Association entre les dérégulations des cellules dendritiques et les altérations des lymphocytes B présentes chez les patients infectés par le VIH

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. 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, mucosaeand 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. 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 HIVinfected 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) -3α and MIP-3β 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. 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.

Keyphrases: BLyS, Inflammation, Human immunodeficiency virus, Blood, Dendritic cells, B cells, Clinical progression, BLyS, Inflammation