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

• Published in: Journal of neuroinflammation 2012-07, Vol.9 (1), p.156-156, Article 602
• Main Authors: van Horssen, Jack, Singh, Shailender, van der Pol, Susanne, Kipp, Markus, Lim, Jamie L, Peferoen, Laura, Gerritsen, Wouter, Kooi, Evert-Jan, Witte, Maarten E, Geurts, Jeroen J G, de Vries, Helga E, Peferoen-Baert, Regina, van den Elsen, Peter J, van der Valk, Paul, Amor, Sandra
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Blood-brain barrier; Brain; Brain - immunology; Brain - metabolism; Brain - pathology; Brain damage; Cohort Studies; Development and progression; Drinking water; Humans; Immune activation; Immunity, Innate; Immunohistochemistry; Interleukins; Lesion development; Microglia - cytology; Microglia - immunology; Microglia - metabolism; Microglial cells; Middle Aged; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Natural immunity; Nerve Fibers, Myelinated - immunology; Nerve Fibers, Myelinated - metabolism; Nitric oxide; Oxidases; Physiological aspects; Preactive lesion; Proteases; Proteins; T cells
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/1742-2094-9-156

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. 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. 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. 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.