Peripherin-IgG association with neurologic and endocrine autoimmunity
Introduction
Neural-restricted autoantibodies serve as valuable serum biomarkers aiding the diagnosis of acquired neurological disorders amenable to immunotherapy, both idiopathic and paraneoplastic. Informative autoantigens defined to date are expressed in neurons, glia or skeletal muscle. Plasma membrane-reactive IgGs have pathogenic potential [1], [2], [3], [4], [5], [6], while IgGs reactive with cytoplasmic antigens [7], [8], [9], [10], [11] are indicative of immunogenic proteins yielding peptide targets for MHC-restricted cytotoxic T cells [12]. In our clinical service laboratory's high-volume experience of screening patients' sera by immunofluorescence for markers of neurological autoimmunity, we identified incidentally a novel IgG that bound selectively to peripheral autonomic neurons and to discrete nerve fiber tracts in the central nervous system. Review of records for initially identified seropositive Mayo Clinic patients suggested that this IgG was a marker of autoimmune dysautonomia. Here we describe the clinical profiles of 26 seropositive patients and define the neuronal intermediate filament protein peripherin as the target autoantigen. Peripherin-IgG has been reported a pertinent autoantibody in non-obese type 1 diabetic (NOD) mice, but it has not previously been recognized in any human disease. We propose a novel hypothesis that plausibly unifies our clinical and immunohistochemical observations.
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Patients and controls
The study was approved by the Mayo Clinic Institutional Review Board (IRB #06-007020). Between January 1, 1998 and December 31, 2008, the clinical Neuroimmunology Laboratory prospectively screened on a service basis sera from approximately 160,000 patients for evidence of neurological autoimmunity using an indirect immunofluorescence assay to detect IgG binding selectively to neural elements in a composite substrate of mouse tissues [9]. An occasionally detected IgG bound to discrete
Clinical-serological correlations of a novel neural autoantibody
We identified a total of 26 seropositive patients for whom clinical records were available (16 women, 10 men). We did not detect the novel autoantibody in any of 173 age-matched healthy control subjects. Table 1 summarizes the 26 seropositive patients' clinical and laboratory information and serological data. Their median age was 46 years (range 21–86); the median titer of the novel IgG was 3,840 (range, 240–30,720). All but 8 patients were evaluated at Mayo Clinic. All had neurological
Discussion
This is the first reported association of peripherin-specific IgG with human disease. Our study has defined peripherin-IgG as a clinically pertinent biomarker of autoimmune neuropathies (somatic and autonomic) often coexisting with endocrine autoimmunity. Peripherin-IgG was not found in any healthy control subject. Fifty-four percent of the 26 seropositive patients we identified had symptoms of limited or generalized dysautonomia, and 27% had a clinically diagnosed endocrinopathy. Collectively,
Acknowledgments
The authors thank Drs. Radhika Dhamija, Shannon Hinson, Christopher Klein and Daniel Lachance, and James Thoreson, James Fryer, Hui Tang and Mayo Core Facilities (Proteomics, Ben Madden, and Confocal Microscopy, Jim Tarara) for their contributions to this study, which was supported by NIH grants R01-DK71209 and P01-DK68055.
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2016, Cell Chemical BiologyCitation Excerpt :Recall that our peripherin preparation was from human cells and, even in this case, a few preparations failed to show significant reactivity with patient IgGs. Finally, Lennon and colleagues reported that some patients with neurological conditions, particularly various neuropathies, have antibodies against peripherin (Chamberlain et al., 2010). However, when they analyzed a number of diabetes patients for these antibodies, almost none of them tested positive.
Autoimmune-mediated peripheral neuropathies and autoimmune pain
2016, Handbook of Clinical NeurologyCitation Excerpt :However, when it is present at greater than 20 nm/L (500 U/ml) it is much more commonly likely to link with neurologic illness, including stiff-man syndrome and neuropathy (Vernino and Lennon, 2004). Autoantibodies to peripherin have recently been identified in a diverse group of neurologic presentations, including autonomic and small-fiber neuropathy (Chamberlain et al., 2010). Specifically, 54% of sera-positive patients had dysautonomia (predominantly gastrointestinal dysmotility), with 30% having neuropathies of varied sensory symptoms and 35% with clinical or serologic evidence of endocrinopathy (type 1 diabetes, thyroiditis, or premature ovarian failure).
Autoimmune autonomic disorders
2016, Handbook of Clinical NeurologyCitation Excerpt :Peripherin is a neuronal intermediate filament protein that is expressed primarily in the peripheral nervous system. In a blinded evaluation of serum for markers of neurologic autoimmunity in a high-volume diagnostic laboratory, peripherin antibody bound selectively to neural elements in enteric ganglia, sympathetic nerve (Chamberlain et al., 2010). Review of clinical histories revealed that 54% of seropositive patients had autonomic symptoms (predominantly gastrointestinal dysmotility), 30% had neuropathies with varied sensory symptoms, and 35% had endocrinopathy (type 1 diabetes, thyroiditis, or premature ovarian failure).
α-Internexin and Peripherin: Expression, Assembly, Functions, and Roles in Disease
2016, Methods in EnzymologyCitation Excerpt :Type 1 diabetes is an autoimmune disease that involves the selective destruction of insulin-producing pancreatic ß-cells (Lehuen, Diana, Zaccone, & Cooke, 2010). Autoantibodies to peripherin have been detected in patients with autoimmune neuropathies and endocrinopathies, as well as in the nonobese diabetic (NOD) mouse model (Boitard et al., 1992; Chamberlain et al., 2010). By using isolated islet-infiltrating B cells and recombinant protein techniques, the epitope was mapped to a fragment in the C-terminal tail of Per-58 and Per-61, but not Per-56, which does not share the identical C-terminal sequence seen in Per-58 and Per-61 (see Fig. 3) (Garabatos et al., 2014; Puertas et al., 2007).
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2015, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders
- 1
Present address: University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
- 2
Present address: Prasat Neurological Institute, Bangkok, Thailand.