An integrated immunopathological model of syphilis serofast: a systematic review and meta-analysis

Objective: 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. Methods: 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 ≤1:8 persisting for ≥12 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. Results: 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, I²=33.5%) and increased CD8+ T cells (SMD = 0.40, I²=66.7%), leading to an inverted CD4+/CD8+ ratio (SMD=-0.44, I²=64.7%); (2) Th1/Th2 shift:suppression of Th1 cytokines (e.g., IFN-γ, SMD=-2.19, I²=95.7%) with a predominant Th2 response (e.g., IL-10, SMD =+ 2.63,I²=92.5%); (3) Humoral abnormalities: persistently elevated IgM (SMD = 0.96,I²=94.4%) and complement consumption (C3,SMD=-0.60, I²=89.0%; C4, SMD=-0.80, I²=87.6%); (4) Signaling dysregulation: downregulated TLR2 expression and disordered chemokine receptors (TLR2 mRNA,SMD=-1.52, I²=36.0%).The substantial heterogeneity (I² > 50%) observed in several analyses was explored in subgroup and sensitivity analyses, as detailed in the main text. Conclusions: The serofast is characterized by a cascade of "cellular immune suppression-Th1/Th2 shift-complement exhaustion." Our findings establish a quantified immunological basis for the serofast state and suggest potential targets for immunomodulatory therapy. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251156478.