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TLR7-mediated autoimmunity targets Robo3 to drive astrogliosis in frontotemporal dementia
Huang E, Lu R, Choi J, Jahan N, Imhof I, Collo S, Eguiguren S, Zhang J et al.. Research Square, 2026-10-07
Topic: Inflammation, microglia and astrocytes
Mutations in GRN and C9orf72 are common causes of frontotemporal dementia (FTD). While it is well-recognized that GRN or C9orf72 mutations also increase the risk of autoimmune diseases, the intersection of innate and adaptive immunity, neuroinflammation, and neurodegeneration in FTD remains unclear. Here we show that concurrent loss of Grn and C9orf72 breaks immune tolerance by activating the pattern recognition receptor, TLR7, leading to clonal expansion of age-associated B cells and activated B cells. Grn-/-;C9orf72-/- B cells exhibited heightened responses upon TLR7 activation and produced autoantibodies that target the axon guidance receptor Robo3 to promote astroglial pathology. Interestingly, immunization with Robo3 extracellular domain in young Grn-/-;C9orf72-/- mice accelerated astrogliosis. Conversely, TLR7 antagonist M5049 treatment rescued B cell defects, reduced anti-Robo3 autoantibodies, and mitigated astrogliosis and synaptic loss in Grn-/-;C9orf72-/- mice. Together, these results offer critical insights into how TLR7-mediated autoimmune dysfunction targets Robo3 to drive neuroinflammation and neurodegeneration in FTD.
Key findings
- Together, these results offer critical insights into how TLR7-mediated autoimmune dysfunction targets Robo3 to drive neuroinflammation and neurodegeneration in FTD.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Huang, E., Lu, R., Choi, J., Jahan, N., Imhof, I., Collo, S., et al. (2026). TLR7-mediated autoimmunity targets Robo3 to drive astrogliosis in frontotemporal dementia. Research Square. https://doi.org/10.21203/rs.3.rs-11236688/v1
Vancouver
Huang E, Lu R, Choi J, Jahan N, Imhof I, Collo S, et al. TLR7-mediated autoimmunity targets Robo3 to drive astrogliosis in frontotemporal dementia. Research Square. 2026. doi:10.21203/rs.3.rs-11236688/v1.
BibTeX
@article{huang2026-f63e9b8e,
author = {Huang, E. and Lu, R. and Choi, J. and Jahan, N. and Imhof, I. and Collo, S. and Eguiguren, S. and Zhang, J. and others},
title = {{TLR7-mediated autoimmunity targets Robo3 to drive astrogliosis in frontotemporal dementia}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11236688/v1},
url = {https://doi.org/10.21203/rs.3.rs-11236688/v1}
}
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