Complement Activation by Post‐Translationally Modified Proteins: Links to Chronic Inflammation and Autoimmunity

Immunological Reviews, vol. 342, pp. e70166

Abstract

Post-translational modifications (PTMs) of proteins are essential to maintain homeostasis as many cellular processes rely on reversible PTMs. However, several PTMs, particularly irreversible PTMs in the extracellular space, can contribute to tissue dysfunction, inflammation, and may even trigger the development of autoimmunity against PTM-proteins. Such disease-associated PTMs are formed under conditions of metabolic stress, renal failure, smoking, or pollutants. Importantly, several of these PTMs have recently been shown to have the capacity to activate the complement system directly. These PTMs recruit C1q or Ficolin-3, thereby initiating complement activation. This induces on the one hand opsonins for clearance of (cellular) debris and on the other hand the production of inflammatory mediators. In many autoimmune diseases, patients develop a variety of autoantibodies against PTMs, further amplifying complement activation on PTM-proteins. Notably, anti-PTM antibodies are also present, albeit in lower concentrations, in diseases that are not characterized as typical autoimmune diseases. We therefore hypothesize that PTM-driven complement activation is an underlying factor for chronic low-level inflammation, thereby predisposing individuals to cardiovascular and metabolic diseases. In addition, the presence of complement activation fragments on PTM-proteins may facilitate the breakdown of immune tolerance towards PTM-proteins, further facilitating the production of anti-PTM autoantibodies. Finally, several interventions are discussed that either decrease the PTM-proteins or provide targeted complement inhibition specifically on PTM-proteins. Altogether, complement activation by PTM-proteins may represent an underestimated contributor to chronic inflammation.

Authors 2

1. Marleen M. J. van Greevenbroek

   Maastricht University

   Affiliation as printed

   Cardiovascular Research Institute Maastricht CARIM Maastricht University Maastricht the Netherlands

   Department of Internal Medicine Maastricht University Maastricht the Netherlands

2. Leendert Adrianus Trouw corresponding Aachen Department of Immunology Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology Leiden University Medical Center Leiden the Netherlands