Complete and partial deficiencies of complement factor D in a Dutch family.

Hiemstra, Pieter S.; Langeler, E.; Compier, B.; Keepers, Y.; Leijh, P. C. J.; Barselaar, M. T. Van Den; Overbosch, David; Daha, M. R.

doi:10.1172/jci114384

Cited by 84 publications

(61 citation statements)

References 17 publications

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“…Furthermore, as fD-depleted serum is totally devoid of alternative pathway activity, and as rMASP-3 does not boost alternative pathway activity in MASP1 2/2 serum above normal levels, we find no evidence in humans of a suggested fD bypass pathway (7) mediated by direct cleavage of fB by MASP-3. This is in agreement with observations that fDdeficient individuals have no detectable alternative pathway activity (42,43). Notably, fD-deficient mice also are reported to have no appreciable alternative pathway activity (44).…”

Section: Discussionsupporting

confidence: 93%

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Degn

Jensen

Hansen

et al. 2012

The Journal of Immunology

142

152

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The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.

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Section: Discussionsupporting

confidence: 93%

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Degn

Jensen

Hansen

et al. 2012

The Journal of Immunology

142

152

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“…Our findings are consistent with a recent report of pneumococcal sepsis and meningitis in a factor D-deficient neonate (41). Factor D deficiency has also been reported in adult patients (42,43). In the most recent case (43), a factor D-deficient individual had a severe Neisseria meningitidis infection and his serum showed a very low capacity in opsonization of Escherichia coli and N. meningitidis for phagocytosis by normal granulocytes.…”

Section: Discussionsupporting

confidence: 92%

Complement activation in factor D-deficient mice

Ippolito

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

173

158

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To assess the contribution of the alternative pathway in complement activation and host defense and its possible role in the regulation of systemic energy balance in vivo, factor D-deficient mice were generated by gene targeting. The mutant mice have no apparent abnormality in development and their body weights are similar to those of factor D-sufficient littermates. Complement activation could not be initiated in the serum of deficient mice by the alternative pathway activators rabbit erythrocytes and zymosan. Surprisingly, injection of cobra venom factor (CVF) caused a profound and reproducible reduction in serum C3 levels, whereas, as expected, there was no C3 reduction in factor B-deficient mice treated similarly. Studies of C3 and factor B activation in vitro by CVF demonstrated that in factor D-deficient serum the ␣ chain of C3 was cleaved gradually over a period of 60 min without detectable cleavage of factor B. CVF-dependent C3 cleavage in the deficient serum required the presence of Mg 2؉ , whereas in normal mouse serum the presence of divalent cations was not required. These results suggest that in mouse proteolytic cleavage of factor B by factor D is not an absolute requirement for the zymogen to active enzyme conformational transition of CVF-bound factor B. Kinetics of opsonization of Streptococcus pneumoniae by C3 fragments was much slower in factor D-deficient serum, suggesting a significant contribution of the alternative pathway to antibacterial host defense early after infection. T he alternative pathway (AP) of complement activation is a self-amplifying mechanism important for pathogen recognition and elimination in the absence of specific antibodies. The AP also amplifies complement activation initiated by the other two pathways of complement activation, classical and lectin (1). The dual function (recognition and amplification) of the AP underlines its importance for host defense against pathogens. The proximal result of complement activation is the formation of convertases, enzymes that activate C3 and C5, generating biologically active protein fragments and complexes (1). In the AP, assembly of the C3͞C5 convertase requires the initial attachment of the C3b fragment of C3 to the surface of a pathogen and proceeds through the formation of a complex with factor B (C3bB) and the subsequent cleavage of factor B by factor D to form C3bBb, the C3͞C5 convertase of the AP.Mouse factor D was initially recognized as a serine protease encoded by a differentiation-specific message present mainly in adipocytes and cells of the nervous system (2). Because its mRNA was significantly reduced in mouse and rat models of obesity, it was thought that the protein was involved in fat metabolism (3). These observations led to naming the protein adipsin, which soon was identified with mouse factor D (4). Subsequently it was demonstrated that adipocytes also synthesize and secrete C3 and factor B, leading to the formation of a C3 convertase in culture supernatants (5). Other results indicated that C3a desArg , the ...

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“…Instead, impaired global complement activity in a sporadic case of Neisseria meningitis led to the discovery of defects in C6 and C8 activity in 1976 (33,34) and, two decades later, to the identification of mutations of the C6, C8B, and C8A genes. Likewise, defective factor D activity was first reported in a sporadic case of meningitis in 1989 (35), and the first causal mutation for this condition was described a decade later. C5 and C9 defects were first identified in 1976 and 1981, in a lupus patient and a healthy individual, respectively (36,37).…”

Section: A Neglected Connection: Neisseria and Complementmentioning

confidence: 95%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

201

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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Complete and partial deficiencies of complement factor D in a Dutch family.

Cited by 84 publications

References 17 publications

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Complement activation in factor D-deficient mice

Severe infectious diseases of childhood as monogenic inborn errors of immunity

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