Yoon Hyunah, Harris Annalie J, Nakouzi Antonio, Day Jeremy, Abers Michael, Holland Steven M, Rosen Lindsey B, Pirofski Liise-Anne
Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
Med Mycol. 2026 Feb 3;64(2). doi: 10.1093/mmy/myag006.
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.
中和性抗细胞因子自身抗体（ACAA）与隐球菌性脑膜炎（CM）有关，但HIV合并感染的影响尚不清楚。我们在一个按HIV和CM状态分层的越南横断面队列中（每组n = 20），研究了血浆ACAA谱及其功能。我们使用基于颗粒的检测方法对针对干扰素（IFN）、白细胞介素（IL）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的血浆ACAA进行定量，并在高滴度样本中评估其中和活性。使用Firth惩罚逻辑回归分析ACAA水平与CM之间的关联，并对年龄、性别和CD4计数进行调整（在HIV阳性模型中）。在HIV阴性个体中，较高的抗GM-CSF水平与CM相关（每对数单位增加的优势比[OR]为1.84；95%置信区间[CI]为1.07 - 3.18）。这种关联主要在加氏隐球菌病例中观察到，并伴有功能性中和活性。此外，加入预先指定的血浆IgG2可改善整体模型拟合，并显示出与CM有强烈的负相关（OR为0.03；95%CI为0.003 - 0.29）相反，HIV阳性的CM病例的总体ACAA水平低于非CM对照。在调整低丙种球蛋白血症/IgG1后，抗IL-10、抗IL-12、抗IL-15和抗IL-22与CM状态之间仍存在显著的负相关。I型干扰素结合ACAA大多无中和作用。这些发现揭示了不同的致病机制。在HIV阴性的CM中，中和性抗GM-CSF抗体（常在加氏隐球菌感染中）和低IgG2与疾病独立相关。在HIV阳性的CM中，ACAA减少但无细胞因子中和可能反映了潜在的抗体和/或B细胞缺陷。需要进行纵向研究以阐明ACCA的临床意义，特别是在HIV阴性的CM中。
