Passive transfer of Sjögren's syndrome IgG produces the pathophysiology of overactive bladder

Abstract

Objective. The presence, in patients with primary and secondary Sjögren'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.Methods. 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.Results. 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.Conclusion. 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.

Frequency of Lower Urinary Tract Symptoms and Effects on Quality of Life in Women with Rheumatoid Arthritis

“…Waterman et al (17) have reported that antimuscarinic receptor antibodies are responsible for bladder irritability and LUTS in the patients with RA and primary concomitant and secondary Sjogren's syndrome. In another study, immunoglobulin G has been regarded as the cause of hypersensitive bladder dysfunction in rats with primary and secondary SS, which suggests an autoimmune background in bladder dysfunction (18). Lee et al (19) have reported that LUTS was not necessarily related with the severity and duration of RA, and the association between LUTS and age was also prompted.…”

“…Recent studies have supported that sicca symptoms in the patients with primary SS may be related to a similar autoantibody-mediated process that can affect the autonomic nervous system. Thus, other body systems under autonomic control, such as bladder, may also be affected (9,18). Walker et al (5) have reported a high rate of bladder storage symptoms in the patients with SS.…”

“…AUASI questionnaire includes seven questions to query the presence of a possible irritative (frequency, urgency, and nocturia) and obstructive (incomplete emptying, decrease in flow rate, and straining) urinary symptoms. A scoring system was utilized to classify the degree of the symptoms as mild (0-7), moderate (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), or severe (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). The final item of the AUASI form investigates the impact of urinary symptoms on QoL, and this entity is scored between 0 and 6 (10).…”

A Potential Role of Autoantibodies against Muscarinic Type 3 Receptor in Pathogenesis of Sjogren’s Syndrome

“…Nevertheless, as early as 2000, the muscarinic agonists, pilocarpine and cevimeline, were approved by the FDA to be a part of therapies for SS because of their partial effect on dryness of the eyes and mouth in a subpopulation of patients with 'moderate dryness' [36]. To directly prove the pathogenic role of anti-M3R autoantibodies in SS, Wang et al [37] performed passive transfer experiments using BALB/c mice. They demonstrated that mice injected with IgG from SS patients having anti-M3R activity showed increased bladder detrusor contractibility in response to carbachol stimulation and a reduction in the bladder wall compliance compared to mice injected with IgG from healthy controls or SS patients lacking anti-M3R activity.…”

Potentiation of a functional autoantibody in narcolepsy by a cholinesterase inhibitor

“…These functional Abs may fail to be detected by less-sensitive immunological methods, such as immunofluorescence and immunoblotting. [16][17][18][19][20] Recently, using a real-time bioassay of spontaneous, neuronally mediated colonic migrating motor complexes (CMMCs), we reported the presence of an immunoglobulin G (IgG) Ab in patients with narcolepsy with cataplexy that abolishes CMMC activity and increases resting tension and atropine-sensitive phasic contractions in colonic smooth muscle, suggesting the emergence of cholinergic responses secondary to a loss of smooth muscle inhibitory tone. We hypothesised that the putative narcoleptic Ab binds to an ion channel or receptor expressed on enteric neurons.…”