The Case of the Smouldering Lesion

I refer, of course, to the splendid work “Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active MS lesions”, a scientific dossier that reads as though the authors had been peering over my shoulder while I inspected the MS-affected brain through my magnifying lens.

🔍 Crime Scene Analysis…visible only to the properly trained eye

The crime scene?
The outer rim of a chronic active MS lesion. To the uninitiated it appears as nothing more than a faintly brightened zone on an MRI. To me, however, it is a stage set for subcellular drama — a pulsating ring where perpetrators, victims and unwilling accomplices enact a molecular choreography intelligible only to a true neuro-detective of my calibre.

The MERFISH map presented in the paper, a veritable masterpiece, charts more than 400,000 cells, each one catalogued as meticulously as case files in a Victorian police archive. Every point a suspect. Every marker a clue.

🦹‍♂️ Moriarty Reborn… and naturally I spotted him at once

Those familiar with my brother and me will know: we sense Moriarty long before we see him.
And here, ladies and gentlemen, I found him reborn as a cluster of hyperactive CD8⁺ T cells, convening like a criminal syndicate at the lesion’s rim.

They did not merely murmur; no, they shouted molecular threats into the neighbourhood.
IFN-γ, that cytokine of ruthless escalation, flooded the micro-environment with all the subtlety of dynamite in a teapot. A molecule fully capable of turning any peaceful neural quarter into a battlefield of utter devastation.

Lesser minds might have dismissed these T cells as “a tad activated”.
I, however, immediately recognised a perfectly organised triad:
the Moriarty Cartel of the immune system.

🧴 The Microglia: Victims of a Diabolical Manipulation

Most intriguing of all were the microglia. The poor creatures stood there like flustered butlers forced to balance far too many silver trays at once, swollen with myelin debris and utterly unable to rid themselves of their cholesterol burden.

A predicament which, as I perceived instantly, was no mere biological mishap but the result of strategic sabotage. IFN-γ had incapacitated the crucial lipid-export transporters ABCA1 and ABCG1, the molecular porters normally responsible for shuttling lipids out of the cell day and night.

The outcome? Foamy microglia, bloated, dysfunctional and tragically trapped in the involuntary role of inflammatory fire-starters.

An infuriating yet undeniably brilliant manoeuvre by Moriarty.

🧪 Experimental Evidence…as though I had ordered the experiments myself

The EAE model replicated the entire affair, admittedly in a manner that came tantalisingly close to my own exacting standards.
Researchers deliberately stripped microglia of their lipid-export abilities, and behold:

• The cells grew even fatter
• The T cells more intrusive
• The inflammation considerably more ferocious

A classic domino effect of villainy.
And, as I often explain to the young Dr Watson:
If you truly wish to understand a mechanism, break it; and watch what collapses.

💊 A Countermeasure – naturally the very solution I would have foreseen

Then came the decisive twist: a compound capable of modulating sterol metabolism and restoring microglial cholesterol export.

The consequences entirely predictable to a man of my disposition were:

• The microglia regained their composure
• The T cells evaporated like common henchmen
• The lesion contracted
• Symptoms improved
  

A perfectly executed countermove against Moriarty’s insidious strategy.

🧠 Closing Remarks from the All-Knowing Neuro-Detective

If decades of investigation have taught me anything, it is this:
The MS lesion is no chaotic accident. It is a meticulously orchestrated crime, a symphony of sabotage, misdirection and coerced complicity.

This extraordinary paper provides us with the full blueprint of a crime scene I have long suspected. And though Moriarty that perennial scoundrel still has his hands in the affair, I see the hour approaching when we shall dismantle his network entirely.

Until then, I remain vigilant, eyes sharpened, elegance unshaken.

In other words: The case is not yet closed.

But we are closer than ever. 🕵️‍♂️🧠✨ SherlockMS