Research: Pre Active Lesions

Epubvan Horssen J et al. Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflammation. 2012 Jul 2;9(1):156.

BACKGROUND: In brain tissues from multiple sclerosis (MS) patients, clusters of activated HLA-DR-expressing microglia, also referred to as pre-active 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-alpha, 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.

If you look at previous posts on Espresso Pathology on lesion formation you will know about the preactive lession. Preactive lesions are clusters of activated (because they express HLA-DR) microglia and have been called a load of different names throughout histroy. Importantly they are not just artifacts of cutting across the tip of  a chronic active lesion (although I think some of them will be; just imagine cutting a slice of a football, because I bet they do not slice through everything to see it is is connected to a regular lesion). They do not centre around a blood vessel but cluster around stressed oligodendrocytes. 

Are they stressed because of the attentions of the microglia or because of the causative trigger of MS?  

The latter seems like a possibility. 

This could be the beginning of the Inside-out theory. They are common in MS, including progressive MS and may be the start of ongoing damage. However they must often resolve because there are too many of them. This may be facilitated by the cytokines such as TNF (a good or bad guy) and IL-10. With a bit of autoimmunity around we can see how this could happen. Understanding more about these pre-active lessions could be the key to understanding the cause. If it was a virus causing this surely it would have been found by now, however every cell has a HERV because they are in our DNA.

CoI: The Senior author is DoctorLove who is part of Team G

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