{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:00:42Z","timestamp":1780470042720,"version":"3.54.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010751","name":"Indian Rheumatology Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010751","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by unpredictable flares and variable clinical quiescence. Despite validated clinical indices like the British Isles Lupus Assessment Group (BILAG) score, reliable molecular biomarkers for monitoring disease activity remain limited, particularly in underrepresented South Asian populations. Weaimed to identify arobust molecular framework to distinguish SLE flares from remission in an Indian cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a discovery-phase study in an Indian cohort (n=16) stratified by Easy-BILAG scoring. Plasma proteomic profiling via LC-MS\/MS was integrated with targeted cytokine quantification using the Olink Proximity Extension Assay (PEA). Differential expression and network analyses delineated immune-regulatory, hypoxic-vascular, and myeloid-activation pathways. A Random Forest classifier was trained on selected biomarkers and evaluated using leave-one-out cross-validation (LOOCV), permutation testing, and bootstrapped AUROC confidence intervals, with model interpretability assessed by SHAP values. Data are available via ProteomeXchange with identifier PXD075349.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Proteomic comparison identified a compact panel of proteins distinguishing flare from remission, characterized by a molecular polarization; flare states exhibited upregulation of COL18A1 and CSF1 (vascular and myeloid activation), while remission showed sustained expression of cytoskeletal scaffolding and immunoregulatory components, including FLNA, SH3BGRL3, and IGHG4. Cytokine analyses identified coordinated chemokine modules (CXCL9, CCL2, CCL3, and CCL13) preferentially upregulated during flare. The machine-learning model achieved robust internal discrimination with a mean AUROC of 0.96. Notably, a COL18A1 normalized protein expression cut-off yielded 100% specificity and 87.5% sensitivity, acting as an objective \u2018rule-in\u2019 adjunct for active disease. Normalized protein expression (NPX) cut-off yielded 100% specificity and 87.5% sensitivity, acting as an objective \u201crule-in\u201d adjunct for active disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study establishes a parsimonious 5-protein biosignature of candidate leads (COL18A1, HYOU1, IGHG4, FLNA, and SH3BGRL3) that effectively captures the multifactorial pathophysiology of SLE flare. By anchoring discovery in a systematically under sampled Indian population, this work enhances global diversity in lupus biomarker research and establishes a scalable, AI-driven framework for precision assessment of disease activity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1819049","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:01:53Z","timestamp":1780466513000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative plasma proteomics and myeloid- interferon profiling reveal an AI-validated vascular- endothelial stress signature distinguishing SLE flare from remission in an Indian cohort a discovery \u2013 phase study"],"prefix":"10.3389","volume":"17","author":[{"given":"Abhibroto","family":"Karmakar","sequence":"first","affiliation":[{"name":"Department of General Medicine, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]},{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santanu","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachana","family":"Kamath","sequence":"additional","affiliation":[{"name":"Department of General Medicine, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Ravindran","sequence":"additional","affiliation":[{"name":"Department of General Medicine, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]},{"name":"Department of Rheumatology, Centre for Rheumatology","place":["Kozhikode, Kerala, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varashree Bolar","family":"Suryakanth","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smitha","family":"Prabhu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kasturba Medical College, Manipal Academy Higher Education","place":["Manipal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shankar Prasad","family":"Nagaraju","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukhyaprana M.","family":"Prabhu","sequence":"additional","affiliation":[{"name":"Department of General Medicine, Kasturba Medical College, Manipal Academy of Higher Education","place":["Manipal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhradip","family":"Karmakar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-45135-w","article-title":"Immunologic findings precede rapid lupus flare after transient steroid therapy","volume":"9","author":"Lu","year":"2019","journal-title":"Sci Rep"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.1093\/rheumatology\/keab883","article-title":"Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index","volume":"61","author":"Carter","year":"2021","journal-title":"Lara D Veeken"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s2665-9913(23)00010-3","article-title":"Artificial intelligence and high-dimensional technologies in the theragnosis of systemic lupuserythematosus","volume":"5","author":"Yaung","year":"2023","journal-title":"TheLancet Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1002\/art.40930","article-title":"2019 European League Against Rheumatism\/American College of Rheumatology classification criteria for systemic lupus erythematosus","volume":"71","author":"Aringer","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1011","article-title":"The PRIDE database at 20 years: 2025 update","volume":"53","author":"Perez-Riverol","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1161\/01.cir.0000140720.79015.3c","article-title":"Loss of collagen XVIII enhances neovascularization and vascular permeability in atherosclerosis","volume":"110","author":"Moulton","year":"2004","journal-title":"Circulation"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4583","DOI":"10.1021\/acs.biochem.5b00653","article-title":"Decoding the matrix: instructive roles of proteoglycan receptors","volume":"54","author":"Neill","year":"2015","journal-title":"Biochemistry"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-0973-6","article-title":"Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis","volume":"18","author":"Garc\u00eda","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/s12950-023-00342-1","article-title":"Dysregulated endothelial cell markers in systemic lupus erythematosus: a systematic review and meta-analysis","volume":"20","author":"Bergkamp","year":"2023","journal-title":"J Inflammation"},{"key":"B10","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/eji.201646387","article-title":"Mapping urinary chemokines in human lupus nephritis: potentially redundant pathways recruit CD4+ and CD8+ T cells and macrophages","volume":"47","author":"Klocke","year":"2016","journal-title":"Eur J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030491","article-title":"Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus","volume":"3","author":"Bauer","year":"2006","journal-title":"PloS Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.14.25340226","article-title":"Mapping the plasma proteomic architecture of systemic lupus erythematosus","author":"Leung","year":"2025"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04897-w","article-title":"Multi-omics delineation of cytokine-induced endothelial inflammatory states","volume":"6","author":"Groten","year":"2023","journal-title":"Commun Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1038\/nature15367","article-title":"Neutrophil ageing is regulated by the microbiome","volume":"525","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-35157-w","article-title":"Metagenomic sequencing of human cardiac tissue reveals microbial RNA which correlates with Toll-like receptor-associated inflammation in patients with heart disease","volume":"13","author":"Sandstedt","year":"2023","journal-title":"Sci Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1093\/ndt\/gfw446","article-title":"Alterations in urinary collagen peptides in lupus nephritis subjects correlate with renal dysfunction and renal histopathology","volume":"32","author":"Wei","year":"2016","journal-title":"Nephrol Dialysis Transplant"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1038\/s44161-024-00525-w","article-title":"An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury","volume":"3","author":"Fleischer","year":"2024","journal-title":"Nat Cardiovasc Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1186\/s12882-025-04434-3","article-title":"Taming renal inflammation: signaling pathways and therapeutic advances in lupus nephritis","volume":"26","author":"Braunstein","year":"2025","journal-title":"BMC Nephrol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01572","article-title":"Targeting the protective arm of the renin-angiotensin system to reduce systemic lupus erythematosus related pathologies in MRL-lpr mice","volume":"11","author":"Soto","year":"2020","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.172569","article-title":"Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis","volume":"9","author":"Fava","year":"2024","journal-title":"JCI Insight"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.833699","article-title":"Multi-platform omics analysis reveals molecular signatures for pathogenesis and activity of systemic lupus erythematosus","volume":"13","author":"Huang","year":"2022","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1685275","article-title":"Soluble checkpoint molecules as predictive biomarker for disease activity and long-term outcome in SLE","volume":"16","author":"Dreveton","year":"2025","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2102","DOI":"10.1021\/acs.jproteome.5b00905","article-title":"Antibody-array-based proteomic screening of serum markers in systemic lupus erythematosus: a discovery study","volume":"15","author":"Wu","year":"2016","journal-title":"J Proteome Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/s12014-023-09420-1","article-title":"Proteomic analysis identifies subgroups of patients with active systemic lupus erythematosus","volume":"20","author":"Su","year":"2023","journal-title":"Clin Proteomics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"14433","DOI":"10.1038\/s41598-019-50231-y","article-title":"SLE plasma profiling identifies unique signatures of lupus nephritis and discoid lupus","volume":"9","author":"Smith","year":"2019","journal-title":"Sci Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.924766","article-title":"The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus","volume":"13","author":"Qiu","year":"2022","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1346671","article-title":"Exploring the depths of IgG4: insights into autoimmunity and novel treatments","volume":"15","author":"\u00dcnl\u00fc","year":"2024","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.48550\/arxiv.2411.11915","article-title":"Phenome-wide causal proteomics enhance systemic lupus erythematosus flare prediction: a study in Asian populations","author":"Chen","year":"2024","journal-title":"arXiv (Cornell University)"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2025.1664622","article-title":"HLA-G regulation through trogocytosis: intercellular membrane transfer mechanisms and immune dysregulation in systemic lupus erythematosus","volume":"13","author":"Karmakar","year":"2025","journal-title":"Front Cell Dev Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.2147\/ott.s297332","article-title":"Biological function of HYOU1 in tumors and other diseases","volume":"14","author":"Rao","year":"2021","journal-title":"OncoTargets Ther"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-024-03327-4","article-title":"Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states","volume":"26","author":"Wang","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.1242454","article-title":"Fueling immunity: insights into metabolism and lymphocyte function","volume":"342","author":"Pearce","year":"2013","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/s41420-025-02403-1","article-title":"Metabolic reprogram and T cell differentiation in inflammation: current evidence and future perspectives","volume":"11","author":"Shi","year":"2025","journal-title":"Cell Death Discov"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02616-20","article-title":"Designing the next generation of vaccines: relevance for future pandemics","volume":"11","author":"Dom\u00ednguez\u2010Andr\u00e9s","year":"2020","journal-title":"mBio"},{"key":"B35","doi-asserted-by":"publisher","first-page":"14862","DOI":"10.18632\/oncotarget.23206","article-title":"Coagulation cascade and complement system in systemic lupus erythematosus","volume":"9","author":"Liang","year":"2017","journal-title":"Oncotarget"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3268","DOI":"10.1038\/s41598-018-20203-9","article-title":"Longitudinal association of type 1 interferon-induced chemokines with disease activity in systemic lupus erythematosus","volume":"8","author":"Connelly","year":"2018","journal-title":"Sci Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1652211","article-title":"Multi-omics-driven biomarker discovery in autoimmune diseases: a comprehensive review","volume":"16","author":"Zhang","year":"2025","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"28765","DOI":"10.1038\/s41598-024-79978-9","article-title":"Machine learning identifies cytokine signatures of disease severity and autoantibody profilesin systemiclupuserythematosus \u2013apilotstudy","volume":"14","author":"Pattanaik","year":"2024","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0208132","article-title":"Identification of alterations in macrophage activation associated with disease activity in systemic lupus erythematosus","volume":"13","author":"Labonte","year":"2018","journal-title":"PloS One"},{"key":"B40","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/s13075-025-03681-x","article-title":"Inflammation-related proteomics of extracellular vesicles as novel biomarkers for systemic lupus erythematosus revealed by proximity extension assay","volume":"27","author":"Zhan","year":"2025","journal-title":"Arthritis Res Ther"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1257085","article-title":"Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus","volume":"14","author":"Lindblom","year":"2023","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.969509","article-title":"Combined proteomics and single cell RNA-sequencing analysis to identify biomarkers of disease diagnosis and disease exacerbation for systemic lupus erythematosus","volume":"13","author":"Li","year":"2022","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1186\/s12014-017-9167-8","article-title":"Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay","volume":"14","author":"Petr\u00e1\u010dkov\u00e1","year":"2017","journal-title":"Clin Proteomics"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1478-7","article-title":"Role of endoplasmic reticulum stress in the protective effects of PPAR\u03b2\/\u03b4 activation on endothelial dysfunction induced by plasma from patients with lupus","volume":"19","author":"Toral","year":"2017","journal-title":"Arthritis Res Ther"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.656090","article-title":"A novel autoantibody induced by bacterial biofilm conserved components aggravates lupus nephritis","volume":"12","author":"Fu","year":"2021","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1136\/annrheumdis-2017-eular.6760","article-title":"THU0018 angiotensinogen as a marker of injury in lupus nephritis","volume":"76","author":"Mas","year":"2017","journal-title":"Ann Rheumatic Dis"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102615","article-title":"Clinical disease activity and flare in SLE: current concepts and novel biomarkers","volume":"119","author":"Thanou","year":"2021","journal-title":"J Autoimmun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1101\/2025.10.06.25336803","article-title":"An integrated large-scale atlas of protein quantitative trait loci across Olink and SomaScan platforms","author":"Khunsriraksakul","year":"2025","journal-title":"medRxiv (Cold Spring Harbor Laboratory)"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184738","article-title":"Transgelin-2 is upregulated on activated B-cells and expressed in hyperplastic follicles in lupus erythematosus patients","volume":"12","author":"Kiso","year":"2017","journal-title":"PloS One"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1369385","article-title":"Longitudinal assessment of urinary ALCAM, HPX, and PRDX6 in Korean patients with systemic lupus erythematosus: implications for disease activity monitoring and treatment response","volume":"15","author":"Kim","year":"2024","journal-title":"Front Immunol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/s42081-024-00276-9","article-title":"Methodological challenges in studying disease processes using observational cohort data","volume":"8","author":"Cook","year":"2024","journal-title":"Jpn J Stat Data Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1819049\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:01:54Z","timestamp":1780466514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1819049\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2026.1819049"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1819049","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]},"article-number":"1819049"}}