Figure - available from: Journal of Clinical Immunology
This content is subject to copyright. Terms and conditions apply.
Capillary electrophoresis analysis of human serum proteins. Patient 2 and control profiles are shown. Blue arrow indicates the β2 zone
Source publication
The complement system is an important effector arm of innate immunity and plays a crucial role in the defense against common pathogens. But effective defense and maintenance of homeostasis requires a careful balance between complement activation and regulation. Factor I (FI) is one of the most important regulators of the complement system. Complete...
Similar publications
Complement factor I (FI) is a central inhibitor of the complement system, and impaired FI function increases complement activation, contributing to diseases such as age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS). Genetic variation in complement factor I (CFI) has been identified in both AMD and aHUS, with more...
Citations
... 8 The G162D variant is a type 1 mutation and has been described at the homozygous state. 9 As previously reported in other cases of complete CFI deficiency, the relatives of our patient are heterozygous for the allelic variants and completely asymptomatic, although theoretically at risk of aHUS. At present, her 18-year-old sister remains healthy, highlighting the variable clinical expression of CFI deficiency. ...
Objectives:
Complement factor I (CFI) deficiency is a rare autosomal recessive inborn error of immunity. In this report, we highlight that complete CFI deficiency may present with isolated and severe CNS inflammation without associated systemic features nor prior non-CNS episodes. This inflammation may respond to complement blockade therapy.
Methods:
This is a case description of a young girl with severe longitudinal transverse myelitis treated with aggressive immunotherapy that included eculizumab. Published cases of CFI-associated CNS inflammation were reviewed and discussed.
Results:
A primary immunodeficiency panel revealed 2 germline pathogenic variants in the CFI gene. Further complement testing of the index case and her family confirmed complete CFI deficiency.
Discussion:
We describe a unique case of severe spinal inflammation secondary to complete CFI deficiency. Although rare, isolated CNS inflammation may be the primary manifestation of complete CFI deficiency. To halt the uncontrolled complement-mediated inflammation associated with CFI deficiency, prompt targeted blockade of the complement pathway using eculizumab may be life changing in the acute phase. Long-lasting blockade of the complement pathway is also essential to prevent relapse in this subgroup of patients.
... deficiency [24][25][26]. Based on the current literature, this variant was classified as a likely pathogenic variant (ACMG category 2). ...
Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Complement and coagulation gene variants have been associated with aHUS susceptibility. We assessed the diagnostic yield of a next-generation sequencing (NGS) panel in a large cohort of Canadian patients with suspected aHUS. Molecular testing was performed on peripheral blood DNA samples from 167 patients, collected between May 2019 and December 2021, using a clinically validated NGS pipeline. Coding exons with 20 base pairs of flanking intronic regions for 21 aHUS-associated or candidate genes were enriched using a custom hybridization protocol. All sequence and copy number variants were assessed and classified following American College of Medical Genetics guidelines. Molecular diagnostic results were reported for four variants in three individuals (1.8%). Twenty-seven variants of unknown significance were identified in 25 (15%) patients, and 34 unique variants in candidate genes were identified in 28 individuals. An illustrative patient case describing two genetic alterations in complement genes is presented, highlighting that variable expressivity and incomplete penetrance must be considered when interpreting genetic data in patients with complement-mediated disease, alongside the potential additive effects of genetic variants on aHUS pathophysiology. In this cohort of patients with suspected aHUS, using clinical pipelines for genetic testing and variant classification, pathogenic/likely pathogenic variants occurred in a very small percentage of patients. Our results highlight the ongoing challenges in variant classification following NGS panel testing in patients with suspected aHUS, alongside the need for clear testing guidance in the clinical setting.
Key messages
• Clinical molecular testing for disease associated genes in aHUS is challenging.
• Challenges include patient selection criteria, test validation, and interpretation.
• Most variants were of uncertain significance (31.7% of patients; VUS + candidates).
• Their clinical significance may be elucidated as more evidence becomes available.
• Low molecular diagnostic rate (1.8%), perhaps due to strict classification criteria.
• Case study identified two likely pathogenic variants; one each in MCP/CD46 and CFI.
... In the large number of publications in aHUS and AMD documenting heterozygous mutations in CFI (see Table 3) there is no reported increased susceptibility to infection although one publication suggested this (Grumach et al., 2006). Additionally asymptomatic completely deficient individuals have been reported (Alba-Dominguez et al., 2012, Franco-Jarava et al., 2017, Nanthapisal et al., 2018, Ugrinovic et al., 2020, Vyse et al., 1994a, Vyse et al., 1994b, Vyse et al., 1996. Prophylactic antibiotics and vaccination against encapsulated bacteria to prevent infections are the standard of care. ...
... Jong et al., 2020, Gleeson et al., 2016, Java et al., 2020, Kavanagh et al., 2015, Tan et al.-Dominguez et al., 2012, de Jong et al., 2020, Franco-Jarava et al., 2017, Hallam et al., 2020, Java et al., 2020, Kavanagh et al., 2015, Le Quintrec et al.-Dominguez et al., 2012, de Jong et al., 2020, Java et al., 2020, Kavanagh et al.et al., 2010, de Jong et al., 2020, Nilsson et al.Jong et al., 2020, Java et al., 2020, Kavanagh et al., 2015, Zhang et al.Jong et al., 2020, Hallam et al., 2020, Tan et al., 2017, Zhang et al.Jong et al., 2020, Java et al., 2020, Kavanagh et al.et al., 2017 de Jong et al., 2020, Hallam et al. ...
Complement factor I (FI) is the nexus for classical, lectin and alternative pathway complement regulation. FI is an 88 kDa plasma protein that circulates in an inactive configuration until it forms a trimolecular complex with its cofactor and substrate whereupon a structural reorganization allows the catalytic triad to cleave its substrates, C3b and C4b. In keeping with its role as the master complement regulatory enzyme, deficiency has been linked to immunopathology. In the setting of complete FI deficiency, a consumptive C3 deficiency results in recurrent infections with encapsulated microorganisms. Aseptic cerebral inflammation and vasculitic presentations are also less commonly observed. Heterozygous mutations in the factor I gene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemic syndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also been associated with decreased retinal thickness and is a strong risk factor for the development of age-related macular degeneration. Supplementation of FI using plasma purified or recombinant protein has long been postulated, however, technical difficulties prevented progression into clinical trials. It is only using gene therapy that CFI supplementation has reached the clinic with GT005 in phase I/II clinical trials for geographic atrophy.
... Recurrent otitis media, bronchitis, sinusitis, tonsillitis, and cutaneous abscesses have been described in factor I-deficient individuals. 31 As with C3 deficiency, invasive infections with S. pneumoniae, H. influenzae, and N. meningitidis (groups B, C, and W-135) have been reported. 17,32 In addition, cases of Streptococcus pyogenes, hemorrhagic measles, and a case where aseptic (non-bacterial) meningitis recurred nine times over a 2 y period 33 have been documented. ...
The alternative pathway (AP) is the phylogenetically oldest arm of the complement system and may have evolved to mark pathogens for elimination by phagocytes. Studies using purified AP proteins or AP‐specific serum showed that C3b amplification on bacteria commenced following a lag phase of about 5 min and was highly dependent on the concentration of complement. Most pathogens have evolved several elegant mechanisms to evade complement, including expressing proteases that degrade AP proteins and secreting proteins that block function of C3 convertases. In an example of convergent evolution, many microbes recruit the AP inhibitor factor H (FH) using molecular mechanisms that mimic FH interactions with host cells. In most instances, the AP serves to amplify C3b deposited on microbes by the classical pathway (CP). The role of properdin on microbes appears to be restricted to stabilization of C3 convertases; scant evidence exists for its role as an initiator of the AP on pathogens in the context of serum. Therapeutic complement inhibition carries with it an increased risk of infection. Antibody (Ab)‐dependent AP activation may be critical for complement activation by vaccine‐elicited Ab when the CP is blocked, and its molecular mechanism is discussed.
... The rarity of FI de ciency translates into a delayed diagnosis for patients and their families. Therefore, it is essential to raise patient and clinician awareness to the existence of FI de ciency as well as warning signs of other complement de ciencies to avoid treatment delay [24]. Previous work calls for greater adoption of complement screening diagnostics, including more specialized markers of C3 activation status like C3d, as well as total C3, AH50, FH, and FB which all positively correlated with FI levels according to our analysis [20,21]. ...
Background: The complement system plays a central role in innate immune response with the recognition and elimination of pathogens through direct killing and/or stimulation of phagocytosis. The complement system is composed of a complex proteolytic cascade of more than 50 soluble and membranous proteins among which the complement Factor I (FI) is a key protease that regulates the cascade through inactivation of C3b and C4b and their downstream effect in terminal membrane attack complex (MAC) formation. A deficiency or absence of endogenous FI results in uncontrolled spontaneous activation of the alternative pathway, leading to continuous, massive consumption of complement component 3 (C3). Low levels of C3 may, in turn, reduce phagocytic activity, opsonization, and antibody production, as well as impair immune complex metabolism. As such, FI deficiency can result in an increased susceptibility to infections by encapsulated bacteria and/or an increased incidence of autoimmune and immune-complex diseases.
Methods: By using a data harmonization method, we created a repository for quantitative interrogation of FI deficiency phenotype and its associated complement markers across 135 cases. In addition, we generated Cfi-/- rats to establish a model that recapitulates the complement biomarker imbalance observed in FI deficient individuals.
Results: Bacterial infections are the most predominant clinical phenotype in FI deficient individuals. Our analysis highlights symptoms often begin early in childhood with ~70% of the cases reported in children < 18 years old, further supporting that FI deficiency is a pediatric disorder. The complement imbalance observed in FI deficient individuals is recapitulated in Cfi-/- rats.
Conclusions: We provide the first robust meta-analysis of FI-deficiency of 135 cases described in the literature and established a new tool to evaluate future therapeutic agents for their capacity to treat FI deficiencies.
... CFI is a serine proteinase that cleaves the α-chain of C3b and plays a key role in inhibition of the alternative pathway amplification loop that generates C3 convertase from C3b. Until now, 23 mutations in CFI have been reported in patients with aHUS, and their functional consequences have been characterized in approximately half of cases [6]. We report herein a novel missense mutation in the CFI that predisposed to aHUS in a sporadic patient. ...
... Till now, nearly 23 mutations have been found in this gene with a predisposition to aHUS [11][12][13][14]. Eighty percent of mutations cluster in the serine protease domain [6]. Approximately 50% of mutants block protein secretion, while some mutants are secreted but have dysfunctional proteolytic activity with altered degradation of C3b/C4b in the fluid phase and on cell surfaces [15]. ...
Background
Atypical hemolytic uremic syndrome, also called the nondiarrheal form of hemolytic uremic syndrome, is a rare disease characterized by the triad of thrombocytopenia, Coomb’s test-negative microangiopathic hemolytic anemia, and acute renal failure. Approximately 60% of cases of atypical hemolytic uremic syndrome are associated with deficiencies of the complement regulatory protein, including mutations in complement factor H, complement factor I, or the membrane co-factor protein.
Case presentation
We report the case of a 26-year-old Asian man who presented with pulmonary infection, elevated blood pressure, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Renal biopsy revealed diffuse capillary fibrin deposition, endothelial swelling, and arteriole narrowing like “onion skinning” consistent with thrombotic microangiopathy. Bidirectional sequencing of CFH, CFHR5, CFHR1, CFI, DGKE, CFB, and MCP confirmed that the patient was heterozygous for a novel missense mutation, p.Cys67Phe, in CFI. This patient had rapid evolution to end-stage renal disease and needed renal replacement therapy. Plasma exchange seemed inefficacious in this patient.
Conclusions
This report confirms the importance of screening patients with atypical hemolytic uremic syndrome for mutations in genes involved in complement system to clarify the diagnosis and demonstrates the challenges in the management of these patients.
... To date, only about 25 cases of genetically confirmed CFI deficiency have been reported. At the time of diagnosis, patient age ranged from infancy to 60 years, and clinical symptoms varied widely from severe bacterial infections to recurrent sterile neuroinflammations [36][37][38]. ...
Differential diagnosis of meningitis and encephalitis is often very challenging because it cannot be determined based on symptoms, and the diseases have various causes. This article explains rare genetic causes of meningitis and encephalitis. Autoinflammatory disorders include cryopyrin-associated periodic syndromes, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. Furthermore, other genetic disorders, such as complement factor I deficiency, phosphatidylinositol glycan anchor biosynthesis class T mutation, and neuronal intranuclear inclusion disease, can present as meningitis and encephalitis.
... Immunoglobulin levels and lymphocyte subsets were normal. She was positive for C3 nephritic factor explaining the impairment of [10]. The patient's 2-month-old brother had the same homozygous mutation in the CFI gene. ...
... This p.His380Arg mutation was predicted to be deleterious by in silico prediction algorithms, including Polyphen-2, SIFT, or GERP++, and is highly conserved between organisms according to the PhyloP algorithm. This homozygous mutation was confirmed to be present using Sanger sequencing in the index case (Figure 1C), and has very recently been described in homozygotic state in a single case with CFI deficiency (24). There were no other class 4 or 5 genetic variants (25) detected by WES in any of the complement pathway genes (including CFH), or in any other gene in the index case. ...
... Dysregulation of the alternative complement pathway also explains the low factor H we observed (in the absence of any CFH mutations detected in this kindred) in our two patients with CFI deficiency ( Table 1), since the principal function of factor H is to regulate the alternative pathway. Low levels of factor H are also described in other reports of CFI deficiency (24,40,41) and is secondary to consumption of the regulatory factor H presumably as a compensatory response to excessive and dysregulated alternate pathway activation. ...
... Antibiotic prophylaxis and vaccination against encapsulated bacteria are pragmatic approaches to prevent infection (31,44), which currently we have recommended for both the children described herein. It is also possible that institution of a tailored vaccination programme may improve outcomes for individuals with partial CFI deficiency as well (24,45). ...
Cutaneous leukocytoclastic vasculitis arises from immune complex deposition and dysregulated complement activation in small blood vessels. There are many causes, including dysregulated host response to infection, drug reactions, and various autoimmune conditions. It is increasingly recognised that some monogenic autoinflammatory diseases cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of consanguineous parents who presented with chronic cutaneous leukocytoclastic vasculitis, recurrent upper respiratory tract infection, and hypocomplementaemia. A homozygous p.His380Arg mutation in the complement factor I (CFI) gene CFI was identified as the cause, resulting in complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum factor I, C3, and factor H. C4 and C2 levels were normal. The same homozygous mutation and immunological defects were also identified in an asymptomatic sibling. CFI deficiency is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4.
Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI’s cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.
