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首页> 美国卫生研究院文献>Clinical and Developmental Immunology >Celiac Disease in Children Particularly with Accompanying Type 1 Diabetes Is Characterized by Substantial Changes in the Blood Cytokine Balance Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa
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Celiac Disease in Children Particularly with Accompanying Type 1 Diabetes Is Characterized by Substantial Changes in the Blood Cytokine Balance Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa

机译：儿童尤其是伴有1型糖尿病的儿童腹腔疾病的特征在于血细胞因子平衡的实质性变化这可能反映了小肠粘膜的炎症过程

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Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.
机译：细胞因子在维持肠道稳态中起着关键作用，在腹腔疾病（CD）和1型糖尿病（T1D）中，诱导肠道内稳态的促炎症反应或消炎反应和粘膜屏障功能。我们旨在比较无T1D和并存T1D的CD患者中促炎和抗炎细胞因子的水平，并评估其与肠病毒（EV），调节性T细胞（Tregs）和树突状细胞的存在的相关性（ DCs）在小肠粘膜中。总共研究了72例行小肠活检的患者（中位年龄10.1岁）。研究组包括24例CD患者（中位年龄为6.5岁），9例CD患者和伴随的T1D患者（中位年龄为7.0岁），2例T1D患者（中位年龄为8.5岁）和37例患者（中位年龄为14.0岁）患有功能性胃肠疾病（FGD）和正常的小肠粘膜作为对照。血清中33种细胞因子的水平是使用Milliplex®MAP磁珠测定法通过多次分析测量的。如我们先前的研究所述，通过免疫组织化学评估了FOXP3 + Treg，CD11c + DC，吲哚胺2,3-二加氧酶+（IDO +）DC，Langerin +（CD207 +）DC和EV的密度。使用ELISA评估循环的抗EV IgA和IgG。该研究最重要的发现是血清IL-5，IL-8，IL-13，IL-15，IL-17F，IL-22，IL-27，IP-10，MIP-与对照组相比，CD患者中的1β，sIL-2Rα，sTNFRII和TNFα及其与小肠粘膜损害程度的相关性根据Marsh分类进行了分级。在所有研究组中，女性的瘦素水平较高。 IL-2，IL-6，IL-12（P70），IL-15，IP-10和IFNγ的水平与小肠粘膜固有层中FOXP3 + Treg的密度显着相关，这支持了有关这些细胞因子在FOXP3 + Tregs外周维持中的信号传导作用。同时，在对照组中，IL-4水平与FOXP3 + Treg的密度之间存在显着的负相关。我们研究的另一个重要发现是IL-17F，IP-10，sTNFRII，MCP-1和GM-CSF与小肠粘膜固有层中EV阳性细胞密度的相关性。 MIP-1（CCL-4）与CD103 + DC和Langerin + DC密度的相关性可能表明它们在将免疫细胞募集到固有层中和驱动CD患者的炎症反应中具有重要意义。我们的结果表明，在CD和T1D患者中，Th1和Th17免疫反应优于EV VP1蛋白。 CD患者中Th2细胞因子（如IL-5和IL-13，而非IL-4）的显着升高及其与小肠粘膜损害程度的相关性可能反映了这些细胞因子在肠道防御和炎症中的作用。

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