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IgM Antibody Repertoire Fingerprints in Mice Are Personalized but Robust to Viral Infection Status.

ABSTRACT: Antibody repertoire sequencing provides a molecular fingerprint of current and past pathogens encountered by the immune system. Most repertoire studies in humans require measuring the B cell response in the blood, resulting in a large bias to the IgM isotype. The extent to which the circulating IgM antibody repertoire correlates to lymphoid tissue-resident B cells in the setting of viral infection remains largely uncharacterized. Therefore, we compared the IgM repertoires from both blood and bone marrow (BM) plasma cells (PCs) following acute or chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Despite previously reported serum alterations between acute and chronic infection, IgM repertoire signatures based on clonal diversity metrics, public clones, network, and phylogenetic analysis were largely unable to distinguish infection cohorts. Our findings, however, revealed mouse-specific repertoire fingerprints between the blood and PC repertoires irrespective of infection status.

SUBMITTER: Yermanos A

PROVIDER: S-EPMC7270205 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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IgM Antibody Repertoire Fingerprints in Mice Are Personalized but Robust to Viral Infection Status.

Yermanos Alexander A Kräutler Nike Julia NJ Pedrioli Alessandro A Menzel Ulrike U Greiff Victor V Stadler Tanja T Oxenius Annette A Reddy Sai T ST

Frontiers in cellular and infection microbiology 20200528

Antibody repertoire sequencing provides a molecular fingerprint of current and past pathogens encountered by the immune system. Most repertoire studies in humans require measuring the B cell response in the blood, resulting in a large bias to the IgM isotype. The extent to which the circulating IgM antibody repertoire correlates to lymphoid tissue-resident B cells in the setting of viral infection remains largely uncharacterized. Therefore, we compared the IgM repertoires from both blood and bon ...[more]

PMID: 32547966

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Project description:Broadly neutralizing antibodies (bnAbs) targeting the receptor binding site (RBS) of hemagglutinin (HA) have potential for developing into powerful anti-influenza agents. Several previously reported influenza B bnAbs are nevertheless unable to neutralize a portion of influenza B virus variants. HA-specific bnAbs with hemagglutination inhibition (HI) activity may possess the ability to block virus entry directly. Polymeric IgM antibodies are expected to more effectively inhibit virus attachment and entry into target cells due to their higher avidity and/or steric hindrance. We therefore hypothesized that certain RBS-targeted IgM antibodies with strong cross-lineage HI activity might display broader and more potent antiviral activity against rapidly evolving influenza B viruses. Methods: In this study, we generated IgM and IgG bnAbs targeting the RBS of influenza B virus using the murine hybridoma technique. IgM and IgG versions of the same antibodies were then developed by isotype switching and characterized in subsequent in vitro and in vivo experiments. Results: Two IgM and two IgG bnAbs against influenza B virus HA were identified. Of these, one IgM subtype antibody, C7G6-IgM, showed strong HI and neutralization activities against all 20 representative influenza B strains tested, with higher potency and broader breadth of anti-influenza activity in vitro than the IgG subtype variant of itself, or other previously-reported influenza B bnAbs. Furthermore, C7G6-IgM conferred excellent cross-protection against distinct lineages of influenza B viruses in mice and ferrets, performing better than the anti-influenza drug oseltamivir, and showed an additive antiviral effect when administered in combination with oseltamivir. Mechanistically, C7G6-IgM potently inhibits infection with influenza B virus strains from different lineages by blocking viral entry. Conclusion: In summary, our study highlights the potential of IgM subtype antibodies in combatting pathogenic microbes. Moreover, C7G6-IgM is a promising candidate for the development of prophylactics or therapeutics against influenza B infection.

Project description:The typical anti-phospholipid antibodies (APLA) in the anti-phospholipid syndrome (APS) are reactive with the phospholipid-binding protein β2GPI as well as a growing list of other protein targets. The relation of APLA to natural antibodies and the fuzzy set of autoantigens involved provoked us to study the changes in the IgM repertoire in APS. To this end, peptides selected by serum IgM from a 7-residue linear peptide phage display library (PDL) were deep sequenced. The analysis was aided by a novel formal representation of the Igome (the mimotope set reflecting the IgM specificities) in the form of a sequence graph. The study involved women with APLA and habitual abortions (n=24) compared to age-matched clinically healthy pregnant women (n=20). Their pooled Igomes (297 028 mimotope sequences) were compared also to the global public repertoire Igome of pooled donor plasma IgM (n=2 796 484) and a set of 7-mer sequences found in the J regions of human immunoglobulins (n=4 433 252). The pooled Igome was represented as a graph connecting the sequences as similar as the mimotopes of the same monoclonal antibody. The criterion was based on previously published data. In the resulting graph, identifiable clusters of vertices were considered related to the footprints of overlapping antibody cross-reactivities. A subgraph based on the clusters with a significant differential expression of APS patients' mimotopes contained predominantly specificities underrepresented in APS. The differentially expressed IgM footprints showed also an increased cross-reactivity with immunoglobulin J regions. The specificities underexpressed in APS had a higher correlation with public specificities than those overexpressed. The APS associated specificities were strongly related also to the human peptidome with 1 072 mimotope sequences found in 7 519 human proteins. These regions were characterized by low complexity. Thus, the IgM repertoire of the APS patients was found to be characterized by a significant reduction of certain public specificities found in the healthy controls with targets representing low complexity linear self-epitopes homologous to human antibody J regions.

Dataset Information

IgM Antibody Repertoire Fingerprints in Mice Are Personalized but Robust to Viral Infection Status.

Publications

IgM Antibody Repertoire Fingerprints in Mice Are Personalized but Robust to Viral Infection Status.

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