title: Small heat shock proteins are induced during multiple sclerosis lesion development in white but not grey matter.
abstract: BACKGROUND
  The important protective role of small heat-shock proteins (HSPs) in regulating cellular survival and migration, counteracting protein aggregation, preventing apoptosis, and regulating inflammation in the central nervous system is now well-recognized. Yet, their role in the neuroinflammatory disorder multiple sclerosis (MS) is largely undocumented. With the exception of alpha B-crystallin (HSPB5), little is known about the roles of small HSPs in disease.
  
  
  RESULTS
  Here, we examined the expression of four small HSPs during lesion development in MS, focussing on their cellular distribution, and regional differences between white matter (WM) and grey matter (GM). It is well known that MS lesions in these areas differ markedly in their pathology, with substantially more intense blood-brain barrier damage, leukocyte infiltration and microglial activation typifying WM but not GM lesions. We analysed transcript levels and protein distribution profiles for HSPB1, HSPB6, HSPB8 and HSPB11 in MS lesions at different stages, comparing them with normal-appearing brain tissue from MS patients and non-neurological controls. During active stages of demyelination in WM, and especially the centre of chronic active MS lesions, we found significantly increased expression of HSPB1, HSPB6 and HSPB8, but not HSPB11. When induced, small HSPs were exclusively found in astrocytes but not in oligodendrocytes, microglia or neurons. Surprisingly, while the numbers of astrocytes displaying high expression of small HSPs were markedly increased in actively demyelinating lesions in WM, no such induction was observed in GM lesions. This difference was particularly obvious in leukocortical lesions covering both WM and GM areas.
  
  
  CONCLUSIONS
  Since induction of small HSPs in astrocytes is apparently a secondary response to damage, their differential expression between WM and GM likely reflects differences in mediators that accompany demyelination in either WM or GM during MS. Our findings also suggest that during MS, cortical structures fail to benefit from the protective actions of small HSPs.
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. l.peferoen@vumc.nl.
authors.forename: Laura A N
authors.initials: LA
authors.lastname: Peferoen
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. w.gerritsen@vumc.nl.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Gerritsen
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. m.breur@vumc.nl.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Breur
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. k.ummenthum@vumc.nl.
authors.forename: Kimberley M D
authors.initials: KM
authors.lastname: Ummenthum
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. r.peferoen-baert@vumc.nl.
authors.forename: Regina M B
authors.initials: RM
authors.lastname: Peferoen-Baert
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. p.vandervalk@vumc.nl.
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.affiliation: Delta Crystallon BV, Leiden, The Netherlands. hans@deltacrystallon.com.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: van Noort
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands. s.amor@vumc.nl.|Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. s.amor@vumc.nl.
authors.forename: Sandra
authors.initials: S
authors.lastname: Amor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002490:Central Nervous System / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D066128:Gray Matter / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D066127:White Matter / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D006684:HLA-DR Antigens; D050888:Heat-Shock Proteins, Small; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger