Control of B Cell Development by the Signaling Proteins Btk and Slp-65
Regulatie van de B cel ontwikkeling door de signaleringseiwitten Btk en Slp-65
All organisms are continuously challenged by a variety of infectious microbial agents such as viruses, bacteria, fungi and parasites. Therefore the simplest up to the most complex organisms have developed defense mechanisms, to block assaults from hostile micro-organisms. In higher vertebrates this resulted in the development of an immune system consisting of an innate and an adaptive arm. After penetration of the epithelia the innate arm is the fi rst defense line that is encountered, consisting of cells equipped with germline encoded receptors such as Toll like receptor’s (TLR’s) that enable pathogen recognition on the basis of ancient molecular patterns or that detect changes in cell surface composition identifying them as virus infected. Examples of such cells are macrophages, granulocytes and natural killer cells. These cells are supported by an intricate system of soluble anti-microbial proteins such as the complement system, lysozyme and lactoferrin that also provide coverage against micro-organisms. The adaptive arm forms the second line of defense and responds in a highly specifi c way by virtue of somatically rearranged receptors to a microbial challenge, simultaneously generating immunological memory allowing swifter more vigorous responses in future challenges with the same pathogen. The adaptive immune response is carried out by two classes of lymphocytes that are generated from a common lymphoid progenitor in the bone marrow (BM). Progenitors for T cells fi rst migrate to the thymus where they differentiate to become mature helper, cytotoxic and regulatory T cells, whereas progenitors for B cells remain in the BM and develop through several stages into mature B cells. Aberrant lymphoid development in humans may result in various diseases such as immunodefi ciency with increased vulnerability to infections, autoimmunity with immune activation to self-antigens or lymphoproliferation and malignancy. This thesis focuses on the function of two signal transduction proteins Btk and Slp-65 in B cell development and their involvement in immunodefi ciency and malignancy.