Research Report 2010 - MDC

Imaging of the Living BrainStructure of the GroupFrauke ZippGroup LeaderProf. Dr. Frauke ZippScientistsPD Dr. Seija LehnardtOA Dr. Friedemann PaulDr. Carmen Infante-DuarteDr. Volker SiffrinDr. Jason MillwardDr. Ulf Schulze-TopphoffDr. Raluca NiesnerMolecular NeurologyThe group works on immune regulation, neural cell damage and neuronal protectionmechanisms in the context of inflammatory pathologies of the nervous system such asmultiple sclerosis. Methodology ranges from murine and human lymphocyte and brain sliceculture to models of neuroinflammation, in vivo multi-photon-microscopy and magneticresonance imaging. The overall goal is to translate resulting knowledge into proof-of-conceptclinical trials. The work is mainly performed within two collaborative research centers: SFB-TRR43 and SFB 650.The role of the immune system in inflammatoryneurodegeneration and repairNeuronal damage has only recently been shown toinfluence the pathology in inflammatory diseases ofthe central nervous system such as meningitis and multiplesclerosis (MS). We have meanwhile experimentaland clinical data for a marked loss of lower motor neuronsin MS patients. We regularly find dying spinalmotor neurons surrounded by CD3+ (CD4+ as well asCD8+) T cells expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in postmortemtissue from MS patients. Based on these findingsand on experimental data in experimental autoimmuneencephalomyelitis (EAE), our study indicates thatdamage to lower motor neurons and TRAIL-mediatedinflammatory neurodegeneration in the spinal cordcontribute to MS pathology (Vogt et al. 2009).Performing two-photon laser scanning microscopy inthe brainstem of living mice suffering from EAE, we furthermorevisualize T cells migrating into the centralnervous system (CNS) and directly attacking neuronsand their processes. Both in mouse and man, we havevery recently in collaboration with M. Bader shown thata system known to play a role in cardio-vascular medicine,namely the kallikrein-kinin-system, is of relevancefor the transmigration of proinflammatory T cell subsetsinto the CNS (Schulze-Topphoff et al, in press).Bradykinin receptor 1 inhibits infiltration, especially of Thelper 17 cells (TH17) which are proinflammatory andencephalitogenic. Prior to their effector function, the Tcells exert distinct behavior at the blood brain barrierwith CD4+ T cell compartmentalization in theparenchyma along CNS vessels. This process is dependenton the chemokine CXCR4, while key adhesion moleculesseem to have no major function in this process(Siffrin et al. 2009). This is in contrast to their essentialrole in the transmigration step, in which integrin-mediatedadhesion is necessary to overcome endothelialbarriers.Within the perivascular compartment, the lymphocytescan interact with each other and/or otherimmune cells as a prerequisite for the sequential stepsinvolved in the process of inflammation and immuneregulation. Collectively, these findings support the ideathat compartmentalization of activated CD4+ T lymphocytesin the target organ serves a similar purpose asin lymph nodes, i.e. increasing the chance of T cell receptorand co-receptor engagement with the whole spectrumof possible outcomes between tolerance andimmunity.176 Function and Dysfunction of the Nervous System