Immune dysregulation from a novel CTLA-4 haploinsufficiency variant
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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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| 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 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".