Antibody Diversity and B Lymphocyte-Mediated Immunity

Abstract

Antibodies are produced by B lymphocytes. Upon binding of antigen to membrane immunoglobulin (mIg), the B lymphocyte becomes activated and differentiates into an antibody producing plasmacell. mIg is the antigen recognition unit of the B cell receptor complex, in which Iga and Igb proteins are signal transduction molecules. Key elements in B lymphocytes signalling are phosphorylation of tyrosine residues within the immunoreceptor tyrosine based activation motifs (ITAM) of Iga and Igb and subsequent activation of a series of cytoplasmic tyrosine kinases. Apart from triggering of mIg, Full B lymphocyte activation requires a number of additional molecular interactions which depend on cognate cellular interaction with T lymphocytes and/or monocytes (T cell dependent B cell activation). The binding of CD40 on the B lymphocyte and CD40L on activated T lymphocytes is an example of these co-stimulatory interactions. Furthermore, cytokines, such as IL-4 and IL-5, promote B lymphocyte proliferation and differentiation. For B lymphocyte activation by polysaccharide antigens, T lymphocytes are not required. Instead, innate lymphoid cells support B cells in their response against polysaccharides. Costimulation in this case is provided by CD21, the complement receptor on B lymphocytes which is activated by C3d, bound to the polysaccharide.

A primary antibody response starts with production of IgM antibodies. During a primary response, class switching to IgG and IgA antibodies takes place. Proliferating B lymphocytes undergo somatic hypermutation which can result in antibodies with a higher affinity. During a primary response, part of the B lymphocytes differentiate into long-lived memory B lymphocytes (and express CD27). In a secondary response the expanded clone of memory B lymphocytes reacts with a short latency period and high antibody production.

Upon interaction with antigen, antibodies exert a variety of biological functions: 1) direct neutralization of bacterial toxins; 2) initiate complement activation which, in case of a cellular antigen, results in cell lysis; 3) augment phagocytosis after interaction with Fc receptors; 4) initiate antibody dependent cellular cytotoxicity.

Towards the end of the 19th century, Koch and Ehrlich discovered that the serum of immunized animals contained substances (antitoxins) with the ability to neutralize the toxins of diphtheria and tetanus. At Christmas 1891 a group of children received diphtheria antitoxin, which cured them from this otherwise fatal disease. These experiments demonstrated that immunization can induce the formation of humoral substances, which have the ability to protect against infectious diseases. Half a century later, in 1952, Bruton described a patient with severe and recurrent respiratory tract infections and an agammaglobulinemia. This milestone demonstrated the significant role of immunoglobulins in the defense against infections. Later on, through the pioneering work of Max Cooper and others it was shown that B- lymphocytes directly give rise to cells that produce antibodies, and that patients such as the one described above (X-linked agammaglobulinemia or XLA) fail to produce antibodies because they lack B-lymphocytes; B-lymphocyte development in the bone marrow stops at the pre-B-cell stage. Forty years after the initial discovery, the molecular basis for this disease was found: XLA is caused by structural defects in the gene encoding an enzyme that has been termed Bruton’s tyrosine kinase (Btk).

Final manuscript submitted on November 28, 2016.