II-16 Protection of lupus nephritis by IRHOM2 deficiency in <i>FCRγIIB-/-</i> mice
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
<h3>Background</h3> Lupus nephritis (LN) is a major cause of morbidity and mortality in lupus. A disintegrin and metalloprotease 17 (ADAM17), is a principal membrane-anchored metalloprotease that cleaves a large spectrum of membrane-bound proteins into their soluble forms. Inactive rhomboid protein 2 (iRhom2), a newly identified regulator of ADAM17, controls maturation and function of ADAM17. Interestingly, in iRhom2<sup>−</sup><sup>/<b>−</b></sup> mice, loss of ADAM17-dependent shedding activity is limited to the immune organs. Accumulating evidence has shown increased protein shedding and possibly activation of ADAM17 in lupus. Among ADAM17 substrates, tumour necrosis factor α (TNF-α) and heparin-binding EGF (HB-EGF) have been reported to play important roles in mediating renal damage in lupus. We hypothesised that the activation of iRhom2/ADAM17 pathway plays a role in the pathogenesis of lupus nephritis. <h3>Materials and methods</h3> We crossed <i>iRhom2<sup>−</sup><sup>/<b>−</b></sup></i> mice with the well-established <i>FcRγIIB-/-</i> lupus-prone mice, and assessed development of lupus-like syndrome in these mice. <h3>Results</h3> We found that <i>iRhom2</i> deficiency protects <i>FcRγIIB<sup>−</sup><sup>/<b>−</b></sup></i> mice from severe kidney damage (Figure 1), with minimal impact on the production of anti-double stranded (ds) DNA antibodies and renal deposition of immune complex and complement C3. In the absence of iRhom2, glomerular and tubule-interstitial structures were preserved, and massive inflammatory infiltrates including myeloid and CD4<sup>+</sup> T cells were alleviated in the lupus kidneys. Protection of kidney injury by <i>iRhom2</i> deficiency is associated with reduced EGFR signalling and ERK1/2 activation in the kidneys of <i>FcRγIIB<sup>−</sup><sup>/<b>−</b></sup></i> mice. Transcriptome analysis of the whole kidneys as well as kidney macrophages from <i>FcRγIIB<sup>−</sup><sup>/<b>−</b></sup></i> mice identified genes encoding pro-inflammatory cytokine/chemokines, fibrosis and tissue remodelling highly upregulated, and many of these genes were significantly reduced in the absence of <i>iRhom2</i>. In addition, kidney biopsies from patients with lupus nephritis show intense staining for HB-EGF, an EGFR ligand, in areas of crescents. <h3>Conclusions</h3> Our findings here provide the first evidence that iRhom2, a major regulator of ADAM17, plays a critical role in the pathogenesis of LN. The role of iRhom2 in a spontaneous chronic mouse model of LN, <i>FcRγIIB</i><sup>−</sup><sup>/<b>−</b></sup> mice, appears to be targeting at the effector arm of the disease, rather than affecting the process of autoimmunity development. iRhom2 may be a potential therapeutic target in LN. <h3>Acknowledgements</h3> Work supported by Lupus Research Institute (JES and CB) and Barbara Volcker Centre of Hospital for Special Surgery (XQ).
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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 | 0.000 | 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) | 0.000 | 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 it