High C5a levels are associated with increased mortality in sepsis patients — No enhancing effect by actin-free Gc-globulin
Introduction
The complement system is part of the innate immune system. It promotes the inflammatory response, eliminates pathogens, and enhances the immune response.
The complement cascade consists of 3 separate pathways that converge resulting in the cleavage of complement factor 5 (C5) to its activated form, C5a, and in the formation of the membrane attack complex (MAC). The MAC exerts powerful killing activity by creating perforations in cellular membranes [1]. Under physiological conditions, relatively low C5a levels are present that promote positive effects on the priming of neutrophils and monocytes as well as on the activation of endothelial cells, supporting efficient innate immune responses in the case of infections [2]. In sepsis, excessive systemic C5a levels have been reported that are associated with the exhaustion of the monocytic and granulocytic response or direct detrimental effects on endothelial cells [2]. The possible dysregulation of serum C5a binding to its proposed binding partners during sepsis or critical illness have not been defined at present.
Group-specific component globulin (Gc-globulin) [3], also known as vitamin D-binding protein (DBP), is a multifunctional plasma protein with a relative molecular mass of 51–58 kDa and belongs to the albumin superfamily of binding proteins, which also includes albumin, α-fetoprotein, and afamin [4]. One well-recognized function of Gc-globulin is to act as a carrier protein for vitamin D and its plasma metabolites, but at least equally important is its ability to bind extracellular actin released into the circulation following necrotic cell destruction and, thus, to protect against disseminated intravascular coagulation induced by polymerized forms of actin [5].
Previous in vitro studies localized a C5a binding region in the Gc-globulin protein between amino acid residues 126 and 175. This common sequence is identical among the 3 major isoforms of Gc-globulin (Gc-1F, Gc-1S, and Gc-2) [6]. While a direct interaction of Gc-globulin with C5a at its receptor was disproved by experiments demonstrating that Gc-globulin does not alter the affinity of C5a for the C5a receptor [7], it was shown that Gc-globulin co-localizes with both CD44 and annexin A2 receptors on the cell surface and, thus, may use these receptors for interaction with C5a [8]. CD44 and annexin A2 receptors are widely expressed on the surface of many cell types, including most leukocytes [9], [10]. Based on these findings, it was proposed that particularly the cell-associated form of Gc-globulin present on the plasma membrane of diverse cell types, also exerts immunomodulatory functions through enhancing C5a-dependent chemotactic activity, primarily on monocytes and neutrophils [11], [12].
The aim of this study was to investigate the predictive value of serum concentrations of C5a and actin-free Gc-globulin as well as their ratio in the assessment of severity of disease and of overall prognosis (mortality) of critically ill patients (septic and non-septic) upon admission to the ICU. In particular, we focussed on examining a possible positive interaction between both parameters.
Section snippets
Study design
The study population consisted of 154 patients (98 male, 56 female, with a median age of 63 years; range 18–86 years) who were admitted to the General Internal Medicine ICU at the University Hospital of the RWTH Aachen, Germany (Table 1A, Table 1B). Patients that were expected to stay < 72 h at the ICU (e.g. post-interventional observation, acute intoxication) were not asked to participate in this study. Written informed consent was obtained from each participant or his/her spouse, and the study
Characteristics of the study population
Of the 154 patients enrolled, 112 (73%) met the criteria for bacterial sepsis (13). The sepsis population consisted of 73 males and 39 females, with a median age of 64 years (Table 1A). In the majority of sepsis patients, the site of infection was pneumonia (Table 1B). Non-sepsis patients did not differ with respect to age or sex and were admitted to the ICU due to cardiopulmonary disorders (myocardial infarction, pulmonary embolism), decompensated liver cirrhosis or other critical conditions (
Discussion
Several in vitro studies point to a positive pathophysiological interaction between the vitamin D carrier and actin-scavenger Gc-globulin and the complement component C5a [6], [7], [8], [11], [12]. In this study, we investigated not just the individual diagnostic and prognostic value of both parameters in septic and non-septic patients both at ICU and during follow-up, but also tested actin-free Gc-globulin for its ability to enhance the C5a impact on severity of inflammatory disease in vivo
Acknowledgments
The authors thank Amelie Behn and Ilknur Hasdemir for their excellent assistance in conducting this study as part of their MD thesis. This work was supported by the German Research Foundation (DFG Ta 434/2-1) and the Interdisciplinary Centre for Clinical Research “BIOMAT.” within the faculty of Medicine at the RWTH Aachen University (to FT).
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The authors contributed equally to this manuscript.