The Adaptive Immune System

Throughout the day our bodies are bombarded with any number of foreign pathogens, some of which are harmless, others of which are potentially lethal. We are constantly fighting off these invaders to keep ourselves healthy — a good thing to keep in mind next time someone accuses you of slacking off. Pathogens exist only to propagate themselves at our expense, spending our hard-earned resources and giving nothing in return. In response to these microscopic parasites, our bodies have evolved a number of barriers, collectively referred to as the immune system, which make it harder for pathogens to thrive. The immune system is comprised of two distinct parts — adaptive and innate.

The use of handkerchiefs to prevent against diseases, shown by a man sneezing in a cinema. Colour lithograph after H.M. Bateman, ca. 1950 (1)

Innate System (in short)

Most animals have similar innate immune systems which function in much the same way. A major shared part of this system is the wide variety of white blood cell types, which actively rove the body to seek out and eliminate invaders. The majority of threats are blocked by the innate immune system — either by its natural barriers (such as skin or mucus) or by these cells — but pathogens have evolved ways to exploit the weaknesses of these defenses. Luckily, the adaptive immune system can pick up the slack.

How The Adaptive System Works

To really appreciate the work the adaptive immune system does, we have to examine the response process in depth. The system cannot act against invaders without first being able to identify them. This means our bodies have to produce an antibody that complements and binds to some protein or other molecule, called an antigen, on the invading pathogen’s surface. The problem of building an antibody to find a new pathogen is analogous to having a million unique padlocks thrown at you and needing to find a key that fits each one before you even get to look at the lock. So, how do our bodies do this? There is no single “master key” that works for every antigen “lock”, but nature has devised a much more ingenious solution — make a million keys! It may not sound clever, but it definitely works.

(fig. 1) An antibody structure with sections highlighted and named including the unique binding region AKA the CDRs (labeled here as “Fv”)

At any given moment, we are churning out millions of keys, or antibodies, that all have a unique binding region. If we’re lucky, a new pathogen our body has never seen before will have an antigen compatible with one of those antibodies. The antibody will lock on and either disable the threat itself or signal to T cells to come eliminate it. There are countless pathogens and antigens in the world, so the diversity of antibodies needed to make this kind of brute force method work is astounding. This raises the question: how do our bodies create such extreme diversity?

Creating Diversity

Remember from our antibody post that the antibody molecule is Y-shaped and has four protein chains linked by disulfide bonds (see fig.1). The CDRs are groups of protein loops that are unique to the antibody protein. The amino acid sequences in these loops vary widely every time a new antibody is produced. In the lock and key metaphor, these loops are analogous to the “teeth” of the key that line up the tumblers of the lock.

So how do our bodies generate all these unique “teeth”? You may remember from our previous post about proteins that DNA sequences code for the amino acid sequences that make up the millions of proteins within our bodies. Antibodies are proteins, and proteins are coded for in DNA, so it’s no surprise that our bodies exploit features of DNA to build out this diverse antibody arsenal.

(fig. 2) A depiction of the VDJ regions and VJ regions that encode the Heavy and Light chains (respectively) at the antibody’s CDRs.

There are several sets of antibody genes. Each set consists of a few segments, which, when put together, code for the variable regions of antibody chains. For heavy chains, these DNA segments are called the variable, diverse, and joining regions (or VDJ for short). Each region, in turn, consists of multiple options that can be chosen when the DNA is read. When a cell matures, it splices out, or removes, all but one of the options for each region, and combines its three choices into a unique VDJ grouping. This VDJ combination is then attached to a constant region gene, forming a complete antibody heavy chain. Light chains are generated in much the same way, but do not have a D region. By selecting different combinations of heavy-chain VDJ choices and light-chain VJ choices, the body is able to produce tens of thousands of different CDRs (fig. 2).

As if that wasn’t enough variability, the antibodies also go through an additional process called somatic hypermutation (SHM). The sequence that codes for the antibody undergoes a high rate of mutation which modify the sequence further. This way our bodies continue to actively adapt to new threats throughout our lives. This active adaptation is very necessary: dangerous pathogens may take generations to evolve immunities — but a bacterial generation can be as short as 30 minutes! The combination of variability from VDJ recombination and SHM puts the number of possible CDRs at 3x10^11. That’s more than the number of stars in the Milky Way!

Biological Keychain

As you can imagine, the odds of any given antibody being able to complement a given antigen are incredibly low, but the system works because there are just so many different antibodies. Once a pair is found, our bodies know the lock, and can keep the key on its biological keychain to mount a more targeted response in the future. Over time, our bodies build up this arsenal, and the next time a recognized pathogen invades, it can be handled quickly.

Citations and Links
1. The Wellcome Collection 
2. Fig. 1 Rodrigo, Gustav; Gruvegard, Mats; Van Alstine, James M. Antibody Fragments and Their Purification by Protein L AFfinity Chromatography.
3. Fig. 2 Boyd, Scott D.; Joshi, Shilpa A.; High-Throughput DNA Sequencing Analysis of Antibody Repertoires.

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