{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:22:30Z","timestamp":1792790550219,"version":"4.5.0"},"reference-count":62,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_med-2026-1429_abs_001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The COVID-19 pandemic has highlighted the importance of understanding immune regulation underlying disease severity. Adenosine deaminase (ADA), an enzyme with ADA1 and ADA2 isoforms, modulates immune responses and is mainly expressed in lymphoid tissues. This study examined ADA activity and its relationship with macrophage polarization in COVID-19.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_med-2026-1429_abs_002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 120\u00a0COVID-19 patients stratified by disease severity and 40 healthy controls were included. Total ADA (tADA), ADA1, and ADA2 activities were measured using the Giusti\u2013Galanti colorimetric method in both patient sera and culture supernatants. Cytokine and chemokine profiles associated with M1- and M2-like macrophages were quantified by ELISA. To mechanistically evaluate macrophage polarization, na\u00efve monocytes were co-cultured with SARS-CoV-2\u2013responsive lymphocytes under a COVID-19 microenvironment (pCOV) generated using viral peptide pools in the presence of COVID-19 patient sera. Macrophage subsets were characterized by flow cytometry using canonical surface markers. The relationship between ADA2 activity and macrophage polarization was functionally assessed using pentostatin, whereas EHNA was used exclusively for the differential measurement of ADA isoenzyme activities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_med-2026-1429_abs_003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Elevated total ADA activity was observed in critical patients, correlating with disease severity. Cytokine profiling revealed a hybrid M1\/M2-like phenotype in severe cases, characterized by simultaneous pro- and anti-inflammatory mediator release. ADA2 activity showed a strong positive correlation with M2-associated factors, and flow cytometry confirmed the presence of CD206\n                      <jats:sup>+<\/jats:sup>\n                      CD86\n                      <jats:sup>+<\/jats:sup>\n                      hybrid macrophages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_med-2026-1429_abs_004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, our findings suggest that ADA2 regulates macrophage plasticity in COVID-19, promoting M1\/M2 hybrid polarization and contributing to immune dysregulation. ADA2 may serve as a biomarker for disease progression and a therapeutic target to modulate macrophage-driven inflammation in severe COVID-19.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/med-2026-1429","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T23:13:39Z","timestamp":1777763619000},"source":"Crossref","is-referenced-by-count":1,"title":["The dynamic interplay of M1\/M2-like macrophages and adenosine deaminase activity modulates COVID-19 severity"],"prefix":"10.1515","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6563-8716","authenticated-orcid":false,"given":"Tugce","family":"Bozkurt","sequence":"first","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8850-0269","authenticated-orcid":false,"given":"Abdurrahman","family":"Simsek","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5334-7911","authenticated-orcid":false,"given":"Muhammed Ali","family":"Kizmaz","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eren","family":"Cagan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Infectious Diseases, Bursa Yuksek Ihtisas Training and Research Hospital, University of Health Sciences , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5727-4075","authenticated-orcid":false,"given":"Hulya","family":"Kose","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali Eren","family":"Iskin","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse Melda","family":"Payaslio\u011flu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Karadag","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emin Halis","family":"Akalin","sequence":"additional","affiliation":[{"name":"Bursa Uludag University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Sebnem","family":"Kilic","sequence":"additional","affiliation":[{"name":"Department of Pediatric Immunology and Rheumatology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7625-9148","authenticated-orcid":false,"given":"Ferah","family":"Budak","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Bursa Uludag University , Bursa , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"2026050223133394663_j_med-2026-1429_ref_001","doi-asserted-by":"crossref","unstructured":"Ombrello, MJ, Schulert, GS. 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