Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice.
Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice.
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DOI：
10.1111/nmo.12030
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发表时间：
2013-01
影响因子：
3.5
通讯作者：
Lennon VA
中科院分区：
文献类型：
--
作者：
Meeusen JW;Haselkorn KE;Fryer JP;Kryzer TJ;Gibbons SJ;Xiao Y;Lennon VA
自身免疫性胃肠动力障碍（Autoimmune gastrointestinal dysmotility，AGID）是一种有限的自主神经功能障碍。迄今为止，唯一被证实的效应物是含有α3亚基的神经节烟碱乙酰胆碱受体（α3*-nAChR）特异性IgG。用重组α3-多肽免疫家兔产生α3*-nAChR自身抗体，并产生了显著的AGID增强。人和兔α3*-nAChR特异性IgG注射到小鼠体内时诱导一过性运动功能减退。在这里，我们描述了成功和遇到的问题诱导小鼠胃肠动力不足的主动免疫。我们重复注射7种不同品系的易患自身免疫（自发性糖尿病或神经抗原免疫诱导的重症肌无力或脑脊髓炎）的年轻成年小鼠：i）皮内注射α3-多肽，或ii）腹腔内注射表达α3*-nAChR的活异种细胞。我们每月两次检测血清α3*-nAChR-IgG，并最终评估蓝色染料胃肠传输，小肠α3*-nAChR总含量（放射化学）和肌间神经丛神经元数量（化学，回肠-空肠整体标本）。用α3-多肽进行标准皮肤接种具有最低免疫原性，与剂量无关。腹腔内注射的活细胞具有很强的免疫原性。自身反应性α3*-nAChR-IgG仅由啮齿类动物免疫原诱导;小肠传输减慢和肠道α3*-nAChR损失需要高血清水平。神经节细胞未丢失。AGID在小鼠中可通过主动免疫诱导。伴随肠道α3*-nAChR减少而无神经元死亡与IgG介导而非T细胞介导的发病机制一致，接受抗体耗竭治疗的患者症状改善也是如此。
Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia. The only proven effector to date is IgG specific for ganglionic nicotinic-acetylcholine receptors containing α3 subunits (α3*-nAChR). Rabbits immunized with recombinant α3-polypeptide produce α3*-nAChR autoantibodies, and profound AGID ensues. Human and rabbit α3*-nAChR-specific-IgGs induce transient hypomotility when injected into mice. Here we describe success and problems encountered inducing gastrointestinal hypomotility in mice by active immunization. We repeatedly injected young adult mice of seven different strains susceptible to autoimmunity (spontaneous diabetes or neural antigen immunization-induced myasthenia gravis or encephalomyelitis) with: i) α3-polypeptide, intradermally, or ii) live α3*-nAChR-expressing xenogeneic cells, intraperitoneally. We measured serum α3*-nAChR-IgG twice monthly, and terminally assessed blue dye gastrointestinal transit, total small intestinal α3*-nAChR content (radiochemically) and myenteric plexus neuron numbers (immunohistochemically, ileal-jejunal whole-mount preparations). Standard cutaneous inoculation with α3-polypeptide was minimally immunogenic, regardless of dose. Intraperitoneally-injected live cells were potently immunogenic. Self-reactive α3*-nAChR-IgG was induced only by rodent immunogen; small intestinal transit slowing and enteric α3*-nAChR loss required high serum levels. Ganglionic neurons were not lost. AGID is inducible in mice by active immunization. Accompanying enteric α3*-nAChR reduction without neuronal death is consistent with an IgG-mediated rather than T cell-mediated pathogenesis, as is improvement of symptoms in patients receiving antibody-depleting therapies.
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影响因子：
3.1
作者：
Kraichely, Robert E.;Farrugia, Gianrico;Pittock, Sean J.;Castell, Donald O.;Lennon, Vanda A.
通讯作者：
Lennon, Vanda A.
影响因子：
9.9
作者：
Wang, Z.;Low, P. A.;Vernino, S.
通讯作者：
Vernino, S.
影响因子：
12.6
作者：
Dhamija, Radhika;Tan, K. Meng;Lennon, Vanda A.
通讯作者：
Lennon, Vanda A.
影响因子：
--
作者：
McKeon, Andrew;Lennon, Vanda A.;Pittock, Sean J.
通讯作者：
Pittock, Sean J.
影响因子：
158.5
作者：
Vernino, S;Low, PA;Lennon, VA
通讯作者：
Lennon, VA