillance. , binding to antigens and neutralizing them. Antibody neutralization can prevent pathogens from entering and infecting host cells. Moreover, antibodies also opsonize pathogen cells, in which they mark them for destruction by phagocytic cells, such as neutrophils and macrophages.

In addition to plasma cells, B cells differentiate into memory B cells after activation. Memory B cells outlive the inflammatory response and “remember” the antigen in the case of re-exposure in the future. Memory B cells facilitate a rapid activation that creates plasma cells and antibodies specific to the same antigen.

Physiological Changes in B Cells After Activation

B cells undergo significant morphology and functional changes during activation to become plasma cells. Activated B cells become larger and metabolically faster than resting or inactive B cells. Activated B cells upregulate certain surface antigens, including CD40, a co-stimulatory molecule responsible for B cell activation in interaction with a helper T cell.

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