Stage: studying neuronal microglial communication in MS
The Huitinga group aims to investigate the molecular and cellular factors underlying multiple sclerosis (MS). Special emphasis is put on the role of microglia in the initiation and expansion of MS lesions. The group studies the influence of e.g. the complement system, CD200 signaling, microglial activation, lesion formation and development and, infiltration of immune cells from the peripheral blood stream.
The group closely collaborates with the Netherlands Brain Bank and therefore has access to a vast collection of MS donors. This collection includes all different types of MS lesions and offers insight into the clinical and pathological background of these brain donors.
In the healthy central nervous system (CNS), neuronal signaling contributes to a homeostatic state in microglia, brain resident macrophages, in part mediated through the immunoglobulin regulatory molecules CD200 and CD47. This neuron-microglia interaction is essential for a healthy functional CNS.
When CD200 and CD47 bind to their microglial receptors, neurons send an inhibitory signal to microglia, keeping them in an inactive and morphologically ramified state. Both CD200 and CD47 are shown to be decreased in and around white matter MS lesions, which contribute to excess activation of microglia. Nonetheless, it is not yet known if CD200 and CD47 expression is altered in the cortex of MS patients compared to healthy controls, or rather, if these molecules are implicated in cortical lesion susceptibility.
Previously, in a pilot study, we found a decrease of CD200 and CD47 expression in cortical layer 1 in the normal appearing gray matter (NAGM) in MS donors with a high cortical lesion load (9+) compared to MS donors with a low cortical lesion load (<5), and a consistent decreasing trend of CD200 in other cortical layers. The aim of this project is to further investigate the differences in CD200 and CD47 expression in the NAGM of MS donors in relation to their cortical lesion load, as well as to set-up and optimize further a co-culture of primary human microglia together with a neuronal cell line. There we aim to functionally study the effect of CD200 on microglia activation and phagocytosis through knock-down/knock-out experiments.
Are CD200 and CD47 implicated in MS gray matter lesion susceptibility?
- CD200 and CD47 are negatively correlated to the gray matter lesion load
- In vitro, CD200/CD47 knock-down activates human microglial cells and stimulates phagocytosis