Potential value of autoantibodies as biomarkers of chronic graft-versus-host disease after allogeneic stem cell transplantation
We investigated the value of autoantibodies as biomarkers of chronic graft-versus-host disease (cGVHD) by analyzing the autoantibody profiles of 65 patients (34 cGVHD and 31 non-cGVHD) surviving longer than three months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Autoantibodies to at least one antigen were detected in 45 patients (70.8%), with multiple autoantibodies detected in 30 patients (46.2%). Antinuclear antibodies (ANAs) were the most frequently detected autoantibodies, with a significantly higher prevalence in non-cGVHD patients and cGVHD patients than that in healthy controls (HCs). ANA-nucleolar (ANA-N) was the main immunofluorescence pattern of ANA-positivity in both the non-cGVHD and cGVHD groups. There was a higher prevalence of anti-Ro52-positivity in non-cGVHD and cGVHD patients than in HC. Liver cGVHD was significantly associated with anti-Ro52-positivity. However, cGVHD activity and severity were not associated with the presence of autoantibodies. Similarly, there were no significant differences in overall survival or relapse among the four groups of patients expressing autoantibodies. Our results suggest that autoantibodies have limited value in predicting cGVHD.
Key wordsAutoantibody Chronic graft-versus-host disease (cGVHD) Anti-Ro52
通过检测慢性移植物抗宿主病 (cGVHD) 病人血清中自身抗体的表达来发现和鉴定新的用于诊断和疾病监测的标志物。
我们创新性地应用了包含核仁形成区抗原成分的自身抗体谱对各实验组进行了超过 30 种自身抗体的筛查, 首次发现 anti-Ro52 抗体可能与肝脏 cGVHD 有关。
联合应用间接免疫荧光、 线性免疫印迹和酶联免疫吸附试验 (ELISA)对各实验组进行自身抗体 谱筛查, 采用统计学软件对实验结果和临床数据进行比对分析。
我们的研究证实异基因造血干细胞移植后各组病人都可能出现以核仁型抗核抗体 (ANA) 为主的自身抗体表达增高, 并且 anti-Ro52 抗体在肝脏 cGVHD 病人血清中显著增高, 然而自身抗体与 cGVHD 的活动性、 严重程度和预后均无明显相关性。 我们的研究结果表明, 自身抗体在预测 cGVHD 方面的价值有限。
关键词自身抗体 慢性移植物抗宿主病 (cGVHD) Anti-Ro52
Unable to display preview. Download preview PDF.
Bing HAO and Song GAO performed the experimental research and data analysis, and wrote and edited the manuscript. Yi-wen SANG and Lin WANG performed the data analysis. Xue-qin MENG and Jing-ya YOU contributed to the ELISA assay. All authors have read and approved the final manuscript. Therefore, all authors have full access to all the data in the study and take responsibility for the integrity and security of the data.
Compliance with ethics guidelines
Bing HAO, Song GAO, Yi-wen SANG, Lin WANG, Xue-qin MENG, and Jing-ya YOU declare that they have no conflicts of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article.
- Arbuckle MR, McClain MT, Rubertone MV, et al., 2003. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med, 349(16): 1526–1533. https://doi.org/10.1056/NEJMoa021933
- Assandri R, Serana F, Montanelli A, 2017. Development of PBC/SSc overlap syndrome in chronic GVHD patient: immunological implications in the presence of mitochondrial, nucleolar and spindle midzone autoantigens. Gastroenterol Hepatol Bed Bench, 10(4):323–331.Google Scholar
- Bell SA, Faust H, Mittermüller J, et al., 1996. Specificity of antinuclear antibodies in scleroderma-like chronic graftversus- host disease: clinical correlation and histocompatibility locus antigen association. Br J Dermatol, 134(5): 848–854. https://doi.org/10.1046/j.1365-2133.1996.116851.x CrossRefGoogle Scholar
- Filipovich AH, Weisdorf D, Pavletic S, et al., 2005. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant, 11(12):945–955. https://doi.org/10.1016/j.bbmt.2005.09.004 CrossRefGoogle Scholar
- Finkielman JD, Merkel PA, Schroeder D, et al., 2007. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med, 147(9):611–619. https://doi.org/10.7326/0003-4819-147-9-200711060-00005 CrossRefGoogle Scholar
- Flynn R, Du J, Veenstra RG, et al., 2014. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood, 123(25): 3988–3998. https://doi.org/10.1182/blood-2014-03-562231
- Fraser CJ, Bhatia S, Ness K, et al., 2006. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the bone marrow transplant survivor study. Blood, 108(8): 2867–2873. https://doi.org/10.1182/blood-2006-02-003954 CrossRefGoogle Scholar
- Fraticelli P, Gabrielli B, Pomponio G, et al., 2014. Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study. Arthritis Res Ther, 16(4):R144. https://doi.org/10.1186/ar4606
- Langford CA, 2004. Antineutrophil cytoplasmic antibodies should not be used to guide treatment in Wegener’s granulomatosis. Clin Exp Rheumatol, 22(6 Suppl 36):S3-S6.Google Scholar
- Panoskaltsis-Mortari A, Tram KV, Price AP, et al., 2007. A new murine model for bronchiolitis obliterans post-bone marrow transplant. Am J Respir Crit Care Med, 176(7): 713–723. https://doi.org/10.1164/rccm.200702-335OC
- Pidala J, Kurland B, Chai XY, et al., 2011. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood, 117(17):4651–4657. https://doi.org/10.1182/blood-2010-11-319509 CrossRefGoogle Scholar
- Przepiorka D, Weisdorf D, Martin P, et al., 1995. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant, 15(6):825–828.Google Scholar
- Quaranta S, Shulman H, Ahmed A, et al., 1999. Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation. Clin Immunol, 91(1): 106–116. https://doi.org/10.1006/clim.1998.4666
- Sinico RA, Radice A, Corace C, et al., 2005. Value of a new automated fluorescence immunoassay (EliA) for PR3 and MPO-ANCA in monitoring disease activity in ANCAassociated systemic vasculitis. Ann N Y Acad Sci, 1050(1): 185–192. https://doi.org/10.1196/annals.1313.019
- Spies-Weisshart B, Schilling K, Böhmer F, et al., 2013. Lack of association of platelet-derived growth factor (PDGF) receptor autoantibodies and severity of chronic graftversus-host disease (GVHD). J Cancer Res Clin Oncol, 139(8):1397–1404. https://doi.org/10.1007/s00432-013-1451-z CrossRefGoogle Scholar
- Svegliati S, Olivieri A, Campelli N, et al., 2007. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood, 110(1):237- 241. https://doi.org/10.1182/blood-2007-01-071043
- Wesierska-Gadek J, Penner E, Hitchman E, et al., 1992. Nucleolar proteins B23 and C23 as target antigens in chronic graft-versus-host disease. Blood, 79(4):1081–1086.Google Scholar