Obesity accelerates age defects in human B cells and induces autoimmunity

衰老与B细胞功能低下和保护性抗体的产生减少有关，两者都 全身性和B细胞内源性炎症起作用。衰老也与增加的产量有关 自身免疫抗体。我们在老鼠身上的研究表明，脂肪组织(AT)，它的大小增加 随着年龄的增长，导致全身性和B细胞内源性炎症，B细胞反应减少和分泌 自身免疫抗体，其特异性尚不清楚。在这笔赠款中，我们建议确认和延长 在人类中，我们在小鼠身上获得的结果，并确定了几种未被研究的机制，通过这些机制 肥胖加速和/或加剧对人类B细胞的年龄效应，并诱导分泌 自身抗体。我们假设1)肥胖相关的慢性炎症是B的主要贡献者 细胞缺陷/抑制体液免疫反应，加速/加剧B细胞中与年龄相关的缺陷； 2)AT参与了以分泌促炎因子为特征的致病性B细胞的产生 介质和自身免疫抗体；3)已识别的炎症分子/途径可能被作为靶点 至少在体外减少致病的B细胞。 在目标1中，我们将确定促炎和抗炎免疫细胞是如何在 皮下脂肪组织(SAT)和内脏脂肪组织(VAT)(和血液中的对照) 不同年龄的个体，以及对此做出贡献的细胞和分子途径。在《目标2》中我们将 评估SAT和VAT在诱导致病/自身免疫B细胞中的作用。我们将衡量 与血液相比，AT中B细胞抗体的分泌和自身免疫特异性 作为释放自身抗原和诱导自身抗体产生的可能机制的细胞毒性；自身抗原 巨噬细胞/NKT细胞对B细胞的呈递。在目标3中，我们将针对炎症分子/途径 目的是至少在体外减少局部炎症和B细胞的致病功能。这个 建议的治疗/机制将为未来的转化/临床研究提供坚实的经验基础。

Aging is associated with poor B cell function and decreased production of protective antibodies to which both systemic and B cell intrinsic inflammation contribute. Aging is also associated with increased production of autoimmune antibodies. Our studies in mice have shown that the adipose tissue (AT), which increases in size with aging, contributes to systemic and B cell intrinsic inflammation, reduced B cell responses and secretion of autoimmune antibodies, the specificity of which is unknown. In this grant we propose toconfirm and extend inhumans our results obtained in miceand identify several uninvestigated mechanisms through which obesity accelerates and/or exacerbates age effects on human B cells and induces the secretion of autoantibodies. We hypothesize that 1) obesity-associated chronic inflammation is a major contributor to B cell defects/depressed humoral immune responses and accelerates/exacerbates age-related defects in B cells; 2) the AT contributes to the generation of pathogenic B cells characterized by the secretion of pro-inflammatory mediators and autoimmune antibodies; 3) identified inflammatory molecules/pathways may be targeted to reduce pathogenic B cells at least in vitro. In Aim 1 we will determine how pro- and anti-inflammatory immune cells are generated in the subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (and in the blood as control) of individuals of different ages, and the cellular and molecular pathways which contribute to this. In Aim 2 we will evaluate the effects of SAT and VAT in the induction of pathogenic/autoimmune B cells. We will measure secretion and autoimmune specificity of antibodies by B cells from the AT as compared to the blood; NK cytotoxicity as a possible mechanism to release autoantigens and induce autoantibody production; autoantigen presentation to B cells by macrophages/NKT cells. In Aim 3 we will target inflammatory molecules/pathways with the goal of reducing local inflammation and the pathogenic function of B cells at least in vitro. The proposed treatments/mechanisms will offer a solid empirical basis for future translational/clinical studies.