Using B cell features to explain heterogeneity in the rate of T1D progression

项目总结/摘要 该网关奖的总体目标是评估B细胞内型，并检查内型如何可能是 与自身抗体阳性个体的T1 D进展相关。重要的是，该奖项将提供 作为早期研究者，PI有机会与1型糖尿病试验网正式合作。 T1 D的自然史是很好理解的，从遗传风险到自身免疫，再到临床疾病， 然后导致贝塔细胞功能进一步丧失然而，这一进程的每一步，以及反应， 疾病修饰免疫疗法的特征在于相当大的异质性。我们自己的很多工作 旨在确定解释这种异质性的免疫标记;我们最近表明， 在B细胞特征增加的年轻受试者中，诊断后疾病进展明显， 这个相同的信号预测了对B细胞靶向药物的反应。总之，这些发现表明，B细胞 在某些T1 D患者中发挥重要作用。我们认为，B细胞的特征可以识别一个 内型或T1 D的潜在疾病机制，其可以选择性地在治疗上靶向，并且 这可以在高危个体中看到，就像在新的发病环境中一样。 尽管有这些发现，但在知识方面仍存在重大差距。首先，是否可以观察到B细胞内型， 诊断解释了从抗体阳性到临床T1 D进展率的异质性？也是未知数 B细胞内型是个体的固定特征还是随着疾病的变化而变化。最后， 目前尚未确定的B细胞亚群，而不是总的人口，机械地解释这些 调查结果。为了解决这些差距，我们建议解决以下假设：B细胞水平和特征 在临床诊断T1 D之前构成稳定的内型，其将与进展为T1 D相关 在携带这种内型的受试者亚组中。

Project Summary / Abstract 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.