What is an Antibody?

In our last post, we discussed what proteins are made of and what these biological machines do for us. Antibodies are a very important subset of proteins that are meant to protect our bodies from harmful foreign invaders by tagging them for destruction. A detailed explanation would require a deep foray into the dedicated field of immunology, so we’ll focus on the big picture.

Antibody Discovery

Paul Ehrlich. Photograph, 1915. Credit: Wellcome Collection (2)

Paul Ehrlich first coined the term “antibody” (or Antikörper in Ehrlich’s native German) in 1891, but the study began a year earlier, in 1890, with the work of Kitasoto Shibasaburo. He was first to propose that the body was able to produce a mediator within serum that could react to foreign toxins. Ehrlich, who had worked with dyes early in his career, realized that the way these mediators bound to toxins may be similar to the way dyes bound to cells. This prompted him to develop the Side-chain theory (1) in 1897, which proposed that antibody-antigen binding was accomplished via specific side chains using a lock-and-key mechanism. Ehrlich’s theory was confirmed by Linus Pauling in the 1940s, when he proved that the interaction between antibody and antigen depended on the highly specialized shape of the antibody’s variable region.

Evolution and Antibody Structure

Antibodies have been around for a long time. They appear in organisms that evolved from jawed fish — even sharks and their cousins, who diverged from other vertebrates around 470 million years ago. This puts the evolution of antibodies at somewhere between 470 and 615 MYA — long before the first animals ever set foot on land. Basically every vertebrate has some kind of antibodies, from humans, to frogs, and even dinosaurs* (we assume — it’s hard to get your hands on dinosaur blood these days). When something works well, evolution tends to conserve it. This is why antibody structure is so similar across so many species.

An antibody molecule is instantly recognizable by its large, Y-shaped structure. Antibodies in humans consist of two long “heavy” chains, and two shorter “light” chains which connect to the “arms” of the heavy chains. All chains have a constant region and variable region. Heavy-chain constant domains are much longer, and contain a region that signals the immune system to respond to a perceived threat. The constant domains of the light chains connect them to the heavy chains. When the heavy and light chains’ variable regions come together, they form the Complementary Determining Region (CDR) of the antibody, commonly referred to as the paratope. The paratope consists of six CDR loops that have varying amino acid sequences. This region gives antibodies the ability to bind very specifically to a surface region called an epitope on some target molecule, referred to as the “antigen”. The variable loops are what Ehrlich was referring to as the “side-chains” and are the source of the antibody’s effectiveness. You can think of them as the “key” that fits into the antigen’s “lock”; hence the lock-and-key mechanism mentioned.

The Y-structure of an antibody includes two long heavy chains connected by disulfide bonds and two short light chains that connect to the heavy chains, also by disulfide bonds. (3)

Antibodies and Immunology

Antibodies are a major part of the adaptive immune system — the part of your immune system that can find, target, and remember new threats. Specialized cells called B-lymphocytes, or B-cells, make antibodies with CDRs that have been randomly mutated. If the “naïve” B-cell’s loops bind to an antigen target, that B-cell becomes “experienced.” Experienced B-cells multiply and proliferate to ensure that enough of their antibodies are made and secreted into the body to attack the newly discovered threat anywhere it might arise. Those antibodies bind to the antigen molecule, where the heavy-chain’s signaling region serves as a marker, tagging the target for destruction by the body’s immune cells.

Doctors and researchers can take advantage of the body’s ability to produce such amazing targeting and binding molecules. The most common way is through the use of vaccines. A preparation of non-threatening antigens extracted from pathogenic viruses or bacteria can be delivered to the body without risk of infection, allowing your B-cells to learn to respond to the threat in a safe environment. Then, when an infection would normally occur, the B-cells that “remember” the vaccine can activate to stop the illness before it ever starts! Antibodies also have a variety of uses outside of the body. By introducing a specific antigen to a laboratory mouse, for instance, researchers can induce antibody production for that new target. That antibody can be extracted, and can eventually be transformed into a new drug, safe for human use! Antibodies designed in this way can also be used for laboratory tests, including the ELISA blood tests used to detect HIV in the bloodstream.

What with all these uses and the possibility of creating remedies across species, it’s no wonder antibodies are the focus of so much attention.

Links and Citations:
1. Ehrlich, Paul. Side-Chain Theory, circa 1900. https://www.the-scientist.com/foundations/side-chain-theory-circa-1900-39091

2. Wellcome Collection. https://wellcomecollection.org/works/y2d2nar6

3. Rodrigo, Gustav; Gruvegard, Mats; Van Alstine, James M. Antibody Fragments and Their Purification by Protein L AFfinity Chromatography. http://www.mdpi.com/2073-4468/4/3/259

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