title: Substrain differences reveal novel disease-modifying gene candidates that alter the clinical course of a rodent model of multiple sclerosis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis that is executed in animals by immunization with myelin Ag in adjuvant. The SJL/J autoimmune-prone strain of mouse has been used to model relapsing-remitting multiple sclerosis. However, significant variations in peak scores, timing of onset, and incidence are observed among laboratories, with the postacute (relapse) phase of the disease exhibiting significant inconsistency. We characterized two substrains of SJL/J mice that exhibit profoundly different EAE disease parameters. Induction of EAE in the first SJL/J substrain resulted in many cases of chronic EAE that was dominated by an aggressive B cell response to the immunizing Ag and to endogenous CNS Ags. In contrast, the other SJL/J substrain exhibited a relapsing-remitting form of EAE concomitant with an elevated number of cytokine-producing CD4(+) T cells in the CNS. Exploiting these interstrain differences, we performed a genome-wide copy number analysis on the two disparate SJL/J substrains and discovered numerous gene-dosage differences. In particular, one inflammation-associated gene, Naip1, was present at a higher copy number in the SJL/J substrain that exhibited relapsing-remitting EAE. These results demonstrate that substrain differences, perhaps at the level of genomic copy number, can account for variability in the postacute phase of EAE and may drive chronic versus relapsing disease.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Leslie E Summers
authors.initials: LE
authors.lastname: deLuca
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Pikor
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Leary
authors.forename: Georgina
authors.initials: G
authors.lastname: Galicia-Rosas
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Ward
authors.forename: Dustin
authors.initials: D
authors.lastname: Defreitas
authors.forename: Trisha M
authors.initials: TM
authors.lastname: Finlay
authors.forename: Shalina S
authors.initials: SS
authors.lastname: Ousman
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Osborne
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
mesh_terms: D000208:Acute Disease; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056915:DNA Copy Number Variations / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D051379:Mice; D008815:Mice, Inbred Strains; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics* / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010641:Phenotype; D012720:Severity of Illness Index; D013045:Species Specificity; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D018991:Myelin Proteolipid Protein; C496801:Naip1 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)