Erschienen:
[Erscheinungsort nicht ermittelbar]: Lund University, Faculty of Medicine, 2021
Sprache:
Englisch
Entstehung:
Hochschulschrift:
Dissertation, Lund University, Faculty of Medicine, 2021
Anmerkungen:
Beschreibung:
Factor H is an inhibitor of the complement system, essential for controlling the alternative pathway and also playing a crucial role in various cellular functions. In this thesis, we identified new intriguing functions of FH as a survival factor for primary human monocytes, promoting their differentiation into immunosuppressive macrophages. We showed that FH is expressed by human breast cancer cells, and that the expression correlates with the presence of immunosuppressive macrophages in the cancer microenvironment, breast cancer recurrence, and severity of the disease. Following this finding, we showed that FH also increases the survival of regulatory T-cells, which is mediated via the binding of FH to the inducible co-stimulator on the surface of the cells. This phenomenon seems to play a role in glioma, an aggressive type of brain tumors, where FH expression positively correlates with the occurrence of regulatory T-cells and a worse prognosis for the patients. In contrast to this detrimental role in cancer, FH was shown to play a beneficial role in the silent removal of apoptotic cells and their remnants. This process is of central importance in the pathogenesis of systemic lupus erythematosus, a severe autoimmune disease. Moreover, we confirmed that a different complement protein, C4d, which is the final cleavage fragment of C4, can be a valuable biomarker to measure the activity of this disease. The loss of sialic acid, an important FH ligand, and diminished binding of FH on platelets and other immune cells was furthermore associated with decreased protection against complement attack in a patient suffering from congenital thrombocytopenia. Altogether this thesis aimed to explore the dual role of complement proteins in cancer and autoimmunity.