Deficiency in Complement Factor B

Slade, Charlotte; Bosco, Julian J.; Unglik, Gary; Bleasel, Karl; Nagel, Mato; Winship, Ingrid

doi:10.1056/nejmc1306326

Cited by 52 publications

(26 citation statements)

References 4 publications

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“…* P < 0.05; by one way ANOVA using Bartlett's test. but no history of any autoimmune disorder (Botto et al, 2009;Slade et al, 2013). The targeted terminal complement inhibitor eculizumab, which was approved for treatment of patients with PNH and HUS, is a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice

et al. 2016

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Systemic lupus erythematosus is an autoimmune disease that manifests in widespread complement activation and deposition of complement fragments in the kidney. The complement pathway is believed to play a significant role in the pathogenesis and in the development of lupus nephritis. Complement factor B is an important activator of the alternative complement pathway and increasing evidence supports reducing factor B as a potential novel therapy to lupus nephritis. Here we investigated whether pharmacological reduction of factor B expression using antisense oligonucleotides could be an effective approach for the treatment of lupus nephritis. We identified potent and well tolerated factor B antisense oligonucleotides that resulted in significant reductions in hepatic and plasma factor B levels when administered to normal mice. To test the effects of factor B antisense oligonucleotides on lupus nephritis, we used two different mouse models, NZB/W F1 and MRL/lpr mice, that exhibit lupus nephritis like renal pathology. Antisense oligonucleotides mediated reductions in circulating factor B levels were associated with significant improvements in renal pathology, reduced glomerular C3 deposition and proteinuria, and improved survival. These data support the strategy of using factor B antisense oligonucleotides for treatment of lupus nephritis in humans.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice

et al. 2016

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“…FB homozygous deficiency (MIM#615561) is extremely rare, and was considered lethal until the recent publication of a complete FB deficient case. The patient presented recurrent bacterial infections from early childhood (pneumococcal peritonitis, meningitis by Neisseria and pneumococcal pneumonia) and was compound heterozygote for two loss-of-function FB mutations (10). Properdin is a trigger and stabilizer factor of AP C3 convertase.…”

Section: Main Complement-mediated Diseases 21 Infectious Diseasesmentioning

confidence: 99%

Complement as a diagnostic tool in immunopathology

López‐Lera

Corvillo

Nozal

et al. 2019

Seminars in Cell & Developmental Biology

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The complement system is a complex and autoregulated multistep cascade at the interface of innate and adaptive immunity. It is activated by immune complexes or apoptotic cells (classical pathway), pathogen-associated glycoproteins (lectin pathway) or a variety of molecular and cellular surfaces (alternative pathway). Upon activation, complement triggers the generation of proteolytic fragments that allow the elimination of the activating surface by enhancing inflammation, opsonization, phagocytosis, and cellular lysis. Moreover, complement efficiently discriminates self from non-self surfaces by means of soluble and membrane-bound complement regulators which are critical for innate self-tolerance. Complement deficiency or dysfunction disturb complement homeostasis and give rise to diseases as diverse as bacterial infections, autoimmunity, or renal and neurological disorders. Research on complement-targeted therapies is an expanding field that has already improved the prognosis of severe diseases such as atypical Haemolytic Uremic syndrome or Paroxysmal Nocturnal Haemoglobinuria. Therefore, complement analysis and monitoring provides valuable information with deep implications for diagnosis and therapy. In addition to its important role as an extracellular defense system, it has now become evident that complement is also present intracellularly, and its activation has profound implications for leukocyte survival and function. In this review, we summarize the essential, up-to-date information on the use of complement as a diagnostic and therapeutic tool in the clinics.

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“…About 20 families with inherited C3 deficiency have been described, with increased risk of infections (mostly by encapsulated bacteria, such as Streptococcus pneumoniae , N. meningitidis , and Haemophilus influenzae ) which tend to be severe and recurrent . Severe or recurrent infections have been associated also with the very rare deficiencies of all the key CAP component, ie, properdin, FB, and FD . However, it has to be remarked that these severe infectious events mostly occur in the childhood, before that adaptative immunity has established, and most subjects carrying these deficiencies remain alive once the diagnosis is done and proper prophylaxis has been started.…”

Section: Recommendations For Future Investigationsmentioning

confidence: 99%

Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria

Risitano

Marotta

2018

American J Hematol

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Therapeutic complement inhibition by eculizumab has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH) with a major impact on its natural history. Nevertheless, emerging unmet clinical needs may benefit from the development of novel complement inhibitors. Novel strategies of complement inhibition exploit different agents targeting C5, as well as compound intercepting the complement cascade at the level of its key component C3, or even upstream at the level of components involved in complement alternative pathway initiation. Many of these agents are already in their clinical development; preliminary data together with a deep understanding of PNH biology may help to anticipate their possible clinical effect. Novel anti-C5 agents include monoclonal antibodies (even long-lasting) as well as other small molecules bioavailable by subcutaneous administration; an anti-C5 small interfering RNA has been developed too. All these anti-C5 agents seem to recapitulate safety and efficacy of current eculizumab treatment; their main improvement pertains to better patient's convenience due to longer dosing interval and/or possible subcutaneous self-administration. The possibility of achieving a deeper C5 inhibition has been shown as well, but its actual clinical meaning remains to be elucidated. Upstream complement inhibitors include the anti-C3 small peptide compstatin (and its derivatives), and small inhibitors of complement factor D or complement factor B. This class of compounds anticipates a possible efficacy in prevention of C3-mediated extravascular hemolysis, in addition to inhibition of intravascular hemolysis, eventually leading to improved hematological responses. The availability of all these compounds will result soon in a substantial improvement of PNH management.

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Deficiency in Complement Factor B

Cited by 52 publications

References 4 publications

Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice

Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice

Complement as a diagnostic tool in immunopathology

Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria

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