B lymphocytes are generated throughout life from hematopoietic stem cells in bone
marrow, and contribute to the immune system by the production of antigen-specific antibodies
(immunoglobulins; Ig). Two distinct phase of B-cell development can be distinguished:
1) antigen-independent precursor-B-cell differentiation in bone marrow, and 2) antigendependent B-cell maturation in peripheral lymphoid organs. The aim of precursor-B-cell
differentiation is to generate a functional Ig receptor by V(D)J recombination of the genes
encoding the Ig heavy (IgH) and Ig light (Ig. or Ig.) chains. When a precursor-B-cell
succeeds in creating a functional Ig receptor, it will migrate to the periphery and become
part of the naive B-cell pool. Because every precursor-B-cell creates a unique Ig receptor,
the peripheral B-cell pool bears a diverse repertoire of specific receptors for antigen.
Naive B lymphocytes are short-lived cells and because new cells are continuously
generated, there is a high turnover. However, once a naive mature B-lymphocyte recognizes
antigen with its specific Ig receptor, it will undergo clonal proliferation and differentiation,
thereby generating a large number of plasma cells that produce and secrete antigen-specific
Igs. During this response, the B-cell initiates additional molecular mechanisms to adapt and
optimize the antigen-binding affinity and the effector function of its Ig molecule.
Generation of a large repertoire of B lymphocytes and the response of one of these
B lymphocytes to antigen is a multi-step process for which multiple proteins are required.
The lack of one of these proteins leads to a problem with the humoral immunity of the
individual, which is seen in patients with primary antibody deficiency diseases. These children
or young adults carry rare inherited disorders and are subject to multiple, recurrent (mainly)
bacterial infections. Several genetic defects have been identified in patients with a primary
antibody deficiency. In many patients, however, the B-cell defect is not well understood.
The studies in this thesis address several aspects of B-cell development and defects that lead
to primary antibody deficiency diseases
