Innate modulation of autoimmune, regulatory, and effector B cells in adipose tissue

肥胖是一种严重的全球流行病，是可预防死亡的主要原因，也是健康状况飙升的原因 护理费用。目前，超过三分之二的美国成年人超重，至少有三分之一的人被认为是超重。 肥胖越来越多的人认识到，肥胖与内脏脂肪组织中的慢性、低度炎症有关。 组织和相关的代谢异常谱，包括胰岛素抵抗，脂肪肝疾病， 和2型糖尿病（T2 D）以及相关病症如心脏病、哮喘、癌症和中风。 为了帮助控制这种流行病，了解调节免疫系统的关键免疫细胞的特定作用至关重要。 或加重肥胖患者的炎症和代谢疾病。 虽然存在于瘦脂肪组织中的许多B细胞是产生IL-10的B调节细胞（布雷格），但B细胞是产生IL-10的调节细胞。 肥胖小鼠脂肪组织中的细胞数量增加，可能在慢性炎症中起作用 肥胖内脏脂肪组织（VAT）的特征。B细胞抗原呈递的联合改变， 在小鼠肥胖和人类T2 D期间，细胞因子谱和抗体库可能有助于代谢 疾病通过支持T细胞介导的炎症和胰岛素抵抗;然而，VAT B细胞的原因 肥胖或T2 D期间的失调仍然未知。iNKT细胞也占健康人T细胞的10-20%。 脂肪组织，但这一比例在肥胖小鼠和人类中降低。剩余iNKT细胞的活化 通过糖脂激动剂，α-半乳糖神经酰胺（α-GalCer），减少了许多炎症症状， 肥胖，这表明它们的损失是另一个重要的贡献者失调的免疫环境明显 肥胖或相关的自身免疫性或炎症性疾病。 我们已经证明，α GalCer激活的鼠iNKT细胞直接与脾B细胞相互作用， 抗原特异性IgG和扩增IL-10+布雷格细胞。有趣的是，我们还看到激活的iNKT细胞可以介导 VAT中IL-10+布雷格细胞的类似增加，表明它们在维持脂肪稳态中起关键作用。 在相关的慢性炎症小鼠模型中，我们发现iNKT细胞也可以被中性粒细胞许可， 调节脾中自身反应性B细胞，但中性粒细胞对iNKT细胞及其下游的影响 对脂肪组织中的B细胞的影响尚未得到表征。我们假设早期中性粒细胞 流入培养肥胖小鼠脂肪组织中的iNKT细胞，以驱动从布雷格到B效应细胞的致病性转变。 iNKT细胞活化也可以部分通过重建健康的代谢系统来减少肥胖期间的代谢疾病。 调节性B细胞群。这些研究将加深我们对关键调节免疫细胞的理解 在健康和慢性炎症性肥胖脂肪组织中的人群中， 炎症性疾病和相关病症，如T2 D、癌症和中风。

Obesity is a critical global epidemic, a leading cause of preventable death, and a source of skyrocketing health care costs. Currently more than two thirds of US adults are overweight and at least one third are considered obese. It is increasingly appreciated that obesity is linked to chronic, low-grade inflammation in visceral adipose tissue and an associated spectrum of metabolic abnormalities including insulin resistance, fatty liver disease, and type-2 diabetes (T2D) in addition to related conditions such as heart disease, asthma, cancer, and stroke. To help control this epidemic, it will be critical to understand the specific roles of key immune cells which regulate or exacerbate inflammation and metabolic disease in obese patients. While many of the B cells resident in lean adipose tissue are IL-10-producing B regulatory cells (Breg), B cell numbers increase in adipose tissue of obese mice and may play a role in the chronic inflammation characteristic of obese visceral adipose tissue (VAT). Combined alterations in B cell antigen presentation, cytokine profile, and antibody repertoire during obesity in mice and T2D in humans likely contributes to metabolic disease by supporting T cell mediated-inflammation and insulin resistance; however, the cause of VAT B cell dysregulation during obesity or T2D remains unknown. iNKT cells also make up 10-20% of T cells in healthy adipose tissue but this proportion is reduced in obese mice and humans. Activation of the remaining iNKT cells by the glycolipid agonist, αGalactosylceramide (αGalCer), reduces many of the inflammatory symptoms of obesity, suggesting their loss is another important contributor to the dysregulated immune environment evident during obesity or related autoimmune or inflammatory diseases. We have shown that αGalCer-activated murine iNKT cells directly interact with splenic B cells to produce antigen-specific IgG and expand IL-10+ Breg cells. Interestingly, we also see that activated iNKT cells can mediate a similar increase in IL-10+ Breg cells in VAT, suggesting they play a key role in maintaining adipose homeostasis. In a related murine model of chronic inflammation, we find that iNKT cells can also be licensed by neutrophils to regulate autoreactive B cells in spleen, but the influence of neutrophils on iNKT cells and their downstream effects on B cells in adipose tissue remains as yet uncharacterized. We hypothesize that an early neutrophil influx educates iNKT cells in adipose tissue of obese mice to drive a pathogenic shift from Breg to B effector cells. iNKT cell activation may also reduce metabolic disease during obesity in part by re-establishing a healthy regulatory B cell population. These studies will enhance our understanding of key regulatory immune cell populations in healthy and chronically inflamed obese adipose tissue with implications for many other inflammatory diseases and related conditions such as T2D, cancer, and stroke.