Faculty of Natural Sciences, Lausitz University of Applied Sciences, Senftenberg, Germany.
Adv Clin Chem. 2013;60:187-208. doi: 10.1016/b978-0-12-407681-5.00006-4.
The pathogenesis of Crohn's disease (CrD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBD), remains poorly understood. Autoimmunity is considered to be involved in the triggering and perpetuation of inflammatory processes leading to overt disease. Approximately 30% of CrD patients and less than 8% of UC patients show evidence of humoral autoimmunity to exocrine pancreas, detected by indirect immunofluorescence. Pancreatic autoantibodies (PAB) were described for the first time in 1984, but the autoantigenic target(s) of PABs were identified only in 2009. Utilizing immunoblotting and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, the major zymogen granule membrane glycoprotein 2 (GP2) has been discovered as the main PAB autoantigen. The expression of GP2 has been demonstrated at the site of intestinal inflammation, explaining the previously unaddressed contradiction of pancreatic autoimmunity and intestinal inflammation. Recent data demonstrate GP2 to be a specific receptor on microfold (M) cells of intestinal Peyer's patches, which are considered to be the original site of inflammation in CrD. Novel ELISAs, employing recombinant GP2 as the solid phase antigen, have confirmed the presence of IgA and IgG anti-GP2 PABs in CrD patients and revealed an association of anti-GP2 IgA as well as IgG levels with a specific clinical phenotype in CrD. Also, GP2 plays an important role in modulating innate and acquired intestinal immunity. Its urinary homologue, Tamm-Horsfall protein or uromodulin, has a similar effect in the urinary tract, further indicating that GP2 is not just an epiphenomenon of intestinal destruction. This review discusses the role of anti-GP2 autoantibodies as novel CrD-specific markers, the quantification of which provides the basis for further stratification of IBD patients. Given the association with a disease phenotype and the immunomodulating properties of GP2 itself, an important role for GP2 in the immunopathogenesis of IBD cannot be excluded.
克罗恩病（CrD）和溃疡性结肠炎（UC）是两种主要的炎症性肠病（IBD），其发病机制仍不清楚。自身免疫被认为参与了导致显性疾病的炎症过程的触发和持续。大约 30%的 CrD 患者和不到 8%的 UC 患者表现出对外分泌胰腺的体液自身免疫的证据，通过间接免疫荧光检测。胰腺自身抗体（PAB）于 1984 年首次被描述，但 PAB 的自身抗原靶标直到 2009 年才被确定。利用免疫印迹和基质辅助激光解吸电离飞行时间质谱，主要酶原颗粒膜糖蛋白 2（GP2）已被发现为主要的 PAB 自身抗原。已经在肠道炎症部位证明了 GP2 的表达，解释了先前未解决的胰腺自身免疫和肠道炎症之间的矛盾。最近的数据表明，GP2 是肠道派尔集合淋巴结的微褶皱（M）细胞上的一种特异性受体，被认为是 CrD 炎症的原始部位。新型 ELISA 采用重组 GP2 作为固相抗原，证实了 CrD 患者存在 IgA 和 IgG 抗-GP2 PAB，并揭示了抗-GP2 IgA 以及 IgG 水平与 CrD 特定临床表型的关联。此外，GP2 在调节先天和获得性肠道免疫中起重要作用。其尿同源物，Tamm-Horsfall 蛋白或尿调蛋白，在泌尿道中也有类似的作用，这进一步表明 GP2 不仅仅是肠道破坏的一种表象。这篇综述讨论了抗-GP2 自身抗体作为新型 CrD 特异性标志物的作用，其定量为进一步分层 IBD 患者提供了基础。鉴于与疾病表型的关联以及 GP2 自身的免疫调节特性，GP2 在 IBD 的免疫发病机制中可能起重要作用。
