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Multiple loci comprising immune-related genes regulate experimental neuroinflammation

Genes & Immunity volume 11, pages 21–36 (2010)Cite this article

Abstract

A 58 Mb region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis (EAE) was genetically dissected. High-resolution linkage analysis in an advanced intercross line (AIL) revealed four quantitative trait loci (QTLs), Eae24–Eae27. Both Eae24 and Eae25 regulated susceptibility and severity phenotypes, whereas Eae26 regulated severity and Eae27 regulated susceptibility. Analyses of the humoral immune response revealed that the levels of serum anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobin G1 (IgG1) antibodies are linked to Eae24 and anti-MOG IgG2b antibodies are linked to both Eae24 and Eae26. We tested the parental DA strain and six recombinant congenic strains that include overlapping fragments of this region in MOG-EAE. Eae24 and Eae25 showed significant protection during the acute phase of EAE, whereas Eae25 and Eae26 significantly modified severity but not susceptibility. The smallest congenic fragment, which carries Eae25 alone, influenced both susceptibility and severity, and protected from the chronic phase of disease. These results support the multiple QTLs identified in the AIL. By demonstrating several QTLs comprising immune-related genes, which potentially interact, we provide a significant step toward elucidation of the polygenically regulated pathogenesis of MOG-EAE and possibly multiple sclerosis (MS), and opportunities for comparative genetics and testing in MS case–control cohorts.

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Acknowledgements

We thank Dr William Valdar for advice on statistical analyses. This study was supported by grants from the Swedish Research Council, The Wadsworth Foundation, Söderbergs Foundation, Petrus and Augusta Hedlunds Foundation, Bibbi and Niels Jensens Foundation, Montel Williams Foundation, Åke-Wibergs Stiftelse and the Swedish Foundation for Neurologically Disabled, EURATools (LSHG-CT-2005–019015) and Neuropromise (LSHM-CT-2005–018637). Monica Marta was supported by a fellowship from the Portuguese Fundação para a Ciência e Tecnologia—POCTI—Formar e Qualificar—Medida 1.1 program.

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  1. M Marta

    Present address: 4Current address: Neuroimmunology Unit, Department of Neurosciences, Institute of Cell and Molecular Sciences, Barts and The London School of Medicine and Dentistry, London, UK.,

  2. M Marta, P Stridh, M Jagodic and T Olsson: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Clinical Neuroscience, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    M Marta, P Stridh, K Becanovic, A Gillett, J Öckinger, M Jagodic & T Olsson

  2. Department of Medicine, Rheumatology Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    J C Lorentzen

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Marta, M., Stridh, P., Becanovic, K. et al. Multiple loci comprising immune-related genes regulate experimental neuroinflammation. Genes Immun 11, 21–36 (2010). https://doi.org/10.1038/gene.2009.62

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