title: Guillain Barré Syndrome is induced in Non-Obese Diabetic (NOD) mice following Campylobacter jejuni infection and is exacerbated by antibiotics.
abstract: Campylobacter jejuni is a leading cause of bacterial gastroenteritis linked to several serious autoimmune sequelae such as the peripheral neuropathies Guillain Barré syndrome (GBS) and Miller Fisher syndrome (MFS). We hypothesized that GBS and MFS can result in NOD wild type (WT) mice or their congenic interleukin (IL)-10 or B7-2 knockouts secondary to C. jejuni infection. Mice were gavaged orally with C. jejuni strains HB93-13 and 260.94 from patients with GBS or CF93-6 from a patient with MFS and assessed for clinical neurological signs and phenotypes, anti-ganglioside antibodies, and cellular infiltrates and lesions in gut and peripheral nerve tissues. Significant increases in autoantibodies against single gangliosides (GM1, GQ1b, GD1a) occurred in infected NOD mice of all genotypes, although the isotypes varied (NOD WT had IgG1, IgG3; NOD B7-2-/-had IgG3; NOD IL-10-/-had IgG1, IgG3, IgG2a). Infected NOD WT and NOD IL-10-/-mice also produced anti-ganglioside antibodies of the IgG1 isotype directed against a mixture of GM1/GQ1b gangliosides. Phenotypic tests showed significant differences between treatment groups of all mouse genotypes. Peripheral nerve lesions with macrophage infiltrates were significantly increased in infected mice of NOD WT and IL-10-/-genotypes compared to sham-inoculated controls, while lesions with T cell infiltrates were significantly increased in infected mice of the NOD B7-2-/-genotype compared to sham-inoculated controls. In both infected and sham inoculated NOD IL-10-/-mice, antibiotic treatment exacerbated neurological signs, lesions and the amount and number of different isotypes of antiganglioside autoantibodies produced. Thus, inducible mouse models of post-C. jejuni GBS are feasible and can be characterized based on evaluation of three factors-onset of GBS clinical signs/phenotypes, anti-ganglioside autoantibodies and nerve lesions. Based on these factors we characterized 1) NOD B-7-/-mice as an acute inflammatory demyelinating polyneuropathy (AIDP)-like model, 2) NOD IL-10-/-mice as an acute motor axonal neuropathy (AMAN)-like model best employed over a limited time frame, and 3) NOD WT mice as an AMAN model with mild clinical signs and lesions. Taken together these data demonstrate that C. jejuni strain genotype, host genotype and antibiotic treatment affect GBS disease outcomes in mice and that many disease phenotypes are possible.
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA; Comparative Medicine and Integrative Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: St Charles
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bell
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA; Comparative Medicine and Integrative Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gadsden
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: A
authors.initials: A
authors.lastname: Malik
authors.affiliation: College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cooke
authors.affiliation: College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: Van de Grift
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Smith
authors.affiliation: Comparative Enteric Diseases Laboratory, Michigan State University, East Lansing, MI 48824, USA; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA; College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. Electronic address: mansfie4@cvm.msu.edu.
authors.forename: L S
authors.initials: LS
authors.lastname: Mansfield
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000494:pharmacology; D000907:Antibodies, Bacterial / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D002169:Campylobacter Infections / Q000150:complications* / Q000188:drug therapy / Q000382:microbiology*; D016123:Campylobacter jejuni; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005727:Ganglia, Spinal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020275:Guillain-Barre Syndrome / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G
keywords: Autoimmunity; Campylobacter jejuni; Guillain Barré Syndrome; Mouse models; Peripheral neuropathy