The role of Bruton’s tyrosine kinase and the spleen in host defense against bacterial pathogens Two essential gears in the immune clockwork

Pneumonia represents a severe health burden, being the 4^th most common cause of death worldwide. When the causative microbe prevails, pneumonia can result in life threatening sepsis. Better understanding of the immune response during pneumonia and sepsis may provide insights that lead to new therapies. In this thesis we focused on the role of the intracellular signaling protein Bruton’s tyrosine kinase (Btk) in host defense against bacterial pathogens. For this we made use of established mouse models for bacterial pneumonia and sepsis. We found that antibacterial defense in Btk deficient mice during pneumosepsis with K. pneumoniae and S. pneumoniae is not abrogated because of the lack of B cells and natural antibodies. Instead, Btk expression in myeloid cells, including macrophages and granulocytes, is essential for antibacterial defense against both pathogens.
In addition to finding new therapies against sepsis, it is important to identify patient at risk so that preventive measures can be taken. Therefore in this thesis we also focused on patients with absent or diminished splenic function that are at risk for developing overwhelming post splenectomy sepsis. We performed a literature review to assess existing tests that measure splenic function and we conducted a study with volunteers that are healthy, asplenic or have sickle cell disease to compare these tests. Our results show that scintigraphy is the most accurate method to asses splenic function. Moreover, we found that analysis of particular erythrocytes and B lymphocytes in blood are a good first line screening methods before the more costly and time consuming scintigraphy is performed.