In a paper to be published on April 29 in the journal Science, Dr Jean van den Elsen of the University of Bath and Dr David Isenman of the University of Toronto show how a new understanding of the structure of this immune system complex has important medical implications.
An atomic structure of the complex, which is key to the development of immunity against microbial pathogens and a potential target for the treatment of autoimmune diseases such as MS and SLE, was first published in Science in 2001, but it was recently determined to be incorrect by the two researchers.
Dr van den Elsen and Dr Isenman have spent a decade studying the complex and decided to reanalyse its structure to develop a correct understanding of its atomic details.
Dr van den Elsen said: “The research looks at a complex between two proteins, one from the complement system – a part of our innate immune system that is present from the beginnings of our lives – and another from the adaptive immune system.
“It has become understood in recent years that the complement system also has a role in ‘kick-starting’ the adaptive immune system – the part of our immune system that reacts to pathogens as we are exposed to them, by developing antibodies.”
The researchers focused on a particular protein, C3, in the complement system and its molecular partner complement receptor 2 (CR2) on the surface of B cells, the antibody producing cells of the adaptive immune system.
C3 breaks down to produce a fragment called C3d when attached to a pathogenic antigen which is then able to act as a ‘bridge’ between the innate and adaptive immune systems by connecting the antigen recognition entity of the B cell (the B cell receptor, BCR) with the complement receptor.
This then boosts the immune system by increasing the production of antibodies that attack the pathogen.
The interaction between C3d and CR2 therefore acts to increase the sensitivity at which a pathogen is recognised and reacted to in the body, which is essential in keeping us healthy from disease.
This characteristic has important implications for the design of new vaccines against diseases caused by microbial pathogens
However, this process can go wrong, with the immune system mistaking a part of the body as a pathogen and attacking it, resulting in an autoimmune disease.
Dr Isenman said: “To treat antibody-mediated autoimmune diseases there is a potential to target the ‘bridging’ action of C3d with CR2, through designing drugs that would inhibit the interaction.
“However, due to the misunderstandings caused by the previous structure of the complex, over the past ten years progress in this field has been delayed.”
The findings will end a decade-long controversy regarding the structure of this important part of the immune system, and marks a turning point in science’s ability to develop treatments for a subset of autoimmune diseases.
Dr van den Elsen said: “The new structure is very different to the previous one, but its features conform to all existing biochemical data.
“With the issues relating to the structure of this complex now resolved we hope to take our research forward and use this as a platform to design inhibitory compounds that may be useful in treating antibody-mediated autoimmune diseases.”
The authors of the current study recognise that this goal will not be easy to achieve and that there is a great deal of research still to be done.
However, this discovery is a key milestone in the development of a treatment for antibody-mediated autoimmune diseases and the structural scaffold on which all future progress is based is now firmly in place.