An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases
Bibliographic record
Abstract
The last 15 years have seen an explosion of new findings on the role of complement, a major arm of the immune system, in the central nervous system (CNS) compartment including contributions to cell migration, elimination of synapse during development, aberrant synapse pruning in neurologic disorders, damage to nerve cells in autoimmune diseases, and traumatic injury. Activation of the complement system in multiple sclerosis (MS) is typically thought to occur as part of a primary (auto)immune response from the periphery (the outside) against CNS antigens (the inside). However, evidence of local complement production from CNS-resident cells, intracellular complement functions, and the more recently discovered role of early complement components in shaping synaptic circuits in the absence of inflammation opens up the possibility that complement-related sequelae may start and finish within the brain itself. In this review, the complement system will be introduced, followed by evidence that implicates complement in shaping the developing, adult, and normal aging CNS as well as its contribution to pathology in neurodegenerative conditions. Discussion of data supporting "outside-in" vs. "inside-out" roles of complement in MS will be presented, concluded by thoughts on potential approaches to therapies targeting specific elements of the complement system.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".