Ficolin-3 Deficiency Research Articles

A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile

The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE.Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.

62 Acquired ficolin-3 deficiency in patients with Systemic Lupus Erythematosus

62 Acquired ficolin-3 deficiency in patients with Systemic Lupus Erythematosus

A new case of congenital ficolin-3 deficiency with primary immunodeficiency

ABSTRACT Objectives Human Ficolin-3 (FCN3) is an oligomeric-structured lectin encoded by the FCN3 gene with a pivotal role in the lectin complement pathway. It has anti-microbial activities against bacterial and viral infections and restrains opportunistic pathogens. Mutation in the FCN3 gene is associated with variable clinical manifestations particularly immunologic (infections and autoimmunity) and neurologic complications. Methods In this study, we report a 5-year-old boy with a biallelic mutation in the FCN3 gene using clinical and immunological and genetic evaluations (whole exome sequencing). Results Our case is the first national and the eighth case worldwide with a confirmed frameshift mutation associated with Ficolin-3 deficiency. He manifested refractory seizures since early infancy, meningitis, pyelonephritis and was diagnosed with severe primary immunodeficiency. Conclusion Our case and literature review indicate Ficolin-3 deficiency should be considered in early-onset, premature neonate with a bacterial infection, neurological manifestation and systemic lupus erythematosus like presentations.

Fatal pneumococcus meningitis in a child with complement factor ficolin-3 deficiency

Fatal pneumococcus meningitis in a child with complement factor ficolin-3 deficiency

Ficolin-3 Deficiency Is Associated with Disease and an Increased Risk of Systemic Lupus Erythematosus.

Ficolin-3 deficiency is caused by a mutation (+1637delC) in the FCN3 gene. It is a rare condition and has been associated with both infection and autoimmune disease including systemic lupus erythematosus (SLE). Here we investigated if ficolin-3 deficiency is more frequent in patients than in controls and tried to identify a common phenotype among ficolin-3 deficient individuals. Since a significant part of patients identified with ficolin-3 deficiency was diagnosed with SLE, we explored whether the heterozygous state of the FCN3+1637delC variant represents a risk factor in the development of SLE. Further, we examined other possible causes of ficolin-3 deficiency when the FCN3+1637delC is not present. A systematic literature search for studies measuring ficolin-3 was carried out. We examined 362 SLE patients and 596 controls for the presence of the variant FCN3+1637delC. We established assays for measurements of ficolin-3 and of auto-antibodies against ficolin-3. We sequenced the coding and non-coding regions of the FCN3 gene in an SLE patient with ficolin-3 deficiency not carrying the +1637delC. Ficolin-3 deficiency leads to an 8-time increased odds of having a disease (p< 0.05). Three out of nine patients with deficiency had SLE. The heterozygous state of the deficiency variant is not associated with increased risk of developing SLE (p= 0.18). By systematically reviewing the literature for the described cases of ficolin-3 deficiency, an autoimmune phenotype is emerging. Thirty-three percent of the ficolin-3 deficient patients had SLE. Heterozygosity for the FCN3 gene deletion causing the deficiency does not seem to be associated with the development of SLE.

Mannan-Binding Lectin (MBL) Deficient Individuals with the O/O Genotype are Highly Susceptible to Gastrointestinal Diseases

Background: Mannan-binding lectin (MBL) and ficolin-3 are initiators of the lectin pathway that is important for clearance of pathogens and apoptotic cells through complement activation. MBL deficiency (MBLD) has been associated with infectious complications but its clinical relevance in adults is unclear. Definition of MBLD is commonly linked to its low serum levels, but is mainly due to functional polymorphisms in the MBL2 gene leading to dysfunctional MBL forms. Homozygotes for dysfunctional alleles (O/O) have the lowest serum levels (<50 ng/ml) with a defect in opsonisation and complement activation. Ficolin-3 deficiency due to homozygosity of a frameshift mutation (1637delC) in the FCN3 gene was recently shown to be associated with pyogenic infections mainly in the lungs. Objective: The aim of the study was to thoroughly evaluate the clinical findings of previously defined MBL deficient cohort in relation to their MBL2 and FCN3 genotypes. Methods: A total of 120 adult individuals previously defined as MBL deficient (≤500 ng/ml) were genotyped for variants in the MBL2 gene and for the 1637delC allele in the FCN3 gene. They answered detailed questionnaire focused on pulmonary and gastrointestinal infections. For comparison, 63 adult individuals were randomly selected from the general population and served as control subjects. Results: In the MBLD cohort the prevalence of genotypes A/A, A/O and O/O was 14.2%, 71.2%, and 14.2%, respectively. Thus, 85% carried the dysfunctional allele O. The MBLD cohort was significantly more prone to a variety of recurrent and severe infections than the control cohort. O/O individuals were more susceptible to oesophagitis and gastritis and had undergone gastroscopy significantly more often than A/A an A/O. Prevalence of heterozygosity (C/-) for the 1637delC allele was 4.2%. Conclusion: MBL deficient individuals suffer from recurrent and severe forms of infections. The O allele might predispose to gastrointestinal diseases.

Arfgengur skortur í ræsisameindum lektínferils komplímentvirkjunar

The complement system is an important immune system. Its activation results in membranolytic elimination of microbes and opsonization. The classical, alternative and lectin pathways (LP) activate complement. Either mannan-binding lectin (MBL), ficolin-1, ficolin-2 or ficolin-3 initiate the LP through associated serine protease (MASP-2) after binding to microorganisms'surface carbohydrate patterns. Genetic polymorphisms behind MBL deficiency are rather common. Numerous studies indicate that MBL deficiency is a risk factor for invasive and recurrent infections, especially when other immune systems are immature, deficient or compromised. Research in ficolins is limited but last year ficolin-3 deficiency was described. This review focuses on these recently WHO defined immunodeficiencies.

Immunodeficiency associated with FCN3 mutation and Ficolin-3 deficiency

Immunodeficiency associated with FCN3 mutation and Ficolin-3 deficiency

Characterization of a polymorphism in the coding sequence of FCN3 resulting in a Ficolin-3 (Hakata antigen) deficiency state

Ficolin-3 (Hakata antigen or H-ficolin) is a soluble pattern recognition molecule in the lectin complement pathway. We speculated whether common genetic variations in the FCN3 gene contribute to deficiency of Ficolin-3. The FCN3 gene was sequenced in 237 healthy Danish Caucasians. The relevance of polymorphisms was assessed with antibodies against Ficolin-3 in a novel ELISA system and by production of recombinant Ficolin-3 variants. Ficolin-3 serum profiles were analyzed by SDS-PAGE and western blotting. Ficolin-3 serum concentration varied 10-fold (median, 24 μg/ml; range, 3–54 μg/ml). Out of several polymorphisms one FCN3 + 1637delC causing a reading frame shift and a distortion of the C-terminal end of the molecule with an allele frequency of 0.011 was particularly interesting. In individuals heterozygous for the FCN3 + 1637delC deletion lowered Ficolin-3 concentration was observed ( P = 0.025). SDS-PAGE and western blotting of serum revealed a weak band corresponding to the truncated molecule in addition to the normal Ficolin-3 pattern. Characterization of recombinant Ficolin-3 derived from FCN3 + 1637delC showed that in the homozygous situation this allelic variant would lead to Ficolin-3 deficiency. In conclusion an FCN3 + 1637delC deletion variant disrupting the possibility for pattern recognition was detected. Characterization of recombinant variant Ficolin-3 shows that homozygosity for the FCN3 + 1637delC deletion may lead to Ficolin-3 deficiency and may thus be the basis for a novel complement deficiency state.