Deciphering the stage specific impact of cellular and humoral components modulating the onset of RA

• Applicants: Professorin Dr. Anja Lux; Professor Dr. Falk Nimmerjahn
• Subject Area: Rheumatology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405969122

Autoantibodies play a central role in a variety of autoimmune diseases, including inflammatory arthritis. Of note, autoantibodies may be present years before the onset of clinical disease, suggesting that checkpoints modulating autoantibody pathology must be in place. Among these potential immune checkpoints, modulation of autoantibody activity via IgG glycosylation or altering the expression of activating versus inhibitory Fcg-receptors on innate immune effector cells may play a key role to switch autoantibodies from a non-pathogenic to a pathogenic form. Thus, the central aim of project B2 was to decipher the molecular and cellular changes occurring during the early phase of the disease in a spontaneous mouse model of inflammatory arthritis (KBxN mice). By broadly analysing changes in humoral and cellular immune function during the indolent and early phase of the disease our study generated a highly detailed, time-resolved map of the molecular and cellular changes during the pre- and early phase of inflammatory arthritis. We demonstrate that the appearance of GPI specific autoantibodies was preceded by a global change of serum glycosylation towards pro-inflammatory glycoforms and an expansion of plasma cells before the onset of joint inflammation. The change in serum IgG glycosylation was paralleled or even preceded by waves of pro-inflammatory cytokines including IL1, IL17, and IL27, while TNF and IL-6 levels were increasing steadily and closely correlated with intensifying clinical disease. In line with the early increase in IL1 an increased expression CD54 (ICAM-1) was noted on T cells and inflammatory monocytes before disease initiation, while changes in FcR expression occurred only during active disease. Based on the results of the first funding period we will focus on identifying which of these early changes in immune system function play a key role in orchestrating the later phases of disease during the second funding period. In addition, we will continue to use the clinical samples and develop a humanized mouse model to translate our findings to the human immune system.

• DFG Programme: Research Units
• Subproject of: FOR 2886: PANDORA - Pathways triggering AutoimmuNity and Defining Onset of early Rheumatoid Arthritis