As for the origin of Loss itself, it's from a comic that was dealing with heavy subject matter (Namely, a miscarriage) in a comic that otherwise was notorious for being silly and not taking anything seriously. It became a meme because of the fact that it was so completely 180 the tone of the normal comic, and the author just expected everyone to take it super seriously, which of course they didn't. The title of the comic was simply called 'Loss'.
The meme basically built up from trying to reference the comic in the most minimalistic way possible, which ended up becoming 4 quadrants with the first one having a vertical line (referencing the main character standing alone in the doorway of the hospital) two vertical lines in the next two panels (representing the character talking to the doctor) and then a vertical and horizontal line (indicating the character standing over his girlfriend in the hospital bed). At this point, organizing anything into a four quadrant layout using that combination of vertical and horizontal lines generally is designed to depict the comic, and even then it's become even more minimalized in which the lines don't even always have to be vertical or horizontal exactly.
In fact the meme's format can be broken down to the point where it simply reads:
I think the funniest instance of this meme occuring was actually on this website in the /k/ thread. Hands had posted a bunch of rifles laying out on the floor in this pattern and was trying to figure out what the reason they took the picture was, and I came in and was like, "Is this Loss?" and he was like, "Oh god fucking damnit."
It was fucking priceless.
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