Misra Maneesh Kumar, McMullen Phillip, Kim Gene H, Marino Susana G
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, United States.
Department of Pathology, The University of Chicago Medicine, Chicago, IL, United States.
Front Immunol. 2025 Apr 2;16:1550779. doi: 10.3389/fimmu.2025.1550779. eCollection 2025.
Humoral autoimmune response may play a significant role in stimulating the alloimmune response, leading to antibody-mediated rejection (ABMR). This study investigated whether the development of IgG donor-specific antibodies (dnDSA) could serve as an independent marker for ABMR diagnosis. Subsequently, we evaluated the synergistic effects of non-HLA anti-nuclear antibodies (ANA) and circulating IgG anti-HLA dnDSA in the development of ABMR.
This retrospective study included 285 patients who underwent heart transplants between January 2007 to November 2020 at the University of Chicago Medical Center and who had sufficient serum collected at the time of protocol or indication biopsy available for antibody testing.
We observed a 23% incidence of ABMR in heart transplant patients at our center. Kaplan-Meier survival analysis revealed the lowest ABMR free survival in recipients that were positive for both ANA and circulating IgG dnDSA (Log rank p = 2 x 10), indicating a synergistic effect of ANA and circulating IgG dnDSA. A univariate stepwise cox proportional hazard model establishes the presence of IgG dnDSA as an independent marker to predict ABMR diagnosis (HR = 8.70, p = 6.15 x 10). Similarly, a synergistic effect was found in the presence of a positive ANA titer and IgG dnDSA for ABMR diagnosis in a univariate model (HR = 13.1, p = 2.73 x 10). A multivariate stepwise cox proportional hazard model showed an almost seven-fold increased risk for ABMR in patients that have developed IgG dnDSA (HR = 6.96, p = 2.33 x 10). Similarly, nearly an eleven-fold enhanced risk for ABMR was found in heart transplant recipients who were positive for ANA and had developed IgG DSA (HR = 10.7, p = 1.25 x 10), suggesting the synergistic effect of ANA and IgG dnDSA in ABMR diagnosis.
This study establishes circulating IgG dnDSA as an independent biomarker for ABMR diagnosis in heart transplantation and confirms the previously known correlation of IgG dnDSA with ABMR. Subsequently, our data revealed that circulating IgG dnDSA and non-HLA antinuclear antibodies have synergistic effects that cause antibody-mediated rejection in heart transplantation.
体液自身免疫反应可能在刺激同种免疫反应中起重要作用，导致抗体介导的排斥反应（ABMR）。本研究调查了IgG供体特异性抗体（dnDSA）的产生是否可作为ABMR诊断的独立标志物。随后，我们评估了非HLA抗核抗体（ANA）和循环IgG抗HLA dnDSA在ABMR发生过程中的协同作用。
这项回顾性研究纳入了285例于2007年1月至2020年11月在芝加哥大学医学中心接受心脏移植的患者，这些患者在方案或指征活检时收集了足够的血清用于抗体检测。
我们观察到本中心心脏移植患者中ABMR的发生率为23%。Kaplan-Meier生存分析显示，ANA和循环IgG dnDSA均呈阳性的受者中无ABMR的生存率最低（对数秩检验p = 2×10），表明ANA和循环IgG dnDSA具有协同作用。单变量逐步Cox比例风险模型确定IgG dnDSA的存在是预测ABMR诊断的独立标志物（风险比[HR]=8.70，p = 6.15×10）。同样，在单变量模型中，ANA滴度阳性和IgG dnDSA同时存在时，对ABMR诊断也有协同作用（HR = 13.1，p = 2.73×10）。多变量逐步Cox比例风险模型显示，已产生IgG dnDSA的患者发生ABMR的风险增加近7倍（HR = 6.96，p = 2.33×10）。同样，ANA呈阳性且已产生IgG DSA的心脏移植受者发生ABMR的风险增加近11倍（HR = 10.7，p = 1.25×10），提示ANA和IgG dnDSA在ABMR诊断中具有协同作用。
本研究确定循环IgG dnDSA是心脏移植中ABMR诊断的独立生物标志物，并证实了此前已知的IgG dnDSA与ABMR的相关性。随后，我们的数据显示，循环IgG dnDSA和非HLA抗核抗体具有协同作用，可导致心脏移植中的抗体介导的排斥反应。
