Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.
Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.
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抗肿瘤坏死因子治疗失败的溃疡性结肠炎患者的先天免疫失调。
DOI：
10.3748/wjg.v22.i41.9104
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发表时间：
2016-11-07
影响因子：
4.3
通讯作者：
Tulic MK
中科院分区：
文献类型：
--
作者：
Baird AC;Mallon D;Radford-Smith G;Boyer J;Piche T;Prescott SL;Lawrance IC;Tulic MK
探讨抗肿瘤坏死因子（TNF）治疗无效的溃疡性结肠炎（UC）患者的天然免疫功能。通过测量18例炎症性肠病患者抗TNF治疗前和治疗后3个月的外周血单核细胞（PBMC）细胞因子表达，评估抗TNF治疗、炎症和药物对先天免疫功能的影响。在UC“应答者”（n = 12）和“无应答者”（n = 12）中评估TLR刺激后Toll样受体（TLR）表达和细胞因子产生，并与健康对照（n = 12）进行比较。测量血液中的红细胞沉降率（ESR）和C-反应蛋白（CRP）水平，以评估疾病严重程度/活动性和炎症。采用酶联免疫吸附试验测定促炎性（TNF、IL-1β、IL-6）、免疫调节性（IL-10）、Th 1（IL-12、IFNγ）和Th 2（IL-9、IL-13、IL-17 A）细胞因子表达，同时采用FACS评估TLR细胞组成和细胞内信号传导。在抗TNF治疗之前，应答者和非应答者的疾病严重程度和活动水平相似。PBMC对TLR刺激的反应能力不受TNF治疗、患者疾病和炎症的严重程度或其药物使用的影响。在基线时，与应答者相比，无应答者具有升高的先天性免疫应答，但没有获得性免疫应答（P < 0.05）。在TLR刺激后，与健康对照相比，无应答者对所有TLR的先天性细胞因子应答持续降低（P < 0.01），与应答者相比，TNF（P < 0.001）和IL-1β（P < 0.01）产生减少。这种先天性免疫功能障碍与循环浆细胞样树突状细胞（pDC）的数量减少（P < 0.01）但CD 4+调节性T细胞（TCR）的数量增加（P = 0.03）以及TLR-2、TLR-4和TLR-7活化后无应答者中IRAK 4的细胞内积累（P < 0.001）相关。无应答者的先天免疫力降低可能解释了抗TNF治疗的疗效降低。这些血清学标志物可能被证明是有用的，在预测昂贵的抗TNF治疗的结果。
To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC “responders” (n = 12) and “non-responders” (n = 12) and compared to healthy controls (n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC’s ability to respond to TLR stimulation was not affected by TNF therapy, patient’s severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders (P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls (P < 0.01) and diminished TNF (P < 0.001) and IL-1β (P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) (P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) (P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation (P < 0.001). Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.
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DOI：
10.1084/jem.194.6.769
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hawiger D;Inaba K;Dorsett Y;Guo M;Mahnke K;Rivera M;Ravetch JV;Steinman RM;Nussenzweig MC
通讯作者：
Nussenzweig MC
NUR77 通过负向调节 TRAF6/TLR-IL-1R 信号轴发挥针对炎症性肠病的保护作用
影响因子：
7.3
作者：
Wu, Hua;Li, Xiu-Ming;Li, Jian-Ming
通讯作者：
Li, Jian-Ming
DOI：
10.1073/pnas.0308496101
发表时间：
2004-03-09
影响因子：
11.1
作者：
Jiang, ZF;Mak, TW;Li, XX
通讯作者：
Li, XX
影响因子：
5
作者：
De Jager, P. L.;Franchimont, D.;Rioux, J. D.
通讯作者：
Rioux, J. D.
影响因子：
24.5
作者：
Franco Leal, Raquel;Planell, Nuria;Salas, Azucena
通讯作者：
Salas, Azucena