The Role of the DNA Sensor AIM2 in B Cell Fate and Function After HCT
Fahmin Basher
MD, PhDDuke University Medical Center
Project Term: July 1, 2024 - June 30, 2027
Altered B cell homeostasis plays a key role in the development of chronic graft-vs-host-disease (cGVHD) after hematopoietic stem cell transplantation (HCT). We hypothesize that the DNA sensor AIM2 plays a critical role in the fate of BCR-activated B cells after HCT. We will utilize novel mouse models to investigate AIM2-BCR modulation with clear translational implications in autoreactivity perpetuating cGVHD as well as functional humoral deficiency and vaccine hyporesponsiveness after HCT.
Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for a number of hematologic malignancies. The success of HCT primarily stems from the graft-versus-leukemia or graft-versus-tumor effects resulting from the genetic disparity between donor and recipient. However, long-term survival after HCT is limited by the development of graft-versus-host disease (GVHD), which is the most significant cause of non-relapse morbidity and mortality after HCT. Chronic GVHD (cGVHD) is a complex multisystem disease characterized by immune dysregulation leading to features that resemble autoimmune diseases. Our lab has demonstrated that the genesis and perpetuation of cGVHD is also driven at least in part by B cells, which are the immune cells responsible for antibody production. Patients with cGVHD exhibit delayed recovery of B cells after the immune system is reconstituting post HCT, and certain subsets of these B cells remain highly activated and are more prone to target the recipient (“self”) and produce pathogenic antibodies that ultimately result in the autoimmune-like manifestations of cGVHD. Despite having highly activated B cells, patients after HCT often are not able to mount sufficient immune responses against pathogens and after vaccination, as these B cells are functionally compromised. Our lab recently performed analyses of B cells in the peripheral blood of patients with and without cGVHD in order to identify genes upregulated in specific B cell subsets. As part of this analysis, we identified the DNA sensor AIM2 to be highly upregulated in an activated B cell subset in patients with cGVHD. Our preliminary studies in mouse models of global AIM2 deficiency have demonstrated that AIM2 restrains B cell survival and antibody production after immunization. The goal of this proposal is to further delineate the role of AIM2 specifically in B cells by using novel mouse models we have recently created with lack of AIM2 expression or with constitutive AIM2 expression. We will investigate immune responses and antibody production after HCT and in the development of cGVHD in established murine models. This work will have significant implications in targeting B cell pathways to enhance vaccine responses after HCT and to eradicate potentially autoreactive B cells that arise after HCT and perpetuate cGVHD.