Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the α‐synuclein‐elicited immune response
Bibliographic record
Abstract
We have investigated the potential role of molecular chaperones as modulators of the immune response by using α‐synuclein (αSyn) as an aggregation‐prone model protein. We first performed an in vitro immunoscreening with 21 preselected candidate chaperones and selected 2 from this set as displaying immunological activity with differential profiles, Grp94/Gp96 and FKBP4/52. We then immunized mice with both chaperone/α‐synuclein combinations using monomeric or oligomeric α‐synuclein (MαSyn or OαSyn, respectively), and we characterized the immune response generated in each case. We found that Grp94 promoted αSyn‐specific T‐helper (T h )1/T h 17 and IgG1 antibody responses (up to a 3‐fold increase) with MαSyn and OαSyn, respectively, coupled to a T h 2‐type general phenotype (generating 2.5‐fold higher IgG1/IgG2 levels). In addition, we observed that FKBP4 favored a T h 1‐skewed phenotype with MαSyn but strongly supported a T h 2‐type phenotype with OαSyn (with a 3‐fold higher IL‐10/IFN‐γ serum levels). Importantly, results from adoptive transfer of splenocytes from immunized animals in a Parkinson's disease mouse model indicates that these effects are robust, stable in time, and physiologically relevant. Taken together, Grp94 and FKBP4 are able to generate differential immune responses to α‐synuclein‐based immunizations, depending both on the nature of the chaperone and on the aggregation state of α‐synuclein. Our work reveals that several chaperones are potential modulators of the immune response and suggests that different chaperones could be exploited to redirect the amyloid‐elicited immunity both for basic studies of the immunological processes associated with neurodegeneration and for immunotherapy of pathologies associated with protein misfolding and aggregation.—Labrador‐Garrido, A., Cejudo‐Guillen, M., Daturpalli, S., Leal, M. M., Klippstein, R., De Genst, E. J., Villadiego, J., Toledo‐Aral, J. J., Dobson, C. M., Jackson, S. E., Pozo, D., Roodveldt, C. Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the α‐synuclein‐elicited immune response. FASEB J. 30, 564‐577 (2016). www.fasebj.org
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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) | 0.001 | 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".