Intragraft B Cells, Just Not Like the Others.
Intragraft B Cells, Just Not Like the Others.
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移植物内 B 细胞，与其他细胞不同。
DOI：
10.1097/tp.0000000000004399
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发表时间：
2023
期刊：
影响因子：
6.2
通讯作者：
Zorn,Emmanuel
中科院分区：
文献类型：
--
作者：
Zorn,Emmanuel
B细胞浸润在大多数人类移植排斥反应中被发现。然而，尽管经过多年的研究，它们在拒绝过程中的作用和确切贡献仍然是个谜。作为破解这一难题的第一步，研究人员已经开始描述这些浸润细胞的表型和特异性。近年来，主要使用人类肾脏和心脏移植标本进行的研究中出现了一些特征。1，2在本期发表的一项研究中，Zheng及其同事使用完全同种异体Balb/c到B6肾移植模型来解决其中的一些问题（见Zhang et al 3）。除了技术上的成功--在你空闲的时候尝试移植一个小鼠肾脏--这个实验模型似乎与临床相关，因为它概括了抗体介导的排斥反应和T细胞介导的排斥反应的大多数特征，如供体特异性抗体、移植物肾小球中的T细胞和B细胞浸润、肾小球炎和类似肾小管周围毛细血管的结构中的C4d沉积。同种异体移植物在1个月内丢失，中位生存时间为21天。以μMT小鼠为受体可减轻排斥反应的严重程度，提示B细胞参与了排斥反应的发生。值得注意的是，这些小鼠中的CD 4 + T细胞浸润没有变化，表明B细胞缺乏并没有明显影响T细胞介导的排斥反应的发展。作者利用该模型进一步表征了移植物浸润B细胞。一些特征已经在人类B细胞中观察到;另一些是新的，并指出这些细胞的未被认识的功能。小鼠和人类之间的共同特征之一是浸润性细胞包括更高比例的记忆细胞。这以前曾在人类肾脏和心脏移植中报道过。1，2，4，5在该模型中发现的移植物内B细胞与在人类中发现的移植物内B细胞之间的另一个惊人的相似性是它们特有的转录组学特征，包括归因于先天样B细胞（如Ahnak）的基因的表达。1与此相反，一些差异也很明显。特别是，移植物B细胞主要表达种系编码的免疫球蛋白基因，并且仅显示低水平的克隆扩增的事实是令人困惑的，并且与过去对人肾和心脏移植浸润的分析不一致。1，6，7这种差异可能是由于移植和排斥反应之间的时间很短，只有20天，而人类同种异体移植受者则需要数月或数年。另一个明显的区别来自这些细胞的反应性。小鼠转换的移植物内B细胞似乎富含同种异体细胞，尽管这在人类中更值得怀疑。1，2，8-10作者随后研究了移植物内B细胞的功能特性，特别是它们促进CD 4 + T细胞增殖的能力。研究的这一部分特别有趣，因为它代表了确定移植物内B细胞功能的首次尝试之一，推测这些细胞与它们的先天样特征有关。结果显示，与淋巴结（LN）B细胞相比，CD 4 T细胞扩增能力降低。此外，使用Foxp 3 IRES − GFP小鼠（该研究小组熟悉的模型），Zheng等人表明，移植物内B细胞以与LN B细胞不同的方式刺激Tfh细胞，导致增殖减少和除粒细胞巨噬细胞集落刺激因子外的细胞因子分泌减少。尽管有其固有的局限性，这个实验模型提供了宝贵的见解肾移植过滤B细胞在主动排斥反应的时间。首先，他们对炎症的贡献...
B-cell infiltrates are found in most human transplants during rejection. Despite years of research, however, their role and exact contribution to the rejection process are still enigmatic. As a first step toward cracking this vexing puzzle, investigators have begun characterizing the phenotype and specificity of these infiltrating cells. In recent years, a few characteristics have emerged from studies conducted primarily with human kidney and heart transplant specimens. 1, 2 In a study published in this issue, Zheng and colleagues used a fully allogeneic Balb/c into B6 kidney transplant model to address some of these questions (see Zhang et al3 in this issue). Aside from its technical prowess—try transplanting a mouse kidney in your spare time—the experimental model appears clinically relevant because it recapitulates most features of antibody-mediated rejection and T cell–mediated rejection such as donor-specific antibodies, T-and B-cell infiltrates in the graft interstitium, glomerulitis, and C4d deposition in structures resembling peritubular capillaries. Allografts are lost within 1 mo with a median survival time of 21 d. Using μMT mice as recipients decreased the severity of rejection, indicating that B cells were involved in the rejection mechanism. Remarkably, CD4+ T-cell infiltrates were unchanged in these mice, suggesting that B-cell deficiency did not overtly impact the development of T cell–mediated rejection. The authors took advantage of the model to further characterize the graft-infiltrating B cells. Some features had already been observed in human B cells; others are novel and point to an unrecognized function of these cells. Among the common characteristics between mice and men is the fact that infiltrates include a higher proportion of memory cells. This had previously been reported for human kidney and heart transplants. 1, 2, 4, 5 Another striking similarity noted between intragraft B cells found in this model and in humans is their peculiar transcriptomic signature, including the expression of genes attributed to innate-like B cells such as Ahnak. 1 In contrast, a number of differences were also noticeable. In particular, the fact that graft B cells predominantly express germline-encoded immunoglobulin genes and show only a low level of clonal expansion is perplexing and in disagreement with the past analysis of human kidney and heart transplant infiltrates. 1, 6, 7 This discrepancy could result from short time, only 20 d, between transplant and rejection compared to months or years in human allograft recipients. Another apparent difference comes from the reactivity of these cells. Mouse-switched intragraft B cells appear enriched for allospecific cells, although this is more questionable in humans. 1, 2, 8-10 The authors then investigated the functional properties of intragraft B cells and especially their capacity to promote the proliferation of CD4+ T cells. This part of the study is particularly interesting because it represents one of the first attempts to determine the function of intragraft B cells presumably associated with their innate-like profile. Results revealed a decreased ability to expand CD4 T cells when compared to lymph node (LN) B cells. Moreover, using Foxp3IRES− GFPmice, a model familiar to this research group, Zheng et al showed that intragraft B cells stimulate Tfh cells in a different manner than LN B cells, resulting in reduced proliferation and diminished cytokine secretion with the exception of granulocytemacrophage colony-stimulating factors. Notwithstanding its inherent limitations, this experimental model offers invaluable insights into kidney graftinfiltrating B cells at the time of active rejection. For one, their contribution to the inflammatory …