Immunoglobulin free light chains in inflammatory diseases; New findings on FLCs fitted into current concepts of immune regulation

Allergy is an exaggerated immune reaction to usually harmless foreign proteins present in food and airborne pollens for example. Allergic hypersensitivity can be subdivided in IgE- and non-IgE-mediated allergies. A critical role for mast cells is extensively described for IgE-mediated allergies, but evidence for their role in non-IgE mediated allergies is convincing as well. IgE can bind antigen with high affinity and crosslinking of mast cell-bound IgE by multivalent antigen causes mast cell activation leading to the release of multiple inflammatory mediators. These mediators initiate or contribute to the persistence of an inflammatory response. Despite this important contribution of IgE in many allergies, many patients (up to 40%) suffer from a non-IgE-mediated allergy (e.g. in food allergy). What causes mast cell activation in patients suffering from this type of allergies or other disorders in which mast cells play an important role? Besides IgE, immunoglobulin free light chains (FLCs) can mediate antigen-specific mast cell activation. A number of studies have indicated a possible functional role of (antigen-specific) FLCs in preclinical models of contact hypersensitivity, cow’s milk allergy, and asthma. The main focus of this thesis is to gain more insight in the production, presence, distribution, and putative functional role of FLCs in different human disorders. Upper and lower airway disorders were studied by analyzing the presence of FLCs in allergic rhinitis and nonallergic rhinitis patients, chronic rhinosinusitis with and without nasal polyposis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. In all disorders, most apparent increases in FLC concentrations were observed at local sites of inflammation. Furthermore, part of the FLC-positive cells in nasal mucosa of rhinitis patients showed to be mast cells supporting a mast cell-mediated effect of FLCs. Extremely high FLC concentrations were found at local sites of inflammation in rheumatoid arthritis (RA) patients, and FLC concentrations showed to correlate with disease severity. In addition, FLC concentrations only significantly decreased in patients that responded to B cell depletion therapy (anti-CD20). Moreover, the abundant presence of FLCs within human cancer tissues of different organs and aetiologies was found, and this showed to be associated with poor clinical outcome in breast cancer patients. In a preclinical melanoma model it was shown that tumour growth was highly dependent on the presence of both FLCs and mast cells. Furthermore, it is demonstrated that FLCs bind to human basophils and that cross-linking of FLCs modulates IgE-mediated basophil activation. Finally, it is demonstrated that FLCs monomers and dimers might be secreted as distinct entities. FLC dimers showed to have a significantly higher antigen-specific binding affinity compared to FLC monomers. In conclusion, current knowledge on the biological activity of FLCs obtained in in vitro research, and preclinical and clinical studies suggests that FLCs possibly affect multiple cell types, including mast cells and basophils, in physiological and pathological conditions. Considering the described pro-inflammatory effects of FLCs, it would be interesting to investigate the therapeutic value of FLC antagonists (such as F991) in further detail.