| First Author | Ferri DM | Year | 2023 |
| Journal | Arthritis Rheumatol | Volume | 75 |
| Issue | 9 | Pages | 1542-1555 |
| PubMed ID | 36807718 | Mgi Jnum | J:359952 |
| Mgi Id | MGI:7788488 | Doi | 10.1002/art.42482 |
| Citation | Ferri DM, et al. (2023) Elevated Levels of Interferon-alpha Act Directly on B Cells to Breach Multiple Tolerance Mechanisms Promoting Autoantibody Production. Arthritis Rheumatol 75(9):1542-1555 |
| abstractText | OBJECTIVE: Elevated levels of serum interferon-alpha (IFNalpha) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNalpha levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNalpha on B cells. METHODS: Two classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNalpha to mimic the sustained elevations of IFNalpha seen in SLE. The role of B cell IFNalpha signaling, T cells, and Myd88 signaling was determined using B cell-specific IFNalpha receptor-knockout, CD4+ T cell-depleted, or Myd88-knockout mice, respectively. Flow cytometry, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNalpha on the immunologic phenotype. RESULTS: Elevation of serum IFNalpha disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNalpha receptor. Many of the IFNalpha-mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNalpha acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells. CONCLUSION: The results provide evidence that elevated IFNalpha levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE. |
