Rethinking the Benign Nature of Class II Lupus Nephritis
Abstract
Introduction: Class II lupus nephritis (LN) is considered clinically benign, yet up to 50% of patients progress to more severe disease and no molecular characterization exists. We aimed to define the single-cell landscape of Class II LN and identify cellular and transcriptional features associated with kidney outcome. Methods: We performed single-cell RNA sequencing on kidney biopsies from fifteen Class II LN patients (eight de novo, seven regressed from prior proliferative or membranous disease) and six healthy controls, integrated with 155 LN and 30 healthy-control samples from the Accelerating Medicines Partnership in SLE spanning proliferative, membranous, and mixed LN. Findings were correlated with 52-week renal response and supported by urinary proteomics. Results: Despite histologically minimal changes, Class II LN exhibited marked immune cell expansion comparable to proliferative and membranous LN, including CCL3+ CCL4+ intermediate monocytes producing TNF, FOLR2+ SIGLEC1+ macrophages producing TGF{beta} and PDGF, and CD69+ CD8+ effector memory T cells producing IFN{gamma}. Fibroblasts and myofibroblasts were significantly expanded and displayed divergent transcriptional programs: pro-fibrotic and inflammatory myofibroblast modules were associated with worse 52-week outcomes, while interferon-responsive and matrix-remodeling fibroblast programs were associated with improvement. Pathogenic and protective fibroblast populations received overlapping immune-derived signals, suggesting that fibroblast transcriptional state, rather than the identity of incoming signals, shapes the stromal response. Baseline chronicity index captured this stromal heterogeneity and was the clinical parameter most associated with outcome. Urinary proteomics aligned Class II with proliferative rather than membranous disease. Conclusions: Class II LN harbors substantial molecular activity not captured by routine histology. Fibroblast transcriptional programs and baseline chronicity index are candidate correlates of kidney outcome that warrant validation in larger, prospectively followed cohorts.
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BibTeX
@misc{shwetar2026rethinking,
title = {{Rethinking the Benign Nature of Class II Lupus Nephritis}},
author = {J. J. Shwetar and A. Fava and S. Keegan and P. M. Carlucci and J. N. Dudley and L. Lama and H. Suryawanshi and P. Morozov and B. J. Mullins and A. Amarnani and L. Procell and D. Annuar and S. Gurajala and P. M. Izmirly and J. A. James and J. M. Guthridge and T. M. Eisenhaure and A. Arazi and C. Putterman and D. A. Rao and B. Diamond and H. M. Belmont and W. Apruzzese and A. Davidson and S. Raychaudhuri and N. Hacohen and M. Dall'Era and C. Loomis and R. M. Clancy and T. Tuschl and M. Wu and D. M. Fine and M. G. Atta and J. Monroy-Trujillo and R. Furie and D. L. Kamen and K. Kalunian and Accelerating Medicine Partnership in RA/SLE and M. Petri and J. P. Buyon and Rovin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.13.751280},
url = {https://www.biorxiv.org/content/10.64898/2026.09.13.751280v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Rethinking the Benign Nature of Class II Lupus Nephritis
AU - J. J. Shwetar
AU - A. Fava
AU - S. Keegan
AU - P. M. Carlucci
AU - J. N. Dudley
AU - L. Lama
AU - H. Suryawanshi
AU - P. Morozov
AU - B. J. Mullins
AU - A. Amarnani
AU - L. Procell
AU - D. Annuar
AU - S. Gurajala
AU - P. M. Izmirly
AU - J. A. James
AU - J. M. Guthridge
AU - T. M. Eisenhaure
AU - A. Arazi
AU - C. Putterman
AU - D. A. Rao
AU - B. Diamond
AU - H. M. Belmont
AU - W. Apruzzese
AU - A. Davidson
AU - S. Raychaudhuri
AU - N. Hacohen
AU - M. Dall'Era
AU - C. Loomis
AU - R. M. Clancy
AU - T. Tuschl
AU - M. Wu
AU - D. M. Fine
AU - M. G. Atta
AU - J. Monroy-Trujillo
AU - R. Furie
AU - D. L. Kamen
AU - K. Kalunian
AU - Accelerating Medicine Partnership in RA/SLE
AU - M. Petri
AU - J. P. Buyon
AU - Rovin
PY - 2026
DA - 2026/09/13
PB - bioRxiv
DO - 10.64898/2026.09.13.751280
UR - https://www.biorxiv.org/content/10.64898/2026.09.13.751280v1
AB - Introduction: Class II lupus nephritis (LN) is considered clinically benign, yet up to 50% of patients progress to more severe disease and no molecular characterization exists. We aimed to define the single-cell landscape of Class II LN and identify cellular and transcriptional features associated with kidney outcome. Methods: We performed single-cell RNA sequencing on kidney biopsies from fifteen Class II LN patients (eight de novo, seven regressed from prior proliferative or membranous disease) and six healthy controls, integrated with 155 LN and 30 healthy-control samples from the Accelerating Medicines Partnership in SLE spanning proliferative, membranous, and mixed LN. Findings were correlated with 52-week renal response and supported by urinary proteomics. Results: Despite histologically minimal changes, Class II LN exhibited marked immune cell expansion comparable to proliferative and membranous LN, including CCL3+ CCL4+ intermediate monocytes producing TNF, FOLR2+ SIGLEC1+ macrophages producing TGF{beta} and PDGF, and CD69+ CD8+ effector memory T cells producing IFN{gamma}. Fibroblasts and myofibroblasts were significantly expanded and displayed divergent transcriptional programs: pro-fibrotic and inflammatory myofibroblast modules were associated with worse 52-week outcomes, while interferon-responsive and matrix-remodeling fibroblast programs were associated with improvement. Pathogenic and protective fibroblast populations received overlapping immune-derived signals, suggesting that fibroblast transcriptional state, rather than the identity of incoming signals, shapes the stromal response. Baseline chronicity index captured this stromal heterogeneity and was the clinical parameter most associated with outcome. Urinary proteomics aligned Class II with proliferative rather than membranous disease. Conclusions: Class II LN harbors substantial molecular activity not captured by routine histology. Fibroblast transcriptional programs and baseline chronicity index are candidate correlates of kidney outcome that warrant validation in larger, prospectively followed cohorts.
ER -