The overall goal for this Gateway Award is to evaluate B cell endotypes and examine how an endotype may be associated with T1D progression in autoantibody-positive individuals. Importantly, this award will provide an opportunity for the PI, as an Early Stage Investigator, to formally collaborate with Type 1 Diabetes TrialNet. The natural history of T1D is well understood, progressing from genetic risk, to autoimmunity, to clinical disease, and then to further ongoing loss of beta cell function. However, each step of this progression, as well as response to disease modifying immune therapy, is characterized by considerable heterogeneity. Much of our own work has aimed to identify immune markers that explain this heterogeneity; we recently showed that more rapid disease progression after diagnosis was evident in younger subjects with an increased B cell signature, and that this same signature predicted response to a B-cell targeting drug. Together, these findings suggest that B cells play an important role in some individuals with T1D. We propose that B cell characteristics may identify an endotype, or underlying disease mechanism of T1D that may be selectively targeted therapeutically, and that this can be seen in at-risk individuals as it was in the new onset setting. Despite these findings, there remain significant gaps in knowledge. First, can B cell endotypes observed after diagnosis explain heterogeneity in rate of progression from antibody positivity to clinical T1D? It is also unknown whether B cell endotypes are fixed characteristics of individuals or change as disease changes. Finally, it is likely that as-yet unidentified subpopulations of B cells, rather than the total population, mechanistically explain these findings. To address these gaps, we propose to address the hypothesis that B cell levels and signatures constitute a stable endotype prior to clinical diagnosis of T1D which will be associated with progression to T1D in the subset of subjects bearing this endotype.
This proposal aims to aide in the understanding of disease etiopathology by helping explain the well-recognized heterogeneity of this disease, and will improve our ability to identify subjects who would respond to anti-B cell therapy. In addition, having previously identified B cell signatures after clinical diagnosis, reproducing these findings in data prior to diagnosis provides assurance of the robustness of the observations and improves the likelihood of use in future prospective clinical studies.
