Homocitrullinated Peptides Drive Pro-Inflammatory T-Cell Responses in a Humanized Mouse Model of Rheumatoid Arthritis
Bibliographic record
Abstract
OBJECTIVE: Anti-homocitrullinated protein/peptide antibodies are specific to rheumatoid arthritis (RA) and predictive of worse prognosis, suggesting a pathogenic role for autoreactivity to homocitrullinated peptides (HomoCitP). However, T cell responses to HomoCitP remain largely unexplored. We investigated these responses in a humanized HLA-DRB1*04-transgenic (DR4tg) mouse model of RA, which expresses the strongest genetic risk factor for this disease. METHODS: DR4tg mice (n = 6-15) were injected subcutaneously with a HomoCitP called HomoCitJED, whereas control mice received phosphate-buffered saline. After 10 days, T cells were analyzed for their phenotypic characteristics, cytokine production, and proliferative capacities in draining lymph nodes (dLNs) and spleens by flow cytometry, enzyme-linked immunosorbent assays, and ProQuantum immunoassays. RESULTS: HomoCitJED immunization, compared with controls, drove robust expansion of T helper subsets in the dLNs, including more than a seven-fold increase in Th1, Th17, and hybrid Th1/Th17 cells (P < 0.0087). Cytokine staining confirmed effector activity, with higher frequencies of IL-17A+, TNF-α+IL-17A+, and IFN-γ+IL-17A+ cells (P < 0.0207). Exhaustion-associated markers were also increased, including lymphocyte activation gene-3 (LAG-3)+ and T cell Ig and mucin-domain-containing protein 3 (Tim-3)+ CD4+ T cells (P < 0.0411). CD8+ T cells mirrored these findings, with a six-fold increase in CD25 and doubled killer cell lectin-like receptor G1 (KLRG1) expression, accompanied by augmented IL-17A and IFN-γ/IL-17A production and antigen-specific proliferation (P < 0.0379). Expression of exhaustion-associated markers Tim-3+ and LAG-3+ on CD8+ T cells was likewise elevated (P < 0.0205). CONCLUSION: HomoCitP elicited Th1/Th17 and Tc1/Tc17 responses marked by concurrent expression of activation and exhaustion-associated markers, consistent with a dysregulated state. These findings position homocitrulline-driven CD4+ and CD8+ T cell imbalance as a potential mechanistic contributor to RA pathogenesis and a target for future immunomodulatory therapies.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".