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, 73% of the patients had autonomic dysfunction or clinical endocrinopathy affecting thyroid, pancreas or ovary. Other neurological manifestations involved the peripheral nervous system more than the central; 30% of seropositive patients had neuropathies with varied sensory symptoms. More than 99% of patients whose sera are referred to the Mayo Clinic Neuroimmunology Laboratory for diagnostic immunofluorescence screening have a neurological disorder (usually subacute). However, only a small minority has dysautonomia, and there is no endocrinologic bias. Neuronal autoantibodies rarely have a syndrome-specific neurological correlate (Pittock et al, 2004). It is therefore remarkable that 76% of seropositive patients had evidence of small fiber neuropathy (autonomic or sensory). The results of our preliminary blinded analysis of sera selected by clinical diagnosis support our conclusion that peripherin autoimmunity is associated with acquired neuropathies with autonomic and varied sensory symptoms and an accompanying endocrinopathy.
Serum autoantibody profiles recognized in the past 2 decades have enabled identification of autoimmune cases of GI dysmotility as a limited form of dysautonomia [2
]. Peripherin-IgG complements an existing informative profile of autoantibodies associated with autoimmune GI dysmotility: anti-neuronal nuclear autoantibody, type 1 (ANNA-1, aka “anti-Hu”), collapsin response-mediator protein-5 (CRMP-5)-IgG, N-type voltage-gated calcium channel, voltage-gated potassium channel, ganglionic and muscle acetylcholine receptor, striational and glutamic acid decarboxylase-65 antibodies [5
]. To date, only ganglionic acetylcholine receptor-specific IgG is proven to be pathogenic for the autonomic nervous system [2
]. Evidence is lacking for in vivo
pathogenicity of IgGs specific for intracellular autoantigens. However, these antibodies are recognized as surrogate markers for antigen-specific T cell activation [12
]. It is plausible that peripherin-containing nerve fibers may be susceptible to attack by activated effector cytotoxic T cells specific for peripherin-derived peptides, in the context of appropriate MHC molecule upregulation.
Peripherin is a type III neuronal intermediate filament protein that forms networks, either alone or complexed with other neurofilament proteins [26
]. It is attributed a role in neuron development and repair [27
] and is distributed widely in the peripheral nervous system. In the central nervous system peripherin is restricted to regions that project to the periphery. Mice lacking peripherin appear surprisingly normal, apart from having reduced numbers of unmyelinated fibers in ventral roots [28
Peripherin has been proposed a candidate autoantigen of type 1 diabetes, based on the detection in diabetic NOD mice of peripherin-IgG in serum and on the specificity of antibodies produced by B lymphocytes infiltrating the pancreas [29
]. The seroprevalence of peripherin-IgG in NOD mice is reported to parallel diabetes progression [32
]. It is therefore remarkable that no previous study has demonstrated peripherin-IgG as a pertinent autoantibody in human disease, either endocrine or neurologic. Type 1 diabetes is estimated to affect 7.8% of the U.S. population, but it was diagnosed in 15% of the patients in this study; an additional patient had documented hyperglycemia. In a series of papers describing the evolution of diabetes in NOD mice, Carrillo and colleagues proposed that nervous tissue-specific B cells are recruited to the region of pancreatic islets as an early event, preceding β-cell destruction. They hypothesized that the expression of peripherin in pancreatic neuronal elements is upregulated by low level inflammation [29
]. Pancreatic islets are richly innervated by autonomic nerves [33
]. Electron microscopy has demonstrated, in pancreatic tissues of NOD mice and humans, that a tight envelope of peri-islet Schwann cells converges at the neuro-insular complex with axons and sympathetic nerve fibers. These Schwann cells have been implicated as the initial target of T lymphocyte attack in pre-diabetes. In male NOD mice, which are relatively resistant to diabetes, the peri-islet Schwann cell barrier remains intact [34
]. The juxtaposition of peripherin-positive autonomic fibers and epithelia in all of the endocrine organs that we identified as targets of autoimmunity in the peripherin-IgG positive patients in our study, suggests that neural elements may be an early target for immune attack in multiple forms of human endocrine autoimmunity, including type 1 diabetes, premature ovarian failure and thyroid disorders. It remains to be determined whether or not peripherin-IgG is predictive for development of small fiber neuropathy (autonomic or somatic).