PDF(Pubmed)
Abstract：
UNASSIGNED: It is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of recipient gut lymphocyte populations in immunosuppressed conditions.
UNASSIGNED: Using polychromatic flow cytometry that includes HLA allele group-specific antibodies distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establishment of recipient B cell populations and BCR repertoire in the allograft mucosa of ITx recipients.
UNASSIGNED: We confirm the early presence of naïve donor B cells in the circulation (donor age range: 1-14 years, median: 3 years) and, for the first time, document the establishment of recipient B cell populations, including B resident memory cells, in the intestinal allograft mucosa (recipient age range at the time of transplant: 1-44 years, median: 3 years). Recipient B cell repopulation of the allograft was most rapid in infant (<1 year old)-derived allografts and, unlike T cell repopulation, did not correlate with rejection rates. While recipient memory B cell populations were increased in graft mucosa compared to circulation, naïve recipient B cells remained detectable in the graft mucosa for years. Comparisons of peripheral and intra-mucosal B cell repertoires in the absence of rejection (recipient age range at the time of transplant: 1-9 years, median: 2 years) revealed increased BCR mutation rates and clonal expansion in graft mucosa compared to circulating B cells, but these parameters did not increase markedly after the first year post-transplant. Furthermore, clonal mixing between the allograft mucosa and the circulation was significantly greater in ITx recipients, even years after transplantation, than in deceased adult donors. In available pan-scope biopsies from pediatric recipients, we observed higher percentages of naïve recipient B cells in colon allograft compared to small bowel allograft and increased BCR overlap between native colon vs colon allograft compared to that between native colon vs ileum allograft in most cases, suggesting differential clonal distribution in large intestine vs small intestine.
UNASSIGNED: Collectively, our data demonstrate intestinal mucosal B cell repertoire establishment from a circulating pool, a process that continues for years without evidence of stabilization of the mucosal B cell repertoire in pediatric ITx patients.
UNASSIGNED: Using polychromatic flow cytometry that includes HLA allele group-specific antibodies distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establishment of recipient B cell populations and BCR repertoire in the allograft mucosa of ITx recipients.
UNASSIGNED: We confirm the early presence of naïve donor B cells in the circulation (donor age range: 1-14 years, median: 3 years) and, for the first time, document the establishment of recipient B cell populations, including B resident memory cells, in the intestinal allograft mucosa (recipient age range at the time of transplant: 1-44 years, median: 3 years). Recipient B cell repopulation of the allograft was most rapid in infant (<1 year old)-derived allografts and, unlike T cell repopulation, did not correlate with rejection rates. While recipient memory B cell populations were increased in graft mucosa compared to circulation, naïve recipient B cells remained detectable in the graft mucosa for years. Comparisons of peripheral and intra-mucosal B cell repertoires in the absence of rejection (recipient age range at the time of transplant: 1-9 years, median: 2 years) revealed increased BCR mutation rates and clonal expansion in graft mucosa compared to circulating B cells, but these parameters did not increase markedly after the first year post-transplant. Furthermore, clonal mixing between the allograft mucosa and the circulation was significantly greater in ITx recipients, even years after transplantation, than in deceased adult donors. In available pan-scope biopsies from pediatric recipients, we observed higher percentages of naïve recipient B cells in colon allograft compared to small bowel allograft and increased BCR overlap between native colon vs colon allograft compared to that between native colon vs ileum allograft in most cases, suggesting differential clonal distribution in large intestine vs small intestine.
UNASSIGNED: Collectively, our data demonstrate intestinal mucosal B cell repertoire establishment from a circulating pool, a process that continues for years without evidence of stabilization of the mucosal B cell repertoire in pediatric ITx patients.
摘要：
■在人类中如何建立和维持肠B细胞群和B细胞受体(BCR)库是未知的。肠道移植（ITx）后，监测回肠粘膜活检为在免疫抑制条件下动态建立受者肠道淋巴细胞群提供了独特的机会。
■使用多色流式细胞术，包括HLA等位基因组特异性抗体区分供体和受体细胞以及高通量BCR测序，我们追踪了ITx受体同种异体移植粘膜中受体B细胞群和BCR库的建立。
■我们确认循环中早期存在原始供体B细胞（供体年龄范围：1-14岁，中位数：3年)和，第一次,文件建立受体B细胞群，包括B驻留记忆单元，在肠道同种异体移植粘膜中（移植时的受体年龄范围：1-44岁，中位数：3年）。在婴儿（<1岁）衍生的同种异体移植物中，同种异体移植物的受体B细胞再增殖最快，与T细胞再增殖不同，与排斥率无关。与循环相比，移植粘膜中的受体记忆B细胞群增加，原始受体B细胞在移植粘膜中保持可检测多年。在没有排斥反应的情况下，外周和粘膜内B细胞库的比较（移植时的受体年龄范围：1-9岁，中位数：2年）与循环B细胞相比，移植物粘膜中的BCR突变率和克隆扩增增加，但这些参数在移植后第一年后没有明显增加.此外，在ITx受者中，同种异体移植粘膜和循环之间的克隆混合明显更大，甚至在移植多年后，而不是已故的成人捐赠者。在可用的儿科受者的全镜活检中，在大多数情况下，与小肠同种异体移植相比，我们观察到结肠移植中原始受体B细胞的百分比更高，并且与天然结肠和回肠同种异体移植相比，天然结肠与结肠同种异体移植之间的BCR重叠增加。提示大肠与小肠的差异克隆分布。
■集体，我们的数据表明肠粘膜B细胞库从循环池建立，这一过程持续多年，没有证据表明儿科ITx患者的粘膜B细胞库稳定。
■使用多色流式细胞术，包括HLA等位基因组特异性抗体区分供体和受体细胞以及高通量BCR测序，我们追踪了ITx受体同种异体移植粘膜中受体B细胞群和BCR库的建立。
■我们确认循环中早期存在原始供体B细胞（供体年龄范围：1-14岁，中位数：3年)和，第一次,文件建立受体B细胞群，包括B驻留记忆单元，在肠道同种异体移植粘膜中（移植时的受体年龄范围：1-44岁，中位数：3年）。在婴儿（<1岁）衍生的同种异体移植物中，同种异体移植物的受体B细胞再增殖最快，与T细胞再增殖不同，与排斥率无关。与循环相比，移植粘膜中的受体记忆B细胞群增加，原始受体B细胞在移植粘膜中保持可检测多年。在没有排斥反应的情况下，外周和粘膜内B细胞库的比较（移植时的受体年龄范围：1-9岁，中位数：2年）与循环B细胞相比，移植物粘膜中的BCR突变率和克隆扩增增加，但这些参数在移植后第一年后没有明显增加.此外，在ITx受者中，同种异体移植粘膜和循环之间的克隆混合明显更大，甚至在移植多年后，而不是已故的成人捐赠者。在可用的儿科受者的全镜活检中，在大多数情况下，与小肠同种异体移植相比，我们观察到结肠移植中原始受体B细胞的百分比更高，并且与天然结肠和回肠同种异体移植相比，天然结肠与结肠同种异体移植之间的BCR重叠增加。提示大肠与小肠的差异克隆分布。
■集体，我们的数据表明肠粘膜B细胞库从循环池建立，这一过程持续多年，没有证据表明儿科ITx患者的粘膜B细胞库稳定。
