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P13 Acquired ficolin-3 deficiency in patients with systemic lupus erythematosus
  1. Linnea Lindelöf1,
  2. Solbritt Rantapää-Dahlqvist2,
  3. Christian Lundtoft3,
  4. Johanna K Sandling3,
  5. Dag Leonard3,
  6. Ahmed Sayadi3,
  7. Lars Rönnblom3,
  8. Helena Enocsson4,
  9. Christopher Sjöwall4,
  10. Andreas Jönsen5,
  11. Anders A Bengtsson5,
  12. Mun-Gwan Hong6,
  13. Lina-Marcela Diaz-Gallo7,
  14. Matteo Bianchi8,
  15. Sergey V Kozyrev8,
  16. Kerstin Lindblad-Toh8,9,
  17. the DISSECT Consortium,
  18. the ImmunoArray Consortium,
  19. Kristina Nilsson Ekdahl1,10,
  20. Bo Nilsson1,
  21. Iva Gunnarsson7,
  22. Elisabet Svenungsson7 and
  23. Oskar Eriksson1
  1. 1Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  2. 2Dept. of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden
  3. 3Dept. of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
  4. 4Dept. of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
  5. 5Dept. of Clinical Sciences Lund, Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden
  6. 6National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Dept. of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
  7. 7Division of Rheumatology, Dept. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  8. 8Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
  9. 9Broad Institute of MIT and Harvard, Cambridge, MA, USA
  10. 10Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden

Abstract

Objective Ficolin-3 is the main initiator of the lectin pathway of complement in humans. Case reports of ficolin-3 deficient patients have suggested that ficolin-3 deficiency may be enriched in patients with Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease where complement plays an important role. Therefore, this study aimed to investigate the activity levels of ficolin-3 and to identify potential ficolin-3 deficient individuals in two Swedish SLE cohorts.

Methods Serum samples from SLE patients (n=786) and matched controls (n=566) were collected from the Karolinska Institute and Umeå University Hospital. The ficolin-3 activity was measured by an in-house developed functional ELISA with a pooled normal human serum sample as a reference. Serial samples were analyzed for ficolin-3 deficient patients when available. Sequencing data were analyzed for FCN3 frame-shift mutation rs532781899 and other potential loss-of-function (LoF) variants.

Results This screening revealed that the ficolin-3 activity varies largely in patients with SLE. The activity levels also show that SLE patients have elevated ficolin-3 activity compared to the control group (p<0.0001). Four SLE patients were determined to be ficolin-3 deficient. For two of these patients, the ficolin-3 activity fluctuated over time, where one even had normal levels at the time of diagnosis with a subsequent depletion over time, indicating an acquired deficiency. For deficient patients, no or very low ficolin-3 protein levels and no lectin pathway-dependent complement activation could be detected. Autoantibodies against ficolin-3 were only detected in serum from one of the deficient patients. No patients were homozygous for the frame-shift mutation rs532781899, whereas 10 patients were determined to be heterozygous carriers. These heterozygous patients displayed lower levels of ficolin-3 activity, but did not include the deficient patients. Additional possible LoF variants were analyzed, but none were enriched in either patients or controls.

Conclusions Contrary to the classical pathway of the complement system, we show no evidence for an association between genetic ficolin-3 deficiency and SLE susceptibility. Instead, acquired ficolin-3 deficiency was observed in a subgroup of SLE patients, possibly due to a potent activation of the lectin pathway that depleted ficolin-3 serum levels in these individuals.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/lupus-2024-el.67

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