Ganglioside reactive antibodies in the neuropathy associated with celiac disease

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Abstract

We tested patients with celiac disease (CD) for the presence of serum anti-ganglioside antibodies. Six of twenty-seven patient sera were reactive against brain gangliosides by an agglutination immunoassay. Neurological examination in all six revealed the presence of distal sensory loss, consistent with the diagnosis of peripheral neuropathy. When tested by ELISA for antibodies to isolated GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides, all six were positive for IgG antibodies to at least one. The neuropathy of celiac disease may be autoimmune and associated with anti-ganglioside antibodies. The presence of IgG reactivity furthermore implicates a T cell-mediated response to ganglioside antigens.

Introduction

Celiac disease (CD) is a chronic inflammatory enteropathy, mediated by T-cell reactivity to ingested gluten proteins, resulting in villous atrophy of the small intestine (Farrell and Kelly, 2002). The disease is familial, and strongly linked to the expression of HLA-DQ2 and/or DQ8 molecules that are implicated in the presentation of gliadin to sensitized T cells infiltrating the lamina propria Howell et al., 1986, Sollid et al., 1989.

Celiac disease is associated with several autoimmune phenomena, including autoantibodies to tissue transglutaminase (tTG) (Dieterich et al., 1998), and increased incidence of type I diabetes, Sjögren syndrome, and autoimmune thyroid disease Ventura et al., 1999, Kumar et al., 2001, Larizza et al., 2001. The mechanism of autoimmunity is unclear, but in the case of tTG, the antibodies are thought to be induced by gliadin–tTg complexes, with activation of tTG-specific B cells by T-cells that recognize gliadin in the complex (Sollid et al., 1997).

Approximately 10% of celiac patients exhibit evidence for neurological disease (Willis and Hovell, 1996), in particular peripheral neuropathy and cerebellar ataxia, but also opthalmoplegia, epilepsy, and dementia Cooke and Smith, 1966, Kaplan et al., 1988, Finelli et al., 1980, Chapman et al., 1978, Collin et al., 1991. These were assumed to be due to malabsorption, although nutritional deficiencies were rarely demonstrated, and no improvement of the neurological diseases was observed following vitamin therapy (Muller et al., 1996). Overall, very little research has been done into the mechanisms of the neurological complications of celiac disease.

As celiac disease is known to be linked to autoimmunity, we tested the patients for the presence of anti-ganglioside antibodies, which are associated with autoimmune neuropathies O'Leary and Willison, 2000, Press et al., 2001. Sera were screened using a newly developed ganglioside agglutination immunoassay that detects antibodies to brain gangliosides, and the reactive sera were then tested by ELISA for binding to purified gangliosides. Patients with demonstrable serum ganglioside reactivity were evaluated neurologically for the presence of neuropathy or other neurological disease.

Section snippets

Sera and diagnostic criteria

Serum samples were obtained from 27 unselected patients with celiac disease followed by the GI service. Diagnosis of celiac disease was based on the criteria of The European Society of Pediatric Gastroenterology and Nutrition (ESPGAN): characteristic histological features of villous atrophy, crypt hyperplasia, and inflammation in small intestinal biopsies, together with clinical and/or histological improvement on a gluten free diet. Sera from 6 patients with ALS, 20 patients with MS, and 40

Results

Of the 27 celiac patients, 6 (22%) were positive for anti-ganglioside antibodies by the agglutination assay. When tested by ELISA for IgG, IgM, and IgA antibodies to GM1, GM2, GD1a, GD1b, GT1b, or GQ1b gangliosides, the same six positive sera exhibited elevated IgG antibody levels to one or more of the gangliosides (Table 1).

Three of the six celiac patients with ganglioside antibodies had been on gluten-free diet for more than 6 months at the time of ganglioside antibody testing, and were found

Discussion

Approximately 20% of the sera from patients with celiac disease had increased anti-ganglioside antibodies, all of whom were found to have a distal sensory neuropathy. It is not known if any of the other 22 celiac patients also had neuropathy or other neurological disease, as they were not examined. The incidence of neuropathy in celiac disease is unknown, and the diagnosis may be missed if the patients are not neurologically evaluated. Routine nerve conduction studies may be normal or only

Acknowledgments

This study was supported in part by a grant from NIH (NINCDS NS11766), and by generous donations from James and Linda Gardner, George Fisher, Peter Bing, and Winston Wolfe.

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