A101 ARPC1B-DEFICIENT B CELLS DISPLAY ABERRANT SPREADING BEHAVIOUR
Bibliographic record
Abstract
ARPC1B-deficiency is a newly described genetic condition with an early age of onset and is clinically similar to Wiskott-Aldrich syndrome (WAS). Nearly all affected patients experience colitis that is eosinophilic in nature, and their immunological profiles show increased peripheral CD19+ cells, IgE, IgA, and detectable auto-antibodies. ARPC1B is a member of the Arp2/3 actin nucleating complex, which is activated by WAS protein and is the rate-limiting step in branched actin polymerization. It is expressed by haematopoietic cells and is important for regulating a dynamic cytoskeleton for essential functions such as migration and intracellular transport. There are currently no data addressing the loss of ARPC1B and its effect on B cell function specifically. We intend to characterize how ARPC1B deficiency affects B cell activation in vitro. EBV-transformed lymphoblastoid (B cell) lines were generated from PBMCs derived from patients and their first-degree relatives. B cell receptor (BCR) internalization was assessed by flow cytometry. Cell spreading was activated by receptor cross-linking: B cells were added to anti-human IgG-coated chamber slides and allowed to spread (2–20 min), then fixed and stained with phalloidin which binds filamentous (F)-actin. Images were acquired and analysed in ImageJ. Our group identified three patients harbouring mutations in ARPC1B: one with a severe phenotype (Pat 1) accompanied by a homozygous 2 bp insertion (c.387_388insCT [L90fs]) resulting in truncation, and two brothers with mild (Pat 2)/very mild (Pat 3) phenotypes caused by 2 homozygous SNPs (c.434C>T [A105V]; c.832G>A [A238T]). In B cell lysates, immunoblots confirmed the loss of ARPC1B in Pat 1, and reduced protein in Pat 2/3 compared to controls; this pattern was inversely correlated with expression of its isoform, ARPC1A. Flow cytometric analysis of phalloidin-stained B cells showed significantly reduced F-actin in all affected patients, while BCR expression was higher (internalization was not affected). Interestingly, a small proportion of unstimulated B cells from Pat 1 spontaneously adhered to tissue culture-treated surfaces after 2 d. Moreover, spreading assays demonstrated that a higher number of B cells from Pat 1 stuck down with no effect on spreading area. Upon closer inspection, structured illumination microscopy of phalloidin-stained B cells revealed a divergent spreading phenotype, with fewer extensive protrusions in cells from Pat 1. B cells deficient in ARPC1B have an inherent defect affecting their activity in vivo, BCR expression, and spreading behaviour in vitro. Further characterization is warranted to define the mechanism underlying this phenotype and its implications in the development of early onset IBD. CAG, CIHRHelmsley Charitable Trust
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".