{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:04:22Z","timestamp":1785434662139,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,15]]},"group-title":"Immunology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["NIH5T32AI1I8684-09"],"award-info":[{"award-number":["NIH5T32AI1I8684-09"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Pediatric Physician Scientist Development Program"],"award-info":[{"award-number":["Pediatric Physician Scientist Development Program"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Lupus nephritis (LN) is a leading cause of morbidity in pediatric systemic lupus erythematosus (pSLE) due to suboptimal kidney remission rates and the sequelae of prolonged intensive immunosuppressive therapy. LN is patchy, with some glomeruli severely damaged while others remain histologically unaffected in the same kidney. Using spatial transcriptomic technology, we interrogated microanatomic transcriptional differences between histologically damaged and unaffected glomeruli in pSLE LN to understand local drivers of renal injury. Despite SLE being a disease of Type I interferon (IFN), IFN gene response does not associate with local glomerular damage. Rather, damage associates with a transcriptional module of higher expression of myeloid cell markers,\n                  <jats:italic>C5AR1<\/jats:italic>\n                  (encoding the receptor for complement component 5a [C5a]), early complement components, and fibrosis genes. Bulk RNA-sequencing of C5a stimulated human monocyte-derived-macrophages revealed upregulation of tissue-remodeling and fibrosis-related pathways reversible by the C5aR1 inhibiting drug avacopan. These same C5a-inducible fibrosis genes were significantly upregulated in histologically damaged versus unaffected LN glomeruli providing a mechanistic link between C5a-C5aR1 signaling and early fibrosis in proliferative lupus nephritis. Our data provide insight into an understudied connection between complement activation and fibrosis relevant in SLE and likely other inflammatory diseases of complement activation.\n                <\/jats:p>","DOI":"10.64898\/2026.03.12.711136","type":"posted-content","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T02:50:20Z","timestamp":1773629420000},"source":"Crossref","is-referenced-by-count":0,"title":["Damaged glomeruli in proliferative pediatric lupus nephritis exhibit a C5a-C5aR1 induced fibrotic transcriptional program"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2304-7739","authenticated-orcid":false,"given":"Sarah","family":"McCuaig","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Easton","family":"Elliott","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2419-0585","authenticated-orcid":false,"given":"Seth","family":"Anderson","sequence":"additional","affiliation":[{"name":"Perleman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0755-8897","authenticated-orcid":false,"given":"Julia","family":"Rood","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jael","family":"Gaines","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Portia A","family":"Kreiger","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4603-7963","authenticated-orcid":false,"given":"Edward M","family":"Behrens","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026031804450632000_2026.03.12.711136v1.1","doi-asserted-by":"publisher","DOI":"10.1177\/0961203311416694"},{"issue":"6","key":"2026031804450632000_2026.03.12.711136v1.2","first-page":"1377","article-title":"Kidney outcomes for children with lupus nephritis","volume":"36","year":"2020","journal-title":"Pediatric Nephrology"},{"issue":"6","key":"2026031804450632000_2026.03.12.711136v1.3","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1093\/rheumatology\/keab746","article-title":"Defining renal remission in an international cohort of 248 children and adolescents with lupus nephritis","volume":"61","year":"2022","journal-title":"Rheumatology"},{"key":"2026031804450632000_2026.03.12.711136v1.4","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.210391"},{"key":"2026031804450632000_2026.03.12.711136v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/art.22044"},{"key":"2026031804450632000_2026.03.12.711136v1.6","doi-asserted-by":"crossref","unstructured":"Castellano G , Cafiero C , Divella C , Sallustio F , Gigante M , Pontrelli P , et al. Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells. Arthritis Research & Therapy. 2015;17(1).","DOI":"10.1186\/s13075-015-0588-3"},{"issue":"7","key":"2026031804450632000_2026.03.12.711136v1.7","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1093\/rheumatology\/keac641","article-title":"Type I interferon and neutrophil transcripts in lupus nephritis renal biopsies: clinical and histopathological associations","volume":"62","year":"2023","journal-title":"Rheumatology"},{"issue":"10","key":"2026031804450632000_2026.03.12.711136v1.8","doi-asserted-by":"crossref","first-page":"6831","DOI":"10.4049\/jimmunol.0900742","article-title":"Type I Interferons Produced by Resident Renal Cells May Promote End-Organ Disease in Autoantibody-Mediated Glomerulonephritis","volume":"183","year":"2009","journal-title":"The Journal of Immunology"},{"issue":"12","key":"2026031804450632000_2026.03.12.711136v1.9","doi-asserted-by":"crossref","first-page":"5976","DOI":"10.4049\/jimmunol.1201477","article-title":"Anti\u2013IFN-\u03b1\/\u03b2 Receptor Antibody Treatment Ameliorates Disease in Lupus-Predisposed Mice","volume":"189","year":"2012","journal-title":"The Journal of Immunology"},{"key":"2026031804450632000_2026.03.12.711136v1.10","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221478"},{"key":"2026031804450632000_2026.03.12.711136v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00443.x"},{"key":"2026031804450632000_2026.03.12.711136v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.11.023"},{"issue":"7","key":"2026031804450632000_2026.03.12.711136v1.13","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/art.42829","article-title":"A Multilayered Post-Genome-Wide Association Study Analysis Pipeline Defines Functional Variants and Target Genes for Systemic Lupus Erythematosus","volume":"76","year":"2024","journal-title":"Arthritis Rheumatol"},{"issue":"8","key":"2026031804450632000_2026.03.12.711136v1.14","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1080\/08916934.2022.2103800","article-title":"HERC6 is upregulated in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and promotes the disease progression","volume":"55","year":"2022","journal-title":"Autoimmunity"},{"key":"2026031804450632000_2026.03.12.711136v1.15","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.2147\/JIR.S419880","article-title":"Identification and Clinical Correlation Analysis of IFI44 in Systemic Lupus Erythematosus Combined with Bioinformatics and Immune Infiltration Analysis","volume":"16","year":"2023","journal-title":"J Inflamm Res"},{"key":"2026031804450632000_2026.03.12.711136v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0398-x"},{"key":"2026031804450632000_2026.03.12.711136v1.17","doi-asserted-by":"crossref","unstructured":"Abraham R , Durkee MS , Ai J , Veselits M , Casella G , Asano Y , et al. Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis. J Clin Invest. 2022;132(13).","DOI":"10.1172\/JCI155350"},{"issue":"6","key":"2026031804450632000_2026.03.12.711136v1.18","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/acr.20441","article-title":"Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring","volume":"63","year":"2011","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"2026031804450632000_2026.03.12.711136v1.19","doi-asserted-by":"crossref","unstructured":"Gartshteyn Y , Wang S , Geraldino-Pardilla L , Mor A , D\u2019Agati VD , Winchester R . Tubulointerstitial inflammation driving interstitial fibrosis and tubular atrophy predicts poor renal outcome in refractory lupus nephritis. Rheumatology (Oxford). 2026;65(1).","DOI":"10.1093\/rheumatology\/keaf530"},{"key":"2026031804450632000_2026.03.12.711136v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.06.002"},{"key":"2026031804450632000_2026.03.12.711136v1.21","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013060664"},{"key":"2026031804450632000_2026.03.12.711136v1.22","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00203.2018"},{"key":"2026031804450632000_2026.03.12.711136v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.10363"},{"key":"2026031804450632000_2026.03.12.711136v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adl1666"},{"key":"2026031804450632000_2026.03.12.711136v1.25","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.add8945"},{"key":"2026031804450632000_2026.03.12.711136v1.26","doi-asserted-by":"crossref","unstructured":"Alasoo K , Martinez FO , Hale C , Gordon S , Powrie F , Dougan G , et al. Transcriptional profiling of macrophages derived from monocytes and iPS cells identifies a conserved response to LPS and novel alternative transcription. Sci Rep. 2015;5:12524.","DOI":"10.1038\/srep12524"},{"key":"2026031804450632000_2026.03.12.711136v1.27","doi-asserted-by":"crossref","unstructured":"Sokhi UK , Yuan R , Mishra B , Chinenov Y , Singaraju A , Chan KK , et al. Opposing regulation of TNF responses by IFN-\u03b3 and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1\u03b2+ macrophages. Elife. 2025;14.","DOI":"10.7554\/eLife.104367.3"},{"key":"2026031804450632000_2026.03.12.711136v1.28","unstructured":"Madhu R BR , STEIN D, Cao J , Tsoi A , Marlin C , Eisenhaure T , Izmirly P , Masson M , Wei K , Werth V , Barnas J , Brenner M , James J , Gudjonsson J , Guthridge J , Hacohen N , Ruggles K , Raychaudhuri S , Buyon J , Petri M , Rovin B , Fava A , Korsunsky i. Integrated spatial and single-cell profiling of treatment-na\u00efve lupus nephritis biopsies [abstract]. Arthritis Rheumatol. 2025;77."},{"key":"2026031804450632000_2026.03.12.711136v1.29","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abn2263"},{"issue":"2","key":"2026031804450632000_2026.03.12.711136v1.30","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1093\/bjd\/ljad089","article-title":"Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers","volume":"189","year":"2023","journal-title":"Br J Dermatol"},{"issue":"11","key":"2026031804450632000_2026.03.12.711136v1.31","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1177\/09612033241273023","article-title":"Anifrolumab for systemic lupus erythematosus with multi-refractory skin disease: A case series of 18 patients","volume":"33","year":"2024","journal-title":"Lupus"},{"key":"2026031804450632000_2026.03.12.711136v1.32","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2007.04.012"},{"key":"2026031804450632000_2026.03.12.711136v1.33","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-0989-y"},{"key":"2026031804450632000_2026.03.12.711136v1.34","doi-asserted-by":"crossref","first-page":"102979","DOI":"10.1016\/j.jaut.2022.102979","article-title":"The complement system and human autoimmune diseases","volume":"137","year":"2023","journal-title":"J Autoimmun"},{"key":"2026031804450632000_2026.03.12.711136v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.03.003"},{"key":"2026031804450632000_2026.03.12.711136v1.36","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005040373"},{"key":"2026031804450632000_2026.03.12.711136v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200526327"},{"key":"2026031804450632000_2026.03.12.711136v1.38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.16.8563"},{"key":"2026031804450632000_2026.03.12.711136v1.39","doi-asserted-by":"crossref","unstructured":"Ramasamy A , Mohan C . Molecular and Cellular Mediators of Renal Fibrosis in Lupus Nephritis. Int J Mol Sci. 2025;26(6).","DOI":"10.3390\/ijms26062621"},{"key":"2026031804450632000_2026.03.12.711136v1.40","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201500044"},{"key":"2026031804450632000_2026.03.12.711136v1.41","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.05.012"},{"key":"2026031804450632000_2026.03.12.711136v1.42","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12024"},{"issue":"8","key":"2026031804450632000_2026.03.12.711136v1.43","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/ndt\/gfx336","article-title":"Complement C5a inhibition moderates lipid metabolism and reduces tubulointerstitial fibrosis in diabetic nephropathy","volume":"33","year":"2018","journal-title":"Nephrol Dial Transplant"},{"issue":"1","key":"2026031804450632000_2026.03.12.711136v1.44","doi-asserted-by":"crossref","first-page":"F35","DOI":"10.1152\/ajprenal.00060.2017","article-title":"Complement C5a receptors C5L2 and C5aR in renal fibrosis","volume":"314","year":"2018","journal-title":"Am J Physiol Renal Physiol"},{"key":"2026031804450632000_2026.03.12.711136v1.45","unstructured":"Genomics x. Loupe Browser [Software]. Version 8.1.1 ed: 10x Genomics; 2025."},{"key":"2026031804450632000_2026.03.12.711136v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.12.711136","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:45:23Z","timestamp":1773834323000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.12.711136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,15]]},"references-count":46,"URL":"https:\/\/doi.org\/10.64898\/2026.03.12.711136","relation":{},"subject":[],"published":{"date-parts":[[2026,3,15]]},"subtype":"preprint"}}