On April 4, 2023, Dr. Ken Smith will be the keynote speaker at our AII Seminar Series. During this seminar, he will deliver a lecture titled Iron Dysregulation and Stress Erythropoiesis Associates with poor Long-Term Outcome of COVID-19. Because of his visit to the Amsterdam Institute for Infection and Immunity, we asked Dr. Smith four questions about his research and lecture on April 4.

What is the topic of your research?

The Smith Laboratory has an experimental medical and translational program focused on understanding the mechanisms underlying immune-mediated diseases. This work ranges from fundamental immunological principles, including the development of complex preclinical models, through experimental medicine and genetics, to clinical trials. In the process, consortia have been established across the EU and the UK. Some of the topics covered in the lab include: Immune regulation and autoimmunity, Vasculitis, Primary Immunodeficiency (PID) and COVID-19.

Immune regulation and autoimmunity: "I described differential selection of memory B and antibody-forming cells, and the role of cell death, in the germinal center (Immunity 1994, PNAS 1995, EMBO 1997, JEM 2000), showed that Lyn was crucial for CD22 inhibitory function (JEM 1998) and described (with Vinuesa) the T follicular regulatory cell, which controls germinal centers and prevents autoimmunity (Nat Med 2011)."

Vasculitis: "We established the European Vasculitis Genetics Consortium: the first ANCA-associated Vasculitis (AAV) GWAS revealed two genetically distinct diseases, resulting in a diagnostic reclassification and a new trial analysis (NEJM 2012)."

Primary Immunodeficiency (PID): "We led the National Institute of Health Research (NIHR) Rare Diseases study in PID, a 27-centre consortium that pioneered the use of whole-genome sequencing for diagnosis in sporadic PID (Nature 2020), demonstrating that a Bayesian approach could identify novel disease-causing genes in a sporadic cohort without familial co-segregation. We described the role of EROS in biology and disease (JEM 2017, JACI 2018), an immune defect associated with NBEAL2 deficiency (JCI 2017) and the first descriptions of monogenic human PID caused by deficiencies in IL2R (JEM 2019a), IL6R (JEM 2019b), SOCS1, PTPN2, IVNS1ABP (all Nature 2020), IL37 (PNAS 2021), TRAF3 (Sci Immunol 2022) and others. We are now leading INTREPID, a £4M+ Wellcome-funded collaborative study to expand this work."

COVID-19: "Until recently, our normal research program was diverted to COVID-19. We initiated a large prospective program to study the immune response to SARS-CoV-2 infection, which is at the core of the NIHR COVID BioResource (with John Bradley), which has defined early immune changes consistent with outcome (Immunity 2021), implicated hypoxia as a direct cause of B-cell immune paresis (EBioMed 2021) and compared the BCR repertoire to changes induced by infection versus vaccination (Cell Reports 2021b). More recently, we have found that defective iron homeostasis and ineffective stress erythropoiesis correlates strongly with "long COVID." My lab also leads the UKRI-funded national anti-cytokine antibody center, which is investigating the impact of anti-interferon and other autoantibodies on disease."

What is the most profound result you have encountered so far in your career?

"Since 2004, we have led a prospective study recruiting and deeply phenotyping patients at diagnosis than long-term, in diseases including vasculitis, SLE and IBD. A CD8 T-cell prognostic signature correlated with long-term outcome in many diseases (Nat Med 2010, JCI 2011, Gut 2019)-driven by T-cell depletion (Nature 2015). This led to a Wellcome-funded prospective study (>£4M) in Crohn's disease and an IBD prognostic test in the clinic via a spin-out, PredictImmune (2017)."

What will be the focus of your research/research group in the near future?

"Understanding how immune pathway dysregulation relates to genetics in immune deficiency and autoimmunity, and how this information can guide therapy. I think this is still the most important unanswered question within my field of research."

Why should members of the Amsterdam institute for Infection and Immunity attend your seminar on April 4?

"My lecture will focus on work outside our normal focus made necessary by the pandemic. It shows how hematology appears to interact with immunology to determine outcomes in COVID-19 - an interface of particular interest to the Sanquin/Amsterdam UMC audience. And the forecast suggests the weather will be bad.”

See you Tuesday! Go to this page for more information and registration.

Text: Esmée Vesseur