Senataxin is required for optimal class switch recombination to the immunoglobulin A isotype

Abstract

Senataxin (SETX) is an RNA/DNA helicase that plays a pivotal role in transcription, R-loop resolution, and the DNA damage response (DDR). Dysfunction of SETX, however, has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis and ataxia with oculomotor apraxia type 2. Importantly, both R-loop resolution and the DDR are essential for class switch recombination (CSR) in B cells, a critical step in generating antibody diversity. Here we demonstrate that ex vivo polyclonal stimulation of SETX+/+ and SETX-/- mouse splenocytes results in equivalent amounts of IgM- and IgG-secreting B cells but significantly fewer IgA-producing B cells in SETX-/- mice. Additionally, SETX-/- mice generate significantly reduced antigen specific IgA titers following infection with influenza A virus. Sequencing of the IgA-secreting B cell repertoire revealed reduced clonal diversity in SETX-/- mice. SETX-/- mice also had increased R-loop formation within the IgA locus. Collectively, these data highlight an important role for SETX in mediating CSR to IgA. As such, a further understanding of SETXs role in the immune response is important for expanding our knowledge of both the general immunobiology relating to CSR as well as the immunological phenotypes associated with neurodegenerative diseases associate with mutations in SETX. One sentence summaryA deficiency in senataxin results in impaired class switching to IgA in vitro with decreased IgA response to infection and IgA repertoire diversity in vivo.