Molecular basis of hereditary C3 deficiency.

Botto, Marina; Fong, Kok Yong; So, Alex; Rudge, A.; Walport, Mark J.

doi:10.1172/jci114821

Cited by 69 publications

(24 citation statements)

References 32 publications

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“…Infections tend to be recurrent and severe. Invasive infections (meningitis, bacteremia, pneumonia, and otitis media) with S. pneumoniae, N. meningitidis, and H. influenzae have been reported (41,43,119,132,172,184,340,386,451).…”

Section: Inherited Deficiencies Of Complement Activationmentioning

confidence: 99%

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010

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SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

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Section: Inherited Deficiencies Of Complement Activationmentioning

confidence: 99%

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010

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“…20 Following the description of the genomic structure of C3 in 1990, 21 a molecular basis for C3 deficiency was first described. 22 Subsequently, inherited C3 deficiency has been identified in 19 families (reviewed in Reis et al 23 ) and the underlying molecular mechanism established in 8 of these. In this study we have identified 9 heterozygous mutations in C3.…”

Section: Org Frommentioning

confidence: 99%

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome

Frémeaux‐Bacchi

Miller

Liszewski

et al. 2008

Blood

360

311

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Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation.In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have dem- IntroductionMutations in the genes encoding the complement regulators factor H, 1-6 factor I, 7,8 and membrane cofactor protein (MCP; CD46), 9,10 as well as in the activating component factor B, 11 have been detected in approximately 50% of patients with atypical hemolytic uremic syndrome (aHUS). 12 A proportion of the remaining patients have persistently low serum levels of C3. In this study we have examined the hypothesis that mutations in the gene encoding C3 could be associated with aHUS in these patients.C3 is the pivotal component of the complement system. 13 Activation of the classical, lectin, and alternative pathways results in cleavage of C3 to generate C3b and the anaphylatoxin C3a. When C3b is produced, the thioester is cleaved, and then this highly reactive species may bind covalently to targets. Interaction of the zymogen factor B with C3b and subsequent cleavage of factor B by factor D results in formation of the alternative pathway C3 convertase C3bBb. This set of reactions represents an amplification loop.A series of complement regulators including factor H and MCP prevent feedback via this loop by increasing the rate of dissociation of C3bBb and/or by serving as cofactors for the serine protease factor I to cleave C3b. Mutations in the gene encoding factor B were recently found to enhance formation of C3bBb or increase resistance to inactivation. 11 The importance of C3 as a susceptibility factor for human disease has been emphasized by recent studies documenting that a common nonsynonymous coding change in C3 (rs2230199, Arg80Gly, corresponding to C3S and C3F) is both a susceptibility factor for age-related macular degeneration 14 and associated with long-term renal allograft survival. 15 Methods SubjectsIn 2 independent cohorts of aHUS patients (Paris, France and Newcastle upon Tyne, United Kingdom), 26 patients (17 Paris, 9 Newcastle) with a serum C3 level persistently below the lower end of the normal range of 680 to 1380 mg/L were identified. In these patients functionally significant mutations in CFH, MCP, CFI, and CFB had not previously been detected. Mutation screening of C3 was undertaken in these patients.Approval for this study was obtained from the Departement de la Rechereche Clinique et du Developement, DRRC Ile de France, France and the Northern and Mutation screeningThe coding sequence of C3 was amplified with flanking primers (Table S1, available on the Blood website; see the Supplemental Materials link at the top of the online article). Direct sequencing was undertaken using a 96-capillary Sequencer 3700 (Applied Biosyst...

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“…Failure to use the normal splice site resulted in the use of a cryptic site within the adjacent downstream exon, leading to an internal deletion and frameshift in the mRNA. Use of the altered reading frame generated a premature stop codon downstream from the cryptic splice site and resulted in the production of a truncated nonfunctional C3 protein (36).…”

Section: Microbial Interactions With Complementmentioning

confidence: 99%

Infectious diseases associated with complement deficiencies

1991

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The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

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Molecular basis of hereditary C3 deficiency.

Cited by 69 publications

References 32 publications

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome

Infectious diseases associated with complement deficiencies

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