Genetic analysis of the influence of neuroantigen-complete Freund's adjuvant emulsion structures on the sexual dimorphism and susceptibility to experimental allergic encephalomyelitis.
Journal: 2003/October - American Journal of Pathology
ISSN: 0002-9440
Abstract:
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.
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Am J Pathol 163(4): 1623-1632

Genetic Analysis of the Influence of Neuroantigen-Complete Freund’s Adjuvant Emulsion Structures on the Sexual Dimorphism and Susceptibility to Experimental Allergic Encephalomyelitis

From the Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois; the Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; and the Department of Medicine, University of Vermont, Burlington, Vermont
Accepted 2003 Jun 27.

Abstract

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 × SJL/J) F2 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, F2 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.

Abstract

The use of complete Freund’s adjuvant (CFA) to induce organ-specific autoimmune disease dates back to 1947 when Freund reported the induction of experimental allergic encephalomyelitis (EAE) in guinea pigs using a single injection of central nervous system (CNS) antigens emulsified in CFA. 1 Before this time, multiple injections without adjuvants were used. 2 Subsequently, the use of CFA resulted in eliciting a plethora of experimental models of organ-specific autoimmune disease in a wide variety of species 3 including humans. 4,5 The initial theories put forth by Freund to explain the adjuvanticity of CFA centered around three mechanisms: 1) persistence of the antigen at the site of injection, 2) transport of the antigen to the lymphatic system, and 3) development of sensitization. 6 These hypotheses served as the impetus for the studies establishing that autoantigen sensitization using CFA emulsions preferentially stimulates delayed-type hypersensitivity reactions mediated by CD4 Th1 effector T cells. 3

Additional adjuvants, such as Bordetella pertussis 7,8 and pertussis toxin (PTX), 9,10 the major exotoxin produced by B. pertussis, 11 were also found to be useful for inducing certain diseases, particularly in rats and mice. However, B. pertussis and PTX elicit both strong DTH and anaphylactic antibody responses. 12 With respect to disease induction, it was recently demonstrated that the histamine H1 receptor underlies Bphs, a shared autoimmune disease susceptibility locus between EAE and autoimmune orchitis, associated with the adjuvanticity of PTX and controlling the development of pathogenic CD4 Th1 effector T cells. 13-15

We recently demonstrated that PTX also overrides many of the genetic checkpoints identified in mapping studies where CFA was used as the sole adjuvant. 16 Additionally, the use of PTX as an ancillary adjuvant resulted in less severe disease in female (B10.S/DvTe × SJL/J) × B10.S/DvTe backcross mice compared to female backcross mice immunized without PTX. In this same study, comparative mapping studies using backcross mice immunized with and without PTX led to the identification of adjuvant-dependent, sex-specific QTL. 16 These results suggest that the sexual dimorphism seen in EAE may be due in part to sex-specific QTL controlling responsiveness to the adjuvants used to induce disease. We report here that immunization of (B10.S/SgMcdJ × SJL/J) F2 mice with CFA emulsions consisting of particles where the Mycobacterium tuberculosis and encephalitogens are localized on the phase surfaces do not exhibit a sexual dimorphism. In contrast, F2 mice immunized with emulsions where the bacteria and neuroantigens are buried inside the water/oil vesicles exhibit a significant sexual dimorphism (5% male versus 10% female) and that QTL on chromosomes 7 and 11 control susceptibility to sexually dimorphic EAE as a function of the particulate structure of neuroantigen-CFA emulsions.

Animals were scored as unaffected or affected (any clinical signs) by D30 post-injection.

*Percent affected.

The average weight loss was calculated using the total loss in grams for each animal from the baseline weight at injection to the peak of clinical disease.

*Percent affected.

The average weight loss was calculated using the total change in grams for each animal from the baseline weight at injection to the peak of clinical disease.

*Mice were classified as susceptible if they exhibited clinical signs for two or more consecutive days. D7Mit281 and D11Mit307 are the chromosome 7 and 11 markers exhibiting maximal linkage.

*Indicates the presence of either the DBA/2J (d) or BALB/c (c) Havcr2 (formerly Timd3) allele as determined by using allele-specific oligonucleotide (ASO) primers. The presence of a signature codon in this fragment was confirmed by the detection of a BstNI site (at position 132 relative to the ATG) in the PCR product from each d strain.

The fragment sizes of a polymorphic microsatellite marker within the Havcr2/Timd3 locus is given in nucleotides, including the primer and flanking sequence.

Indicates the presence of a polymorphic AflIII restriction site at position 277 relative to the ATG.

Havcr2/Timd3 haplotypes based on the combined genotypes at the three polymorphic regions are indicated by a letter (a–e). The AKR/J subline sample (DNA from Jackson Laboratory) showed a different haplotype than the sequence in NCBI (AF450241).

Indicates if either significant or suggestive linkage of EAE to the eae6b region of chromosome 11 was observed in previous publications of the progeny of pairs indicated. For the RIII.S/J × B10.RIII/SnJ cross, the haplotype of B10.RIII/SnJ is inferred from the haplotype found in B10.S/DvTe and B10.A/SgSnJ.

Footnotes

Address reprint requests to Dr. Cory Teuscher, C317 Given Medical Building, University of Vermont, Burlington, VT 05405. E-mail: .ude.mvu.ooz@ehcsuetc

Supported by National Institutes of Health grants NS36526, AI41747, and AI45105 (to C.T.), NS255195 (to E. P. B.), and National Multiple Sclerosis Society Grant RG3129 (to C.T.).

Footnotes

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