1. J Immunol. 2010 Dec 1;185(11):6883-90. doi: 10.4049/jimmunol.1001392. Epub 2010
Nov 1.
IL-22RA2 associates with multiple sclerosis and macrophage effector mechanisms in
experimental neuroinflammation.
Beyeen AD(1), Adzemovic MZ, Ockinger J, Stridh P, Becanovic K, Laaksonen H,
Lassmann H, Harris RA, Hillert J, Alfredsson L, Celius EG, Harbo HF, Kockum I,
Jagodic M, Olsson T.
Author information:
(1)Neuroimmunology Unit, Department of Clinical Neuroscience, Center for
Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
amennai.beyeen@ki.se
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.
PMID: 21041731 [PubMed - indexed for MEDLINE]
PUBMED: 21041731
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