Dr Denis Stanworth - a major international figure in immunology has died at the age of 91

Dr Denis Raymond Stanworth PhD DSc FRCPath (1928 – 2020)

Obituary

Denis Stanworth, retired immunochemist who spent his entire academic career at the University of Birmingham, United Kingdom, 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 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 1950s [2] 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, that was discovered in 1967 in Uppsala, Sweden, by Johansson and Bennich [4, 5]. He found that IgND could block the Prausnitz-Kustner test for reagin [6] and that this activity was mediated by the Fc fragment [7]. In 1968 the World Health Organisation named IgND and its equivalent, gE, 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 Ce4 domain of IgE which might be used in blocking certain allergic reactions [10]. However, this approach was initially dismissed, particularly when the high-affinity receptor binding site was found to lie in the Ce3 domain at the interface with Ce2. 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 Ce2 domain contacted the Ce4 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 Ce4, would undoubtedly interfere with the bending – perhaps “unbending” the IgE-Fc. This would prevent receptor binding, allosterically rather than by steric blocking [11]. Interestingly, omalizumab, the anti-allergy therapeutic antibody, is now known to act allosterically to inhibit IgE/FceRI 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) immunochemically [13] – 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 immunoglobulin-interacting 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 Fcg 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 organizations 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.

References

James K, Henney CS, Stanworth DR. Structural changes occurring in 7Sg-globulins. Nature 1964; 202: 563 – 566.
Stanworth DR. Studies on the physico-chemical properties of reagin to horse dandruff. Immunology 1959; 2: 384 – 401.
Stanworth DR. The discovery of IgE. Allergy 1993; 48: 67 – 71.
Johansson SGO. Raised levels of a new immunoglobulin class (IgND) in asthma. Lancet 1967; ii: 951 – 953.
Johansson SGO, Bennich H. Immunological studies of an atypical (myeloma) immunoglobulin. Immunology 1967; 13: 381 – 394.
Stanworth DR, Humphrey J, Bennich H, Johansson SGO. Specific inhibition of the Prausnitz-Kustner reaction by an atypical human myeloma protein. Lancet 1967; ii: 330 – 332.
Stanworth DR, Humphrey JH, Bennich H, Johansson SGO. Inhibition of the Prausnitz-Kustner reaction by proteolytic cleavage fragments of a human myeloma protein of class E. Lancet 1968; ii: 17 – 18.
Ishizaka K, Ishizaka T. Identification of gE-antibodies as a carrier of reaginic activity. J Immunol 1967; 99: 1187.
Bennich H, Ishizaka K, Johansson SGO, Rowe DS, Stanworth DR, Terry WD. Immunoglobulin E, a new class of human immunoglobulin. Bull World Health Organ 1968; 38: 151 – 152.
Stanworth DR, Jones VM, Lewin IV, Nayyar S. Allergy treatment with a peptide vaccine. Lancet 1990; 336: 1279 – 1281.
Wan T, Beavil RL, Fabiane SM, Beavil AJ, Sohi MK, Keown M, Young RJ, Henry AJ, Owns RJ, Gould HJ, Sutton BJ. The crystal structure of IgE Fc reveals an asymmetrically bent conformation. Nat Immunol 2002; 3: 681 – 686.
Davies AM, Allan EG, Keeble AH, Delgado J, Cossins BP, Mitropoulou AN, Pang MOY, Ceska T, Beavil AJ, Craggs G, Westwood M, Henry AJ, McDonnell JM, Sutton BJ. Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab. J Biol Chem 2017; 292: 9975 – 9987.
Franklin EC, Stanworth DR. Antigenic relationships between immunoglobulins and certain related paraproteins in man. J Exp Med 1961; 114: 521 – 533.