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IgM, IgG, and IgA Influenza-Specific Plasma Cells Express Divergent Transcriptomes.

ABSTRACT: Ab-secreting cells (ASC) or plasma cells are essential components of the humoral immune system. Although Abs of different isotypes have distinct functions, it is not known if the ASC that secrete each isotype are also distinct. ASC downregulate their surface BCR upon differentiation, hindering analyses that couple BCR information to other molecular characteristics. In this study, we developed a methodology using fixation, permeabilization, and intracellular staining coupled with cell sorting and reversal of the cross-links to allow RNA sequencing of isolated cell subsets. Using hemagglutinin and nucleoprotein Ag-specific B cell tetramers and intracellular staining for IgM, IgG, and IgA isotypes, we were able to derive and compare the gene expression programs of ASC subsets that were responding to the same Ags following influenza infection in mice. Intriguingly, whereas a shared ASC signature was identified, each ASC isotype-specific population expressed distinct transcriptional programs controlling cellular homing, metabolism, and potential effector functions. Additionally, we extracted and compared BCR clonotypes and found that each ASC isotype contained a unique, clonally related CDR3 repertoire. In summary, these data reveal specific complexities in the transcriptional programming of Ag-specific ASC populations.

SUBMITTER: Price MJ

PROVIDER: S-EPMC6783370 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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IgM, IgG, and IgA Influenza-Specific Plasma Cells Express Divergent Transcriptomes.

Price Madeline J MJ Hicks Sakeenah L SL Bradley John E JE Randall Troy D TD Boss Jeremy M JM Scharer Christopher D CD

Journal of immunology (Baltimore, Md. : 1950) 20190909 8

Ab-secreting cells (ASC) or plasma cells are essential components of the humoral immune system. Although Abs of different isotypes have distinct functions, it is not known if the ASC that secrete each isotype are also distinct. ASC downregulate their surface BCR upon differentiation, hindering analyses that couple BCR information to other molecular characteristics. In this study, we developed a methodology using fixation, permeabilization, and intracellular staining coupled with cell sorting and ...[more]

PMID: 31501259

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Project description:BackgroundChronic pulmonary aspergillosis (CPA) is an underdiagnosed and misdiagnosed disease and now increasingly recognised. However, the diagnosis of CPA remains challenging. In this study, we aimed to investigate the diagnostic values of serum Aspergillus-specific IgG, IgA and IgM antibodies in patients with CPA.MethodsThe prospective study was performed at Chinese People's Liberation Army General Hospital in Beijing, from January 2017 to December 2017. Adult patients with lung lesions presented as cavity, nodule, mass, bronchiectasis or severe fibrotic destruction with at least two lobes in CT imaging were enrolled. One hundred healthy persons were also enrolled as additional controls. The serum levels of Aspergillus-specific IgG, IgA and IgM antibodies and galactomannan (GM) levels were measured simultaneously by plate ELISA kit.ResultsA total of 202 patients were enrolled in this study, including 42 CPA patients, 60 non-CPA patients and 100 healthy persons. The most common underlying lung diseases in CPA patients were bronchiectasis (28.6%) and COPD (19.0%). The most common symptoms in the CPA patients were cough (76.2%), sputum (71.4%), and fever (45.2%); chest pain (4.8%) was infrequent. Receiver operating characteristic (ROC) curve analysis revealed that the optimal CPA diagnostic cut-off of Aspergillus-specific IgG, IgA and IgM assays and GM test were 89.3 AU/mL, 8.2 U/mL, 73.3 AU/mL and 0.5μg/L, respectively. The serum levels of Aspergillus-specific IgG and IgA in CPA patients were higher than these in non-CPA patients or healthy persons. The sensitivities and specificities of Aspergillus-specific IgG, IgA, IgM tests and GM test were 78.6 and 94.4%, 64.3 and 89.4%, 50.0 and 53.7% and 71.4 and 58.1%, respectively.ConclusionsThe sensitivity and specificity of serum Aspergillus-specific IgG assay are satisfactory for diagnosing CPA, while the performance of Aspergillus-specific IgA assay is moderate. Aspergillus-specific IgM assay and serum GM test have limited value for CPA diagnosis.Trial registrationNCT03027089 . Registered 20 January 2017.

Project description:Both IgA and IgG antibodies are known to play important roles in protection against influenza virus infection. While IgG is the major isotype induced systemically, IgA is predominant in mucosal tissues, including the upper respiratory tract. Although IgA antibodies are believed to have unique advantages in mucosal immunity, information on direct comparisons of the in vitro antiviral activities of IgA and IgG antibodies recognizing the same epitope is limited. In this study, we demonstrate differences in antiviral activities between these isotypes using monoclonal IgA and IgG antibodies obtained from hybridomas of the same origin. Polymeric IgA-producing hybridoma cells were successfully subcloned from those originally producing monoclonal antibody S139/1, a hemaggulutinin (HA)-specific IgG that was generated against an influenza A virus strain of the H3 subtype but had cross-neutralizing activities against the H1, H2, H13, and H16 subtypes. These monoclonal S139/1 IgA and IgG antibodies were assumed to recognize the same epitope and thus used to compare their antiviral activities. We found that both S139/1 IgA and IgG antibodies strongly bound to the homologous H3 virus in an enzyme-linked immunosorbent assay, and there were no significant differences in their hemagglutination-inhibiting and neutralizing activities against the H3 virus. In contrast, S139/1 IgA showed remarkably higher cross-binding to and antiviral activities against H1, H2, and H13 viruses than S139/1 IgG. It was also noted that S139/1 IgA, but not IgG, drastically suppressed the extracellular release of the viruses from infected cells. Electron microscopy revealed that S139/1 IgA deposited newly produced viral particles on the cell surface, most likely by tethering the particles. These results suggest that anti-HA IgA has greater potential to prevent influenza A virus infection than IgG antibodies, likely due to increased avidity conferred by its multivalency, and that this advantage may be particularly important for heterosubtypic immunity.

Dataset Information

IgM, IgG, and IgA Influenza-Specific Plasma Cells Express Divergent Transcriptomes.

Publications

IgM, IgG, and IgA Influenza-Specific Plasma Cells Express Divergent Transcriptomes.

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