Oral Clarithromycin Enhances Airway Immunoglobulin A (IgA) Immunity through Induction of IgA Class Switching Recombination and B-Cell-Activating Factor of the Tumor Necrosis Factor Family Molecule on Mucosal Dendritic Cells in Mice Infected with Influenza A Virus

Abstract

We previously reported that the macrolide antibiotic clarithromycin (CAM) enhanced the mucosal immune response in pediatric influenza, particularly in children treated with the antiviral neuraminidase inhibitor oseltamivir (OSV) with low production of mucosal antiviral secretory IgA (S-IgA). The aims of the present study were to confirm the effects of CAM on S-IgA immune responses, by using influenza A virus (IAV) H1N1-infected mice treated with or without OSV, and to determine the molecular mechanisms responsible for the induction of mucosal IgA class switching recombination in IAV-infected CAM-treated mice. The anti-IAV S-IgA responses and expression levels of IgA class switching recombination-associated molecules were examined in bronchus-lymphoid tissues and spleens of infected mice. We also assessed neutralization activities of S-IgA against IAV. Data show that CAM enhanced anti-IAV S-IgA induction in the airway of infected mice and restored the attenuated antiviral S-IgA levels in OSV-treated mice to the levels in the vehicle-treated mice. The expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iμ-Cα transcripts on B cells were enhanced by CAM, compared with the levels without CAM treatment, but CAM had no effect on the expression of the BAFF receptor on B cells. Enhancement by CAM of neutralization activities of airway S-IgA against IAV in vitro and reinfected mice was observed. This study identifies that CAM enhances S-IgA production and neutralizing activities through the induction of IgA class switching recombination and upregulation of BAFF molecules in mucosal dendritic cells in IAV-infected mice.

Immunomodulator Clarithromycin Enhances Mucosal and Systemic Immune Responses and Reduces Re-Infection Rate in Pediatric Patients with Influenza Treated with Antiviral Neuraminidase Inhibitors: A Retrospective Analysis

“…Subsequently, IgA-committed B cells migrate to mucosal effector tissues including the nasal passages [26]. We reported recently that CAM enhances IgA class switching recombination through upregulation of BAFF in mucosal dendritic cells and activation-induced cytidine deaminase in B cells [14]. The present clinical results add support to these early studies.…”

“…Of interest, we have also reported that 75% of patients treated with the combination of CAM and OSV show increases in S-IgA production to levels similar to those seen in patients treated with CAM alone and untreated patients. In addition, we recently determined the molecular mechanisms responsible for the enhanced induction of mucosal IgA class switching recombination in CAM-treated mice [14]. The obtained data indicated that CAM significantly enhances the expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iμ-Cα transcripts on B cells [14].…”

“…In addition, we recently determined the molecular mechanisms responsible for the enhanced induction of mucosal IgA class switching recombination in CAM-treated mice [14]. The obtained data indicated that CAM significantly enhances the expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iμ-Cα transcripts on B cells [14]. The results indicated that CAM enhances S-IgA production through the induction of IgA class switching recombination in IAV-infected mice.…”

Anti-Influenza Activity of C60 Fullerene Derivatives

“…After incubation, the cells were fixed with 4% paraformaldehyde in phosphate-buffered saline (-) for 30 min at 4°C and then permeabilized with 0.3% Triton X-100 for 20 min at room temperature. A mouse anti-influenza A NP antibody (FluA-NP 4F1; SouthernBiotech, Birmingham, AL, USA) and horseradish peroxidase-conjugated goat anti-mouse IgG antibody (SouthernBiotech) were used as primary and secondary antibodies, respectively [44]. To visualize the infected cells, TrueBlue peroxidase substrate (KPL, Gaithersburg, MD, USA) was added, and color development was terminated after 15 min of incubation by washing with H 2 O.…”

Secretory IgA in Mucosa of Pharynx and Larynx Plays an Important Role against Influenza A Virus Infection in Kidney Yang Deficiency Syndrome Model

“…In order to collect bronchoalveolar lavage fluids (BALF) and tracheal lavage fluids (TLF), these animals were divided into six groups: normal control group-intubation (NC-I), normal control group-nasal drop (NC-D), normal intubation (NI) group, normal nasal drop (ND) group, model intubation (MI) group, and model nasal drop (MD) group. On the 14 th day, tracheal lavage fluids and bronchoalveolar fluids of 5-7 animals in each group were collected and subjected to the enzyme-linked immunosorbent assay (ELISA) to determine secretory IgA[29,30].…”