45 CD11c-hi T-bet+ B cells contribute to the pathogenesis of SLE through generation of autoreactive plasma cells
Bibliographic record
Abstract
Background The etiology of systemic lupus erythematosus (SLE) is unclear, though dysregulated B cells play a key role. Several unconventional B cell subsets that associate with autoantibodies have been described in SLE. The aim of this study was to further evaluate B cell subsets in SLE and their connection to autoreactive specificities and disease manifestations. Methods The frequency and phenotype of CD11c+Tbet+B cells were determined by flow cytometry. Autoantibodies were measured at the UT Southwestern core facility. The presence of CD11c+B cells in nephritic kidney was determined with IHC. IgH repertoires and mutational frequencies as well as transcriptome profile of CD11c+B cells were analyzed from RNA isolated from CD11c+B cells from SLE patients and compared to other B cell subsets from the same individual. Purified B cells from HD or SLE donors were cultured with either CD3-activated T cells or IL-21 co-stimulation and evaluated for B cell phenotype or production of auto-antibodies. Results We found a CD11c hi T-bet +B cell subset highly expanded in SLE with a unique expression profile including chemokine receptors consistent with migration to target tissues. Notably, these cells were enriched for autoreactive specificities, present in nephrotic kidney and significantly correlated with specific clinical manifestations. IL-21 was a potent inducer of CD11c hi T-bet +B cells that further promoted the differentiation of these cells into Ig-secreting plasma cells. IgH repertoire analysis showed CD11c hi T-bet +B cells displayed a diverse repertoire with high levels of somatic hypermutation similar to memory B cells and plasma cells. This diverse repertoire suggests that CD11c hi T-bet +B cells accumulate in response to a plethora of antigens overtime, including self-antigens in SLE. Conclusions These results show that CD11c-hi T-bet +B cells are polyclonally expanded, and highly somatically hypermutated in SLE. Furthermore, IL-21 may be involved in their expansion and differentiation into autoreactive plasma cells, which in turn may contribute to autoimmune manifestations in SLE. Funding Source(s): This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and National Institute of Arthritis and Musculoskeletal and Skin Diseases and MedImmune, LLC.
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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) | 0.003 | 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".