A family with complement factor D deficiency

Biesma, Douwe H.; Hannema, André J.; Velzen‐Blad, Heleen van; Mulder, Leontine; Zwieten, Rob van; Kluijt, Irma; Roos, Dirk

doi:10.1172/jci200112023

Cited by 90 publications

(42 citation statements)

References 22 publications

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“…2). Moreover, we note that there are no reports of 3MC patients who suffer from infections by Gram-negative bacteria (28,29,37,50), whereas FD-deficient patients are known to be prone to recurrent Gramnegative bacterial infections (14,(51)(52)(53). This may suggest that the MASP-3-independent maturation of pro-FD provides sufficient AP activity to protect against these pathogens.…”

Section: Discussionmentioning

confidence: 86%

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Pihl

Jensen

Hansen

et al. 2017

The Journal of Immunology

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Factor D (FD), which is also known as adipsin, is regarded as the first-acting protease of the alternative pathway (AP) of complement. It has been suggested that FD is secreted as a mature enzyme that does not require subsequent activation. This view was challenged when it was shown that mice lacking mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation. However, the necessity of MASP-3 for pro-FD cleavage has been questioned, because AP activity is still observed in sera from MASP-1/3-deficient Malpuech-Michels-Mingarelli-Carnevale (3MC) patients. The identification of a novel 3MC patient carrying a previously unidentified MASP-3 G665S mutation prompted us to develop an analytical isoelectric focusing technique that resolves endogenous FD variants in complex samples. This enabled us to show that although 3MC patients predominantly contain pro-FD, they also contain detectable levels of mature FD. Moreover, using isoelectric focusing analysis, we show that both pro-FD and FD are present in the circulation of healthy donors. We characterized the naturally occurring 3MC-associated MASP-3 mutants and found that they all yielded enzymatically inactive proteins. Using MASP-3-depleted human serum, serum from 3MC patients, and mice, we found that lack of enzymatically active MASP-3, or complete MASP-3 deficiency, compromises the conversion of pro-FD to FD. In summary, our observations emphasize that MASP-3 acts as an important maturase in the AP of complement, while also highlighting that there exists MASP-3-independent pro-FD maturation in 3MC patients.

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Section: Discussionmentioning

confidence: 86%

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Pihl

Jensen

Hansen

et al. 2017

The Journal of Immunology

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“…The most well studied family cluster of factor D deficiency in the Netherlands, with 21 heterozy-gotes available for study, describes low normal factor D levels and no clinical disease in heterozygotes, supporting autosomal recessive inheritance. 87 Clinical disease from factor D deficiency occurs from a lack of alternative pathway hemolytic activity and greatly reduced opsonization of encapsulated bacteria. 3 Invasive meningococcal infections have been seen in multiple individuals with factor D deficiency.…”

Section: Factor B Deficiencymentioning

confidence: 99%

“…3 Invasive meningococcal infections have been seen in multiple individuals with factor D deficiency. [87][88][89] Risk of infection with E. coli and Streptococcus pneumoniae is also increased. Factor D deficiency has not been associated with autoimmunity.…”

Section: Factor B Deficiencymentioning

confidence: 99%

Clinical Significance of Complement Deficiencies

Pettigrew

Teuber

Gershwin

2009

Annals of the New York Academy of Sciences

134

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The complement system is composed of more than 30 serum and membrane-bound proteins, all of which are needed for normal function of complement in innate and adaptive immunity. Historically, deficiencies within the complement system have been suspected when young children have had recurrent and difficult-to-control infections. As our understanding of the complement system has increased, many other diseases have been attributed to deficiencies within the complement system. Generally, complement deficiencies within the classical pathway lead to increased susceptibility to encapsulated bacterial infections as well as a syndrome resembling systemic lupus erythematosus. Complement deficiencies within the mannose-binding lectin pathway generally lead to increased bacterial infections, and deficiencies within the alternative pathway usually lead to an increased frequency of Neisseria infections. However, factor H deficiency can lead to membranoproliferative glomerulonephritis and hemolytic uremic syndrome. Finally, deficiencies within the terminal complement pathway lead to an increased incidence of Neisseria infections. Two other notable complement-associated deficiencies are complement receptor 3 and 4 deficiency, which result from a deficiency of CD18, a disease known as leukocyte adhesion deficiency type 1, and CD59 deficiency, which causes paroxysmal nocturnal hemoglobinuria. Most inherited deficiencies of the complement system are autosomal recessive, but properidin deficiency is X-linked recessive, deficiency of C1 inhibitor is autosomal dominant, and mannose-binding lectin and factor I deficiencies are autosomal co-dominant. The diversity of clinical manifestations of complement deficiencies reflects the complexity of the complement system.

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“…The extent of complement inhibition defines the risk of infection; complete absence of a complement component greatly enhances the predisposition to infection, exemplified by individuals with congenital complement deficiencies (1). In contrast, subtotal complement deficiencies are associated with a lower risk of infection (52)(53)(54). Titrating complement inhibition to a level that controls disease symptoms yet provides enough complement activity to combat infections may substantially reduce the risk of infection, as opposed to completely blocking complement function.…”

Section: Discussionmentioning

confidence: 99%

Effect of a C1s Inhibitor on the Efficacy of Anti-Capsular Antibodies againstNeisseria meningitidisandStreptococcus pneumoniae

Lewis

Panicker²,

DeOliveira

et al. 2019

ImmunoHorizons

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Terminal complement pathway inhibition at the level of C5 alleviates symptoms of several diseases associated with complement overactivation. However, C5 blockade is associated with an increased risk of invasive meningococcal disease despite immunization. Targeting specific complement pathways proximal to C5 provides the theoretical advantage of leaving the other pathways (including the terminal pathway) intact for immune surveillance. We aimed to address the risk of Neisseria meningitidis and Streptococcus pneumoniae infections when inhibiting the classical pathway (CP) using a specific C1s inhibitor (TNT005). Addition of TNT005 to 20% normal human serum that contained anti-meningococcal capsular Ab decreased C4 deposition 8-fold and abrogated killing of N. meningitidis, despite leaving C3 deposition intact. TNT005 impaired killing of N. meningitidis in 78% nonimmune human plasma and 78% whole blood but permitted killing in both when specific anti-capsular Ab was added. Simultaneously inhibiting both the CP and alternative pathway (AP) blocked killing of Ab-coated N. meningitidis in whole blood. Blocking the AP alone abrogated C3 deposition, whereas TNT005 only partially inhibited (;40% decrease) C3 deposition on S. pneumoniae coated with anti-capsular Ab. Blocking either the CP or AP alone did not impair killing of pneumococci in whole blood containing specific Ab (,10% survival at 3 h); however, blocking both pathways resulted in ;35% bacterial survival. These data suggest that killing of N. meningitidis or S. pneumoniae in whole blood containing specific anti-capsular Abs is unimpeded by TNT005. Meningococcal and pneumococcal capsular conjugate vaccines may mitigate risk of these infections in patients receiving C1s inhibitors.

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A family with complement factor D deficiency

Cited by 90 publications

References 22 publications

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Clinical Significance of Complement Deficiencies

Effect of a C1s Inhibitor on the Efficacy of Anti-Capsular Antibodies againstNeisseria meningitidisandStreptococcus pneumoniae

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