Wang Fang, Jackson Michael W, Maughan Vicki, Cavill Dana, Smith Anthony J, Waterman Sally A, Gordon Tom P
Flinders Medical Centre and University, Bedford Park, Adelaide, South Australia 5000, Australia.
Arthritis Rheum. 2004 Nov;50(11):3637-45. doi: 10.1002/art.20625.
The presence, in patients with primary and secondary Sjogren's syndrome (SS), of autoantibodies that acutely inhibit M(3) muscarinic receptor (M3R)-mediated bladder contractions is difficult to reconcile with the fact that symptoms of detrusor overactivity and other features of cholinergic hyperresponsiveness occur in this disease. This study was undertaken to examine the in vivo effects of these autoantibodies on bladder function by examining bladder responsiveness and compliance following passive transfer of patient IgG to mice.
Contractile responses of isolated bladder strips both to the muscarinic agonist carbachol and to electrically evoked acetylcholine release were measured 48 hours after injection of mice with patient or control IgG. A whole bladder assay with intact neuronal pathways was developed to assess bladder wall compliance on filling cystometry. Expression of M3R in bladders from IgG-injected mice was assessed by immunohistochemistry.
Passive transfer of SS IgG with inhibitory anti-M3R activity produced a paradoxical increase in contractile responses of detrusor strips to cholinergic stimulation. Cystometry of whole bladders revealed a corresponding decrease in bladder wall compliance and phasic detrusor contractions upon filling, replicating the urodynamic features of an overactive bladder. The features of cholinergic hyperresponsiveness were associated with increased postsynaptic M3R expression and were reproduced by injecting mice with a rabbit antibody against the second extracellular loop of M3R.
These findings are consistent with the notion that there is initial inhibition of parasympathetic neurotransmission by antagonistic autoantibodies to M3R, which produces a compensatory increase in M3R expression in vivo. The enhanced cholinergic responses during bladder distention result in detrusor overactivity. We conclude that the overactive bladder associated with SS is an autoantibody-mediated disorder of the autonomic nervous system, which may be part of a wider spectrum of cholinergic hyperresponsiveness.
在原发性和继发性干燥综合征（SS）患者体内，存在可急性抑制M3毒蕈碱受体（M3R）介导的膀胱收缩的自身抗体，这一现象难以与该疾病中逼尿肌过度活动症状及其他胆碱能高反应性特征并存的事实相协调。本研究旨在通过将患者IgG被动转移至小鼠后检测膀胱反应性和顺应性，来研究这些自身抗体对膀胱功能的体内影响。
给小鼠注射患者或对照IgG 48小时后，测量离体膀胱条对毒蕈碱激动剂卡巴胆碱以及电诱发乙酰胆碱释放的收缩反应。开发了一种具有完整神经通路的全膀胱检测方法，以在充盈膀胱测压时评估膀胱壁顺应性。通过免疫组织化学评估注射IgG小鼠膀胱中M3R的表达。
具有抑制性抗M3R活性的SS IgG被动转移导致逼尿肌条对胆碱能刺激的收缩反应出现反常增加。全膀胱测压显示，膀胱壁顺应性相应降低，且充盈时逼尿肌出现相性收缩，重现了膀胱过度活动的尿动力学特征。胆碱能高反应性特征与突触后M3R表达增加有关，给小鼠注射抗M3R第二细胞外环的兔抗体可重现这些特征。
这些发现与以下观点一致，即针对M3R的拮抗自身抗体最初会抑制副交感神经传递，从而在体内导致M3R表达代偿性增加。膀胱扩张期间增强的胆碱能反应导致逼尿肌过度活动。我们得出结论，与SS相关的膀胱过度活动是一种自身抗体介导的自主神经系统疾病，可能是更广泛的胆碱能高反应性的一部分。
