Anti-Cytokine Autoantibodies in Cryptococcal Meningitis Differ by HIV Status: A Cross-Sectional Analysis

Neutralizing anti-cytokine autoantibodies (ACAAs) have been associated with cryptococcal meningitis (CM), but the influence of HIV co-infection remains undefined. We investigated plasma ACAA profiles and function in a cross-sectional Vietnamese cohort stratified by HIV and CM status (n=20 per group). We quantified plasma ACAAs against interferons (IFNs), interleukins (ILs), and granulocyte-macrophage colony-stimulating factor (GM-CSF) using a particle-based assay, and assessed their neutralizing activity in high-titer samples. Associations between ACAA levels and CM were analyzed using Firth-penalized logistic regression, adjusting for age, sex, and CD4 count (in HIV-positive models). In HIV-negative individuals, higher anti-GM-CSF levels were associated with CM (odds ratio [OR] per log-unit increase, 1.84; 95% confidence interval [CI], 1.07-3.18). This association was predominantly observed in Cryptococcus gattii cases and was accompanied by functional neutralizing activity. Furthermore, adding pre-specified plasma IgG2 improved overall model fit and showed a strong inverse association with CM (OR, 0.03; 95% CI, 0.003-0.29). Conversely, HIV-positive CM cases had lower overall ACAA levels than non-CM controls. After adjusting for hypogammaglobulinemia/IgG1, significant inverse associations persisted for anti–IL-10, anti–IL-12, anti–IL-15, and anti–IL-22 with CM status. Type I IFN-binding ACAAs were largely non-neutralizing. These findings reveal distinct pathogenic mechanisms. In HIV-negative CM, neutralizing anti-GM-CSF antibodies, often in C. gattii infection, and low IgG2 were independently associated with disease. In HIV-positive CM, ACAA reductions without cytokine neutralization may reflect underlying antibody and/or B-cell deficiency. Longitudinal studies are needed to clarify the clinical implications of ACCAs, particularly in HIV-negative CM.