Immune dysregulation from a novel CTLA-4 haploinsufficiency variant
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a key immune checkpoint receptor that regulates T cell activation through ligand competition and transendocytosis. Heterozygous loss-of-function variants in CTLA4 result in CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI), characterized by immune dysregulation and autoimmunity. We report a multigenerational family carrying a novel heterozygous CTLA4 variant, c.654T>A (p.Tyr218*), which truncates the cytoplasmic tail. Affected individuals presented with recurrent infections and autoimmune manifestations. Patient T cells showed reduced CTLA-4 expression at baseline and after stimulation, suggesting impaired stability. Jurkat cells expressing CTLA-4 Y218* exhibited enhanced degradation, partially rescued by lysosomal inhibition, and reduced transendocytosis of CD80. Together, these findings suggest that the CTLA-4 p.Tyr218* variant compromises protein stability and ligand uptake, contributing to CTLA-4 haploinsufficiency and immune dysregulation. This work broadens the spectrum of CTLA4 variants and underscores the importance of the C-terminal cytoplasmic domain in CTLA-4 function and immune regulation.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 it