Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Department of Microbiology and Immunology, Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven, University of Leuven, Leuven, Belgium.
Clin Transl Gastroenterol. 2018 Nov 19;9(11):208. doi: 10.1038/s41424-018-0076-6.
Achalasia is a primary esophageal motility disorder resulting from selective loss of inhibitory neurons in the esophageal myenteric plexus, likely due to an autoimmune response with involvement of the adaptive immune system. Innate immune processes of the host constitute the bridge between environmental etiological factors and the adaptive immune system. Although these remain poorly investigated, they might be of diagnostic and therapeutic relevance. In view of the role of extracellular proteolysis in organ-specific autoimmunity, we studied gelatinases of the matrix metalloproteinase (MMP) family in achalasia patients.
The presence of MMP-2 and MMP-9 proteoforms was analyzed in sera of two cohorts of achalasia patients. Additionally, with the use of immunohistopathological analysis, in situ MMP-2 and MMP-9 expression was investigated. Finally, we tested the paradigm of remnant epitopes generating autoimmunity (REGA) for achalasia-associated autoantigens by evaluating whether autoantigenic proteins are cleaved by MMP-9 into remnant epitopes.
We showed significantly increased ratios of MMP-9/MMP-2 and activated MMP-9/proMMP-9 in sera of achalasia patients (n = 88) versus controls (n = 60). MMP-9-positive and MMP-2-positive cells were more abundant in achalasia (n = 49) versus control biopsies from transplant donors (n = 10). Furthermore, extensive damage within the plexus was found in the tissues with more MMP-9-positive cells. Additionally, we documented achalasia-associated autoantigens PNMA2, Ri, GAD65, and VIP as novel MMP-9 substrates.
We provide new biomarkers and insights into innate immune mechanisms in the autoimmune pathology of achalasia. Our results imply that extracellular protease inhibition is worthwhile to test as therapeutic intervention in achalasia.
贲门失弛缓症是一种原发性食管运动障碍，由食管肌间神经丛抑制性神经元选择性缺失引起，可能是适应性免疫系统参与的自身免疫反应所致。宿主的固有免疫过程构成了环境病因与适应性免疫系统之间的桥梁。尽管这些过程仍未得到充分研究，但它们可能具有诊断和治疗意义。鉴于细胞外蛋白水解在器官特异性自身免疫中的作用，我们研究了贲门失弛缓症患者基质金属蛋白酶（MMP）家族中的明胶酶。
分析了两批贲门失弛缓症患者血清中 MMP-2 和 MMP-9 蛋白的存在。此外，通过免疫组织病理学分析，研究了 MMP-2 和 MMP-9 的原位表达。最后，我们通过评估自身抗原是否被 MMP-9 切割成残余表位来测试与贲门失弛缓症相关的自身抗原产生自身免疫的残余表位生成自身免疫（REGA）范例。
与对照组（n=60）相比，贲门失弛缓症患者（n=88）血清中 MMP-9/MMP-2 和激活 MMP-9/proMMP-9 的比值显著升高。与对照组移植供体活检组织（n=10）相比，贲门失弛缓症活检组织中 MMP-9 阳性和 MMP-2 阳性细胞更丰富（n=49）。此外，在 MMP-9 阳性细胞较多的组织中发现了丛内广泛的损伤。此外，我们还证明了 PNMA2、Ri、GAD65 和 VIP 等贲门失弛缓症相关自身抗原是新型 MMP-9 底物。
我们提供了新的生物标志物，并深入了解了贲门失弛缓症自身免疫病理学中的固有免疫机制。我们的研究结果表明，细胞外蛋白酶抑制作为贲门失弛缓症的治疗干预措施值得进一步研究。
