No abstract

The lack of draining lymphatic vessels in the central nervous system (CNS) contributes to the so-called "CNS immune privilege." However, despite such a unique anatomic feature, dendritic cells (DCs) are able to migrate from the CNS to cervical lymph nodes through a yet unknown pathway. In this report, labeled bone marrow-derived myeloid DCs were injected stereotaxically into the cerebrospinal fluid (CSF) or brain parenchyma of normal rats. We found that DCs injected within brain parenchyma migrate little from their site of injection and do not reach cervical lymph nodes. In contrast, intra-CSFinjected DCs either reach cervical lymph nodes or, for a minority of them, infiltrate the subventricular zone, where neural stem cells reside. Surprisingly, DCs that reach cervical lymph nodes preferentially IntroductionUnder normal conditions, the transport of immune cells from blood to the central nervous system (CNS) is restricted by 2 physical barriers: the blood-brain barrier formed by CNS parenchymal microvessels and the blood cerebrospinal fluid (CSF) barrier formed by the choroid plexuses. Also, the circulation of immune cells from brain to lymphoid organs is hampered by the lack of CNS-draining lymphatic vessels. Nevertheless, immune responses may develop in the CNS, and cervical lymph nodes are considered as major sites of antigen presentation during neuroinflammatory diseases. 1,2 Indeed, antigens are drained from the CNS to cervical lymph nodes along the axons of craniofacial peripheral nerves. 3,4 Also, it was reported that dendritic cells (DCs) are able to migrate out of the CNS and, in turn, to elicit a CNS-targeted immune response. 5,6 However, it is not clear whether DCs circulating out of the CNS actually migrate from brain parenchyma or from the CSF compartment. This point is of importance because DCs are absent from normal CNS parenchyma, 7 but they can be detected in CSF and in compartments associated with CSF circulation or production, including meninges and choroid plexuses. [8][9][10] Moreover, under neuroinflammatory conditions, DCs accumulate in the CSF 11,12 as well as in perivascular spaces, 13,14 anatomic compartments draining into the CSF. These findings, along with others, suggest that the CSF may be a major transport route for DCs circulating in the CNS and migrating either from CSF to CNS parenchyma or from CSF to the lymphoid organs. 11,12,15,16 In the present study, we tracked bone marrow-derived myeloid DCs injected stereotaxically into the CSF or brain parenchyma of rats under normal conditions. Materials and methods AnimalsAnimal care and procedures were conducted according to the guidelines approved by the French Ethical Committee (decree 87-848) and the European Community directive 86-609-EEC and meet the Neuroscience Society guidelines. The study protocol was approved by the ethical committee of Faculté de Médecine Laennec, Lyon, France. Eight-to 10-week-old female Sprague Dawley rats were obtained from Harlan (Gannat, France). ReagentsMurine GM-CSF, human Flt3-L, murine IL-4, and h...

Human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, has been described to be associated with mutations affecting the immunoreceptor tyrosine-based activation motif-bearing KARAP/DAP12 immunoreceptor gene. Patients present bone fragilities and severe neurological alterations leading to presenile dementia. Here we investigated whether the absence of KARAP/DAP12-mediated signals in loss-of-function (KDelta75) mice also leads to bone and central nervous system pathological features. Histological analysis of adult KDelta75 mice brains revealed a diffuse hypomyelination predominating in anterior brain regions. As this was not accompanied by oligodendrocyte degeneration or microglial cell activation it suggests a developmental defect of myelin formation. Interestingly, in postnatal KDelta75 mice, we observed a dramatic reduction in microglial cell numbers similar to in vitro microglial cell differentiation impairment. Our results raise the intriguing possibility that defective microglial cell differentiation might be responsible for abnormal myelin development. Histomorphometry revealed that bone remodeling is also altered, because of a resorption defect, associated with a severe block of in vitro osteoclast differentiation. In addition, we show that, among monocytic lineages, KARAP/DAP12 specifically controls microglial and osteoclast differentiation. Our results confirm that KARAP/DAP12-mediated signals play an important role in the regulation of both brain and bone homeostasis. Yet, important differences exist between the symptoms observed in Nasu-Hakola patients and KDelta75 mice.

An inappropriate cross talk between activated T lymphocytes infiltrating the CNS and neural cells can sustain the onset and progression of demyelination and axonal degeneration in neuroinflammatory diseases. To mimic this deleterious cross talk, we designed an experimental paradigm consisting of transient cocultures of T lymphocytes chronically activated by retrovirus infection (not virus productive) with human multipotent neural precursors or primary oligodendrocytes from rat brain. We showed that activated T lymphocytes induced apoptotic death of multipotent neural progenitors and immature oligodendrocytes after a progressive collapse of their process extensions. These effects were reminiscent of those induced by brain semaphorin on neural cells. Blockade by specific Abs of soluble CD100 (sCD100)/semaphorin 4D released by activated T cells, or treatment with rsCD100, demonstrated that this immune semaphorin has the ability to collapse oligodendrocyte process extensions and to trigger neural cell apoptosis, most likely through receptors of the plexin family. The specific presence of sCD100 in the cerebrospinal fluid and of CD100-expressing T lymphocytes in the spinal cord of patients suffering with neuroinflammatory demyelination pointed to the potential pathological effect of sCD100 in the CNS. Thus, our results show that CD100 is a new important element in the deleterious T cell-neural cell cross talk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and human T lymphotropic virus type 1-associated myelopathy.