The role of semaphorin 4C in B cells during allergic airways disease
Bibliographic record
Abstract
Allergic airways disease (AAD) is an inflammatory disorder of the airways that is associated with airway hyperresponsiveness (AHR) and airway remodeling.It is characterized by narrowed airways with marked pulmonary eosinophilia, elevated Th2 cytokines and increased peripheral IgE.IgE-producing cells -B lymphocytes -are considered important for AAD progression.Upon allergen exposure, B cells undergo IgE class switching in the presence of Th2 cytokines IL-4 and IL-13.Our laboratory detected a significant increase in Semaphorin 4C (Sema4C) mRNA levels in isolated human tonsillar B cells that were stimulated with anti-CD40 antibodies and IL-4r or L-13.Class 4 semaphorins are of particular importance in immune responses, however, the function of Sema4C in the immune system has never been studied.Our aim was to delineate the function of Sema4C in B cells during Th2 immune responses.Immunofluorescent staining revealed that Sema4C expression was induced by Th2 cytokine stimulation on human activated memory B cells.Sema4C co-localized with its binding partner, Plexin B2, at a synapse-like pole of activated B cells.Sema4c-deficient (Sema4c -/-) B cells failed to polarize and form a synapse-like structure when stimulated in vitro.The decreased polarization was associated with decreased B cell receptor (BCR) signaling and impaired immunoglobulin production.These results suggest that Sema4C is required for polarization and potentialy immune synapse formation, which contributes to B cell differentiation.Using a murine ovalbumin (OVA)-driven AAD model, we determined using both Sema4C deficient mice (Sema4C -/-) as well as chimeric mice with Sema4C deleted specifically in B cells (S4C-B mice) demonstrated exacerbated pulmonary eosinophilia, elevated IL-4 and IL-5 in iv bronchial alveolar lavage fluid (BAL), and increased peripheral OVA-specific IgE.Further analysis showed that in CD138 + B cells, Sema4c -/-B cells exhibited increased IL-4 and decreased IL-10 production, as compared to wild-type (WT) B cells.Transferring Sema4c -/-CD19 + CD138 + cells to WT recipients reproduced the increased Th2 inflammation in S4C-B mice.We also showed that transfer of WT CD19 + CD138 + IL-10 + cells to Sema4C deficient mice suppressed Th2 inflammation in the antigen-driven AAD model.We therefore concluded that Sema4C is required for the differentiation of a novel regulatory B cell population, CD19 + CD138 + IL-10 + , in AAD.In summary, we identified Sema4C as a critical protein for polarization and immune synapse formation in activated B cells.It is required for regulatory cytokine production from CD19 + CD138 + cells.Our studies highlight the importance of B-lymphocytes as regulatory cells in allergic inflammation, as well as providing evidence that regulatory B cell development requires functional immune synapse formation.
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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) | 0.001 | 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".