Antibodies (singular: ‘antibody’; officially known as ‘immunoglobulin’ or ‘Ig’) are glycoprotein (i.e. proteins containing carbohydrate moieties on them) molecules present in the serum (the non-cellular part of blood); these molecules, with diverse functions, play a very important role in defending the body against a variety of microbial pathogens, their deleterious by-products, or other foreign substances. These foreign substances, a part or the whole of which is capable of eliciting an immune response from the body, are referred to as ‘Antigens‘.

Immunoglobulin G

Each basic antibody molecule is composed of two larger proteins (called ‘Heavy chains’) and two smaller proteins (called ‘Light chains’), which are connected to each other via a chemical structure containing two sulfur atoms (a.k.a. disulfide linkages). The portions of the heavy and light chains involved in binding to the antigen are called Variable (V) regions, VH and VL respectively. The remaining portions of the protein molecules are called Constant (C) regions of each chain. The heavy chain constant regions (CH) constitute the Fc fragment of the antibody molecule, which is responsible to binding to other immune cells; the upper parts of the antibody molecule, involved in antigen recognition, constitute the Fab fragment. Based on the structure of the CH region, mammalian antibodies are grouped into five classes: IgM, IgD, IgG, IgE and IgA, each with closely related but different functions.

Now, antibodies are produced in the body by a special type of white blood cells (‘leukocytes’) called B-lymphocytes, or simply B-cells. When an antigen enters the body, B-cells will get to see it either alone, or in conjunction with other types of immune cells. In this event, B-cells undergo a rearrangement in their genes to produce antibody molecules which are capable of interacting with the antigen in a highly specific manner. Through such interactions, antibodies are able to:

  1. neutralize toxic substances (‘toxins’) of microbial origin;
  2. agglutinate (i.e. cause to clump) bacteria and other microbes;
  3. coat the microbes (a process called ‘opsonization’) such that certain immune effector cells (such as macrophages, dendritic cells and neutrophils) can recognize and destroy the microbes by internalizing (via a process called ‘phagocytosis’) and breaking them down;
  4. induce certain immune effector cells (such as neutrophils, basophils, eosinophils, mast cells and cytotoxic T and Natural Killer lymphocytes) to release potent antimicrobial molecules (via a process called ‘degranulation’) that can destroy invading microbes;
  5. directly kill certain microbes by interfering with their uptake of essential substances, or damaging their outer membrane (a few examples here); and
  6. activate certain serum proteins (called ‘complements’) to form a complex that can poke holes into the membrane of certain bacteria, causing them to lyse (i.e. be destroyed by dissolution).

Certain beneficial antibodies, in addition, are known to influence the overall host immune response (a process called ‘immunomodulation’) to benefit the host by restricting the collateral damage of host tissue and cells caused during the fight between host immune cells and the pathogen (an example here). All in all, pretty useful things to have around, right?

The different biological effects of antibodies

The different biological effects of antibodies.
Image ©Nature; Used with permission. Source: Casadevall, et al. (2004) Nature Reviews Microbiology 2: 695-703; doi:10.1038/nrmicro974

In fact, this unique feature of the physiological defence system is responsible for the benefits of the prophylactic (i.e. ‘preventive’) treatment known as immunization or vaccination, first tested in the eighteenth century by Edward Jenner, and elucidated by experimental work of Louis Pasteur. This treatment introduces a relatively harmless, attenuated or inactivated substance, a microbe or its product, into the body, and the immune system generates a relatively mild response. However, B- and T-lymphocytes retain the information about the antigen in their genetic codes (a phenomenon referred to as ‘immunologic memory’); the next time the body encounters the actual microbe or microbial product (as during an infection), the B-cells are able to quickly produce a rapid, strong and prolonged antibody response that adequately defends the body.

There is another interesting aspect of the antibody response. When the body encounters an antigen via inoculation/immunization or disease, various different populations of B-cells come across the same antigen, and produce antibodies that specifically recognize different parts of the antigen structure. The specific chemical structure  – the bare molecular structure (‘primary’) as defined by arrangement of atoms, or more complex secondary, tertiary or quaternary structures in three dimensions – of a part of the antigen, that is recognized by an antibody, is referred to as an ‘epitope’ of that antibody. Therefore, a normal B-cell response may produce antibodies against various epitopes of the same antigen; this is known as a polyclonal response, where each epitope-specific antibody comes from a genetically identical (i.e. ‘clonal’) subset of the total B-cell pool. This works out well, because this way the body manages to produce high titer (a measure of concentration) antibodies with high affinity for the target antigen. Such antibodies to specific antigens, produced via immunization in various laboratory animals (such as mice, rats, guinea pigs, rabbits, pigs, goats, sheep and horses), are used extensively for biomedical research as well as disease diagnostics. The presence of multiple epitopes offers more robust detection, as well as utility when the exact nature of the antigen is unknown.

However, in another application of the same principle, it is possible to generate in vitro Monoclonal antibodies, antibodies from identical B-cells which are clones of a unique parent B-cell. Naturally, all such antibodies recognize the exact same epitope. This technique, which has been around since early 1970s (and led to the 1984 Nobel Prize in Physiology/Medicine to Georges Köhler, César Milstein, and Niels Kaj Jerne), involves selection and isolation of a single clone of B-cells from a polyclonal pool, and fusing cells of that clone to a myeloma partner (a cancerous B-cell that has lost its ability to secrete antibodies). This makes the hybrid B-cell clone (now called a ‘hybridoma’) immortal – just like its cancer cell partner – and it can be grown indefinitely in artificial medium in which the unique and homogeneous monoclonal antibodies would be secreted. Purified monoclonal antibodies are immensely important as laboratory reagents because their high antigen-specificity helps reduce background noise and cross-reactivity in immuno-assays.

Given these interesting and useful properties of antibodies, it is not a surprise that scientists would consider their usage in a therapeutic manner, too. Indeed, Antibody Therapeutics is a fascinating field of study, which I shall discuss in the next post.

This is the FIRST PART of a multi-part series on exciting new developments in the world of antibodies.