B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis
Ulutekin, C. et al. (MedRxiv) DOI: 10.1101/2022.10.17.22281079
B cell depletion
B cell depletion therapy (e.g. using anti-CD20 monoclonal antibodies Rituximab or Ocrelizumab) is an effective treatment for many autoimmune conditions but the mechanism of action has been elusive. Using mass cytometry analysis of peripheral blood from three cohorts of patients with multiple sclerosis or myasthenia gravis, the authors demonstrate that B cell depletion therapy results in a sustained reduction of Tfh cells and increased levels of surface CD27, a positive costimulatory receptor, on CD4 memory and Tfh cells. The ligand for CD27, CD70, is predominantly expressed on B cells. Thus, it is hypothesised that the efficacy of B cell depletion may be because it modulates the CD4 compartment by disrupting the CD27-CD70 costimulation axis.
This study raises a convincing hypothesis based on observational data. Further study is needed (likely in animal models) to prove the relevance of the CD27/CD70 axis in the response to B cell depletion
No information is provided about the clinical response to B cell depletion in the cohorts. It would be informative to know if changes in CD27 correlated with clinical response.
During our discussion of the paper, it was raised that measuring soluble (shed) CD27 in the serum could be very informative as, based on the hypothesis, one would expect it to be elevated in BCDT-treated individuals.
Although the CD27/CD70 axis has been studied in the context of MS and animal models of autoimmunity, this study extends this by implicating this pathway as a potential mechanism by which B cell depletion exerts beneficial immunoregulation in human diseases. If the hypothesis is correct, the CD27/CD70 pathway is a promising therapeutic target.
From a methodological standpoint, the observed changes in CD27 protein (the levels of which are regulated post-translationally by shedding from the cell surface) reinforces the importance of proteomic and cytometry methods, even as transcriptomic methods become so prevalent.
Reviewed by Graham Britton as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.