McQuiston Alexander, Scott Danielle, Nord Dianna, Langerude Logan, Pelaez Andres, Machuca Tiago, Mehta Anand, Drake Richard R, Christie Jason D, Angel Peggi, Atkinson Carl
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
Transpl Immunol. 2022 Apr;71:101491. doi: 10.1016/j.trim.2021.101491. Epub 2021 Nov 10.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The pathogenesis of COPD is complex; however, recent studies suggest autoimmune changes, characterized by the presence of autoantibodies to elastin and collagen, may contribute to disease status. COPD patients make up approximately 30% of all lung transplants (LTx) annually, however, little is known regarding the relationship between COPD-related autoantibodies and LTx outcomes. We hypothesized that COPD patients that undergo LTx and develop primary graft dysfunction (PGD) have altered circulating autoantibody levels and phenotypic changes as compared those COPD-LTx recipients that do not develop PGD. We measured total immunoglobulin and circulating elastin and collagen autoantibody levels in a cohort of COPD lung transplant recipients pre- and post-LTx. No significant differences were seen in total, elastin, or collagen IgM, IgG, IgG1, IgG2, IgG3, and IgG4 antibodies between PGD+ and PGD- recipients. Antibody function can be greatly altered by glycosylation changes to the antibody Fc region and recent studies have reported altered IgG glycosylation profiles in COPD patients. We therefore utilized a novel mass spectrometry-based multiplexed N-glycoprotein imaging approach and measured changes in IgG-specific antibody N-glycan structures. COPD-LTx recipients who developed PGD had significantly increased IgG1 N-glycan signatures as compared PGD- recipients. In conclusion, we show that immunoglobulin and autoreactive antibody levels are not significantly different in COPD LTx recipients that develop PGD. However, using a novel IgG glycomic analysis we were able to demonstrate multiple significant increases in IgG1 specific N-glycan signatures that were predictive of PGD development. Taken together, these data represent a potential novel method for identifying COPD patients at risk for PGD development and may provide clues to mechanisms by which antibody N-glycan signatures could contribute to antibody-mediated PGD pathogenesis.
慢性阻塞性肺疾病（COPD）是全球第三大致死原因。COPD的发病机制复杂；然而，最近的研究表明，以抗弹性蛋白和胶原蛋白自身抗体的存在为特征的自身免疫变化可能与疾病状态有关。COPD患者每年约占所有肺移植（LTx）患者的30%，然而，关于COPD相关自身抗体与LTx结果之间的关系却知之甚少。我们假设，与未发生原发性移植物功能障碍（PGD）的COPD-LTx受者相比，接受LTx并发生PGD的COPD患者循环自身抗体水平和表型发生了改变。我们在一组COPD肺移植受者LTx前后测量了总免疫球蛋白以及循环中的弹性蛋白和胶原蛋白自身抗体水平。在发生PGD和未发生PGD的受者之间，总抗体、弹性蛋白或胶原蛋白的IgM、IgG、IgG1、IgG2、IgG3和IgG4抗体水平均未发现显著差异。抗体功能可因抗体Fc区域的糖基化变化而发生极大改变，最近的研究报道了COPD患者IgG糖基化谱的改变。因此，我们采用了一种基于质谱的新型多重N-糖蛋白成像方法，测量了IgG特异性抗体N-聚糖结构的变化。与未发生PGD的受者相比，发生PGD的COPD-LTx受者的IgG1 N-聚糖特征显著增加。总之，我们表明，发生PGD的COPD LTx受者的免疫球蛋白和自身反应性抗体水平并无显著差异。然而，通过一种新型的IgG糖组学分析，我们能够证明IgG1特异性N-聚糖特征有多个显著增加，这些增加可预测PGD的发生。综上所述，这些数据代表了一种潜在的新方法，用于识别有发生PGD风险的COPD患者，并可能为抗体N-聚糖特征可能导致抗体介导的PGD发病机制提供线索。
