{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:15:24Z","timestamp":1787681724511,"version":"build-2784847793"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The immunological mechanisms underlying the syphilis serofast remain incompletely elucidated. This systematic review and meta-analysis aims to quantify the association between key immune indicators and serofast.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically searched PubMed, Embase, Web of Science, Google Scholar and Chinese databases (CNKI, VIP, and CBMdisc) until December 31, 2024, for case-control, cross-sectional or cohort studies meeting serofast criteria (RPR\/TRUST titer \u22641:8 persisting for \u226512 months). Random-effects models were used to calculate standardized mean differences (SMD) with 95% confidence intervals (CIs). The risk of bias was assessed using the Newcastle-Ottawa Scale (for observational studies) by two independent reviewers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 38 studies involving 5082 patients were included. The serofast group exhibited significant immune dysregulation: (1) Cellular immune suppression:decreased CD4+ T cells (SMD=-0.61, I\u00b2=33.5%) and increased CD8+ T cells (SMD = 0.40, I\u00b2=66.7%), leading to an inverted CD4+\/CD8+ ratio (SMD=-0.44, I\u00b2=64.7%); (2) Th1\/Th2 shift:suppression of Th1 cytokines (e.g., IFN-\u03b3, SMD=-2.19, I\u00b2=95.7%) with a predominant Th2 response (e.g., IL-10, SMD =+ 2.63,I\u00b2=92.5%); (3) Humoral abnormalities: persistently elevated IgM (SMD = 0.96,I\u00b2=94.4%) and complement consumption (C3,SMD=-0.60, I\u00b2=89.0%; C4, SMD=-0.80, I\u00b2=87.6%); (4) Signaling dysregulation: downregulated TLR2 expression and disordered chemokine receptors (TLR2 mRNA,SMD=-1.52, I\u00b2=36.0%).The substantial heterogeneity (I\u00b2 &amp;gt; 50%) observed in several analyses was explored in subgroup and sensitivity analyses, as detailed in the main text.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The serofast is characterized by a cascade of \u201ccellular immune suppression-Th1\/Th2 shift-complement exhaustion.\u201d Our findings establish a quantified immunological basis for the serofast state and suggest potential targets for immunomodulatory therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n                      , identifier CRD420251156478.\n                    <\/jats:p>\n                  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