The mutation <i>PTPN6</i>Ala455Thr causing pulmonary emphysema affects B lymphocyte populations and causes spontaneous pulmonary tertiary lymphoid tissue formation
Bibliographic record
Abstract
Abstract Background A new mutation responsible for causing severe and early pulmonary emphysema was recently discovered in a French-Canadian family. The mutation is located in the PTPN6 gene (PTPN6Ala455Thr) leading to a reduction in the activity of SHP-1, a phosphatase that regulates numerous pathways including B cell differentiation and activation. Here, we aimed to characterize B cell abnormalities in both humans and mice carrying this mutation. Methods Circulating B cell populations in humans carrying the PTPN6Ala455Thr mutation were analyzed by flow cytometry and immunoglobulin levels were measured in serum. In mice carrying the same mutation (Ptpn6Ala457Thr) aged up to 12 months, B cell populations were analyzed by flow cytometry and lung tissue histology performed. Mice were immunized with the T cell-independent antigen NP-Ficoll and plasma was collected to assess NP-specific antibodies. Results Human carriers of the PTPN6Ala455Thr mutation had reduced IgG1 and IgG4, and increased IgG3 levels as well as high circulating immature/mature B cell ratio compared to controls. Aging Ptpn6Ala457Thr mice developed spontaneous pulmonary tertiary lymphoid tissues and exhibited higher B-1 cells and lower B-2 cells proportions in the lung and spleen. Ptpn6Ala457Thr mice had lower levels of NP-specific IgG1 antibodies compared to the wild-type group, but normal IgG3 in response to NP-Ficoll immunization. Conclusion SHP-1 appears to be important to B cell development and functions, as the PTPN6Ala455Thr mutation seems to cause a form of subclinical immunodeficiency that affects B cell populations and immunoglobulin levels. The link between B cell abnormalities and development of pulmonary emphysema requires further investigation. Supported by grants from Canadian Institutes of Health and Research and Fonds de Recherche du Québec- Santé
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".