Smith Anthony J, Jackson Michael W, Wang Fang, Cavill Dana, Rischmueller Maureen, Gordon Tom P
Department of Immunology, Allergy, and Arthritis, Flinders Medical Centre and Flinders University, Bedford Park, South Australia.
Hum Immunol. 2005 Apr;66(4):411-6. doi: 10.1016/j.humimm.2005.01.020.
Autoantibodies that inhibit M3 muscarinic receptor (M3R)-mediated neurotransmission and cause bladder and bowel dysfunction have been reported in patients with Sjögren syndrome and belong to a family of functional autoantibodies that includes the thyroid-stimulating hormone receptor antibody present in Graves disease. We have recently reported that antiidiotypic antibodies present in pooled immunoglobulin (Ig) G or IgG from healthy individuals neutralize anti-M3R antibody-mediated inhibition of smooth muscle contraction in vitro. Here we extend these studies to the clinic by examining whether therapeutic doses of intravenous immunoglobulin (IVIG) provided to patients with autoimmune diseases neutralize anti-M3R activity in vivo and improve bladder and bowel symptoms. Three patients with primary Sjögren syndrome, dermatomyositis, and celiac disease, respectively, all of whom had anti-M3R activity on a functional bladder contractile assay, were provided a single course of IVIG at a dose of 400 mg/kg per day for 5 days. Anti-M3R activity was neutralized at 4 weeks after IVIG infusion, whereas levels of specific autoantibodies (anti-La, anti-Jo-1, and anti-tissue transglutaminase) were unchanged. Bladder and bowel scores revealed variable improvement after IVIG. Neutralization of anti-M3R activity by IVIG in vivo, presumably as a result of antiidiotypic antibodies directed specifically against anti-M3R autoantibodies, provides a clinical correlate of our in vitro findings. This offers a rationale for IVIG as a treatment for parasympathetic dysfunction in patients with autoantibodies inhibiting postganglionic cholinergic neurotransmission. We suggest the presence of a network of naturally occurring antiidiotypic antibodies that regulate the expression of functional autoantibodies against neuronal receptors and ion channels.
在干燥综合征患者中，已报道存在抑制M3毒蕈碱受体（M3R）介导的神经传递并导致膀胱和肠道功能障碍的自身抗体，这些自身抗体属于功能性自身抗体家族，其中包括格雷夫斯病中存在的促甲状腺激素受体抗体。我们最近报道，健康个体混合免疫球蛋白（Ig）G或IgG中存在的抗独特型抗体可在体外中和抗M3R抗体介导的平滑肌收缩抑制作用。在此，我们通过检查给予自身免疫性疾病患者的治疗剂量静脉注射免疫球蛋白（IVIG）是否能在体内中和抗M3R活性并改善膀胱和肠道症状，将这些研究扩展到临床。分别有三名原发性干燥综合征、皮肌炎和乳糜泻患者，他们在功能性膀胱收缩试验中均具有抗M3R活性，接受了一个疗程的IVIG治疗，剂量为每天400mg/kg，共5天。IVIG输注后4周，抗M3R活性被中和，而特异性自身抗体（抗La、抗Jo - 1和抗组织转谷氨酰胺酶）水平未改变。IVIG治疗后膀胱和肠道评分显示有不同程度的改善。IVIG在体内中和抗M3R活性，推测是由于特异性针对抗M3R自身抗体的抗独特型抗体所致，这为我们的体外研究结果提供了临床关联。这为IVIG作为抑制节后胆碱能神经传递的自身抗体患者副交感神经功能障碍的治疗方法提供了理论依据。我们认为存在一个天然抗独特型抗体网络，可调节针对神经元受体和离子通道的功能性自身抗体的表达。
