Thread by @udarnik

Been busy this holiday break. First PTO I've taken all year, and I'm losing some even with being off since Dec. 8, so catching up on a lot of stuff.

But, as promised, here's the Somatic Hypermutation thread to accompany the Omicron vaccine response thread, yesterday.

Sorry, lots of family and professional stuff to do, today, threads get interrupted.

So. I'm gonna skip a LOT of Immunology, here, so if you have questions or need to fill in gaps in your understanding, feel free to ask questions on the thread or DM.

Down to brass tacks: B Cells mature into Plasma Cells that make antibodies. But the core of antibody diversity is controlled by your B cell population.

Your B Cells contain the genes to make antibodies, which are proteins. DNA is nothin' but a blueprint to make proteins.

Evolution is a slow motherfucker, even allowing for the background rate of mutations (each of your cells has about 150 - 200 mistakes in their nuclear DNA that make your DNA different from that you received from your parents).

Nature, on the other hand, is beautiful in its diversity, & that diversity includes a plethora of ways to kill you in both spectacularly gruesome and boringly mundane ways.

Most of which involve foreign proteins of some type, against which, your immune system maintains defenses.

Now, if we waited for normal DNA mutation to shape our evolutionary response against new threats, nature would far outstrip our ability to create antibodies that bind to new threats.

In the bone marrow, as B cells for, the genes that code for the B cell receptors (which are just surface bound antibodies, for all practical purposes) are to some degree mixed and matched.

So your naive B cell population has a variety of antibody prototypes ready to go, just nowhere near enough to keep up with nature's assaults.

When an invader pops up and its proteins get presented to T helper cells, the T helpers that recognize proteins similar (but probably not exactly matched) to the invader proteins, go find a B cell in the lymph node that has the closest-matching proto-antibody to the invader.

Those B cells then get cloned in the lymph node at a tremendous rate. But they're not exactly matched to the invader, they're just close enough.

To get better affinity (binding strength) for the antibodies expressed on those B cells, mutations are deliberately introduced during the cloning process.

This process of deliberate mutation is called omatic hypermutation. It's about one million fold faster than normal evolution, and its why you can produce a massive variety of antibodies without altering your DNA.

(Sorry - SOMATIC Hypermutation - my S key is sticking).

These mutations are unique to your B cells (which are somatic, or post-germinal cells). You will not pass these mutation on to your children.

Your children can benefit from your immune memory, however, and your mother's IgGs were transported across the placenta to your by the FcRn receptor, and after birth you got more of them in breast milk.

This is one reason why breastfeeding is so important - maternal IgGs in breast milk provide a substrate for jumpstarting the infant's immune system.

IgGs are a specific type of antibody - sorry for the jargon - the kind elicited by the vaccines we have right now for COVID and also the only kind passed across the placenta.

Back to the cloned B cells in the lymph nodes:

The cloned B cells express a variety of antibodies - variations on a theme of the invader protein. Some are good matches, some just kinda match. But those kinda matches are important: they are they key to why boosting against original flavor SARS-CoV-2 will help against Omicron.

Those mutated B Cells are culled. Any that stray *too* far from the original are killed, as are any that happen to land on sequences expressed by your own proteins - but when that editing function breaks down, you can get certain kinds of B cell-driven autoimmune diseases.

(Those auto-immune diseases are one of my professional specializations).

But there is still a decent spread of randomly mutated antibodies in the remaining B Cell population.

The reason for that is that evolution has landed on this elegant solution to viral evolution - those random mutations will, by chance, contain some antibodies that will respond to any given mutation the virus may undergo.

Now, this is an iterative process, so the first exposure does not produce that large a repertoire of slightly off-target B Cells, but the second one makes more, and a third exposure really shoots them through the roof.

So you see what I am getting at, tight? Your first vaccination made a lot of antibodies against original flavor spike, the second got you a few Omicron killers and the third got you a lot more Omicron killers.

Now, even after the third shot, the Omicron killers are in the minority of antibodies you make, but there are a lot more of them than before.

So post-boost, after just one or two somatic hypermutation passes after you get infected with Omicron, you are ready to go, rather than the (for example) 8 or more passes you'd need if you were completely unexposed, or the 4 or more you'd need after just a double vax.

You'll probably still get some symptoms if boosted, but in most people, they'll go away quickly as the B Cell population homes in post haste.

So, this is the mechanism by which you can develop immunity to a variant you've never encountered by repeatedly boosting against the original.

Is it as good as an Omicron booster?

No.

Is it a damn sight better than just the two-shot original vax?

Damn straight.

For the curious, here's a decent video on the somatic hypermutation process:

Udarnik out. Night, all.