IKBKB gain of function: An inborn error with clinical heterogeneity progressing toward combined immunodeficiency
Bibliographic record
Abstract
BACKGROUND: The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway is a key regulator of immune responses, cell survival, and proliferation. Dysregulation of this signaling pathway is implicated in various human diseases, including inborn errors of immunity. OBJECTIVE: We describe the clinical heterogeneity in 16 patients from 4 unrelated families with missense variants in the kinase domain of IKK2 encoded by IKBKB. METHODS: Genetic variants (p.V203I and p.M65T) in the patients were identified by whole-exome sequencing. An NF-κB reporter assay was performed to investigate NF-κB activity. Extensive immunophenotyping, a lymphocyte proliferation assay, and signaling pathway analysis were performed to gain biological insight into the impact on B- and T-cell phenotype and function. RESULTS: Whole-exome sequencing revealed 2 gain-of-function variants in the IKBKB gene, of which one was a novel variant. While lymphocyte cell numbers are generally normal at young ages, most adult patients exhibit strongly reduced B- and T-cell numbers. Although still normal in their proliferative capacity, B and T cells show defective activation at day 3 (CD70, CD25, and CD40L expression) and impaired B-cell differentiation into plasmablasts. Altered NF-κB signaling was evidenced by phosphoflow experiments. These findings coincide with autoinflammatory skin manifestations, systemic infections with progressive lymphopenia, and potentially fatal diseases occurring later in life. CONCLUSION: This study broadens the clinical spectrum of IKBKB gain-of-function variants as a progressive immunodeficiency in adulthood.
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How this classification was reachedexpand
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 | 0.002 | 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 | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".