Heterozygous and homozygous factor H deficiency states in a Dutch family

Fijen, C. A. P.; Kuijper, E. J.; Bulte, M T te; Heuvel, M. M. Van De; Holdrinet, A.; Sim, R. B.; Daha, Mohamed R.; Dankert, J.

doi:10.1046/j.1365-2249.1996.d01-777.x

Cited by 49 publications

(31 citation statements)

References 29 publications

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“…In both humans (9) and mice (39), the factor I-mediated cleavage of fluid-phase C3b in vitro does not occur in the absence of a cofactor such as factor H. Hence, the presence of C3b metabolites in factor H-deficient human sera is most likely a consequence of alternative factor I cofactors in circulation. These include CR1 on erythrocytes (36,37), plasma factor H-like protein 1 (38), and plasma factor H-related protein 5 (40). Our data demonstrated that there was no evidence of C3b fragments in EDTA plasma in mice with factor I deficiency, irrespective of the factor H genotype.…”

Section: Discussionmentioning

confidence: 56%

“…In factor I-deficient individuals, plasma C3 circulates predominantly as C3b, while C3b metabolites such as C3dg are not detectable in plasma (13). In contrast, studies of humans with complete absence of factor H have demonstrated that iC3b (36), C3c (37), and C3dg (37,38) are present in the circulation in addition to C3dg present on erythrocytes (25). In both humans (9) and mice (39), the factor I-mediated cleavage of fluid-phase C3b in vitro does not occur in the absence of a cofactor such as factor H. Hence, the presence of C3b metabolites in factor H-deficient human sera is most likely a consequence of alternative factor I cofactors in circulation.…”

Section: Discussionmentioning

confidence: 99%

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Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Rose¹,

Paixão-Cavalcante²,

Fish³

et al. 2008

J. Clin. Invest.

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The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I-mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Rose¹,

Paixão-Cavalcante²,

Fish³

et al. 2008

J. Clin. Invest.

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“…Recurrent Neisseria meningitidis infection with C3 hypocomplementemia and positive C3NeF have also been reported in a patient who did not have APL or MPGN 168,169 . Meningococcal meningitis has also been described in a patient with familial factor H deficiency with C3 hypocomplementemia 51 . Low C3 levels may impair complementmediated phagocytosis 54 and bacterial killing.…”

Section: Susceptibility To Infectionsmentioning

confidence: 97%

Clinical Features and Metabolic and Autoimmune Derangements in Acquired Partial Lipodystrophy

Misra

Peethambaram

Garg³

2004

Medicine

257

252

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We describe clinical features, body fat distribution, and prevalence of metabolic abnormalities in 35 patients with acquired partial lipodystrophy (APL) seen by us over 8 years, and also review 220 cases of APL described in the literature. Based on the review and our experience, we propose that the essential diagnostic criterion for APL is the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. Analysis of the pooled data revealed that female patients were affected approximately 4 times more often than males. The median age of the onset of lipodystrophy was 7 years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Approximately 83% of APL patients had low complement (C) 3 levels and the presence of polyclonal immunoglobulin C3 nephritic factor. Twenty-two percent of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of approximately 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 +/- 10.3 yr vs 7.7 +/- 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02). The pathogenesis of fat loss and MPGN in patients with APL remains unclear, but activation of an alternate complement pathway has been implicated. Treating the cosmetic disfigurement by surgical procedures has yielded inconsistent results. The use of thiazolidinediones to treat fat loss in patients with APL remains anecdotal. Prognosis is mainly determined by renal insufficiency due to MPGN.

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“…Complete deficiency of factor H is also associated with an increased incidence of infections, including recurrent otitis media and bronchitis (250), H. influenzae otitis media (445), and invasive disease with N. meningitidis (groups B and X) (133,320). About half of the reported patients with factor H deficiency do not have infectious complications.…”

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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Heterozygous and homozygous factor H deficiency states in a Dutch family

Cited by 49 publications

References 29 publications

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Clinical Features and Metabolic and Autoimmune Derangements in Acquired Partial Lipodystrophy

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

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