Human newborn B cells mount an interferon-α/β receptor-dependent humoral response to respiratory syncytial virus

Abstract

high doses of IVIG; however, it is probable that passive immunization may play a predominant role in controlling the ongoing viral infections. Therefore it could be argued that IgG replacement therapy might be beneficial for STAT2-deficient patients during childhood, until their adaptive immune system has sufficiently developed, as shown in patients with defects in the Toll-like receptor pathways. E4 The history of P1 indeed demonstrates that patients may still be at risk for overwhelming viral illness beyond early childhood. Based on our limited experience, we recommend monthly IVIG substitution to prevent infections and high dose IVIG treatment in the course of severe (viral) infectious episodes with signs of emerging coagulopathy and/or immune dysregulation. The protective effect of in vitro infection with Vesicular stomatitis virus in P2's fibroblast culture by preincubation with IFN-g invites speculation on the prophylactic or therapeutic use of IFN-g. However, the long-term use of IFN-g is not without side effects, and at the time of severe infection, its use may enhance macrophage activation. Therefore at present, IVIG seems to be the safer alternative. Our findings also add to the growing consensus that any fatal or life-threatening viral infection should not be seen simply as a case of ''bad luck,'' but should instead trigger comprehensive genetic analysis even in the absence of identifiable immunological (blood) anomalies. E5 This will allow for genetic counseling of the family, individualized directed treatment, and a better understanding of the immune system. We would like to thank Greet Wuyts, Doreen Dillaerts, and Irina Thiry for their technical assistance. We thank François Vermeulen for guiding the clinical care for these patients and Barbara Bosch for helping editing the text. We are very much indebted to the patient and her parents.

Definition of erythroid cell‐positive blood transcriptome phenotypes associated with severe respiratory syncytial virus infection

“…11 The role of type I interferons per se is not widely reported, but a recent study describes a dependency on interferon alpha and beta for developing antibody-mediated responses. 28 Several reports, however, have identified reduced interferon gamma responses in the context of RSV infection, especially when compared to the response observed during influenza virus infection. [29][30][31][32] This finding is also consistent with our observation of a somewhat muted interferon response in RSV patients compared to what we measured in response to not only influenza, but also to HIV or TB infection, as well as in patients with SLE.…”

“…Others have also described robust interferon responses as measured via blood transcriptome profiling in RSV patients 11 . The role of type I interferons per se is not widely reported, but a recent study describes a dependency on interferon alpha and beta for developing antibody‐mediated responses 28 . Several reports, however, have identified reduced interferon gamma responses in the context of RSV infection, especially when compared to the response observed during influenza virus infection 29–32 .…”

Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation

“…A subset of these antibodies showed potent neutralizing activity despite lacking SHM. Recent work has shown that polyclonal IgM antibodies purified from RSV-naïve infant sera are capable of neutralizing RSV, and it was suggested that these antibodies may represent natural anti-RSV antibodies that react with the N - and O -linked glycans present on the RSV surface glycoproteins (Jans et al, 2017). However, unlike natural IgM antibodies—which rely on avidity, typically recognize common surface antigens, and exhibit some degree of polyreactivity (Panda and Ding, 2015)—the site III-directed antibodies described here bound with high affinity in an IgG backbone, specifically recognized an epitope on RSV F that lacks N -linked glycans, and generally showed little to no polyreactivity, suggesting that they are distinct from previously described natural IgM antibodies.…”

Strategies for active and passive pediatric RSV immunization

“… 60 – 62 Following RSV exposure in human infants, plentiful IgM is produced by B cells whereas IgG is produced in relatively low quantities compared to adults, despite similar levels of the B-cell activation markers, CD69 and CD86. 63 The relatively low antibody response to infection suggests infants may elicit predominantly short-lived effector B-cell responses rather than production of long-lived plasma cells. Indeed, this was observed in a neonatal mouse model of tetanus toxoid vaccination, in which early life immunization led to the development of significantly fewer bone marrow plasma cells compared to immunized adult mice.…”