DEFENDING THE BODY FROM WITHIN

An Amazing View — Antibodies and Antigens

It is sometimes difficult to decide which is the more extraordinary — the workings of the human body or the degree to which scientists have been able to piece together a coherent picture of those workings. The specialized defenses of the immune system are a case in point.

Pathogens bear distinctive surface components that trigger antibody production. These are known as antigens. Working in concert — and communicating through direct physical contact and by releasing chemical messages — the cells of the immune system identify pathogens by their surface structures and then mass-produce antibodies whose unique configurations recognize specific antigens. This recognition drives major parts of the immune system by identifying pathogens for destruction.

The complexity of the antibody system has long fascinated scientists and has proved fertile ground for research. Ongoing research carries immense practical significance that goes beyond clarifying our understanding of one of the most potent aspects of the immune system. These findings may also potentially suggest novel approaches to drugs that enhance the immune system and foil pathogens.

Susumu Tonegawa — Explaining antibody diversity

In the 1970s, Susumu Tonegawa, working at the Basel Institute for Immunology in Basel, Switzerland, examined one of the major mysteries of the immune system — antibody diversity. Humans can produce upwards of a trillion different antibody molecules, each capable of recognizing a distinct antigen. How can humans produce such an extraordinary repertoire of antibodies, with a mere 100,000 or more genes, most of which are not even involved in antibody production? The answer, which won Tonegawa a Nobel Prize in 1987, is that the Y-shaped antibodies (below, right) are generated from gene components that are selected almost at random and spliced together by the B cells (below, left).

Peter Doherty and Rolf Zinkernagel — Identifying the role of MHC molecules

In the early 1970s, Peter Doherty and Rolf Zinkernagel identified the crucial role of the major histocompatibility complex (MHC), which displays antigen fragments to T cells. The two men won a Nobel Prize for their ground-breaking research, which helped resolve a major question in immunology: what tips the immune system off to the presence of a foreign invader in the body? They also described an essential principle of the immune system: the immune system not only distinguishes between "self" and "non-self" antigens, it also recognizes a third state that they called "altered self." After a pathogen such as a virus infects a cell, the cell is recognized as an "altered self" and is destroyed.

Well, of course, you don't set out to make a discovery. What you're doing is checking a hypothesis... . - Peter Doherty, 1996.

The role of MHC molecules in pathogen recognition. In the decades since MHC molecules were identified, their precise role in antibody production has become clearer. As shown in this diagram, they are one of three different elements that must fit together to trigger a T-cell immune response — the others being the T cell receptor and fragments of pathogen proteins (antigenic peptides) that are presented to T cells by accessory cells, such as macrophages. The grooves in MHC sites are crucial to this presentation.

The role and structure of the MHC grooves. This computer model depicts the dimensional structure of an MHC groove and shows how it can cradle and display antigenic peptides from two different viruses. Numerous researchers have focused on the physical structure of MHC binding sites, in particular the grooves that hold and "display" the antigenic peptides.

Philippa Marrack and John Kappler — Identifying "superantigens"

While studying the mechanisms by which T cells and B cells recognize and attack pathogens, Philippa Marrack and John Kappler discovered an interesting type of pathogen-related antigen — which they named superantigen. These superantigens do not behave as normal antigens. Rather than attaching to the MHC groove and triggering a normal immune response, superantigens glom onto the sides of the binding site and gum up the system. As a result, T-cells go on an unregulated rampage, uncontrollably releasing regulatory molecules — such as interferons — in toxic amounts.

Left: Superantigen diagram with labels.

Right: Staphylococcus aureus:the staph of research. In the course of their research, Marrack and Kappler shed some light on S. aureus, a clinically important organism. The bacterium can release toxins that act as superantigens. These in turn can induce toxic shock syndrome, as happened from the use of contaminated tampons some years ago.