The role of b2-glycoprotein i-reactive t cells in the development of systemic lupus erythematosus
Bibliographic record
Abstract
This thesis examines the role of β2-glycoprotein I (β2GPI)-reactive T cells in the development of systemic lupus erythematosus (SLE). SLE is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting phospholipids and phospholipid-binding proteins, particularly β2-glycoprotein I (β2GPI). Our laboratory has developed a model of SLE in which mice immunized with β2GPI and lipopolysaccharide (LPS) display a remarkably similar pattern of autoantibody emergence to that seen in human SLE, as well as SLE-like kidney disease. Here we use this model to investigate whether epitope spread to SLE autoantibodies is associated with a unique or limited β2GPI-reactive T cell response. We ask whether MHC class II haplotype, and its associated T cell epitope restriction, impacts epitope spread to SLE autoantibodies. Furthermore, we investigate the origin of β2GPI-reactive T cells initiating this epitope spread. We hypothesize that binding of β2GPI to necroptotic cells presents the immune system with a "scaffold" of cellular self-antigens in a pro-inflammatory and immunogenic context, leading to a robust β2GPI-reactive T cell response. Splenocytes from β2GPI/LPS-immunized mice with different MHC class II haplotypes were used to determine β2GPI-reactive T cell epitopes, using a peptide library spanning the entire sequence of human β2GPI. One β2GPI-reactive T cell epitope (LYRDTAVFECLPQHAMFG) in Domain III appeared to be a dominant epitope, since it was recognized in β2GPI/LPS-immunized mice with different MHC class II haplotypes, as well as in SLE-prone MRL/lpr mice. We next showed that β2GPI binds to necroptotic, as well as apoptotic, L929 cells but that necroptotic, not apoptotic, cells enhance pro-inflammatory cytokine (TNF-α) secretion by activated macrophages and dendritic cells in vitro. Necroptotic cells promoted MHC class II and costimulatory molecule expression in immature dendritic cells, leading to an enhanced CD4 T cell response to β2GPI in vitro. Finally, we show that mice deficient in Ripk3 (receptor-interacting serine/threonine-protein kinase 3), and hence necroptosis, show poor induction of SLE. In summary, we propose that factors enabling a β2GPI-reactive T cell response may predispose individuals to the development of SLE autoantibodies independent of their MHC class II haplotype. Furthermore, our findings suggest that necroptotic cells provide both self-antigens and pro-inflammatory signals that may be sufficient to overcome immune tolerance and induce SLE.
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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".