Immunoglobulin free light chains: new insights in mast cell activation and immunology

In this thesis, several studies are described that elaborate on the biological properties of immunoglobulin free light chains (Ig-fLC) related to the activation of mast cells and effects on other cells. Mast cell degranulation through Ig-fLC requires two events. At first, mast cell-bound Ig-fLCs should be able to recognize and bind antigen to facilitate crosslinking. Subsequently, receptor crosslinking must be translated into an intracellular signal that initiates a downstream signalling pathway eventually leading to mast cell activation. The second chapter describes the identification of the key intracellular signal transducing element responsible for transmitting the activating signal inside mast cells after Ig-fLC binding and crosslinking. In chapter three, we provide further insight in the binding of antigen by Ig-fLC in vitro through various techniques. We also show that crosslinking is crucial to initiate an Ig-fLC-mediated hypersensitivity response in vivo. Ig-fLC may also exert biological effects via other cells than mast cells. We show that Ig-fLC can activate neutrophils to release CXCL8. In the last part of this thesis, research is expanded towards other myeloid cells and provides new insights into the capability of Ig-fLC to induce immunological effects. In conclusion, studies in this thesis further delineate the mast cell-activating potential of IgLCs and expands our current knowledge about their role in immunology.