Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark.
PLoS One. 2009 Nov 12;4(11):e7794. doi: 10.1371/journal.pone.0007794.
Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants.
METHODOLOGY/PRINCIPAL FINDINGS: By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes.
CONCLUSIONS/SIGNIFICANCE: These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing.
在患有与疾病相关的 CARD15（半胱氨酸天冬氨酸蛋白酶激活和募集域 15）基因突变的克罗恩病（CD）患者中，对 muramyl dipeptide（MDP）的感应受损。动物研究表明，正常的 CARD15 信号传导可预防炎症性肠病，并且可能对 CD 中的疾病发展很重要。但是，只有一小部分 CD 患者携带与疾病相关的 CARD15 变体。因此，本研究旨在调查在没有与疾病相关的 CARD15 变体的 CD 患者中是否可以发现 CARD15 信号传导的变化。
方法/主要发现：通过对处于缓解期且未接受免疫抑制剂治疗的 CD 患者外周血单核细胞中 MDP 反应进行作图，发现与对照单核细胞相比，无疾病相关 CARD15 变体的 CD 患者对 MDP 的反应受损。这种损伤伴随着 IkappaB 激酶 alpha/beta（IKKalpha/beta）的活化减少，这是核因子 kappaB（NFkappaB）途径的初始步骤，而丝裂原激活的蛋白（MAP）-激酶的激活不受影响。MDP 还可刺激炎症小体，这对细胞因子的加工很重要。炎症小体在 CD 中持续激活，但在 CD 和对照单核细胞中对 MDP 均无反应。
结论/意义：这些结果表明，在不携带疾病相关 CARD15 变体的 CD 患者中，受抑制的 MDP 依赖性途径可能对 CD 的发病机制很重要。这些结果揭示了 CD 患者免疫反应失调，一方面不能感知相关刺激，另一方面又具有组成性激活的细胞因子加工。
