{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T20:32:21Z","timestamp":1770496341689,"version":"3.49.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013409","name":"Sistema General de Regal\u00edas de Colombia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020905","name":"Universidad Surcolombiana","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020905","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Identifying immune markers driving early and effective antibody response in patients with severe coronavirus disease 2019 (COVID-19) is critical due to the threat of future coronavirus pandemics, incomplete global vaccination, and suboptimal booster coverage. Patients with life-threatening severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by dysregulated thromboinflammation and cytokine storm that could influence the isotype virus-specific antibody response and the subsequent clinical outcome. We investigated the association between COVID-19-related mortality with the dynamics, magnitude, and relative avidity of nucleoprotein (N), spike (S), and receptor-binding domain (RBD)-specific IgM, IgA, and IgG in circulation. We also assessed the relationship between the virus-specific antibody responses and cytokine patterns, as well as systemic and pulmonary thromboinflammation markers. This multicenter study included COVID-19 patients hospitalized early in the pandemic, classified as survivors (n=62) and non-survivors (n=17). We developed indirect enzyme-linked immunosorbent assays (ELISAs) to evaluate each virus-specific isotype using well-characterized outpatient COVID-19 (n=180) and pre-pandemic cohorts (n=111). The pro-inflammatory interleukin (IL)-6 and tumor necrosis factor (TNF)-\u03b1, as well as the regulatory IL-10, transforming growth factor (TGF)-\u03b21, and soluble tumor necrosis factor receptor I (sTNFRI) levels were evaluated. The ELISAs performed highly for all virus-specific isotypes, although modest for IgM-N. Non-survivors increased N-specific, but no S-specific, IgM and IgA responses throughout the disease course and, more notably, a delayed class switching to IgG-S and IgG-RBD compared to survivors. No differences were observed in the virus-specific IgG relative avidity. Survivors exhibited an antibody response proportional to the degree of systemic and pulmonary thromboinflammation, whereas non-survivors showed those dissociated because of their uncontrolled severe thromboinflammation. Only the survivors showed a dominant regulatory cytokine pattern in the early phase of infection (&amp;lt;10 days after symptoms onset), which strongly correlated with developing IgG-S and IgG-RBD protective antibodies. We developed easy-to-use immune assays that enable patient monitoring and identify at-risk populations in low- to middle-income regions. Non-survivors displayed an ineffective N-mediated antibody response, marked by an inability to control inflammation and a compromised time-dependent class switching toward S and RBD-specific IgG. The regulatory cytokine axis, including TGF-\u03b21, maybe a critical immune correlate of effective antibody-mediated immunity in COVID-19.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1543626","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T05:26:15Z","timestamp":1745472375000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Regulatory cytokines modulate early isotype-specific response associated with COVID-19 survival"],"prefix":"10.3389","volume":"16","author":[{"given":"Sebasti\u00e1n","family":"Castro-Trujillo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanita","family":"Castro-Meneses","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda 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