The generation of plasma cells and CD27⁻IgD⁻B cells during Hantavirus infection are associated with distinct pathological findings

Abstract

Human hantavirus infections can cause hemorrhagic fever with renal syndrome (HFRS), major signs of the disease being thrombocytopenia and transient kidney dysfunction. By a comprehensive and longitudinal study of circulating B cells, we demonstrate that these two pathologies associate with distinct effects on the humoral immune system during HFRS. Low thrombocyte counts strongly associated with an abnormal frequency of plasmablasts in circulation, whereas kidney dysfunction was indicative of an accumulation of CD27 -B cells and plasmablasts. Finally, we provide evidence that high levels of extracellular ATP in circulation during HFRS correlates with shedding of surface CD27 on B cells via a metallomatrix proteinase-8-mediated mechanism. Since extracellular ATP is known to regulate kidney function, our study reveals a link between kidney dysfunction and the generation of CD27 -IgD -B cells, and a potential molecular target for treatment of the symptomatic phase of HFRS. Dobrava, Seol and Puumala (PUUV) strains, where PUUV is endemic to Scandinavia. To date, no efficacious treatment or vaccination regimen exists to protect against severe hantavirus infections.Well controlled human studies have shown that hantavirus infections cause aberrant activation of both innate and adaptive immunity (5)(6)(7)(8). A potent antiviral IgG-response is associated with protection from severe disease during both HPS and HFRS (9-12) and passive transfer of serum antibodies could reduce case fatality rate in a small cohort of HPS patients (13). These findings clearly demonstrate that activation of the humoral immune system and subsequent elicitation of antiviral antibodies play a central role in the control of viremia and/or pathogenesis during hantavirus infections.A recent study of HPS demonstrated that very high levels of plasmablasts (PBs) and CD27 -IgD -B cells were detected in circulation of patients (14). The rapid and extensive PB-response is similar to that reported during acute dengue virus infection and contrasts to the comparably moderate levels of PBs that are found in circulation during influenza infection or after influenza vaccination (15). An expansion of the CD27 -IgD -B cell subset has previously been shown for numerous inflammatory and infectious diseases, as well as during ageing and cancer (16-21), yet their functional role in humoral immunity remains undetermined. The CD27 -IgD -B cells resemble memory B cells, have isotype switched and hypermutated B cell receptors and therefore likely originate from T cell-dependent germinal center reactions in secondary lymphoid organs (16, 20). In systemic lupus erythematosus (SLE), an expanded population of CD27 -IgD -B cells was associated with the manifestation of nephritis in patients (16). This suggests that their detection in blood may be linked to reduced kidney function, but the cause for their expansion remains to be determined.During HFRS-causing hantavirus infections, reduced kidney function occurs independently of the induced thrombocytopenia (22, 23). We therefor...

Longevity, clonal relationship and transcriptional program of celiac disease-specific plasma cells

“…15 Heterogeneous expression of CD27 has previously been reported in multiple myeloma, 62 and plasma blasts/PCs in patients with hemorrhagic fever with renal syndrome were found to have very low surface expression of CD27. 63 We observed a somewhat higher frequency of TG2-specific PCs in UCeD and TCeD patients than previously reported. 10,18,19 This discrepancy could be due to the fact that previous studies have focused on CD27 + IgA PCs, while we here made no such restrictions, and many of the TCeD patients in this study had been on a GFD for little more than one year.…”

Longevity, clonal relationship, and transcriptional program of celiac disease–specific plasma cells

“…Up-regulation of CD27 in non–TG2-specific compared with TG2-specific PCs has also been observed in bulk RNA-seq ( Snir et al, 2019 ). Heterogeneous expression of CD27 has previously been reported in multiple myeloma ( Guikema et al, 2003 ), and plasmablasts/PCs in patients with hemorrhagic fever with renal syndrome were found to have very low surface expression of CD27 ( Kerkman et al, 2019 Preprint ).…”

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

“…Recombinant hantaviral Gn/Gc proteins that recapitulate the tetrameric structure of the virion-bound glycoprotein complex are not currently available ( 11 , 32 ). To sample antibody specificities recognizing conformational and quaternary epitopes, we used entry-competent rVSV-Gn/Gc particles bearing fluorescent mNeonGreen (mNG)–labeled cores (rVSV-mNG-Gn/Gc) ( 29 , 33 ) as baits for single-cell sorting of class-switched (swIg + ), antigen-specific B cells (CD19 + /IgM − /IgD − /virus + ) from peripheral blood. Across donors, up to 2.8% of swIg + B cells specifically bound rVSV-mNG-PUUV-Gn/Gc, whereas a smaller fraction (~0.4%) was reactive to rVSV-mNG-ANDV-Gn/Gc, which was concordant with our donors’ exposure history, the sequence divergence between these glycoproteins, and the lower but detectable cross-neutralizing serum activity against ANDV Gn/Gc (Fig.…”