Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation

Background: in brain tissues from multiple sclerosis (ms) patients,clusters of activated hla-dr-expressing microglia,also referred to as preactive lesions,are located throughout the normal-appearing white matter. the aim of this study was to gain more insight into the frequency,distribution and cellular architecture of preactive lesions using a large cohort of well-characterized ms brain samples.methods: here,we document the frequency of preactive lesions and their association with distinct white matter lesions in a cohort of 21 ms patients. immunohistochemistry was used to gain further insight into the cellular and molecular composition of preactive lesions.results: preactive lesions were observed in a majority of ms patients (67%) irrespective of disease duration,gender or subtype of disease. microglial clusters were predominantly observed in the vicinity of active demyelinating lesions and are not associated with t cell infiltrates,axonal alterations,activated astrocytes or blood-brain barrier disruption. microglia in preactive lesions consistently express interleukin-10 and tnf-α,but not interleukin-4,whereas matrix metalloproteases-2 and -9 are virtually absent in microglial nodules. interestingly,key subunits of the free-radical-generating enzyme nadph oxidase-2 were abundantly expressed in microglial clusters.conclusions: the high frequency of preactive lesions suggests that it is unlikely that most of them will progress into full-blown demyelinating lesions. preactive lesions are not associated with blood-brain barrier disruption,suggesting that an intrinsic trigger of innate immune activation,rather than extrinsic factors crossing a damaged blood-brain barrier,induces the formation of clusters of activated microglia. © 2012 van horssen et al.; licensee biomed central ltd.