Early B cell development and B cell maturation are impaired in patients with active hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and multi-organ dysfunction. Infections, including the reactivation of viruses, contribute to significant disease mortality in HLH. While T and NK cell-driven immune activation and dysregulation are well described, limited data exist on the status of the B cell compartment and humoral immune function in HLH. We noted marked suppression of early B cell development in patients with active HLH. In vitro B cell differentiation studies following exposure to HLH-defining cytokines, such as interferon-gamma (IFN-g) and tumor necrosis factor, recapitulated B cell development arrest. mRNA sequencing of human CD34+ cells exposed to IFN-g demonstrated changes in genes and pathways affecting B cell development and maturation. In addition, patients with active HLH exhibited a marked decrease in class-switched memory B (CSMB) cells and a decrease in bone marrow plasmablast/plasma cell compartments. The decrease in CSMB cells was associated with a decrease in circulating T follicular helper (cTfh) cells. Finally, lymph node and spleen evaluation in a patient with HLH revealed absent germinal center formation and hemophagocytosis with associated lymphopenia. Reassuringly, the frequency of CSMB and cTfh improved with control of T cell activation. Taken together, in patients with active HLH, these changes in B cells may affect the humoral immune response; however, further immune studies are needed to determine its clinical significance.