Ikaros regulates B-cell tolerance

Abstract B-cell development and activation are tightly regulated at multiple steps to ensure a protective immune response, and at the same time avoiding harmful self-reactivity and autoimmunity. Ikaros is a transcription factor that is critical for B-cell development, as demonstrated by the complete lack of B-cells in Ikaros-null mice. Furthermore, Ikaros is shown to play important roles also at later stages of B-cell development, but the precise roles of Ikaros at different stages of B-cell development is still not fully understood. In recent years, Ikaros (encoded by the IKZF1 gene) has been linked to autoimmune disease in humans through both genome-wide association studies (GWAS) as well as recent reports of germline IKZF1 mutations in patients with autoimmune disease. However, the mechanisms underlying altered Ikaros function and the development of autoimmunity are not known. We previously developed Ikaros-mutant mouse models with targeted deletions of the exons encoding the DNA-binding zinc finger 1 (ZnF1) or ZnF4, and found that both mutants have B cells, but display selective partial defects at different stages of B-cell development. We recently found that the Ikzf1-ZnF4-mutant strain displays very high levels of serum Anti-Nuclear Antibodies (ANA) at young age, a hallmark of autoimmune disease. This indicates that Ikaros (and specifically exon 6 encoding ZnF4) is required to regulate B-cell tolerance, and we hypothesize that Ikaros regulates this, at least in part, by establishing a chromatin structure that sets restrictions on B-cell responses to limit autoreactive B cells. We are using our Ikaros-mutant mice to further study the role of Ikaros in B-cell development and tolerance, and will present our results to-date at the meeting.