Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic and persistent inflammation of the joints. Around 50-80% of the RA patients harbour either one or multiple types... Show moreRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic and persistent inflammation of the joints. Around 50-80% of the RA patients harbour either one or multiple types of autoantibodies, under which also Anti-Citrullinated Protein Antibodies (ACPA). ACPA are highly specific for RA and are strongly associated with the severity of arthritis. The studies described in this thesis aim to explore the structure and biological function of ACPA and the B cells producing these ACPA.The studies highlight the importance of the synovial environment for the survival of ACPA B cells. Moreover, we demonstrate that the variable region of ACPA-IgG differs from that of ACPA-IgM by the introduction of glycans, and that glycans in the constant part of antibodies can be modulated by influences from the micro-environment. This may affect the biological functions of the antibodies. Furthermore, we show that ACPA can bind to so-called Fc gamma receptor I on immune cells which could be a potential effector mechanisms of ACPA. These findings demonstrate that the structure and environment of ACPA play an important role in the ACPA immune response and provide multiple arguments for the active contribution of ACPA in the chronic inflammation of RA. Show less
Donk, N.W.C.J. van de; Casneuf, T.; Cara, A. di; Parren, P.W.; Zweegman, S.; Kessel, B. van; ... ; Sasser, A.K. 2019
Ischemia-reperfusion injury (IRI) is a pathophysiological event that occurs in many clinical conditions, ranging from surgery, acute artery occlusion to transplantation. Complement activation is... Show moreIschemia-reperfusion injury (IRI) is a pathophysiological event that occurs in many clinical conditions, ranging from surgery, acute artery occlusion to transplantation. Complement activation is thought to be a crucial step in IRI, because complement inhibition and complement deficiency considerably attenuate irreversible injury. However, the specific complement pathway remains unclear. All three complement pathways: the classical, the alternative, and the mannose-binding lectin dependent pathway may be involved in the development of IRI, depending on the model, the tissue, and the time course of inflammation. Ischemia leads to the exposition of neoantigens on the jeopardized tissues, which could be recognized by C-reactive protein (CRP) and natural IgM antibodies. The binding of CRP and IgM to these neoepitopes is followed by complement activation. In this thesis, we demonstrated that both proteins bind to jeopardized tissues and activate the complement system, in particular intestines from rats subjected to IRI. Furthermore, it was shown that IgM levels against altered phospholipids correlated with the levels of inflammatory mediators in patients subjected to tissue damage suggesting that IgM participates in amplification of inflammation. The development of strategies to prevent binding of CRP and/or IgM is an attractive approach for a therapy for reducing IRI. Show less
