T. brucei infection reduces B lymphopoiesis in bone marrow and truncates compensatory splenic lymphopoiesis through transitional B-cell apoptosis.
T. brucei infection reduces B lymphopoiesis in bone marrow and truncates compensatory splenic lymphopoiesis through transitional B-cell apoptosis.
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DOI：
10.1371/journal.ppat.1002089
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发表时间：
2011-06
期刊：
影响因子：
6.7
通讯作者：
Black SJ
中科院分区：
文献类型：
--
作者：
Bockstal V;Guirnalda P;Caljon G;Goenka R;Telfer JC;Frenkel D;Radwanska M;Magez S;Black SJ
布氏锥虫物种的非洲锥虫是一种胞外原生动物寄生虫，会导致人类患上致命的非洲锥虫病，并对动物的对应物Nagana做出贡献。锥虫体从血流中的清除是由针对其变异型表面糖蛋白(VSG)外壳抗原的抗体介导的。然而，布氏毛滴虫感染可导致多克隆B细胞激活、B细胞克隆性耗竭、成熟脾边缘B区(MZB)和卵泡B细胞(FOB)持续耗竭，以及B细胞记忆室的破坏。为了确定锥虫感染如何损害体液免疫防御系统，我们使用了C57BL/6布氏毛滴虫AnTat 1.1小鼠模型和多色流式细胞术来记录感染过程中B细胞的发育和成熟。我们的结果显示，骨髓中CLP、Pre-Pro-B、Pro-B、Pre-B和未成熟B细胞阶段的B细胞前体数量减少了95%以上。在脾中，布氏毛滴虫诱导髓外B淋巴细胞生成，表现为HSC-LMPP、CLP、Pre-Pro-B、Pro-B和Pre-B细胞数量显著增加。然而，最终的B细胞成熟被感染诱导的T1和T2群体中的过渡性B细胞的凋亡所废除，这并不是唯一依赖于肿瘤坏死因子、Fas或前列腺素依赖的死亡途径。活体血液、锥体和脾细胞体外共培养的结果表明，锥体表面与T1/2B细胞的表面涂层依赖的接触触发了它们的缺失。我们得出结论，感染诱导并可能依赖于寄生虫接触的过渡性B细胞的缺失阻止了感染期间成熟B细胞室的补充，从而导致宿主对反复出现的寄生虫波维持抗体反应的能力的丧失。由布氏锥虫引起的非洲锥虫病对人和动物都是致命的，由于寄生虫抗原的广泛变异，无法通过接种疫苗来抗击。有效的锥虫控制和清除血流涉及针对寄生虫高度多样化的可变表面糖蛋白抗原的抗体的作用。然而，小鼠的实验性感染表明，锥虫病会引起B细胞迅速耗尽和保护性抗体反应丧失的过程。事实上，边缘带B细胞和滤泡B细胞在感染期间都会耗尽，前者是抵御布氏毛滴虫等血液传播病原体的第一道防线，后者是形成高亲和力抗体产生浆细胞和记忆B细胞的主要来源。此外，现有的针对寄生虫抗原和无关病原体的B细胞记忆在感染早期就被破坏了。在这里，我们证明了在感染期间，骨髓中的B细胞发育减少，早期的B细胞发育被脾取代。然而，发育中的B细胞的充分成熟被过渡性B细胞的发生所破坏。这损害了成熟的边缘地带和滤泡B细胞池的补充，并阻止了针对连续寄生虫波的保护性免疫力的建立。
African trypanosomes of the Trypanosoma brucei species are extracellular protozoan parasites that cause the deadly disease African trypanosomiasis in humans and contribute to the animal counterpart, Nagana. Trypanosome clearance from the bloodstream is mediated by antibodies specific for their Variant Surface Glycoprotein (VSG) coat antigens. However, T. brucei infection induces polyclonal B cell activation, B cell clonal exhaustion, sustained depletion of mature splenic Marginal Zone B (MZB) and Follicular B (FoB) cells, and destruction of the B-cell memory compartment. To determine how trypanosome infection compromises the humoral immune defense system we used a C57BL/6 T. brucei AnTat 1.1 mouse model and multicolor flow cytometry to document B cell development and maturation during infection. Our results show a more than 95% reduction in B cell precursor numbers from the CLP, pre-pro-B, pro-B, pre-B and immature B cell stages in the bone marrow. In the spleen, T. brucei induces extramedullary B lymphopoiesis as evidenced by significant increases in HSC-LMPP, CLP, pre-pro-B, pro-B and pre-B cell populations. However, final B cell maturation is abrogated by infection-induced apoptosis of transitional B cells of both the T1 and T2 populations which is not uniquely dependent on TNF-, Fas-, or prostaglandin-dependent death pathways. Results obtained from ex vivo co-cultures of living bloodstream form trypanosomes and splenocytes demonstrate that trypanosome surface coat-dependent contact with T1/2 B cells triggers their deletion. We conclude that infection-induced and possibly parasite-contact dependent deletion of transitional B cells prevents replenishment of mature B cell compartments during infection thus contributing to a loss of the host's capacity to sustain antibody responses against recurring parasitemic waves. African trypanosomiasis caused by Trypanosoma brucei species is fatal in both humans and animals and cannot be combated by vaccination because of extensive parasite antigenic variation. Effective trypanosome control and clearance from the bloodstream involves the action of antibodies specific for the parasite's highly diverse variable surface glycoprotein antigens. However, experimental infections in mice have shown that trypanosomiasis elicits a rapid process of B cell exhaustion and loss of protective antibody responses. Indeed, both marginal zone B cells, the first line of defense against blood-borne pathogens like T. brucei parasites, and follicular B cells, which are the major source for developing high-affinity antibody-producing plasma cells and memory B cells, become depleted during infection. In addition, existing B-cell memory, both against parasite antigens and non related pathogens, is destroyed early on in infection. Here, we demonstrate that during infection, B cell development is decreased in the bone marrow and early B cell development is taken over by the spleen. However, full maturation of developing B cells is abrogated by the occurrence of transitional B cell apoptosis. This impairs the replenishment of the mature marginal zone and follicular B cell pools and prevents the buildup of protective immunity against successive parasitemic waves.
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影响因子：
2.1
作者：
LANHAM, SM;GODFREY, DG
通讯作者：
GODFREY, DG
影响因子：
12.4
作者：
Figarella, K;Rawer, M;Duszenko, M
通讯作者：
Duszenko, M
DOI：
10.1016/s0923-2494(93)80082-a
发表时间：
1993-06-01
期刊：
RESEARCH IN IMMUNOLOGY
影响因子：
--
作者：
LUCAS, R;MAGEZ, S;DEBAETSELIER, P
通讯作者：
DEBAETSELIER, P
影响因子：
4.4
作者：
Allman, D;Lindsley, RC;Hardy, RR
通讯作者：
Hardy, RR
影响因子：
5.8
作者：
Magez, S;Stijlemans, B;De Baetselier, P
通讯作者：
De Baetselier, P