Genetic analysis of the influence of neuroantigen-complete Freund's adjuvant emulsion structures on the sexual dimorphism and susceptibility to experimental allergic encephalomyelitis.
The induction of organ-specific autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) the principal animal model of multiple sclerosis (MS), relies on the use of complete Freund's adjuvant (CFA) emulsions. In this study we report that the physical structure of the particles comprising neuroantigen-CFA emulsions significantly influences the genetic control of the incidence and sexual dimorphism seen in EAE. Immunization of (B10.S/SgMcdJ x SJL/J) F(2) mice segregating the quantitative trait loci (QTL) controlling EAE in susceptible SJL/J and resistant B10.S/SgMcdJ mice with emulsions consisting of particles where the Mycobacterium tuberculosis and neuroantigens are localized on the phase surfaces led to severe EAE in 98.8% of the mice, overriding all sex-specific and non-sex-specific genetic checkpoints. In contrast, F(2) mice immunized with emulsions where the bacterial products and encephalitogens are buried inside the water/oil vesicles exhibited a significant reduction in disease incidence (7.5%) and a sexual dimorphism (5% male versus 10% female). A genome scan identified QTL on chromosomes 7 and 11 controlling the sexual dimorphism as a function of the physical structure of the emulsion. The chromosome 11 QTL co-localizes with eae6b, and with Il12b and heptatitis A virus cellular receptor 2 (Havcr2, formerly known as Timd3), both of which are candidate genes for this QTL. Sequence analysis of the SJL/J and B10.S/SgMcdJ alleles indicates that both gene products are structurally monomorphic. Expression analysis also excluded both as candidates for this sex-specific QTL. These results reinforce the importance of gene-environment interactions in initiating and propagating autoimmune disease of the central nervous system, particularly in the context of susceptibility to MS and disease heterogeneity.
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology*; D002874:Chromosome Mapping; D018076:DNA, Complementary / Q000235:genetics; D004338:Drug Combinations; D004655:Emulsions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D016678:Genome; D000072597:Hepatitis A Virus Cellular Receptor 2; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D040641:Quantitative Trait Loci; D011991:Receptors, Virus / Q000235:genetics; D012727:Sex Characteristics
D000942:Antigens, Bacterial; D018076:DNA, Complementary; D004338:Drug Combinations; D004655:Emulsions; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D011991:Receptors, Virus; D005620:Freund's Adjuvant