An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.
An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.
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DOI：
10.1111/acel.12114
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发表时间：
2013-10
期刊：
影响因子：
7.8
通讯作者：
Lord JM
中科院分区：
文献类型：
--
作者：
Duggal NA;Upton J;Phillips AC;Sapey E;Lord JM
自身免疫力随着年龄的增长而增加，表明免疫耐受性降低，但涉及的机制尚不清楚。近年来，在自身免疫性疾病的小鼠模型中发现了具有免疫调节特性的B细胞亚群，这些细胞通过分泌IL10来下调免疫反应。在人类中，具有CD19+CD24hiCD38hi表型的未成熟过渡性B细胞被报道通过产生IL10来调节免疫反应。我们发现CD19+CD24hiCD38hi细胞在PBMC池中的频率和数量随着年龄的增长而减少。健康老年供者CD19+CD24hiCD38hi B细胞经CD40或Toll样受体激活后IL10的表达和分泌也受到抑制。在研究相关机制时，我们发现CD19+CD24hiCD38hi B细胞的功能受到与年龄相关的T细胞和B细胞的影响：具体地说，CD3刺激后老年供者的CD4T细胞中CD40配体的表达较低，而老年人CD19+CD24hiCD38hi B细胞中通过CD40的信号传递受到损害，证明为磷酸化(Y705)和STAT3的激活减少。然而，CD19+CD24hiCD38hi细胞表面共刺激分子CD80和CD86的表达没有随着年龄的变化而变化，这表明IL10依赖的免疫抑制受到了损害，但接触依赖的抑制能力随着年龄的增长保持不变。最后，我们发现在老年人中CD19+CD24hiCD38hiB细胞IL10的产生与自身抗体(类风湿因子)水平呈负相关。因此，我们认为与年龄相关的CD19+CD24hiCD38hi B细胞数量和功能的下降可能是导致自身免疫增强和免疫耐受性降低的原因之一。
Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19+CD24hiCD38hi phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19+CD24hiCD38hi cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19+CD24hiCD38hi B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19+CD24hiCD38hi B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19+CD24hiCD38hi B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19+CD24hiCD38hi cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19+CD24hiCD38hi B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19+CD24hiCD38hi B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging.
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DOI：
10.4049/jimmunol.0803052
发表时间：
2009-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Blair PA;Chavez-Rueda KA;Evans JG;Shlomchik MJ;Eddaoudi A;Isenberg DA;Ehrenstein MR;Mauri C
通讯作者：
Mauri C
免疫调节配体的B7家族。
影响因子：
12.3
作者：
Collins, Mary;Ling, Vincent;Carreno, Beatriz M
通讯作者：
Carreno, Beatriz M
影响因子：
32.4
作者：
Neves, Patricia;Lampropoulou, Vicky;Fillatreau, Simon
通讯作者：
Fillatreau, Simon
影响因子：
5.3
作者：
Leng, QB;Bentwich, Z;Borkow, G
通讯作者：
Borkow, G
影响因子：
4.4
作者：
Lampropoulou, Vicky;Hoehlig, Kai;Fillatreau, Simon
通讯作者：
Fillatreau, Simon