Abstract
IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12Rbeta1/IL-12Rbeta2), whose beta2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12Rbeta2 would protect from EAE, we found that IL-12Rbeta2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4(+) T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12Rbeta2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-alpha, GM-CSF, IL-17, IL-18/IL-18Ralpha, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12Rbeta2(-/-) mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12Rbeta2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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B-Lymphocyte Subsets / immunology
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B-Lymphocyte Subsets / pathology
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CD4-Positive T-Lymphocytes / pathology
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Demyelinating Autoimmune Diseases, CNS / genetics
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Demyelinating Autoimmune Diseases, CNS / immunology
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Demyelinating Autoimmune Diseases, CNS / pathology
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Encephalomyelitis, Autoimmune, Experimental / genetics*
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Epitopes, B-Lymphocyte / immunology
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Epitopes, T-Lymphocyte / immunology
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Genetic Predisposition to Disease / genetics
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Glycoproteins / administration & dosage
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Glycoproteins / immunology
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Inflammation / genetics
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Inflammation / immunology
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Interleukin-12 / metabolism
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Interleukin-12 / physiology*
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Interleukin-18 / biosynthesis
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Interleukin-18 / metabolism
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Interleukin-18 Receptor alpha Subunit
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Interleukin-23
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Interleukin-23 Subunit p19
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Interleukins / biosynthesis
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Interleukins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology
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RNA, Messenger / biosynthesis
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin / deficiency*
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Receptors, Interleukin / genetics*
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Receptors, Interleukin-12
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Receptors, Interleukin-18
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Severity of Illness Index
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / pathology
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Epitopes, B-Lymphocyte
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Epitopes, T-Lymphocyte
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Glycoproteins
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Il12rb2 protein, mouse
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Il18r1 protein, mouse
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Il23a protein, mouse
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Interleukin-18
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Interleukin-18 Receptor alpha Subunit
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Interleukin-23
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Interleukin-23 Subunit p19
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Interleukins
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-12
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Receptors, Interleukin-18
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myelin oligodendrocyte glycoprotein (35-55)
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Interleukin-12