Physiology and pathology of the C3 amplification cycle: A retrospective

Abstract

In the Spring of 1970, a few months after I had started as a Lecturer in Renal Medicine at the Royal Postgraduate Medical School (RPMS) at Hammersmith Hospital in London, I arranged to meet Peter Lachmann, then in Cambridge, to set up a program studying the metabolism of complement proteins in patients with immunological disease. I was fortunate that he was enthusiastic about the idea but doubly so because the following year he accepted the Foundation Chair of Immunology at the RPMS, where we established a close collaboration and a lifetime friendship. Peter had worked with Henry Kunkel at the Rockefeller and was imbued with Henry's philosophy of combining information gleaned from patients with molecular analysis in the laboratory, a perfect fit for the RPMS, an institution which attached the highest priority to clinical research. Peter spent 1971-6 at the Hammersmith before returning to Cambridge, but more than half a century later related research is flourishing at the Hammersmith, driven first by his graduate student Mark Walport and subsequently by Marina Botto and MatthewPickering-I refer to their work later. I feel greatly privileged to be asked to contribute this review and I want to take the opportunity to illustrate the many clues to complement physiology, its role in disease, and ideas for therapy that arose from the detailed study (in the Kunkel tradition) of a small number of patients with exceptionally rare diseases. In the 1970s, complement was not even considered a mainstream aspect of immunology, and international meetings were easily accommodated in coastal resort hotels. The complement world was transformed with the discovery of its potential role in age-related macular degeneration (AMD) in 2005. Peter had a long-term belief in complement therapeutics based on his ideas of modulating the physiology of the C3 feedback cycle. These eventually materialized in his 80 s with the formation in 2014 of Gyroscope Therapeutics, a gene therapy company.

The complement alternative pathway in health and disease—activation or amplification?

“…In his introduction to AP/AL‐driven diseases, Peters, gives a highly personal view of a journey that takes us from the initial tickover hypothesis through basic mechanistic understanding and roles in disease to seminal and ground‐breaking therapeutic strategies to target complement‐mediated disease 30 . It is worth noting just how much of our current understanding has come from the study of patients with rare diseases.…”