Department of Gastroenterology, Oslo University Hospital-Ullevål, Oslo, Norway.
Am J Gastroenterol. 2013 May;108(5):842-50. doi: 10.1038/ajg.2013.91. Epub 2013 Apr 16.
In celiac disease (CD), gluten induces both adaptive and innate immune responses. Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the immune response is less characterized. The aim of our study was to explore and compare the early mucosal immunological events in CD and NCGS.
We challenged 30 HLA-DQ2(+) NCGS and 15 CD patients, all on a gluten-free diet, with four slices of gluten-containing bread daily for 3 days. Duodenal biopsy specimens were collected before and after challenge. The specimens were examined for cytokine mRNA by quantitative reverse transcriptase-PCR and for MxA-expression and CD3(+) intraepithelial lymphocytes (IELs) by immunohistochemistry and compared with specimens from untreated CD patients and disease controls.
In CD patients, tumor necrosis factor alpha (P=0.02) and interleukin 8 (P=0.002) mRNA increased after in vivo gluten challenge. The interferon gamma (IFN-γ) level of treated CD patients was high both before and after challenge and did not increase significantly (P=0.06). Four IFN-γ-related genes increased significantly. Treated and untreated CD patients had comparable levels of IFN-γ. Increased expression of MxA in treated CD patients after challenge suggested that IFN-α was activated on gluten challenge. In NCGS patients only IFN-γ increased significantly (P=0.03). mRNA for heat shock protein (Hsp) 27 or Hsp70 did not change in any of the groups. Importantly, we found that the density of IELs was higher in NCGS patients compared with disease controls, independent of challenge, although lower than the level for treated CD patients.
CD patients mounted a concomitant innate and adaptive immune response to gluten challenge. NCGS patients had increased density of intraepithelial CD3(+) T cells before challenge compared with disease controls and increased IFN-γ mRNA after challenge. Our results warrant further search for the pathogenic mechanisms for NCGS.
在乳糜泻（CD）中，麸质会引起适应性和固有免疫反应。非乳糜泻麸质敏感性（NCGS）是另一种形式的麸质不耐受，其免疫反应特征不那么明显。我们研究的目的是探索和比较 CD 和 NCGS 中的早期黏膜免疫事件。
我们用含有麸质的面包片每天给 30 名 HLA-DQ2(+) NCGS 和 15 名 CD 患者进行 3 天的挑战，每位患者每天吃 4 片。在挑战前后采集十二指肠活检标本。通过定量逆转录酶 PCR 检测细胞因子 mRNA，通过免疫组织化学检测 MxA 表达和 CD3(+)上皮内淋巴细胞（IEL），并与未经治疗的 CD 患者和疾病对照组的标本进行比较。
在 CD 患者中，肿瘤坏死因子-α（P=0.02）和白细胞介素 8（P=0.002）mRNA 在体内麸质挑战后增加。治疗后的 CD 患者的干扰素 γ（IFN-γ）水平在挑战前后均较高，且无显著增加（P=0.06）。4 种 IFN-γ 相关基因显著增加。治疗和未经治疗的 CD 患者的 IFN-γ 水平相当。治疗后的 CD 患者在挑战后 MxA 的表达增加表明 IFN-α 在麸质挑战时被激活。在 NCGS 患者中，只有 IFN-γ 显著增加（P=0.03）。各组中热休克蛋白（Hsp）27 或 Hsp70 的 mRNA 均无变化。重要的是，我们发现，与疾病对照组相比，NCGS 患者的 IEL 密度在未经挑战时就较高，尽管低于治疗后的 CD 患者。
CD 患者对麸质挑战产生了同时的固有和适应性免疫反应。NCGS 患者在挑战前与疾病对照组相比，上皮内 CD3(+) T 细胞密度较高，在挑战后 IFN-γ mRNA 增加。我们的结果证明需要进一步研究 NCGS 的致病机制。
