Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques
Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques
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DOI：
10.1172/jci43271
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Amara, Rama R.
中科院分区：
文献类型：
--
作者：
Titanji, Kehmia;Velu, Vijayakumar;Amara, Rama R.
迅速发展为艾滋病是一个重大问题，特别是在大多数艾滋病毒感染者居住的发展中国家。由于在SIV感染的猕猴中也经常观察到疾病的快速进展，因此它们代表了研究人类这种疾病发病机制的有价值的工具。在这里，我们已经表明，致病性Sly感染恒河猴导致激活的记忆B（CD 21（-）CD 27（+）; mB（Act））细胞的快速耗竭（早在第2周），这与疾病的快速进展密切相关。这种消耗在快速进展者中是进行性和持续的，但在典型进展者中不太严重和短暂。由于mB（Act）细胞的快速和持续消耗，快速进展者未能产生SIV特异性Ab应答，显示非SIV特异性Ab滴度下降，并且更快地死于肠道细菌感染。mBAct细胞的消耗与表达程序性死亡-1（PD-1）的mB（Act）细胞的优先消耗密切相关，并且PD-1的体外阻断改善了它们的存活。此外，在SIV感染的猕猴中的体内PD-1阻断增强了对非SIV以及SIV Ag的Ab应答。我们的研究结果确定mB（Act）细胞的耗竭是致病性SW感染中疾病快速进展的一个非常早期的预测因子，并表明PD-1通路在mBAct细胞耗竭和SIV感染猕猴的体液免疫应答受损中起重要作用。
Rapid progression to AIDS is a significant problem, especially in developing countries, where the majority of HIV-infected individuals reside. As rapid disease progression is also frequently observed in SIV-infected macaques, they represent a valuable tool to investigate the pathogenesis of this condition in humans. Here, we have shown that pathogenic Sly infection in rhesus macaques resulted in a rapid depletion (as early as week 2) of activated memory B (CD21(-)CD27(+); mB(Act)) cells that was strongly associated with rapid disease progression. This depletion was progressive and sustained in rapid progressors, but less severe and transient in typical progressors. Because of the rapid and sustained depletion of mB(Act) cells, rapid progressors failed to develop SIV-specific Ab responses, showed a decline in non-SIV-specific Ab titers, and succumbed faster to intestinal bacterial infections. Depletion of mBAct cells was strongly associated with preferential depletion of mB(Act) cells expressing programmed death-1 (PD-1), and in vitro blockade of PD-1 improved their survival. Furthermore, in vivo PD-1 blockade in SIV-infected macaques enhanced Ab responses to non-SIV as well as SIV Ags. Our results identify depletion of mB(Act) cells as a very early predictor of rapid disease progression in pathogenic SW infection and suggest an important role for the PD-1 pathway in depletion of mBAct cells and impaired humoral immune responses in SIV-infected macaques.