Abstract
BackgroundIn many neuroinflammatory diseases, dendritic cells (DCs) accumulate in several compartments of the central nervous system (CNS), including the cerebrospinal fluid (CSF). Myeloid DCs invading the inflamed CNS are thus thought to play a major role in the initiation and perpetuation of CNS-targeted autoimmune responses. We previously reported that, in normal rats, DCs injected intra-CSF migrated outside the CNS and reached the B-cell zone of cervical lymph nodes. However, there is yet no information on the migratory behavior of CSF-circulating DCs under neuroinflammatory conditions.Methodology/Principal FindingsTo address this issue, we performed in vivo transfer experiments in rats suffering from experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. EAE or control rats were injected intra-CSF with bone marrow-derived myeloid DCs labeled with the fluorescent marker carboxyfluorescein diacetate succinimidyl ester (CFSE). In parallel experiments, fluorescent microspheres were injected intra-CSF to EAE rats in order to track endogenous antigen-presenting cells (APCs). Animals were then sacrificed on day 1 or 8 post-injection and their brain and peripheral lymph nodes were assessed for the presence of microspheres+ APCs or CFSE+ DCs by immunohistology and/or FACS analysis. Data showed that in EAE rats, DCs injected intra-CSF substantially infiltrated several compartments of the inflamed CNS, including the periventricular demyelinating lesions. We also found that in EAE rats, as compared to controls, a larger number of intra-CSF injected DCs reached the cervical lymph nodes. This migratory behavior was accompanied by an accentuation of EAE clinical signs and an increased systemic antibody response against myelin oligodendrocyte glycoprotein, a major immunogenic myelin antigen.Conclusions/SignificanceAltogether, these results indicate that CSF-circulating DCs are able to both survey the inflamed brain and to reach the cervical lymph nodes. In EAE and maybe multiple sclerosis, CSF-circulating DCs may thus support the immune responses that develop within and outside the inflamed CNS.
Highlights
dendritic cells (DCs) are the most powefull antigen presenting-cells of the immune system
DCs are the most powefull antigen presenting-cells of the immune system. They sequentially capture antigens in inflamed tissues, reach the lymphatic vessels, migrate toward lymphoid organs and induce the antigen-specific proliferation of T-cells [1,2]. This functional scheme does not apply to central nervous system (CNS) for the following reasons: i) in contrast with all other tissues, there is no DCs residing in the CNS parenchyma, ii) the so-called ‘‘blood-brain barrier’’ considerably limits the penetration of blood-circulating immune cells, including DCs and their precursors, into the CNS parenchyma; iii) the CNS is devoided of lymphatic vessels
We reported that in normal rats, DCs injected into the cerebrospinal fluid reached the cervical lymph nodes (CLNs) while DCs injected into the brain parenchyma stayed confined to the CNS [10]
Summary
DCs are the most powefull antigen presenting-cells of the immune system. They sequentially capture antigens in inflamed tissues, reach the lymphatic vessels, migrate toward lymphoid organs and induce the antigen-specific proliferation of T-cells [1,2]. (iii) Migration of CSF DCs in the brain parenchyma and perivascular spaces On day 1 or 8 post-injection, microspheres+/MHC class II+ cells as well as CFSE+ DCs localized in parenchymal areas, distant away from the site of injection (Fig 5 and 6). In injected EAE rats sacrificed on day 1 post-injection (n = 4), we found that 2.26+/20,11% CFSE+ cells could be detected in the CLNs as compared to 1.37+/20,03% in the axillary lymph nodes (p = 0.02, Mann and Whitney test)(Fig 8A, C–D). Such an increased antibody response was not observed when considering myelin basic protein (MBP) as a target antigen (Fig 10C) Overall, these data demonstrate that injection of DCs into the CSF of EAE rats induces an exacerbation of clinical signs along with an increased systemic antibody response against MOG
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