Genetic and epigenetic dysregulation of CR1 is associated with catastrophic antiphospholipid syndrome
Bibliographic record
Abstract
OBJECTIVES: Catastrophic antiphospholipid syndrome (CAPS) is a complement-driven thrombotic disorder, characterised by widespread thrombosis and multiorgan failure. We identified rare germline variants including complement receptor 1 (CR1) in 50% of patients with CAPS. Here, we define CR1 dysregulation mechanisms (genetic/epigenetic) underlying complement-mediated thrombosis in CAPS and support C5 inhibition as a potential therapy. METHODS: We quantified CR1 expression by flow cytometry across haematopoietic cell types. CRISPR/Cas9 genome editing of TF-1 (erythroleukaemia) cells was performed to generate CR1 'knock-out' and 'knock-in' lines with patient-specific CR1 variants. Multiomics analysis was performed to investigate the role of methylation in patients with reduced CR1 expression. Functional impact of low CR1 was assessed by complement-mediated cell killing using modified Ham assay, cell-bound complement degradation products through flow cytometry, and circulatory immune complexes in serum samples through ELISA. RESULTS: CR1 expression in erythrocytes was markedly reduced on CAPS erythrocytes (n = 9, 21.80%) compared to healthy controls (HCs; n = 35, 84.04%), with promoter hypermethylation emerging as a plausible epigenetic mechanism for CR1 downregulation. Novel germline variant (CR1-V2125L; rs202148801) mitigated CR1 expression and increased complement-mediated cell death of knock-in cell lines. Erythrocytes from the patient with the CR1-V2125L variant had low CR1 expression. Levels of circulating immune complexes, which are bound and cleared by CR1 on erythrocytes, were higher in acute CAPS (n = 3, 25.55 µg Eq/mL) than HCs (n = 3, 7.445 µg Eq/mL). Five patients were treated with C5 inhibition which mitigated thrombosis. CONCLUSIONS: Genetic or epigenetic-mediated CR1 deficiency is a potential hallmark of CAPS and predicts response to C5 inhibition.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".