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首页> 外文学位 >Association entre les deregulations des cellules dendritiques et les alterations des lymphocytes B presentes chez les patients infectes par le VIH.
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Association entre les deregulations des cellules dendritiques et les alterations des lymphocytes B presentes chez les patients infectes par le VIH.

机译：HIV感染患者中树突状细胞失调与B细胞变化之间的关联。

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摘要

Dysregulations of the B cell compartment are an important consequence of human immunodeficiency (HIV) infection, which can lead to auto-immune manifestations and ultimately to B cell lymphomas. One of the first alterations is polyclonal activation, reflected by hyperglobulinemia (hyper-Ig) and elevated autoantibody titers. We can also observe alterations in population dynamics, namely an expansion of the pool of activated B cells. Furthermore, HIV infected patients evolve towards the incapacity to generate effective humoral responses, and experience a loss of immunological memory in the chronic phase, characterized by a decrease in the memory B cell pool and cell exhaustion. The mechanisms involved in this phenomenon are poorly understood and thus remain to be elucidated.;DC play an important role in T-dependent and T-independent B cell development, survival and activation, namely through the production of growth factors such as B Lymphocyte Stimulator (BLyS). Therefore, we hypothesize that B cell abnormalities in HIV-infected individuals may be modulated by altered DC populations.;The main objective of this study is to evaluate DC involvement in the establishment of B cell alterations related to HIV infection. We have thus first characterized the DC status by longitudinally assessing the dynamics of peripheral blood DC populations of HIV infected individuals with different rates of disease progression. This allowed us to evaluate the potential correlation between DC population dynamics and rate of disease progression. We have then evaluated BLyS expression by mDC and their precursors, and measured plasma concentrations of BlyS and other cytokines with B cell growth factor properties. Finally, we have characterized the dynamics of blood B cell populations, with regard to the phase of HIV infection and the rate of clinical progression.;We demonstrate a decrease in the frequencies of blood myeloid DC (mDC) in HIV progressors. This drop was observed as early as in the acute phase and following the initiation of ART. Elevated blood concentrations of monocyte chemotactic protein (MCP) -1, macrophage inflammatory protein (MIP) -3alpha and MIP-3beta suggest that the observed decrease is due to recruitment to peripheral sites. However, this hypothesis will be tested in a subsequent projet. We have also observed an increase of monocytic CD11c+CD14 +CD16-DC precursors in chronic phases, possibly reflecting the high DC turnover. Furthermore, chronically infected HIV progressors present elevated blood BLyS concentrations, and high BLyS expression by DC and DC precursors. In parallel, these patients present increased frequencies of blood mature activated B cells as well as hyper IgG and IgA. Interestingly, we also observe expansion of a B cell population with features of precursors/activated marginal zone (MZ) B cells.;Mucosal dendritic cells (DC) are among the first cell populations to encounter HIV during an infection and are directly and indirectly affected by the virus and viral components. Indeed, HIV infected individuals present decreased DC frequencies in their blood, mucosae and lymphoid organs, as well as a block in DC maturation process. However, whether these defects appear as soon as the acute phase and persist beyond ART, remains controversial. This is mainly due to the scarcity of longitudinal studies including patients' visits from the earliest phases of infection and following ART.;On the other hand, slow progressors show a better preservation of their mDC compartment, accompanied by an increase in DC precursors with a CD11c +CD14+CD16+ phenotype. These patients present normal BLyS plasma concentrations and membrane expression on DC and precursors. In parallel, they have normal frequencies of blood mature activated B cells and precursors/activated MZ B cells. However, we found decreased frequencies of mature MZ B cells, suggesting recruitment to peripheral sites and involvement in active control of disease progression.;Our results suggest that, in an HIV infection, alterations observed in the DC compartment contribute to B cell abnormalities. Therefore, it is crucial to maintain the equilibrium of DC fonctions, namely non-inflammatory functions, in order to prevent progression of disease attributable to dysregulation of the B cell compartment.;Keywords : Human immunodeficiency virus, blood, dendritic cells, B cells, clinical progression, BLyS, inflammation
机译：B细胞区室的失调是人类免疫缺陷（HIV）感染的重要结果，可导致自身免疫表现并最终导致B细胞淋巴瘤。最初的变化之一是多克隆激活，反映为高球蛋白血症（高Ig）和自身抗体滴度升高。我们还可以观察到种群动态的变化，即活化B细胞池的扩展。此外，HIV感染的患者逐渐变得无能力产生有效的体液反应，并在慢性期经历免疫记忆的丧失，其特征在于记忆B细胞池减少和细胞衰竭。对该现象涉及的机制了解甚少，因此尚待阐明。DC在T依赖性和T依赖性B细胞的发育，存活和激活中起着重要作用，即通过产生生长因子（如B淋巴细胞刺激物） （BLyS）。因此，我们假设HIV感染者的B细胞异常可能是由DC种群的改变所调节的。本研究的主要目的是评估DC参与与HIV感染有关的B细胞变异建立的过程。因此，我们首先通过纵向评估具有不同疾病进展速度的HIV感染者的外周血DC种群动态来表征DC状态。这使我们能够评估DC人口动态与疾病进展率之间的潜在相关性。然后，我们通过mDC及其前体评估了BLyS的表达，并测量了具有B细胞生长因子特性的BlyS和其他细胞因子的血浆浓度。最后，我们就HIV感染的阶段和临床进展的速度对血液B细胞种群的动态进行了特征描述。我们证明了HIV进展者中血液髓样DC（mDC）频率的降低。早在急性期和ART开始后就观察到了这种下降。单核细胞趋化蛋白（MCP）-1，巨噬细胞炎性蛋白（MIP）-3alpha和MIP-3beta的血药浓度升高，表明观察到的下降是由于募集到周围部位。但是，此假设将在后续的项目中进行检验。我们还观察到慢性期单核细胞CD11c + CD14 + CD16-DC前体的增加，可能反映了高DC转换率。此外，慢性感染的HIV进展者表现出升高的血液BLyS浓度，以及DC和DC前体的高BLyS表达。同时，这些患者血液成熟的活化B细胞以及高IgG和IgA的频率增加。有趣的是，我们还观察到具有前体/活化边缘区（MZ）B细胞特征的B细胞群体的扩张。;粘膜树突状细胞（DC）是感染期间首批遇到HIV的细胞群体之一，并受到直接和间接影响由病毒和病毒成分组成。确实，HIV感染者的血液，粘膜和淋巴器官中的DC频率降低，并且阻碍了DC成熟过程。但是，这些缺陷是否在急性期就出现并持续超过ART仍存在争议。这主要是由于缺乏纵向研究，包括从感染的最早阶段到接受抗逆转录病毒治疗的患者就诊。另一方面，进展缓慢的患者表现出更好的mDC腔室保存，同时伴随着DC前体的增加。 CD11c + CD14 + CD16 +表型。这些患者在DC和前体上呈现正常的BLyS血浆浓度和膜表达。同时，它们具有正常频率的血液成熟激活的B细胞和前体/激活的MZ B细胞。然而，我们发现成熟MZ B细胞的频率降低，表明其募集到外周部位并参与疾病进展的主动控制。我们的结果表明，在HIV感染中，在DC隔室中观察到的改变会导致B细胞异常。因此，至关重要的是保持DC功能的平衡，即非炎性功能，以防止可归因于B细胞区室调节异常的疾病进展。关键词：人免疫缺陷病毒，血液，树突状细胞，B细胞，临床进展，BLyS，炎症

著录项

  • 作者

    Fontaine, Julie.;

  • 作者单位

    Universite de Montreal (Canada).;

  • 授予单位 Universite de Montreal (Canada).;
  • 学科 Biology Cell.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 241 p.
  • 总页数 241
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

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