Multiple sclerosis (MS) is caused by T cells that are reactive for brain antigens. In experimental autoimmune encephalomyelitis, the animal model for MS, myelin-reactive T cells initiate the autoimmune process when entering the nervous tissue and become reactivated upon local encounter of their cognate CNS antigen. Thereby, the strength of the T-cellular reactivation process within the CNS tissue is crucial for the manifestation and the severity of the clinical disease. Recently, B cells were found to participate in the pathogenesis of CNS autoimmunity, with several diverse underlying mechanisms being under discussion. We here report that B cells play an important role in promoting the initiation process of CNS autoimmunity. Myelin-specific antibodies produced by autoreactive B cells after activation in the periphery diffused into the CNS together with the first invading pathogenic T cells. The antibodies accumulated in resident antigen-presenting phagocytes and significantly enhanced the activation of the incoming effector T cells. The ensuing strong blood–brain barrier disruption and immune cell recruitment resulted in rapid manifestation of clinical disease. Therefore, myelin oligodendrocyte glycoprotein (MOG)-specific autoantibodies can initiate disease bouts by cooperating with the autoreactive T cells in helping them to recognize their autoantigen and become efficiently reactivated within the immune-deprived nervous tissue.

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival, regeneration, and plasticity. Emerging evidence also indicates an essential role for BDNF outside the nervous system, for instance in immune cells. We therefore investigated the impact of BDNF on T cells using BDNF knockout (KO) mice and conditional KO mice lacking BDNF specifically in this lymphoid subset. In both settings, we observed diminished T-cell cellularity in peripheral lymphoid organs and an increase in CD4 + CD44 + memory T cells. Analysis of thymocyte development revealed diminished total thymocyte numbers, accompanied by a significant increase in CD4/CD8 double-negative (DN) thymocytes due to a partial block in the transition from the DN3 to the DN4 stage. This was neither due to increased thymocyte apoptosis nor defects in the expression of the TCR-β chain or the pre-TCR. In contrast, pERK but not pAKT levels were diminished in DN3 BDNF-deficient thymocytes. BDNF deficiency in T cells did not result in gross deficits in peripheral acute immune responses nor in changes of the homeostatic proliferation of peripheral T cells. Taken together, our data reveal a critical autocrine and/or paracrine role of T-cell-derived BDNF in thymocyte maturation involving ERK-mediated TCR signaling pathways. Keywords: BDNF Neurotrophins T cells Thymus developmentAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNeurotrophins and other neurotrophic factors play an essential role in the development and maintenance of the peripheral and central nervous systems (CNS). They are involved in neuronal survival, axonal growth, generation of new synaptic connections, regulation of neuronal activity as well as synaptic and dendritic plasticity. Moreover, they exert profound effects in a wide variety of neuropsychiatric conditions including (de)myelination, pain, aggression, and depression as well as drug abuse [1][2][3][4][5][6][7][8] and modulate food intake [9]. Furthermore, neurotrophic factors are essential for axonal maintenance [10] and are thought to contribute to regenerative processes after traumatic injury [11][12][13]. These functions could be correlated with the expression and secretion of neurotrophic factors, not only in the CNS but also in immune cells (reviewed in [14]). In particular, mRNA of all known neurotrophins and their receptors were detected in the thymus, spleen, and other lymphoid organs [15][16][17], where they probably act in an autocrine and/or paracrine manner. However, the neurotrophin action on immune cells is much less well defined.The most widely studied neurotrophin, nerve growth factor, has been reported to impact on thymic epithelium differentiation and organogenesis [18], to influence the function of activated CD4 + T cells [19] and B cells [20,21] and to regulate cytokine expression [22]. In addition, nerve growth factor acts on cells of the myeloid-cell lineage by influencing microglial expression of costimulatory and MHC class II molecules [23,...

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The CNS is effectively shielded from the periphery by the blood-brain barrier (BBB) which limits the entry of cells and solutes. However, in autoimmune disorders such as multiple sclerosis, immune cells can overcome this barrier and induce the formation of CNS inflammatory lesions. Recently, two-photon laser scanning microscopy (TPLSM) has made it possible to visualize autoimmune processes in the living CNS in real time. However, along with a high microscopy standard, this technique requires an advanced surgical procedure to access the region of interest. Here, we describe in detail the necessary methodological steps to visualize (auto)immune processes in living rodent tissue. We focus on the procedures to image the leptomeningeal vessels of the thoracic spinal cord during transfer experimental autoimmune encephalomyelitis in LEW rats (AT EAE) and in active EAE in C57BL/6 mice (aEAE).