A humoral approach

Let's set the stage. It's 2021, COVID-19 has hit the world, but scientists have moved so fast on producing effective vaccines that they've basically broken the sound barrier. But many questions around the vaccines are still swirling. How many antibodies will people make in response to the different vaccines now available? And how long will those antibodies last? On top of that, what is the 'best' way to make those antibodies in the first place - a vaccine or so-called 'natural infection' - i.e. just getting sick?

This is a stage upon which we are all walking as of the time of writing, and these questions have been swirling around through the news cycle and in private conversations since the debut of several vaccines over the winter of 2020-2021. But in discussing all of these questions, I've realized that one important piece of the puzzle is often missing in conversation and in the news. Namely, an understanding of how our bodies make antibodies in the first place.

Well, in keeping with that image of a stage, the production of antibodies by our immune systems is like a grand opera, with many different characters involved. The name of our protagonist, however, is clear.

It's the great, the antibody-producing, the one and only B cell.

Today on Microbial Mondays, we'll follow the path of a B cell from birth, through to two potential endings: death or (nearly) everlasting life.

Born in the bone marrow, B cells begin their development with, essentially, a game of cards. You can imagine antibodies as being a hand made up of two playing cards - but two playing cards pulled from an infinite deck, that includes every single type of card on earth, from playing cards and tarot cards, to ID cards and credit cards, to punch cards and greeting cards. So, if every antibody is composed of a unique pair of two of these cards, one of the first steps of B cell development involves shuffling the infinite deck, and picking out the cards within the bone marrow.

After this first round, the young B cells then travel out from the bone marrow, venturing into the 'secondary lymphoid organs' across your body. Secondary lymphoid organs include places like your spleen, your tonsils, and your so-called gut-associated lymphoid tissue. Once the cohort of young B cells have undergone this great diaspora, venturing out and finding new homes within secondary lymphoid organs, it is time for them to take the next step in their development. In their new abodes, the young B cells will then modify their cards - kind of like drawing some doodles on their duo, to make their hand even more unique. Together, these two cards form a random duo that may, or may not, perfectly match the exact two cards held by a potential adversary: a microbe.

For a B cell to recognize a microbe, a rather random match made in heaven has to happen. A microbe invading the body must have the exact same pair of cards as the maturing B cell, in order for that B cell to become activated, and jump into action. The potential success of this random match made in heaven - in other words, the success of your B cells in protecting you against an incoming microbe - relies heavily on the fact that you simply have a lot of unique B cells, which are constantly being born, growing up, and picking new cards. That means a lot of different random card pairs. Because your immune system can't predict what hand of cards a newly encountered microbe might hold, it randomly arms itself with every potential card hand possible.

But let's get back to the action. When a B cell meets its perfect match, it indeed jumps into action. But, alas, it is a somewhat slow-paced action scene. Before ever producing any antibodies, the B cell first must make more of itself. Why? Because, remember, every B cell is unique, holding its own individual pair of cards. This lucky B cell that has found its matching microbe, is just one lonely B cell. And one B cell alone is no match for an army of incoming viruses or bacteria. Your body knows that. And that's why the first thing that B cell must do is to build up an army of B cells, that all hold the same hand of cards. Scientists call this process "clonal proliferation" - meaning that that one lucky B cell divides to make many copies of itself. It makes its own co-workers.

All of those B cell copies will at first look exactly the same as the original, but just as there are different roles within a human army - snipers versus foot soldiers versus commanders - there must be different roles within a B cell army. The B cell copies will grow into several different roles, including the hard-hitting 'plasma cells', and the long-living 'memory B cells'.

The plasma cells are, indeed, the heavy hitters for managing the current threat. These cells are entirely dedicated to producing and sending out antibodies, which can both directly neutralize viruses, bacteria, and other microbial invaders, as well as help inform other arms of the immune system on exactly what to attack. However, as soon as the present microbial invader is wiped out, many of these plasma cells will also die out.

But that's where the memory B cells come in. These cells, as their name implies, will hang around in your body long after the current threat is diffused, to form a living memory of the hand needed to fight back. And as soon as they see the same bug back in the body again, they will quickly re-form a B cell army to vanquish the enemy once more. What's more, these little memory B cell guys can live for decades. For a cell, it's a sort of everlasting life - at least for as long as the rest of your body lives.

A key point here is that memory B cells can quickly help re-form a B cell army. The existence of memory B cells underlies the fact that the second time that your body sees the same bug, it can react much quicker. Upon a second sighting, the long process of young B cells undergoing all that card-picking, clonal proliferation, and growth, or 'differentiation', into plasma cells, that is necessary for the first response to a new bug, is then already done. The memory of all that exists in the form of the memory B cells that arose during that first encounter.

The best part of all this, is that this whole grand opera can be simulated by vaccination. In other words, getting vaccinated will help your body form a pool of memory B cells, which can quickly make a robust response the second time that a bug is encountered - without having to go through a long waiting period as you would for a 'natural infection'. Vaccines give you the benefit of an immunological memory, without the downside of first getting really sick over the one to two weeks that your body requires to build up a B cell army. As far as your immune system is concerned, vaccines cause the exact same process to happen as just getting infected with something does, but in a much more controlled way.

One final note - this isn't a comprehensive overview of B cell development. There are more steps, and more complexities in how they help protect us against incoming microbes. But having said that, I hope it can be a first step towards understanding how these defenders of our bodies work.

So, until next time - train your B cells! It's flu vax time ;)

~ Alex