Sanne Hoeks

Chapter 5 72 babies might have an increased vulnerability for WMI. In this study, three preterm born infants were studied however they were infected at late preterm or term equivalent age. They demonstrated a systemic immune response upon viral infection similar to term born infants. They did not develop cysts in the white matter. To the best of our knowledge this study is the first to show that a complex network of immune- related proteins shapes the neonatal immune response to invasive viral infections. This immune response is not characterized with a classical IFN or T H 1 signature but it reveals the importance of a good functioning complex network of immune proteins. In the present study, we demonstrate in all studied neurotropic viruses similar connections between immune- related proteins (Fig 2 A ). This finding implies that immune-related proteins act in cooperation rather than alone. We could not identify in CSF similar correlations of immune-related proteins and neurodevelopmental outcome. This compartment might not representative for the injured cerebral tissue. Furthermore, rapid and tightly controlled immune responses are required to restrain the viral infection within the CNS while limiting tissue damage. 34 However, it is not clear which pathophysiological pathways are involved in development of WMI after viral encephalitis. Sincemost cells of the CNS are non-regenerative, preferentially immune responses that combat the virus and simultaneously promote cell survival are first applied. 35 Different ratio and type of cytokines will affect barrier integrity, 36, 37 which subsequently may lead to cerebral injury. 38 Different immune mechanisms in CNS infections have been described, besides peripheral immune cells that cross the BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses and have the ability to direct neuroprotective lymphocyte responses. 39-41 In addition to cytokine secretion, T cells kill infected T cells through perforin- and/or granzyme- mediated mechanisms. Secretion of granzymes in some CNS infections does not lead to lysis but prevents viral replication while sparing the infected neuron. 42 Lastly, IP-10 and MIG are IFN- inducible CXC chemokines and potent chemoattractants for activated T-cells, memory T-cells and NK cells by signaling through the CXCR3 receptor. 43 IP-10 enhances the BBB and early expression within the CNS after viral infection might be important in initiating and maintaining a protective immune response. 44 Exaggerated activation of IP-10 and MIG has been proposed to be associated with adverse outcomes of viral infections. 45-47 In the present study we could not associate the concentration of IP-10 and MIG in CSF with the development of WMI or with an impaired neurodevelopmental outcome. Altogether, both disturbance of CNS barrier integrity and the local immune responses in brain parenchyma in response to viral infections, might explain the absence of a connection between the concentration of immune proteins in the CSF and the development of WMI.