INTRODUCTION Chronic histiocytic intervillositis (CHI) is associated with adverse pregnancy outcomes and high recurrence risk. Recent studies suggest that CHI may represent a host-vs-graft rejection, and that C4d immunostain can be used as a marker for complement activation and antibody-mediated rejection in the CHI. MATERIALS AND METHODS This retrospective cohort study focused on 5 fetal autopsy cases associated with CHI (5 index cases) from 5 women. We analyzed placentas from the index cases (fetal autopsy cases associated with CHI) and placentas from the women's previous and subsequent pregnancies. We assessed the presence and extent of CHI and C4d immunostaining in these placentas. We evaluated each available placenta and graded the severity of CHI as either <50% or ≥50%. Additionally, we conducted C4d immunostaining on one representative section from each placenta and graded the staining levels as follows: 0+ for staining <5%; 1+ for staining between 5% and <25%; 2+ for staining between 25% and <75%; and 3+ for staining ≥75%. RESULTS Three of the 5 women had pregnancies prior to their index cases (fetal autopsy cases associated with CHI). Despite the absence of CHI in their initial pregnancies, the placentas displayed positive C4d staining with grades of 1+, 3+, and 3+, respectively. These results suggest the presence of complement activation and antibody-mediated rejection in placentas from their prior pregnancies without CHI. Three of the 5 women received immunomodulatory therapy after experiencing pregnancy losses associated with CHI. After treatment, 2 of these women had live births at 35 and 37 gestational weeks, respectively, while the third had a stillbirth at 25 gestational weeks. The severity of CHI and the degree of C4d staining in the placentas decreased in all 3 cases following immunomodulatory therapies. Specifically, the level of C4d staining decreased from 3+ to 2+, 2+ to 0+, and 3+ to 1+ in these 3 cases, respectively. DISCUSSION In women with a history of recurrent pregnancy loss associated with CHI, C4d immunostaining was present in the placentas from their previous non-CHI pregnancies, suggesting activation of the classical complement pathway and antibody-mediated reaction in their prior non-CHI pregnancies before the development of CHI in subsequent pregnancies. Immunomodulatory therapy may improve pregnancy outcomes by reducing complement activation, as shown by the reduction of C4d immunopositivity in the placentas after immunomodulatory treatment. Although we believe that the study provides valuable insights, we acknowledge that there are limitations to the findings. Therefore, to further elucidate the pathogenesis of CHI, additional research efforts with a collaborative and multidisciplinary approach are necessary.

中文翻译：

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C4d 染色存在于与慢性组织细胞绒毛间炎相关的妊娠流产之前的正常胎盘中，并且在随后的妊娠中通过免疫调节治疗而减少。

简介 慢性组织细胞绒毛间炎 (CHI) 与不良妊娠结局和高复发风险相关。最近的研究表明，CHI 可能代表宿主抗移植物排斥，并且 C4d 免疫染色可用作 CHI 中补体激活和抗体介导的排斥反应的标记。材料和方法 这项回顾性队列研究重点关注来自 5 名女性的 5 例与 CHI 相关的胎儿尸检病例（5 例指标病例）。我们分析了指示病例（与 CHI 相关的胎儿尸检病例）的胎盘以及女性先前和随后怀孕的胎盘。我们评估了这些胎盘中 CHI 和 C4d 免疫染色的存在和程度。我们评估了每个可用的胎盘，并将 CHI 的严重程度分级为 <50% 或 ≥50%。此外，我们对每个胎盘的一个代表性切片进行了 C4d 免疫染色，并将染色水平分级如下：0+ 表示染色 <5%；0+ 表示染色 <5%；1+ 表示染色介于 5% 和 <25% 之间；2+ 表示染色介于 25% 和 <75% 之间；3+ 表示染色≥75%。结果 5 名妇女中有 3 名在她们的指示病例（与 CHI 相关的胎儿尸检病例）之前怀孕过。尽管在初次妊娠时没有 CHI，但胎盘显示 C4d 染色阳性，等级分别为 1+、3+ 和 3+。这些结果表明，在没有 CHI 的情况下，先前妊娠的胎盘中存在补体激活和抗体介导的排斥反应。5 名女性中的 3 名在经历了与 CHI 相关的流产后接受了免疫调节治疗。治疗后，其中 2 名妇女分别在妊娠 35 周和 37 周时产下活产，而第三名妇女则在妊娠 25 周时产下死产。免疫调节治疗后，所有 3 例病例的 CHI 严重程度和胎盘 C4d 染色程度均有所下降。具体而言，这3例中C4d染色水平分别从3+下降到2+、2+下降到0+、3+下降到1+。讨论 在有与 CHI 相关的反复性流产史的女性中，之前非 CHI 妊娠的胎盘中存在 C4d 免疫染色，这表明在之前的非 CHI 妊娠中经典补体途径和抗体介导的反应被激活。随后怀孕时 CHI 的发展。免疫调节治疗可以通过减少补体激活来改善妊娠结局，免疫调节治疗后胎盘中 C4d 免疫阳性的减少就表明了这一点。尽管我们相信这项研究提供了有价值的见解，但我们承认研究结果存在局限性。因此，为了进一步阐明 CHI 的发病机制，需要采取协作和多学科方法进行额外的研究工作。