Massive plasmablast response elicited in the acute phase of hantavirus pulmonary syndrome

Abstract

Beside its key diagnostic value, the humoral immune response is thought to play a protective role in hantavirus pulmonary syndrome. However, little is known about the cell source of these antibodies during ongoing human infection. Herein we characterized B-cell subsets circulating in Andes-virus-infected patients. A notable potent plasmablast (PB) response that increased 100-fold over the baseline levels was observed around 1 week after the onset of symptoms. These PB present a CD3 CD19 CD20 CD38 CD27 CD138 IgA surface phenotype together with the presence of cytoplasmic functional immunoglobulins. They are large lymphocytes (lymphoblasts) morphologically coincident with the 'immunoblast-like' cells that have been previously described during blood cytology examinations of hantavirus-infected patients. Immunoreactivity analysis of white blood cell lysates suggests that some circulating PB are virus-specific but we also observed a significant increase of reactivity against virus-unrelated antigens, which suggests a possible bystander effect by polyclonal B-cell activation. The presence of this large and transient PB response raises the question as to whether these cells might have a protective or pathological role during the ongoing hantavirus pulmonary syndrome and suggest their practical application as a diagnostic/prognostic biomarker.

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

“…Strikingly, several of the HFRS patients showed an extreme elevation of the frequency of PBs/PCs (comprising up to 80% of all circulating CD19 + B cells) (Figure 2A). A similar extensive elevation of PB frequency had been reported to occur during HPS (14). Surface expression of HLA-DR was reduced on recently formed (HLA-DR high Ki67 + ) PB during acute infection compared to convalescent phase and healthy controls (A vs C: p=0.0013; A vs. H p<0.0001), whereas surface expression of CD38 was increased at the same time points (A vs. C: p=0.0047; A vs. H: p=0.0024) (Figure 2B).…”

“…While a massive PB expansion in circulation has previously been shown during HPS and Dengue virus infection (14, 15), our data reveal that this expansion may be linked to thrombocytopenia, a common symptom in both hantavirus and dengue virus infections. We show that the expansion is, at least partially, due to mobilization of both activated and resting PBs/PCs into circulation.…”

“…Normalization of N- and Gn-binding IgG with total IgG levels showed similar results, with a relative increase of N-binding IgG, and a trend of increased Gn-binding IgG over time (Figure S2B). In patients with HPS, it was demonstrated that a similar extensive PB-expansion leads to increased levels of autoantibodies in circulation (14). Here, we could not find an association with anti-dsDNA or anti-Sjögrens-Syndrome related antigen A, and while five patients had elevated anti-rheumatoid factor IgM antibodies this did not correlate with the levels of PBs/PCs in circulation (Figure S2C).…”

“…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).…”

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

“…That percentage can still rise if a more severe DENV infection or a secondary viral exposure with a distinct serotype is considered (11,12). Quantitatively, this DENV-specific ASC response presents a much higher magnitude than the counterparts induced by viral infections (Ebola, Andes, Influenza) (13)(14)(15), immunisations (attenuated Yellow Fever virus 17DD or inactivated Influenza vaccine) (11)(12)(13)(14)(15)(16), and plasma cell lymphoma (17).…”