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Denis Raymond Stanworth PhD DSc FRCPath 1928 – 2020

Denis Stanworth, retired immunochemist who spent his entire academic career at the University of Birmingham, UK, has died, aged 91. He was a major international figure in immunology and a pioneer in the study of immunoglobulin structure and function.1


Denis StanworthDenis graduated with a degree in chemistry from the University of Birmingham, where he also earned a PhD for his work on the physico-chemical characterisation of reagin to horse dander, under the then head of the Department of Experimental Pathology (the late Professor John Squire). This seminal work on reagins during the 1950s2 put him in a key position to participate in the momentous events which culminated in the discovery of IgE.3

In his lab in Birmingham, he carried out the functional characterisation of a rare myeloma protein, IgND, which was discovered in 1967 in Uppsala, Sweden, by Johansson and Bennich.4, 5 He found that IgND could block the Prausnitz-Kustner test for reagin6 and that this activity was mediated by the Fc fragment.7 In 1968 the World Health Organization named IgND and its equivalent, γE, described by the Ishizakas in Denver, Colorado,8 the fifth human immunoglobulin class, IgE.9

In the decades that followed, Denis continued his interest in the molecular pathology of IgE, describing a candidate vaccine peptide derived from the Cε4 domain of IgE which might be used in blocking certain allergic reactions.10 However, this approach was initially dismissed, particularly when the highaffinity receptor binding site was found to lie in the Cε3 domain at the interface with Cε2. But, surprisingly, when the crystal structure of the entire IgE-Fc region was solved,11 it was found to be acutely bent, and that the Cε2 domain contacted the Cε4 domain – in the very region of Denis's peptide!

We now know that the bent IgE-Fc conformation is critical for high-affinity receptor binding, and thus antibodies raised to the peptide, binding to this region of Cε4, would undoubtedly interfere with the bending – perhaps ‘unbending’ the IgE-Fc. This would prevent receptor binding, allosterically rather than by steric blocking. Interestingly, omalizumab, the anti-allergy therapeutic antibody, is now known to act allosterically to inhibit IgE/FcεRI binding, as demonstrated by solving the crystal structure of the omalizumab/IgE-Fc complex.12

Early in his career, Denis spent a year working in Ed Franklin’s lab in New York, where he raised antisera against paraproteins which were capable for the first time of distinguishing the then known classes of immunoglobulins (IgG, IgM and IgA) immunochemically13 – he often referred fondly to his time there and to the thrill of seeing, at first hand, Kennedy’s run for the presidency and Martin Luther King Jr. preach at a local church.

During the 1970s and 1980s, Denis published extensively on human IgG subclasses (particularly IgG4) and his interests expanded into the biology and functions of immunoglobulininteracting cells, especially mast cells, macrophages and B-cells.He also developed broad interests and expertise in the role of rheumatoid factors and complement in immune complex formation and how these elements contributed to the development of rheumatoid arthritis. He forged a strong friendship and research collaboration with the late Hungarian immunologist Janos Gergely, with whom he pursued his research interest in Fcγ receptors, and he often spoke of his visits to Budapest where he also enjoyed listening to the sound of gypsy violin over dinner!

Denis enjoyed travelling abroad and did so widely, often as a keynote speaker at international conferences. His lab in Birmingham was a magnet for young and seasoned immunologists from all over the world and he would normally have a dozen nationalities represented in his lab at any one time. He was very inclusive and would always bring his distinguished visitors into the lab for a chat with staff and PhD students. He was also a great believer in the social dimension of being part of a research community and through his numerous friendships he advanced science, forging productive research collaborations across diverse scientific and medical specialties. There was always excitement, energy and a new discovery to hear about and enjoy. Denis had a defining and lasting impact on the careers of many immunologists around the world, including us. We were all PhD students of Denis’s and like many of his postgraduate students (around 80 in total) we owe Denis an immense debt of gratitude for his guidance and advice, for the rich research discipline he instilled in us and for the continuing friendship we shared over several decades.

Following his retirement from the University of Birmingham, Denis set up Peptide Therapeutics Ltd in Cambridge, where he and his team continued their work on his novel anti-allergy peptide vaccine. In the late 1990s, he was awarded a special professorship by the University of Nottingham in recognition of his exceptional and long-standing contribution to the science of immunology and in particular to our understanding of allergies. He was a prolific author and a member of numerous national and international immunology organisations and committees, and was active in the Medical Research Council (London), the World Health Organization (Geneva) and the Royal College of Pathologists (London).

Denis spent his retirement years in his beloved Malvern, Worcestershire and was an avid listener to the music of its famous son, the English composer Sir Edward Elgar. Denis will be sorely missed by his family and friends. His wife Barbara passed away in 2013 and he is survived by his two daughters, Deborah and Sarah, and four grandchildren, David and Elizabeth, and Daniel and Francesca.

Farouk Shakib, Emeritus Professor of Experimental Allergy, University of Nottingham;
Keith James, Emeritus Professor of Immunology, University of Edinburgh;
Christopher S Henney, Former Professor of Immunology, University of Washington, WA, USA;
David W H Riches, Professor, Pulmonary Sciences & Critical Care Medicine, University of Colorado, CO, USA.


REFERENCES

  1. James et al. 1964 Nature 202 563–566
  2. Stanworth 1959 Immunology 2 384–401
  3. Stanworth 1993 Allergy 48 67–71
  4. Johansson 1967 Lancet ii 951–953
  5. Johansson & Bennich 1967 Immunology 13 381–394
  6. Stanworth et al. 1967 Lancet ii 330–332
  7. Stanworth et al. 1968 Lancet ii 17–18
  8. Ishizaka & Ishizaka 1967 Journal of Immunology 99 1187
  9. Bennich et al. 1968 Bulletin of the World Health Organization 38 151–152
  10. Stanworth et al. 1990 Lancet 336 1279–1281
  11. Wan et al. 2002 Nature Immunology 3 681–686
  12. Davies et al. 2017 Journal of Biological Chemistry 292 9975–9987
  13. Franklin & Stanworth DR 1961 Journal of Experimental Medicine 114 521–533