Mechanisms of demyelination and axonal damage in a CD8+ T cell-mediated model of spontaneous demyelinating disease
Bibliographic record
Abstract
Autoimmune demyelinating diseases of the nervous system are a major cause for neurological impairment in humans. Recent evidence indicates that CD8+ T cells may contribute significantly to pathogenesis in these conditions but the mechanisms by which CD8+ T cells induce damage remain to be established. To understand the mechanisms by which CD8+ T cells may induce nervous tissue injury in vivo, we study an animal model (referred to as L31) that spontaneously develops CD8+ T cell-mediated demyelination and axonal damage in the central nervous system (CNS). In this project, we revealed that CD8+ T cells located in clusters at specific sites within the CNS of L31 mice and their location was associated with areas of demyelination. We showed that oligodendrocytes, but not neurons, from L31 mice up-regulated their expression of major histocompatibility complex class I (MHC I) molecules and had thus the potential to interact with CNS-infiltrating CD8+ T cells in a MHC I-dependent manner before clinical manifestations of disease. We reported that active caspase 3 was present in oligodendrocytes, suggesting that oligodendrocytes undergo apoptosis in L31 mice. We found that CNS-infiltrating CD8+ T cells from L31 mice were activated effector cells and we provided evidence showing that these cells degranulated in situ; nonetheless, we found that demyelination did not occur through either perforin- or Fas/FasL-dependent mechanisms. We also determined the upregulation of the chemokines CCL5 and CXCL9 and the chemokine receptor CXCR3 in the CNS of L31 mice and established that absence of CXCR3 expression was sufficient to inhibit CD8+ T cell accumulation in the CNS, microglial activation, demyelination and disease development in the L31 model, although CXCR3 deficiency did not alter the functional phenotype of transgenic CD8+ T cells. In addition, no compensatory effect for CCR5 could be detected in L31 mice. Finally, we established the presence of CD8+ T cells and tissue damage
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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 | 0.000 |
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".