A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile
(2024) In Journal of Autoimmunity 143.- Abstract
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... (More)
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.
(Less)
- author
- author collaboration
- organization
- publishing date
- 2024-02
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Autoantibodies, Complement system, Ficolin-3, Lectin pathway, Systemic lupus erythematosus
- in
- Journal of Autoimmunity
- volume
- 143
- article number
- 103166
- publisher
- Elsevier
- external identifiers
-
- pmid:38219652
- scopus:85182582637
- ISSN
- 0896-8411
- DOI
- 10.1016/j.jaut.2023.103166
- language
- English
- LU publication?
- yes
- id
- baba9340-0f9e-4781-a4cb-eaccf3e9b0ed
- date added to LUP
- 2024-04-10 14:05:20
- date last changed
- 2024-04-24 17:01:38
@article{baba9340-0f9e-4781-a4cb-eaccf3e9b0ed,
abstract = {{<p>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.</p>}},
author = {{Lindelöf, Linnea and Rantapää-Dahlqvist, Solbritt and Lundtoft, Christian and Sandling, Johanna K. and Leonard, Dag and Sayadi, Ahmed and Rönnblom, Lars and Enocsson, Helena and Sjöwall, Christopher and Jönsen, Andreas and Bengtsson, Anders A. and Hong, Mun Gwan and Diaz-Gallo, Lina Marcela and Bianchi, Matteo and Kozyrev, Sergey V. and Lindblad-Toh, Kerstin and Nilsson Ekdahl, Kristina and Nilsson, Bo and Gunnarsson, Iva and Svenungsson, Elisabet and Eriksson, Oskar}},
issn = {{0896-8411}},
keywords = {{Autoantibodies; Complement system; Ficolin-3; Lectin pathway; Systemic lupus erythematosus}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Journal of Autoimmunity}},
title = {{A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile}},
url = {{http://dx.doi.org/10.1016/j.jaut.2023.103166}},
doi = {{10.1016/j.jaut.2023.103166}},
volume = {{143}},
year = {{2024}},
}