Elsevier

Molecular Immunology

Volume 114, October 2019, Pages 299-311
Molecular Immunology

Review
Complement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management

https://doi.org/10.1016/j.molimm.2019.08.002Get rights and content

Highlights

  • Complement deficiencies are increasingly recognized and present an unexpected wide spectrum of diseases.

  • Modern comprehensive complement analysis allows early detection of complement deficiencies.

  • Advanced molecular analysis sheds new light on the importance of complement in organ-specific severe inflammatory disorders and even developmental processes.

Abstract

Complement defects are associated with an enhanced risk of a broad spectrum of infectious as well as systemic or local inflammatory and thrombotic disorders. Inherited complement deficiencies have been described for virtually all complement components but can be mimicked by autoantibodies, interfering with the activity of specific complement components, convertases or regulators. While being rare, diseases related to complement deficiencies are often severe with a frequent but not exclusive manifestation during childhood. Whereas defects of early components of the classical pathway significantly increase the risk of autoimmune disorders, lack of components of the terminal pathway as well as of properdin are associated with an enhanced susceptibility to meningococcal infections. The impaired synthesis or function of C1 inhibitor results in the development of hereditary angioedema (HAE). Furthermore, complement dysregulation causes renal disorders such as atypical hemolytic uremic syndrome (aHUS) or C3 glomerulopathy (C3G) but also age-related macular degeneration (AMD). While paroxysmal nocturnal hemoglobinuria (PNH) results from the combined deficiency of the regulatory complement proteins CD55 and CD59, which is caused by somatic mutation of a common membrane anchor, isolated CD55 or CD59 deficiency is associated with the CHAPLE syndrome and polyneuropathy, respectively. Here, we provide an overview on clinical disorders related to complement deficiencies or dysregulation and describe diagnostic strategies required for their comprehensive molecular characterization – a prerequisite for informed decisions on the therapeutic management of these disorders.

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):

  • Meningococcal meningitis at >5 years of age

  • Recurrent systemic bacterial infections with encapsulated organisms (particularly S. pneumoniae and more rarely gonococcal disease)

  • Autoimmune diseases (particularly SLE)

  • Angioedema without urticaria

  • 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

References (196)

  • S.R. de Cordoba

    Complement genetics and susceptibility to inflammatory disease. Lessons from genotype-phenotype correlations

    Immunobiology

    (2016)
  • M.A. Dragon-Durey et al.

    Autoantibodies against complement components and functional consequences

    Mol. Immunol.

    (2013)
  • C.A. Fijen et al.

    Complement deficiencies in patients over ten years old with meningococcal disease due to uncommon serogroups

    Lancet

    (1989)
  • R. Flierman et al.

    The clearance of apoptotic cells by complement

    Immunobiology

    (2007)
  • D.P. Gale et al.

    Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis

    Lancet

    (2010)
  • M.I. Garcia-Laorden et al.

    Low clinical penetrance of mannose-binding lectin-associated serine protease 2 deficiency

    J. Allergy Clin. Immunol.

    (2006)
  • M.J. Geerlings et al.

    The complement system in age-related macular degeneration: a review of rare genetic variants and implications for personalized treatment

    Mol. Immunol.

    (2017)
  • A.S. Grumach et al.

    Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach

    Mol. Immunol.

    (2014)
  • S. Heitzeneder et al.

    Mannan-binding lectin deficiency - Good news, bad news, doesn’t matter?

    Clin. Immunol.

    (2012)
  • M.L. Hibberd et al.

    Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease

    Meningococcal Research Group. Lancet

    (1999)
  • T. Hummelshoj et al.

    Comparative study of the human ficolins reveals unique features of Ficolin-3 (Hakata antigen)

    Mol. Immunol.

    (2008)
  • S.S. Jamuar et al.

    Somatic mosaicism and neurological diseases

  • M. Jozsi et al.

    Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome

    Blood

    (2007)
  • T. Kinoshita

    Congenital defects in the expression of the glycosylphosphatidylinositol-anchored complement regulatory proteins CD59 and decay-accelerating factor

    Semin. Hematol.

    (2018)
  • M. Konar et al.

    Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults

    Blood

    (2017)
  • E. Lebel et al.

    Post-eculizumab meningococcaemia in vaccinated patients

    Clin. Microbiol. Infect.

    (2018)
  • M. Levi et al.

    Hereditary angioedema: linking complement regulation to the coagulation system

    Res Pract Thromb Hemost

    (2019)
  • C. Licht et al.

    Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II)

    Kidney Int.

    (2006)
  • E. Almarza Novoa et al.

    Leukocyte adhesion deficiency-I: a comprehensive review of all published cases

    J. Allergy Clin. Immunol. Pract.

    (2018)
  • F.A. Andrade et al.

    Association of a new FCN3 haplotype with high ficolin-3 levels in leprosy

    PLoS Negl. Trop. Dis.

    (2017)
  • J. Andreoni et al.

    Vaccination and the role of capsular polysaccharide antibody in prevention of recurrent meningococcal disease in late complement component deficient individuals

    J. Infect. Dis.

    (1993)
  • G.B. Appel et al.

    Membranoproliferative glomerulonephritis type II (dense deposit disease): an update

    J. Am. Soc. Nephrol.

    (2005)
  • K. Azukaitis et al.

    The phenotypic Spectrum of nephropathies associated with mutations in diacylglycerol kinase epsilon

    J. Am. Soc. Nephrol.

    (2017)
  • E. Ballanti et al.

    Complement and autoimmunity

    Immunol. Res.

    (2013)
  • N.A. Bishof et al.

    C4B deficiency: a risk factor for bacteremia with encapsulated organisms

    J. Infect. Dis.

    (1990)
  • S. Blazina et al.

    Functional complement analysis can predict genetic testing results and long-term outcome in patients with complement deficiencies

    Front. Immunol.

    (2018)
  • M. Bock et al.

    Anti-C1q antibodies as a follow-up marker in SLE patients

    PLoS One

    (2015)
  • A.B. Boldt et al.

    Leprosy association with low MASP-2 levels generated by MASP2 haplotypes and polymorphisms flanking MAp19 exon 5

    PLoS One

    (2013)
  • A.B. Boldt et al.

    Susceptibility to leprosy is associated with M-ficolin polymorphisms

    J. Clin. Immunol.

    (2013)
  • K. Bork et al.

    Treatment with C1-esterase inhibitor concentrate in type I or II hereditary angioedema: a systematic literature review

    Allergy Asthma Proc.

    (2013)
  • M. Bottermann et al.

    Complement C4 Prevents Viral Infection through Capsid Inactivation

    Cell Host Microbe

    (2019)
  • A. Bousfiha et al.

    The 2017 IUIS phenotypic classification for primary immunodeficiencies

    J. Clin. Immunol.

    (2018)
  • I. Brandslund et al.

    Plasma concentrations of complement split product C3d and immune complexes after procainamide induced production of antinuclear antibodies

    Acta Med. Scand.

    (1986)
  • M.T. Brady et al.

    Recommendations for serogroup B meningococcal vaccine for persons 10 years and older

    Pediatrics

    (2016)
  • S. Caccia et al.

    Pathophysiology of hereditary angioedema

    Pediatr. Allergy Immunol. Pulmonol.

    (2014)
  • M.C. Carroll

    A protective role for innate immunity in systemic lupus erythematosus

    Nat. Rev. Immunol.

    (2004)
  • K.L. Cates et al.

    C4B deficiency is not associated with meningitis or bacteremia with encapsulated bacteria

    J. Infect. Dis.

    (1992)
  • G. Choi et al.

    Recombinant human C1-inhibitor in the treatment of acute angioedema attacks

    Transfusion

    (2007)
  • M. Cicardi et al.

    Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema

    N. Engl. J. Med.

    (2010)
  • P. Conigliaro et al.

    Complement, infection, and autoimmunity

    Curr. Opin. Rheumatol.

    (2019)
  • Cited by (0)

    View full text