Susceptibility for inflammation of the immature CNS

The central nervous system (CNS) of children and juveniles differs from the adult CNS in its susceptibility towards inflammation. It has been described that children with head trauma or infections have a significantly higher risk for developing a permanent brain damage or for death as a result of these diseases than adults. Similar observations were made in animal models: Juvenile mice or rats develop inflammatory reactions in the CNS significantly faster, if IL-1 is expressed in the CNS, or if other noxious stimuli are present. The exact reasons for the enhaced susceptibility of the juvenile CNS for inflammation are not yet known. Previous observations from our laboratory suggest that chemokines expressed in the juvenile CNS, and a subtle activation of the CNS blood vessel endothelium might play a crucial role in this process. We propose to extend these studies, and to analyze the consequences of chemokine/cytokine expression in the juvenile CNS for endothelial cell activation and immune cell recruitment. We expect that our work will provide the molecular and cellular basis for the "window of susceptibility" to enhanced CNS inflammation in the juvenile organism, and will lead to the identification of novel target structures for therapeutic intervention. As a long term perspective of our studies, we hope that blockade of the identified target molecules could lower the risk of children/juveniles to develop lethal inflammatory reactions of the CNS as a result of CNS trauma or infections.

The window of susceptibility for CNS inflammation defines a period in postnatal development where brain and spinal cord are more susceptible to inflammation than their adult counterparts. We could show that this period is jointly influenced by the presence of a leaky blood brain barrier and by a global chemokine expression profile characterized by the production of distinct chemokines and pro-inflammatory cytokines. Moreover, this expression profile is not stable, but can be shaped by pathological changes like oligodendrocyte stress/death and associated myelin repair processes. We could identify a number of chemokines and cytokines which are expressed at higher levels in the immature CNS than in its adult counterpart. These molecules do not only play an important role in the growth and differentiation of neuronal and glial cells, but also attract and activate cells of the immune system, and also prepare endothelial cells of the blood-brain barrier for the interaction with these cells. We could demonstrate that the particular chemokine-/cytokine profile of the immature CNS paves the ground for an accelerated development of CNS inflammation in the context of an exclusively T-cell mediated CNS disease, but that it is not sufficient for the formation of lesions initiated by the combined action of pathogenic serum autoantibodies targeted against CNS-specific proteins and complement.