Characterization of Switched Memory B Cells (SMB) in Patients with Secondary Antibody Deficiency due to Hematological Malignancies

Abstract

The global incidence of secondary antibody deficiency (SAD), an acquired immunodeficiency associated with increased risk of infections and infection-related morbidity and mortality, is on the rise. Immunoglobulin replacement therapy (IGRT) is the standard treatment for SAD associated with hematological malignancies (HM). However, SAD may be reversible in some patients and prolonged IGRT use may not be necessary. Currently, no standardized algorithm exists to guide the safe discontinuation of IGRT, and decisions largely rely on clinical judgement. This highlights the need for a reliable biomarker of humoral immune reconstitution. We hypothesized that switched memory B cells (SMB) may be associated with humoral immune reconstitution and can serve as a biomarker to guide safe IGRT discontinuation.

The primary objective of this thesis is to characterize the SMB cell proportion in patients with HM-associated SAD (HM-SAD) every 3-6 months over a one-year follow-up period. A prospective observational study was conducted involving 25 eligible adults with history of HM and receiving IGRT. Peripheral blood mononuclear cells were isolated and analyzed using spectral flow cytometry. SMB cells were defined as CD19⁺ CD27⁺ IgM⁻ IgD⁻ B cells and expressed as a percentage of total B lymphocytes, with normal values defined as ≥2%.

Low SMB cell frequencies were observed in 68% of participants and persisted long after disease remission despite normal total B cell frequencies in 56% of participants. No significant changes in SMB cell proportions were observed over the one-year follow-up period. Low SMB cell frequencies were not associated with age, sex, infection history, HM subtypes or duration of IGRT, but were common in participants with history of hematopoietic stem cell transplantation (83.3%) or rituximab exposure (75%). SMB cells also showed a strong positive correlation with IgG⁺ SMB cells and moderate positive correlation with IgA⁺ SMB cells. These findings suggest disturbed humoral immunity characterized by sustained reductions in SMB cell proportions despite recovery of total B cells and durable disease remission. Further studies are required to determine the utility of SMB cells, alone or in combination with other immunological markers, in guiding safe IGRT discontinuation.