Ongoing Immunoglobulin Class Switch DNA Recombination in Lupus B Cells: Analysis of Switch Regulatory Regions
Bibliographic record
Abstract
Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated by class-switched autoantibodies reactive with nucleic acids, nucleic acid-binding proteins, phospholipids and other self-antigens. While some healthy individuals produce IgM antibodies with specificities similar to those of lupus patients, immunoglobulin class switching to mature downstream isotypes appears to be required for the generation of pathogenic autoantibodies. To characterize the cellular and molecular basis of pathogenic autoantibody production in SLE, we studied the capacity of peripheral blood B cells of naive phenotype from patients with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously switch to IgG and IgA. In addition, we determined the DNA sequences of the upstream evolutionary conserved sequence (ECS)-Igamma promoter regulatory regions that control germline IH-CH transcription and class switch DNA recombination (CSR) to IgG1, IgG2 and IgG4. IgM+IgD+ B cells from patients with SLE, but not those from RA or healthy control subjects, underwent spontaneous CSR, as assessed by expression of germline Igamma1-Cgamma1, Igamma2-Cgamma2, Igamma3-Cgamma3, Igamma4-Cgamma4 and Ialpha1-Calpha1 transcripts, mature (switched) VHDJH-Cgamma1, VHDJH-Cgamma2, VHDJH-Cgamma3 and VHDJH-Calpha1 transcripts and secreted IgG and IgA. Although polymorphic DNA sequences were identified in the ECS-Igamma1, ECS-Igamma2 and ECS-Igamma4 promoter regions, the transcription factor-binding sites that mediate germline Igamma-Cgamma transcription were conserved in patients and controls. However, distinct patterns of nuclear protein binding to an ECS-Igamma promoter sequence that contains both positive and negative regulatory elements were observed in SLE patients and controls. These results support a role for exogenous signals, such as through CD40 ligation, rather than altered genomic sequence, in the increased production of class switched autoantibodies in SLE.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".