Neuropathy and ataxia are among the most common and debilitating extraintestinal complications occurring in patients with celiac disease or gluten sensitivity. These neurologic deficits are believed to be immune mediated, possibly driven by molecular mimicry. However, until now, no putative neural target antigen had been identified. In preliminary studies, we found that antibodies to wheat gliadin immunostain neurons in the nervous system. Using immunoblotting, immunoaffinity chromatography, 2- dimensional gel electrophoresis, and nano-LC/MS/MS techniques, we identified the cross-reactive autoantigen as synapsin I, a central and peripheral nervous system protein involved in neurotransmitter release. Epitope mapping revealed the major immunoreactive sites to be located in the functionally important C domain of synapsin I, which is known to mediate the interaction of the protein with synaptic vesicles. In addition, affinity purified human IgG and IgA anti-gliadin antibodies were also found to cross- react with synapsin I. Our hypothesis is that in some patients with celiac disease, the anti-gliadin antibody response cross-reacts with synapsin I and that the immune reactivity is associated with neurologic deficits in celiac disease, such as cerebellar ataxia or peripheral neuropathy. The following specific aims are proposed to address our hypothesis: i) To determine whether there is an association between antibody reactivity to synapsin I and celiac neuropathy or ataxia. 2) To determine whether specific antibody isotype or affinity is associated with the presence of neurological disease or particular phenotypes. 3) To map the epitope(s) of synapsin I targeted by human antibodies, determining whether reactivity against certain epitopes is associated with the occurrence of neurologic disease or a particular syndrome. The proposed studies are expected to shed light on how central and peripheral nervous system deficits may be associated with gluten sensitivity. They may also serve to provide a useful marker for the diagnosis of the associated peripheral neuropathy or cerebellar ataxia, and offer a rationale for examining the efficacy of therapies that target autoimmune mechanisms in affected individuals. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS055323-02
Application #
7364150
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Gwinn, Katrina
Project Start
2007-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$183,750
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Samaroo, Diana; Dickerson, Faith; Kasarda, Donald D et al. (2010) Novel immune response to gluten in individuals with schizophrenia. Schizophr Res 118:248-55