Pathogenic Autoantibodies

Autoantibodies potentially contribute to neuropathology by a variety of mechanisms, including immune complex mediated vasculitis, direct targeting of surface antigen leading to injury to myelin or neuronal tissue, and targeting of postganglionic receptors by functional autoantibody. Antiphospholipid antibodies (aPL) are associated with stroke, migraine, seizures, and transverse myelitis.73 Although described in 5% to 14% of pSS patients, aPL antibody seems not to be associated with CNS disease in pSS.9,74,75 However, a single small study suggested a possible role for aPL antibody in hearing loss in pSS. Clinically significant sensorineural hearing loss was found in 5 of 30 women and hearing loss correlated with the presence of anticardiolipin anti-bodies.76 Patients with pSS and CNS disease have not been found to have evidence of antineuronal antibodies or antiribosomal antibodies. Neither antibody was found in paired serum/CSF samples from patients with active CNS-SS, suggesting that different immunopathologic mechanisms are responsible for CNS disorders in SLE and pSS.21

Whether anti-Ro/SSA has a direct pathophysiologic role in mediating vasculopathy resulting in neuronal damage remains speculative, despite previous studies that linked anti-Ro/SSA antibody to vasculopathy in both SLE and pSS.77,78 In Western blot experiments using human umbilical vein endothelial cells, sera containing anti-Ro/ SSA antibodies from patients with CNS-SS bound to 50 out of 54 and 60-kDa pep-tides, providing support for the hypothesis that anti-Ro/SSA antibodies bind to brain endothelial cells and play a role in the inflammatory process.71 Ro52 expression was recently shown to be localized and highly enriched in the brain microvascular compartment in a recent study that used bovine brain tissue.79 The mechanism by which circulating IgG might interact with brain endothelial Ro52 is unclear. A single report described three patients with pSS in whom cerebrospinal fluid anti-Ro/SSA antibody was detected along with intrathecal IgG synthesis.80 Demonstration for the first time of intrathecal anti-Ro/SSA synthesis in two out of three patients with pSS who had CNS manifestations suggests that even in the absence of disruption of the blood brain barrier, anti-Ro/SSA may play a role in mediating CNS disorders.

Sera positive for antibody to extractable nuclear antigens (ENA) based on enzyme immunoassay, despite negative antinuclear antibodies, were recently studied and the associated clinical characteristics reported by Davis and colleagues.81 Neurologic disorders, specifically peripheral neuropathy, were the predominant manifestation. The autoantibodies detected by ENA were anti-Ro/SSA or anti-La/SSB (in 33 out of

39 patients), with a minority of sera positive for U1 RNP or Scl -70. The neurologic manifestations based on retrospective chart review were sensorimotor polyneuropathy, small fiber neuropathy, ataxia, sensory neuronopathy, and progressive dementia with seizure disorder, a profile very similar to that described in neurologic SS.

Recently, a novel family of autoantibodies directed against cytoplasmic antigens has been added to the family of RNA-binding autoantibodies detectable in sera from patients with SS and other autoimmune disorders. GW/P antibodies target cytoplasmic structures that are involved in mRNA processing, RNA interference, and mRNA degradation. Proteins targeted by GW/P antibodies contain a glycine/tryptophan rich mRNA-binding sequence.82 Preliminary data from a single study have suggested that the clinical presentations most commonly associated with seropositiv-ity to GW body epitopes are neurologic disorders. Selection of sera reactive against GW body autoantigens identified a cohort of 55 patients with a mean age of 61, the majority of whom had SS and neurologic disease.83 The most common clinical presentation, based on retrospective review of 42 patients in whom clinical data was available, was neurologic in 33% (ataxia, motor, and sensory neuropathy). Interestingly, 44% of the patients with anti-GWB had reactivity to Ro52 as well. Other autoimmune diseases associated with GW/P reactivity in less than 15% of the patients included SLE, primary biliary cirrhosis, RA, and MS.

Aquaporin (AQP) family proteins are differentially distributed in endovascular and neuronal tissue throughout the central and peripheral nervous system. Abnormal distribution of AQP in the salivary and lacrimal glands has been described in pSS.84,85 Increasing evidence also suggests that autoantibodies directed against AQPs mediate neurologic disease. A unique association of antibody directed against AQP4, a member of the family of water channel proteins, has been described in association with neuromyelitis optica. The histopathology of NMO is that of both necrotizing vasculitis and demyelination, which by definition extends over three or more segments of spinal cord. Immunohistologic examination of spinal tissue has demonstrated deposition of NMO antibody,86 which detects clinically-defined NMO with high sensitivity and specificity.87 Elegant immuno-histochemical studies by Lennon and colleagues88 demonstrated that AQP4 is the autoantigen targeted by NMO-pos-itive sera, providing evidence of an autoimmune "channelopathy," although the precise mechanism whereby autoimmunity to AQP4 results in the restricted immunopathology of NMO is yet to be clarified. Patients with classic MS are uniformly sero-negative for NMO antibody.87

A variety of mechanisms have been explored in animal models, which suggest a role for AQP autoantibodies in mediating neurologic disorders. AQP1 is expressed in the CNS in the trigeminal nucleus, the retina, and the choroid plexus epithelial cells. Both AQP1 and AQP4 are expressed in dorsal root ganglia. Within the dorsal root and trigeminal sensory ganglia, AQP1 is concentrated in small diameter cell bodies, which give rise to unmyelinated C-fibers. Deletion of AQP1 in mice is associated with decreased response to pain and thermal stimuli, suggesting the possibility that antibody targeting AQP could have a functional role in modulating nociception.89 An immune role in mediating neuropathic pain in SS is suggested by the observation that lymphocyte infiltration of dorsal root ganglia can be a histologic feature of sensory neuronopathy, and the demonstration that inflammation of neuronal tissue can result in activation of microglia and lead to expression of inflammatory cytokines that potentially mediate neuronal injury.90,91

Of additional interest are studies of salivary gland function, suggesting that stimulation of the muscarinic 3 receptor (M3R) found in salivary gland tissue results in translocation of AQP5 from the basal to apical plasma membrane of salivary myoepithelial cells.92 The inhibitory effect of SS IgG on the expression of AQP5 has been examined in a model using rat parotid acinar cells and pilocarpine-induced AQP5 trafficking to the apical membrane. After incubating the cells for 12 hours with SS IgG, compared with control sera, Calcium mobilization, and AQP5 trafficking was reduced, suggesting a possible mechanism whereby antibody directed against AQP5 might mediate autonomic dysfunction.93

Antibodies against cholinergic receptors have attracted considerable interest as potential mediators of parasympathetic nervous system dysfunction in SS.94 M3R is restricted to expression in peripheral autonomic organs, with the highest expression in salivary gland and smooth muscle cells.95 Recent work from several groups using a variety of techniques including immunohistochemistry and Western blotting,96 radioligand binding,97,98 enzyme-linked immunosorbent assay (ELISA),99 and bioassay have suggested the presence of autoantibody in pSS IgG that recognize

M3R.100,101 Animal studies have suggested a role for antibody-targeting cell surface M3 signal transduction receptor as a primary event in autoimmune exocrinopathy.102 Passive transfer experiments in NOD/SCID mice and in vitro studies with a muscarinic agonist provide evidence for a negative effect on the secretory response of submandibular gland cells treated with anti-M3 receptor antibody.103

The putative role of antibodies to the acetylcholine receptor as a mediating of autonomic neuropathy in pSS was investigated by Waterman and colleagues.104 IgG autoantibody found in patients with both primary and secondary SS induces cholinergic hyper-responsiveness and detrusor instability on passive transfer to normal mice potentially through, compensatory up-regulation of postsynaptic M3R receptor number, consistent with the hypothesis that the overactive bladder in pSS is an autoantibody mediated disorder.101 Proof of a pathogenic role for anti-M3R antibody in autonomic dysfunction in pSS will require purification and characterization of the antibody. Conventional immunologic techniques have not confirmed detectable binding of pSS IgG to M3R, and studies to date have relied on biologic assays that have proven difficult to replicate.105 The most compelling evidence for functional M3R antibody in pSS remains a bioassay capable of detecting circulating antibody at concentrations below the nanogram threshold for detection of antibody using whole-cell ELISA or immunoblotting.105 Recently, it was reported that an unusual low affinity muscarinic receptor blocking antibody detectable in picogram concentrations in sera was detectable by bioassay in the majority of patients with pSS and in patients with scleroderma.100 Passive transfer experiments demonstrated functional properties in a biologic preparation in exceedingly low concentrations. Treatment with intravenous immunoglobulin (IVIG) prevented the functional consequences. Demonstration of the clinical relevance of anti-M3 receptor antibody will require development of a standardized assay for detection of antimuscarinic receptor antibody.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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