Immunology Human T cell

Antibodies are an important defense mechanism against all kinds of foreign invaders, be it bacteria, viruses, or toxins. Without this defense, we couldn’t survive very long. Remember the “bubble boy”? He was a kid who had a genetic defect that deprived him of antibody protection. He had to spend his life in a sterile plastic bubble in order to survive.

 

How do antibodies do it?

We are endowed from birth with a library of antibodies that are structurally designed to recognize and bind to these foreign invaders; each antibody recognizes a specific molecule of organism or something structurally very close to it. This raises several obvious questions:

  • How can the antibody recognize a certain organism from birth, not having seen this organism before? The answer is that the repertoire of antibodies we are born with is directed against invaders that our species has encountered in its evolutionary history, probably from as long ago as when the first vertebrates trod the earth.
  • Does that mean that we are born with all the conceivable antibody specificities we are likely to ever need? Absolutely not. Immunological research has shown that our immune response can create antibodies to almost any molecule one can synthesize. Well, now we are talking about many millions of possible molecular structures, and the sheer number of genes required to make so many antibodies would overwhelm the capacity of our DNA.
  • If our immunological memory recognizes ancient organisms that attacked us millions of years ago, is it not reasonable to assume that those organisms evolved during the eons, and thereby changed some of their structure? The answer is yes, and consequently the antibodies we have in our library bind only loosely to the invader. This kind of binding is not very effective in neutralizing the action of the virus or the bacteria.

 

GOD to the rescue

These two questions occupied immunologists for almost a century. If we cannot accommodate all the possible antibody specificities in our genome, how do we create antibodies to almost anything imaginable? And if the antibodies that we do have can only loosely bind to the microorganism, and don’t do a very good job at neutralizing it, how are we to be protected?

It was demonstrated early on that once we are exposed to a new antigen, be it a microorganism, a virus, or a simple molecule, an explosive increase in antibody synthesis occurs. But not just any antibody. The gene that codes for the antibody that recognizes the offending antigen becomes super activated and churns out huge amounts of antibodies. But if all these antibodies originate from the same gene, aren’t they supposed to be identical, and hence only loosely bind to the antigen just like the original antibody?

Here we have to introduce the hypothetical concept of GOD. No, it is not the religious kind; it is the theoretical mechanism that immunologists invoked to explain the infinite diversity of antibodies. This hypothetical Generator Of Diversity (come to think of it, could be a nice attribute to describe the religious kind as well) creates somehow, during this explosive expansion of antibodies, a whole range of antibody specificities, all very similar, but not identical, to the original antibody that recognized the antigen.

This concept is theoretical no more. In a paper published in the May issue of the Journal of Experimental Medicine (vol. 204, pp. 1145-1156, 2007), Raphael Casellas and his colleagues at NIH tagged with fluorescent dyes an enzyme called AID (no, it has nothing to do with AIDS), which stands for Activation-Induced Cytidine Deaminase. This enzyme has long been suspected as the hypothetical GOD.

 

How does GOD/AID work?

It randomly attacks the nucleic acid base Cytidine in the antibody gene and converts it to another base called Thymine. In other words, it causes a mutation in the code for the antibody, which in turn would result in an antibody molecule of a slightly altered structure. Since there are hundreds of cytidine bases in the gene coding for the antibody, you can see that the number of possible permutations is mind-boggling, all of them only slightly different from the original antibody structure. Now, this is an ingenious way to create diversity.

 

Enter Darwin

Now we are left with the task of selecting the most effective antibody, that is to say, the one that binds most tightly to the antigen. And here comes Darwinian competition and selection in all its glory. The antibody that has the highest affinity (or binding) to the antigen will obviously have an advantage; even if another antibody, with lesser affinity, binds first to the antigen, it will be displaced by the more avidly binding antibody. And if later on another antibody comes along, with yet higher affinity, it will displace the lesser binding antibody. And so on and so on, in a process that ends up with highly specific, high-affinity antibodies binding to the antigen and neutralizing it. The whole process takes 1-2 weeks and is called antibody maturation. This is the reason why vaccination does not work instantaneously; protection is acquired only 7-10 days post vaccination.

The importance of the Casellas paper is that tagging the AID enzyme with fluorescent dyes will allow scientists to visualize it in vivo (in life) and follow its actions as it performs them. In fact, they have already saw (yes, actually saw) the enzyme doing its GODly work in the region of the chromosome where the immune response genes reside.

 

Why is it important?

This is important from a basic science point of view because it allows us to understand how immunity—so basic life—operates. But wait, there is more. Immunity also plays a major role in health and disease. When the immune response goes awry and recognizes the body’s own tissues as foreign invaders, an autoimmune disease ensues. Such attacks on self-tissues cause diseases such as rheumatoid arthritis, lupus, autoimmune thyroiditis, Diabetes type 1, and many others. It will now be possible to investigate these diseases on a much more detailed level and, hopefully, find their root causes. It will then be infinitely easier to devise therapies for these debilitating diseases.

Isn’t science fascinating?

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.