Cai Qi, Moore Samantha A, Hendricks Allen R, Torrealba José R
University of Texas Southwestern Medical Center, Dallas, Texas.
University of Texas Southwestern Medical Center, Dallas, Texas.
Transplant Proc. 2020 May;52(4):1192-1197. doi: 10.1016/j.transproceed.2020.01.049. Epub 2020 Mar 18.
In 2013, the International Society of Heart and Lung Transplant (ISHLT) introduced the working classification for pathologic changes associated with antibody-mediated rejection (AMR) of the heart allograft, known as pathologic AMR (pAMR). With 2 components associated with AMR, histopathologic changes) and immunopathologic markers, the proposed classification also suggests the use of class II HLA as a marker of endothelial integrity. It is known that during allograft rejection, endothelial cells are activated, therefore, we hypothesized that endothelial class II HLA rather than a marker of mere endothelial presence, is a marker of endothelial activation and becomes upregulated in AMR. Eight hundred thirty-eight heart allograft biopsies, collected from January 2016 to September 2018 at a single institution from patients with a current or recent diagnosis of AMR, were evaluated for both histopathologic and immunopathologic changes of AMR. Biopsies were labeled with immunofluorescence with antibodies against C4d and for immunohistochemistry with antibodies against C3d, CD68, and class II HLA. ISHLT criteria were used to classify the biopsies, and for class II HLA, both the percentage and the stain intensity were evaluated. Biopsies (74.8%) from our cohort showed either histopathologic pAMR-1, immunopathologic pAMR-1, or combined histopathologic and immunopathologic pAMR-2 evidence of AMR. Expression of endothelial HLA class II was significantly correlated with the diagnosis of AMR by percentage area (P < .0001) and intensity of staining (P < .0001). The diagnosis of AMR significantly correlated with moderate (+2) and strong (+3) staining intensity for class II HLA as follows: histopathologic and immunopathologic pAMR-2 with odds ratio (OR) = 28.3 (P < .0001);histopathologic pAMR-1 alone with OR = 22.7 (P < .0001); and immunopathologic pAMR-1 alone with OR = 32.6 (P < .0001). Interestingly, our study also suggested that the inclusion of C4d focally positive cases also significantly correlates with the diagnosis of AMR (P < .003). We confirmed our hypothesis that in heart allograft biopsies, there is a spectrum of both percentage and intensity of HLA class II expression due to endothelial activation, and that class II HLA by immunohistochemistry is a marker significantly correlated with the diagnosis of AMR. In addition, the group of focally positive C4d biopsies (10%-50%) should be considered positive for the immunopathologic component of the 2013 ISHLT classification, as this group of biopsies also correlated with the diagnosis of AMR.
2013年，国际心肺移植协会（ISHLT）推出了心脏同种异体移植抗体介导排斥反应（AMR）相关病理变化的工作分类，即病理AMR（pAMR）。该分类包含与AMR相关的两个部分，即组织病理学变化和免疫病理学标志物，同时建议将II类HLA用作内皮完整性的标志物。已知在同种异体移植排斥反应期间，内皮细胞会被激活，因此，我们推测内皮II类HLA并非仅仅是内皮存在的标志物，而是内皮激活的标志物，并且在AMR中会上调。对2016年1月至2018年9月在单一机构收集的838例心脏同种异体移植活检标本进行评估，这些患者目前或近期诊断为AMR，评估其AMR的组织病理学和免疫病理学变化。活检标本用抗C4d抗体进行免疫荧光标记，并用抗C3d、CD68和II类HLA抗体进行免疫组织化学标记。采用ISHLT标准对活检标本进行分类，对于II类HLA，评估其百分比和染色强度。我们队列中的活检标本（74.8%）显示出组织病理学pAMR-1、免疫病理学pAMR-1或组织病理学和免疫病理学联合的pAMR-2的AMR证据。内皮HLA II类的表达与AMR诊断在面积百分比（P <.0001）和染色强度（P <.0001）方面显著相关。AMR诊断与II类HLA中度（+2）和强（+3）染色强度显著相关，如下所示：组织病理学和免疫病理学pAMR-2，比值比（OR）= 28.3（P <.0001）；单独的组织病理学pAMR-1，OR = 22.7（P <.0001）；单独的免疫病理学pAMR-1，OR = 32.6（P <.0001）。有趣的是，我们的研究还表明，纳入C4d局灶阳性病例也与AMR诊断显著相关（P <.003）。我们证实了我们的假设，即在心脏同种异体移植活检中，由于内皮激活，HLA II类表达在百分比和强度上存在一系列变化，并且免疫组织化学检测的II类HLA是与AMR诊断显著相关的标志物。此外，C4d局灶阳性活检标本组（10%-50%）应被视为2013年ISHLT分类免疫病理学成分的阳性，因为该组活检标本也与AMR诊断相关。
