In Pocket Guide to the Empire, Third Edition: Black Marsh we learn that (most likely) the Argonians created a flu that wiped out large parts of Tamriel. As you can see in the quote it started in 2E 560 and thus coincides pretty well with ESO's timeline.
Whether the terrible Khahaten Flu arose from natural causes, or was created by an Argonian shaman in retaliation for his people's oppression, is still a matter of debate. But its result was clear. The plague began in Stormhold in 2E 560, and quickly spread to every corner of Black Marsh, killing all those not reptilian stock. For over forty years, it held the Province in its grip, decimating entire cultures (notably, the Kothringi) and driving outsiders from the land.
It could be interesting to imagine having large parts of Tamriel change through a DLC/Chapter, perhaps through phasing(?).
What do you guys think of this?