Alevtina Gall, Marita Bosticardo, Stacey Ma, Karin Chen, Kayla Amini, Francesca Pala, Ottavia M. Delmonte, Tara Wenger, Michael Bamshad, John Sleasman, Matthew Blessing, Nicolai S. C. van Oers, Luigi D. Notarangelo, M. Teresa de la Morena
{"title":"病例报告:人工胸腺组织有助于为一名患有 TP63 变异和严重持续性 T 细胞淋巴细胞减少症的患者做出临床决定","authors":"Alevtina Gall, Marita Bosticardo, Stacey Ma, Karin Chen, Kayla Amini, Francesca Pala, Ottavia M. Delmonte, Tara Wenger, Michael Bamshad, John Sleasman, Matthew Blessing, Nicolai S. C. van Oers, Luigi D. Notarangelo, M. Teresa de la Morena","doi":"10.3389/fimmu.2024.1438383","DOIUrl":null,"url":null,"abstract":"Pathogenic variants in the transcription factor <jats:italic>TP63</jats:italic> are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with <jats:italic>TP63</jats:italic> variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with <jats:italic>TP63</jats:italic>-related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A <jats:italic>de novo</jats:italic> heterozygous pathogenic variant c.1040 G&gt;A (C347Y) in exon 8 of <jats:italic>TP63</jats:italic> was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient’s hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. <jats:italic>Ex vivo</jats:italic> T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that <jats:italic>TP63</jats:italic> expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with <jats:italic>TP63</jats:italic> variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. She will continue regular monitoring to ensure restoration of T cell immunity.","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":null,"pages":null},"PeriodicalIF":8.3000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Case report: Artificial thymic organoids facilitate clinical decisions for a patient with a TP63 variant and severe persistent T cell lymphopenia\",\"authors\":\"Alevtina Gall, Marita Bosticardo, Stacey Ma, Karin Chen, Kayla Amini, Francesca Pala, Ottavia M. Delmonte, Tara Wenger, Michael Bamshad, John Sleasman, Matthew Blessing, Nicolai S. C. van Oers, Luigi D. Notarangelo, M. Teresa de la Morena\",\"doi\":\"10.3389/fimmu.2024.1438383\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Pathogenic variants in the transcription factor <jats:italic>TP63</jats:italic> are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with <jats:italic>TP63</jats:italic> variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with <jats:italic>TP63</jats:italic>-related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A <jats:italic>de novo</jats:italic> heterozygous pathogenic variant c.1040 G&gt;A (C347Y) in exon 8 of <jats:italic>TP63</jats:italic> was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient’s hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. <jats:italic>Ex vivo</jats:italic> T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that <jats:italic>TP63</jats:italic> expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with <jats:italic>TP63</jats:italic> variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. 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引用次数: 0
摘要
转录因子 TP63 的致病变体与临床上重叠的综合征有关,这些综合征包括外耳道畸形-外胚层发育不良-唇腭裂(EEC)和颧骨发育不全-外胚层缺陷-唇腭裂(AEC)。TP63变异型患者很少出现T细胞淋巴细胞减少症,T细胞缺陷的原因尚不清楚。在这里,我们介绍了一例患有 TP63 相关综合征和严重 T 细胞淋巴细胞减少症的女婴,该病例是通过新生儿筛查首次发现的。流式细胞术分析显示,CD4+幼稚T细胞较少,CD8+T细胞几乎没有,但B细胞和NK细胞完整。在TP63的第8外显子中发现了一个新的杂合致病变体c.1040 G>A (C347Y)。为了评估患者造血细胞发育成 T 细胞的内在能力,研究人员两次使用不同的外周血样本进行了人工胸腺器官系统的研究。人工类器官系统显示体内T细胞分化明显,这表明胸腺基质细胞缺陷可能是导致T细胞淋巴细胞减少症的原因。与此相一致的是,对公开数据的分析表明,TP63在人类胸腺中的表达仅限于胸腺上皮细胞。根据这些数据,我们怀疑患者患有先天性无胸腺症,并为其植入了异基因培养胸腺组织(CTTI)。这是首例与 TP63 变异相关的疑似先天性无胸腺症并尝试用 CTTI 治疗的报告。移植后 9 个月时,外周淋巴细胞分析显示有可测量的 T 细胞受体切除圈和 CD4+ 新近胸腺移植物的存在,提示早期胸腺生成。她将继续接受定期监测,以确保 T 细胞免疫的恢复。
Case report: Artificial thymic organoids facilitate clinical decisions for a patient with a TP63 variant and severe persistent T cell lymphopenia
Pathogenic variants in the transcription factor TP63 are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with TP63 variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with TP63-related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A de novo heterozygous pathogenic variant c.1040 G>A (C347Y) in exon 8 of TP63 was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient’s hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. Ex vivo T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that TP63 expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with TP63 variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. She will continue regular monitoring to ensure restoration of T cell immunity.
期刊介绍:
ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.