Daniel Diatlov

All Publications

• Comprehensive analysis of complement activation in a hydroxyurea-treated patient cohort with sickle cell disease BLOOD ADVANCES Diatlov, D., Bohorquez-Hernandez, A., Kirby-Allen, M., Licht, C. 2026; 10 (4): 1168-1178

  Abstract

  Sickle cell disease (SCD) is an understudied, life-threatening genetic disorder affecting ∼300 000 infants yearly with limited treatment options. The complement system, a critical part of innate immunity, has emerged as a contributor to SCD pathophysiology, thus presenting a potential new treatment target. Our aim was to assess complement activity in children with SCD receiving hydroxyurea (HU) therapy during vaso-occlusive crisis (VOC) and steady state. Blood samples were collected from 46 pediatric patients with SCD during VOC (early and late) and steady state, with control samples from healthy volunteers. Clinical data were obtained from patient records, and patient heme levels were measured using colorimetric assay. Complement deposition on endothelial cells (ECs) was quantified using high-throughput automated immunofluorescence imaging. Complement protein concentration was measured using enzyme-linked immunosorbent assay and multiplex assays. We found that, in vitro, heme drove C3b and C5b-9 deposition on ECs. Patients had increased heme levels during both VOC and steady state compared with healthy controls. However, complement activation correlated with total hemoglobin (Hb) concentration in patients during steady state, but not heme levels. C5b-9 deposition on ECs was significantly higher in patients during early crisis compared with late crisis, suggesting heightened complement activity early in VOC, with C5b-9 deposition also strongly correlating with circulating soluble C5b-9 levels. A significant increase in the C3b/C3 ratio further indicated early complement activation during VOC. In conclusion, complement activity is likely highest in early VOC in patients with SCD, and presents a critical potential treatment target, but is overall attenuated by HU therapy despite elevated heme or Hb levels.

  View details for DOI 10.1182/bloodadvances.2025016958

  View details for Web of Science ID 001695464500001

  View details for PubMedID 41733936

• Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation. Med (New York, N.Y.) Bowen, E. E., Hurcombe, J. A., Barrington, F., Keir, L. S., Farmer, L. K., Wherlock, M. D., Ortiz-Sandoval, C. G., Bruno, V., Bohorquez-Hernandez, A., Diatlov, D., Rostam-Shirazi, N., Wells, S., Stewart, M., Teboul, L., Lay, A. C., Butler, M. J., Pope, R. J., Larkai, E. M., Morgan, B. P., Moppett, J., Satchell, S. C., Welsh, G. I., Walker, P. D., Licht, C., Saleem, M. A., Coward, R. J. 2023

  Abstract

  BACKGROUND: Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear.METHODS: Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied.FINDINGS: Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype.CONCLUSIONS: This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease.FUNDING: This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).

  View details for DOI 10.1016/j.medj.2023.09.002

  View details for PubMedID 37863058