IL-22RA2 associates with multiple sclerosis and macrophage effector mechanisms in experimental neuroinflammation

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS. Recent advances in whole-genome screening tools have enabled discovery of several MS risk genes, the majority of which have known immune-related functions. However, disease heterogeneity and low tissue accessibility hin...

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Veröffentlicht in:The Journal of immunology (1950) Jg. 185; H. 11; S. 6883
Hauptverfasser: Beyeen, Amennai D, Adzemovic, Milena Z, Ockinger, Johan, Stridh, Pernilla, Becanovic, Kristina, Laaksonen, Hannes, Lassmann, Hans, Harris, Robert A, Hillert, Jan, Alfredsson, Lars, Celius, Elisabeth G, Harbo, Hanne F, Kockum, Ingrid, Jagodic, Maja, Olsson, Tomas
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.12.2010
Schlagworte:
Animals
Animals, Congenic
Crosses, Genetic
Encephalomyelitis, Autoimmune, Experimental - genetics
Encephalomyelitis, Autoimmune, Experimental - immunology
Encephalomyelitis, Autoimmune, Experimental - pathology
False Positive Reactions
Female
Follow-Up Studies
Genetic Association Studies - methods
Genetic Predisposition to Disease
Humans
Immunity, Innate - genetics
Macrophages, Peritoneal - immunology
Macrophages, Peritoneal - metabolism
Macrophages, Peritoneal - pathology
Male
Multiple Sclerosis - genetics
Multiple Sclerosis - immunology
Multiple Sclerosis - pathology
Rats
Rats, Inbred Strains
Receptors, Interleukin - genetics
Receptors, Interleukin - metabolism
Receptors, Interleukin - physiology
Risk Factors
Severity of Illness Index
ISSN:1550-6606, 1550-6606
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Zusammenfassung:Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS. Recent advances in whole-genome screening tools have enabled discovery of several MS risk genes, the majority of which have known immune-related functions. However, disease heterogeneity and low tissue accessibility hinder functional studies of established MS risk genes. For this reason, the MS model experimental autoimmune encephalomyelitis (EAE) is often used to study neuroinflammatory disease mechanisms. In this study, we performed high-resolution linkage analysis in a rat advanced intercross line to identify an EAE-regulating quantitative trait locus, Eae29, on rat chromosome 1. Eae29 alleles from the resistant strain both conferred milder EAE and lower production of proinflammatory molecules in macrophages, as demonstrated by the congenic line, DA.PVG-Eae29 (Dc1P). The soluble IL-22R α2 gene (Il-22ra2) lies within the Eae29 locus, and its expression was reduced in Dc1P, both in activated macrophages and splenocytes from immunized rats. Moreover, a single nucleotide polymorphism located at the end of IL-22RA2 associated with MS risk in a combined Swedish and Norwegian cohort comprising 5019 subjects, displaying an odds ratio of 1.26 (p = 8.0 × 10(-4)). IL-22 and its receptors have been implicated in chronic inflammation, suggesting that IL-22RA2 regulates a central immune pathway. Through a combined approach including genetic and immunological investigation in an animal model and large-scale association studies of MS patients, we establish IL-22RA2 as an MS risk gene.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1550-6606
1550-6606
DOI:10.4049/jimmunol.1001392