<scp>d</scp>-Penicillamine-Induced Autoimmunity: Relationship to Macrophage Activation
Bibliographic record
Abstract
Idiosyncratic drug reactions represent a serious health problem, and they remain unpredictable largely due to our limited understanding of the mechanisms involved. Penicillamine-induced autoimmunity in Brown Norway (BN) rats represents one model of an idiosyncratic reaction, and this drug can also cause autoimmune reactions in humans. We previously demonstrated that penicillamine binds to aldehydes on the surface of macrophages. There is evidence that an imine bond formed by aldehyde groups on macrophages and amine groups on T cells is one type of interaction between these two cells that is involved in the induction of an immune response. We proposed that the binding of penicillamine with aldehyde groups on macrophages could lead to their activation and in some patients could lead to autoimmunity. In this study, the transcriptome profile of spleen macrophages 6 h after penicillamine treatment was used to detect effects of penicillamine on macrophages with a focus on 20 genes known to be macrophage activation biomarkers. One biological consequence of macrophage activation was investigated by determining mRNA levels for IL-15 and IL-1 beta which are crucial for NK cell activation, as well as levels of mRNA for selected cytokines in spleen NK cells. Up-regulation of the macrophage activating cytokines, IFN-gamma and GM-CSF, and down-regulation of IL-13 indicated activation of NK cells, which suggests a positive feedback loop between macrophages and NK cells. Furthermore, treatment of a murine macrophage cell line, RAW264.7, with penicillamine increased the production of TNF-alpha, IL-6, and IL-23, providing additional evidence that penicillamine activates macrophages. Hydralazine and isoniazid cause a lupus-like syndrome in humans and also bind to aldehyde groups. These drugs were also found to activate RAW264.7 macrophages. Together, these data support the hypothesis that drugs that bind irreversibly with aldehydes lead to macrophage activation, which in some patients can lead to an autoimmune syndrome.
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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 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.003 |
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".