Hantavirus infection-induced B cell activation elevates free light chains levels in circulation

Abstract

In humans, orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). An earlier study reported that acute Andes virus HPS caused a massive and transient elevation in the number of circulating plasmablasts with specificity towards both viral and host antigens suggestive of polyclonal B cell activation. Immunoglobulins (Igs), produced by different B cell populations, comprise heavy and light chains; however, a certain amount of free light chains (FLCs) is constantly present in serum. Upregulation of FLCs, especially clonal species, associates with renal pathogenesis by fibril or deposit formations affecting the glomeruli, induction of epithelial cell disorders, or cast formation in the tubular network. We report that acute orthohantavirus infection increases the level of Ig FLCs in serum of both HFRS and HPS patients, and that the increase correlates with the severity of acute kidney injury in HFRS. The fact that the kappa to lambda FLC ratio in the sera of HFRS and HPS patients remained within the normal range suggests polyclonal B cell activation rather than proliferation of a single B cell clone. HFRS patients demonstrated increased urinary excretion of FLCs, and we found plasma cell infiltration in archival patient kidney biopsies that we speculate to contribute to the observed FLC excreta. Analysis of hospitalized HFRS patients’ peripheral blood mononuclear cells showed elevated plasmablast levels, a fraction of which stained positive for Puumala virus antigen. Furthermore, B cells isolated from healthy donors were susceptible to Puumala virus in vitro, and the virus infection induced increased production of Igs and FLCs. The findings propose that hantaviruses directly activate B cells, and that the ensuing intense production of polyclonal Igs and FLCs may contribute to acute hantavirus infection-associated pathological findings.

Neutralizing Antibody Titers in Hospitalized Patients with Acute Puumala Orthohantavirus Infection Do Not Associate with Disease Severity

“…This is contrary to what has been reported for infections with Sin Nombre orthohantavirus [ 40 ], which causes a different disease phenotype (HCPS) with a different organ targeting (lungs instead of kidneys). Interestingly, our previous results have shown that severe NE patients have higher circulating free light chain levels [ 41 ], which are considered as markers of polyclonal B cell activation and increased total humoral responses. This serves as a speculative support for the observed higher neutralizing antibody levels, being part of a general increase in antibody production in severe NE cases.…”

“…This serves as a speculative support for the observed higher neutralizing antibody levels, being part of a general increase in antibody production in severe NE cases. Importantly, while similarly upregulated, free light chains do not correlate with disease severity in acute HCPS [ 41 ], further suggesting variable pathogenic mechanisms between the two orthohantaviral diseases in which increased humoral response might be contributing to NE (and HFRS) pathogenesis, whereas HCPS would be dominated by direct virus infection-related mechanisms. It should be noted that this lower level of eGFR in patients with higher NAb is likely not due to immunocomplex deposition in kidneys since previous works on the matter had shown no evidence of such complexes by immunofluorescence methods in kidney biopsies [ 42 ].…”

Puumala Hantavirus Infections Show Extensive Variation in Clinical Outcome

“…Human CD8 T-cell response in PUUV infection occurs after the acute phase and, curiously, is associated with boosting of EBV-specific CD8 memory T-cells and transient presence of EBV DNA in some patients, indicative of viral reactivation [ 36 ]. These findings may be because EBV is a polyclonal B-cell activator and can also explain the following findings in PUUV infection: nonrelated toxoid immunity in PUUV infection (tetanus-specific and pertussis-specific IgG as well as T-cells) [ 37 ], the free immunoglobulin light chains in hantavirus infection [ 38 ], and the observed [ 39 ] increased risk (73%) for lymphoma (resembling mononucleosis-associated Hodgkin lymphoma) after PUUV HFRS.…”

Lambda-free light chain: A serum marker of dengue disease via NS3 protease-mediated antibody cleavage

“…Serum FLC levels are also affected by viral infections. Previous studies have shown that serum levels of κ and λ FLCs are significantly increased in acute hantavirus diseases [ 10 ]. Additionally, notable elevations in serum κ and λ FLC levels have been observed in severe cases of SARS-CoV-2-infected patients [ 11 ].…”