MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION
MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION
复制标题
MO064组织驻留 B 细胞通过协调巨噬细胞极化来确定尿路感染的易感性
DOI：
10.1093/ndt/gfaa140.mo064
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发表时间：
2020
影响因子：
6.1
通讯作者：
Clatworthy M
中科院分区：
文献类型：
--
作者：
Clatworthy M
背景尿路感染（UTI）是临床上的一个重要问题。超过一半的女性和十分之一的男性在其一生中会受到影响。其中许多影响下尿路，但复发性肾盂肾炎可导致疤痕和慢性肾脏疾病。越来越多的人认识到，组织驻留免疫细胞，如巨噬细胞，在防御感染中发挥重要作用，但在这种情况下，对B淋巴细胞知之甚少。在此，我们试图解决B细胞是否以稳态存在于肾脏和膀胱中的问题，并确定它们的表型和对局部器官免疫的贡献。方法和结果使用静脉内标记和联体共生，我们鉴定了一群真正的自我更新的、组织驻留的B细胞，其包括非幼稚的和先天样的CD 5 + B-1细胞，在小鼠肾脏和膀胱中（但也在肝脏和肺中）。这种B细胞亚群的大小和表型受到遗传背景、年龄和微生物组的影响，与宠物商店小鼠共养后明显扩大了种群。虽然肾脏B细胞的免疫组化谱比血液少，但它们的接种在很大程度上不依赖于它们的B细胞受体特异性。在人类肾脏中，我们发现与血液和脾脏相比，非幼稚B细胞的富集相似。我们使用两种具有较高（PI 3 K δ E1020 K-B）或较低（μMT-）组织驻留B细胞数量的转基因小鼠，测试这些细胞在UTI期间的功能。令人惊讶的是，组织驻留B细胞的数量与细菌清除率呈负相关。我们发现这些B细胞与肾脏巨噬细胞在空间上共定位，并使其极化偏向抗炎M2表型，导致抗微生物反应降低。结论总之，我们的数据确定了组织驻留B细胞在调节泌尿道局部免疫，确定驻留和招募的髓系细胞的炎症“设定点”中的关键作用，对B细胞耗竭疗法和感染，移植排斥，纤维化或自身免疫。图形摘要
BackgroundUrinary tract infection (UTI) is an important clinical problem. More than half of women and 1 in 10 men will be affected during their lifetime. Many of these affect the lower urinary tract but recurrent pyelonephritis can lead to scarring and chronic kidney disease. There is an increasing appreciation that tissue-resident immune cells, such as macrophages, play an important role in defence against infection, but only little is known about B lymphocytes in this context. Here we sought to address the question of whether B cells reside in the kidney and bladder in homeostasis and to determine their phenotype and contribution to local organ immunity.Methods and ResultsUsing intravenous labelling and parabiosis, we identified a population of bona-fide self-renewing, tissue-resident B cells that included non-naïve and innate-like CD5+ B-1 cells, in murine kidneys and urinary bladder (but also in liver and lung). The size and phenotype of this B cell subset was influenced by genetic background, age, and microbiome, with an expanded population evident after co-housing with pet-store mice. Although kidney B cells had less diverseIghrepertoire compared to blood, their seeding was largely independent of their B-cell receptor specificity. In human kidneys we found a similar enrichment for non-naïve B cells compared to blood and spleen.Using two strains of genetically modified mice with higher (PI3KδE1020K-B) or lower (μMT-) numbers of tissue-resident B cells, we tested the function of these cells during UTI. Surprisingly, the number of tissue-resident B cells inversely correlated with bacterial clearance. We found that these B cells were spatially co-localised with kidney macrophages and skewed their polarization towards an anti-inflammatory M2 phenotype, leading to reduced anti-microbial responses. This effect was, at least in part, driven via IL-10.ConclusionIn conclusion, our data identify a critical role for tissue-resident B cells in modulating local immunity in the urinary tract, determining the inflammatory ‘set-point’ of resident and recruited myeloid cells, with important clinical implications for the use of B-cell depleting therapies and conditions such as infection, transplant rejection, fibrosis or autoimmunity.Graphical Abstract