title: Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation.
abstract: 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.
authors: Department of Molecular Cell Biology and Immunology/Neuropathology, VU University Medical Center, Van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands. j.vanhorssen@vumc.nl
authors: Jack
authors: J
authors: van Horssen
authors: Shailender
authors: S
authors: Singh
authors: Susanne
authors: S
authors: van der Pol
authors: Markus
authors: M
authors: Kipp
authors: Jamie L
authors: JL
authors: Lim
authors: Laura
authors: L
authors: Peferoen
authors: Wouter
authors: W
authors: Gerritsen
authors: Evert-Jan
authors: EJ
authors: Kooi
authors: Maarten E
authors: ME
authors: Witte
authors: Jeroen J G
authors: JJ
authors: Geurts
authors: Helga E
authors: HE
authors: de Vries
authors: Regina
authors: R
authors: Peferoen-Baert
authors: Peter J
authors: PJ
authors: van den Elsen
authors: Paul
authors: P
authors: van der Valk
authors: Sandra
authors: S
authors: Amor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D006801:Humans; D007113:Immunity, Innate; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000276:immunology / Q000378:metabolism