ReviewComplement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management
Introduction
The complement system is a highly conserved part of the innate immune system (Merle et al., 2015). More than 50 soluble and membrane-bound proteins are involved in a complex mode of activation, serve as regulators or receptors (Ricklin et al., 2010). Upon activation complement significantly contributes to immune surveillance and homeostasis. Complement-mediated opsonisation, as well as the recruitment and activation of inflammatory cells leads to the cytotoxic destruction of microbial pathogens. Complement bridges the innate and adaptive immunity by augmenting the antibody response and supporting the immunological memory. Disposal of waste is mediated through effective clearance of apoptotic cells, cell debris, and immune complexes (Flierman and Daha, 2007). Furthermore, complement has been associated with early embryonic development and tissue repair (Mastellos et al., 2013; Stephan et al., 2012). Multiple interactions exist between the coagulation, fibrinolytic and complement systems where enzymes can cleave and activate one another (Foley, 2016; Oikonomopoulou et al., 2012). This provides a good explanation why many complement-driven diseases (e.g. PNH, aHUS, CHAPLE syndrome) express thrombosis as a hallmark of clinical manifestation (Baines and Brodsky, 2017).
Complement is activated via three distinct enzymatic pathways, the classical, alternative and lectin pathways (Merle et al., 2015; Ricklin et al., 2010). Each of these converge towards the cleavage of the central component C3, followed by the formation of a C5 convertase, which initiates the formation of the lytic membrane attack complex (MAC; terminal complement complex (TCC; C5b-9n) that destroys or damages targeted cells.
The proinflammatory anaphylatoxins C3a and C5a, released upon the activation of C3 and C5, act as potent chemotactic fragments, recruiting immune cells to the site of activation and prime them. Neutrophils and macrophages recognize C3-derived opsonins (C3b, iC3b) on the tagged particles by complement receptors (CR) 1 (CD35) and 3 (CD11b/CD18) and mediate their effective phagocytic removal.
Multiple soluble and membrane-bound regulatory proteins are required that act to prevent complement-mediated damage to the host (Zipfel and Skerka, 2009).
A broad spectrum of clinical disorders is associated either with complement deficiencies or – even more prevalent – with an overactivated and / or dysregulated complement system (Hajishengallis et al., 2017; Ricklin et al., 2017; Thurman and Holers, 2006).
In this review, we wished to address clinical disorders associated with the various forms of complement abnormalities going beyond classical complement protein deficiencies, by including also mutations leading to loss- or gain-of-function of complement proteins but also clinical relevant autoantibodies mimicking primary defects by their stabilizing or blocking properties.
Section snippets
Complement deficiencies
Complement deficiencies can be either primary (hereditary) or acquired (Figueroa and Densen, 1991; Pettigrew et al., 2009; Grumach and Kirschfink, 2014). The mode of inheritance is usually autosomal recessive (exception: properdin deficiency: X-linked) where heterozygous carriers usually remain clinically silent. They need to be identified through accurate medical history and extended laboratory analysis of the entire family (Botto et al., 2009).
Complete defects are described for virtually all
Clinical and laboratory assessment of complement abnormalities
Recognition of the following warning signs may help clinicians in the diagnosis of complement deficiencies (Grumach and Kirschfink, 2014):
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Meningococcal meningitis at >5 years of age
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Recurrent systemic bacterial infections with encapsulated organisms (particularly S. pneumoniae and more rarely gonococcal disease)
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Autoimmune diseases (particularly SLE)
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Angioedema without urticaria
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Inflammatory disorders involving the kidney or eyes
Conclusions
In recent years, the spectrum of clinical disorders associated with complement deficiencies and dysregulation has been expanding. An in-depth knowledge of their pathophysiology, clinical phenotypes and their diagnostic evaluation will be helpful for clinicians in order to timely identify complement deficient patients. Recently discovered complement deficiencies such as the CHAPEL syndrome and the 3MC syndrome shed new light on the importance of complement in organ-specific severe inflammatory
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