Peripherin-IgG association with neurologic and endocrine autoimmunity

https://doi.org/10.1016/j.jaut.2009.12.004Get rights and content

Abstract

Peripherin-IgG has been reported a pertinent autoantibody in non-obese type 1 diabetic (NOD) mice. However, it has not previously been recognized in any human disease. In blinded evaluation of serum for markers of neurological autoimmunity in a high-volume diagnostic laboratory, we incidentally identified 26 patients (61% female) with an IgG that bound selectively to neural elements in enteric ganglia, sympathetic nerve trunks and discrete nerve tracts in mid-brain and hind-brain. The target antigen was identified as peripherin, a 55 kDa – type III intermediate filament protein. Review of clinical histories revealed that 54% of seropositive patients had dysautonomia (predominantly gastrointestinal dysmotility), 30% had neuropathies with varied sensory symptoms and 35% had clinical or serological evidence of endocrinopathy (type 1 diabetes, thyroiditis or premature ovarian failure). Collectively, 73% had autonomic dysfunction or endocrinopathy. None of 173 healthy subjects was seropositive. Subsequent western blot evaluation of archival sera from patients with small fiber/autonomic neuropathies (with or without endocrinopathy) revealed a 33% seropositivity rate for peripherin-IgG. Our further demonstration that peripherin-immunoreactive autonomic fibers in pancreas, thyroid and ovary are juxtaposed to endocrine epithelium, complement our clinical observations in suggesting that neuronal elements may be a pertinent initial target for immune attack in multiple forms of endocrine autoimmunity (intermolecular epitope spreading). It remains to be determined whether or not peripherin-IgG is predictive for development of small fiber neuropathy (autonomic or somatic).

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.

Section snippets

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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    1

    Present address: University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

    2

    Present address: Prasat Neurological Institute, Bangkok, Thailand.

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