{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:44:50Z","timestamp":1785437090358,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFE0131700"],"award-info":[{"award-number":["2022YFE0131700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Research ward excellence Clinical research program","award":["BRWEP2024W034080206"],"award-info":[{"award-number":["BRWEP2024W034080206"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271835"],"award-info":[{"award-number":["82271835"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071813"],"award-info":[{"award-number":["82071813"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82271835"],"award-info":[{"award-number":["82271835"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82071813"],"award-info":[{"award-number":["82071813"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Low-density granulocytes (LDGs) have been implicated in the pathogenesis of several autoimmune diseases, yet their role in Sj\u00f6gren\u2019s disease (SjD) remains poorly understood. We enrolled 90 SjD patients and 30 healthy controls (HCs) and identified LDGs as CD14\u2212\/lowCD15+ cells by flow cytometry, with intracellular interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-\u03b1) staining, and further analyzed CD16 as a maturation marker in LDGs and T helper 17 (Th17) cell frequency. LDG percentages were significantly elevated in active SjD compared with inactive patients (p &lt; 0.001) and HCs (p &lt; 0.0001), and correlated positively with EULAR Sj\u00f6gren\u2019s Syndrome Disease Activity Index (ESSDAI) (r = 0.355, p = 0.0006), erythrocyte sedimentation rate (ESR) (r = 0.325, p = 0.0061), \u03b3-globulin (r = 0.334, p = 0.0177), and Th17 frequency (r = 0.537, p = 0.0068). LDG expansion was accompanied by enrichment of immature CD16\u2212\/low cells (r = \u22120.798, p = 0.0100). Patients with renal or pulmonary involvement showed higher LDG levels (p = 0.0004), and in SjD -associated interstitial lung disease (SjD-ILD) patients, LDG percentage showed a positive but non-significant trend with serum Krebs von den Lungen-6 (KL-6) levels (r = 0.497, p = 0.102). LDG levels decreased following treatment in longitudinally followed patients, and LDGs from active patients exhibited higher IL-6 and TNF-\u03b1 production ratios relative to monocytes than those from inactive patients. Stratification by LDG levels revealed significant associations with disease activity, laboratory parameters, and organ involvement. These findings suggest that LDGs are associated with disease activity and organ involvement, may serve as potential biomarkers, and may contribute to the pathogenesis of SjD.<\/jats:p>","DOI":"10.3390\/ijms27156722","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:55:41Z","timestamp":1785225341000},"page":"6722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low-Density Granulocytes Link to Disease Activity, Organ Involvement, and Cytokine Production in Sj\u00f6gren\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3367-3980","authenticated-orcid":false,"given":"Jing","family":"Ning","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-Invasive Diagnosis and Immunotherapy for Rheumatic and Immune Diseases (BZ-2025-127), Peking University People\u2019s Hospital, 11 Xizhimen South St, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3379-8998","authenticated-orcid":false,"given":"Yuebo","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-Invasive Diagnosis and Immunotherapy for Rheumatic and Immune Diseases (BZ-2025-127), Peking University People\u2019s Hospital, 11 Xizhimen South St, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-Invasive Diagnosis and Immunotherapy for Rheumatic and Immune Diseases (BZ-2025-127), Peking University People\u2019s Hospital, 11 Xizhimen South St, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-Invasive Diagnosis and Immunotherapy for Rheumatic and Immune Diseases (BZ-2025-127), Peking University People\u2019s Hospital, 11 Xizhimen South St, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linger","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-Invasive Diagnosis and Immunotherapy for Rheumatic and Immune Diseases (BZ-2025-127), Peking University People\u2019s Hospital, 11 Xizhimen South St, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"He","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-Invasive Diagnosis and Immunotherapy for Rheumatic and Immune Diseases (BZ-2025-127), Peking University People\u2019s Hospital, 11 Xizhimen South St, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1056\/NEJMcp1702514","article-title":"Primary Sj\u00f6gren\u2019s Syndrome","volume":"378","author":"Mariette","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_2","unstructured":"Retamozo, S., Brito-Zeron, P., Zeher, M., Kathy, L.S., Seror, R., Mandl, T., Li, X., Baldini, C., Gottenberg, J.-E., and Danda, D. (2017). Epidemiologic subsets drive a differentiated clinical and immunological presentation of primary Sj\u00f6gren syndrome: Analysis of 9302 patients from the Big Data International Sj\u00f6gren Cohort. Arthritis Rheumatol., 69."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.3899\/jrheum.200733","article-title":"National Sj\u00f6gren\u2019s Foundation Survey: Burden of Oral and Systemic Involvement on Quality of Life","volume":"48","author":"McCoy","year":"2021","journal-title":"J. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrrheum.2018.1","article-title":"B cells in the pathogenesis of primary Sj\u00f6gren syndrome","volume":"14","author":"Nocturne","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jaut.2017.11.003","article-title":"Th17 cells in primary Sj\u00f6gren\u2019s syndrome: Pathogenicity and plasticity","volume":"87","author":"Verstappen","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sequ\u00ed-Sabater, J.M., and Beretta, L. (2022). Defining the Role of Monocytes in Sj\u00f6gren\u2019s Syndrome. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112765"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1093\/rheumatology\/key360","article-title":"Innate immunity and interferons in the pathogenesis of Sj\u00f6gren\u2019s syndrome","volume":"60","author":"Bodewes","year":"2021","journal-title":"Rheumatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41584-024-01135-3","article-title":"Update on the pathophysiology and treatment of primary Sj\u00f6gren syndrome","volume":"20","author":"Baldini","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.it.2019.04.012","article-title":"Neutrophil Diversity in Health and Disease","volume":"40","author":"Fridlender","year":"2019","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41577-022-00787-0","article-title":"Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases","volume":"23","author":"Wigerblad","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1136\/annrheumdis-2018-214335","article-title":"Critical role of neutrophil extracellular traps (NETs) in patients with Behcet\u2019s disease","volume":"78","author":"Martos","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13075-018-1800-z","article-title":"Increased neutrophil extracellular traps activate NLRP3 and inflammatory macrophages in adult-onset Still\u2019s disease","volume":"21","author":"Hu","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1097\/BOR.0000000000000197","article-title":"The role of neutrophils in the pathogenesis of systemic lupus erythematosus","volume":"27","author":"Smith","year":"2015","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/art.1780291105","article-title":"Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever","volume":"29","author":"Hacbarth","year":"1986","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"538","DOI":"10.4049\/jimmunol.1100450","article-title":"Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus","volume":"187","author":"Villanueva","year":"2011","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.4049\/jimmunol.0902199","article-title":"A Distinct Subset of Proinflammatory Neutrophils Isolated from Patients with Systemic Lupus Erythematosus Induces Vascular Damage and Synthesizes Type I IFNs","volume":"184","author":"Denny","year":"2010","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1093\/rheumatology\/kead296","article-title":"Platelet TLR7 is essential for the formation of platelet-neutrophil complexes and low-density neutrophils in lupus nephritis","volume":"63","author":"Tay","year":"2024","journal-title":"Rheumatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e99276","DOI":"10.1172\/jci.insight.99276","article-title":"Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus","volume":"3","author":"Carlucci","year":"2018","journal-title":"JCI Insight"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1136\/annrheumdis-2018-214620","article-title":"Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus","volume":"78","author":"Rahman","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1136\/annrheumdis-2020-218338","article-title":"Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus","volume":"80","author":"Bashant","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s13075-022-02860-4","article-title":"The potential roles of type I interferon activated neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of primary Sj\u00f6gren\u2019s syndrome","volume":"24","author":"Peng","year":"2022","journal-title":"Arthritis Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13075-019-1835-9","article-title":"Serum KL-6 levels reflect the severity of interstitial lung disease associated with connective tissue disease","volume":"21","author":"Lee","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/rheumatology\/keaa324","article-title":"Elevated circulating pro-inflammatory low-density granulocytes in adult-onset Still\u2019s disease","volume":"60","author":"Liu","year":"2021","journal-title":"Rheumatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e48","DOI":"10.1136\/annrheumdis-2020-219472","article-title":"Correspondence on \u2018Critical role of neutrophil extracellular traps (NETs) in patients with Behcet\u2019s disease\u2019","volume":"82","author":"Chen","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"240139","DOI":"10.1183\/16000617.0139-2024","article-title":"Neutrophil dynamics in pulmonary fibrosis: Pathophysiological and therapeutic perspectives","volume":"33","author":"Crowley","year":"2024","journal-title":"Eur. Respir. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3904\/kjim.2023.402","article-title":"Long-term outcome of interstitial lung disease in patients with primary Sj\u00f6gren\u2019s syndrome: A retrospective observational study","volume":"40","author":"Koh","year":"2025","journal-title":"Korean J. Intern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1080\/14397595.2016.1179861","article-title":"Abnormally increased low-density granulocytes in peripheral blood mononuclear cells are associated with interstitial lung disease in dermatomyositis","volume":"27","author":"Zhang","year":"2017","journal-title":"Mod. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111330","DOI":"10.1016\/j.intimp.2023.111330","article-title":"Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease","volume":"127","author":"Poole","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"331ra340","DOI":"10.1126\/scitranslmed.aae0482","article-title":"Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus","volume":"8","author":"Wu","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_30","first-page":"1089","article-title":"Salivary and serum interleukin 6 in primary Sj\u00f6gren\u2019s syndrome","volume":"24","author":"Grisius","year":"1997","journal-title":"J. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1136\/ard.2007.077891","article-title":"Lack of efficacy of etanercept in Sj\u00f6gren syndrome correlates with failed suppression of tumour necrosis factor alpha and systemic immune activation","volume":"67","author":"Moutsopoulos","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_32","first-page":"970","article-title":"Salivary cytokine profiles in primary Sj\u00f6gren\u2019s syndrome differ from those in non-Sj\u00f6gren sicca in terms of TNF-\u03b1 levels and Th-1\/Th-2 ratios","volume":"29","author":"Kang","year":"2011","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ma, W.T., Gao, F., Gu, K., and Chen, D.K. (2019). The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01140"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s13075-020-02249-1","article-title":"Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sj\u00f6gren\u2019s syndrome","volume":"22","author":"Yoshimoto","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00262-019-02302-2","article-title":"Deciphering myeloid-derived suppressor cells: Isolation and markers in humans, mice and non-human primates","volume":"68","author":"Cassetta","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.4049\/jimmunol.1801051","article-title":"Increased GITRL Impairs the Function of Myeloid-Derived Suppressor Cells and Exacerbates Primary Sj\u00f6gren Syndrome","volume":"202","author":"Tian","year":"2019","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/s41423-022-00943-5","article-title":"Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sj\u00f6gren\u2019s syndrome","volume":"19","author":"Wei","year":"2022","journal-title":"Cell Mol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1136\/ard.61.6.554","article-title":"Classification criteria for Sj\u00f6gren\u2019s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group","volume":"61","author":"Vitali","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s00296-022-05242-w","article-title":"Renal involvement in Sj\u0151gren\u2019s syndrome: Predictors and impact on patient outcomes","volume":"43","author":"Chatterjee","year":"2023","journal-title":"Rheumatol. Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:25:55Z","timestamp":1785385555000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":39,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156722"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156722","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}