Increased severity of experimental allergic encephalomyelitis in lyn-/- mice in the absence of elevated proinflammatory cytokine response in the central nervous system.
lyn, a member of the src kinase family, is an important signaling molecule in B cells. lyn(-/-) mice display hyperactive B-1 cells and IgM hyperglobulinemia. The role of lyn on T cell function and development of Th1-mediated inflammatory disease is not known. Therefore, we examined the effect of disruption of the lyn gene on the development of experimental allergic encephalomyelitis (EAE), a well-established Th1-mediated autoimmune disease. Following immunization with myelin oligodendrocyte protein (MOG) p35-55, lyn(-/-) mice had higher clinical and pathological severity scores of EAE when compared with wild type (WT). The increase in the severity of EAE in lyn(-/-) mice was not associated with a commensurate increase in the production of proinflammatory cytokines in the CNS. lyn(-/-) mice with EAE showed elevation in serum anti-IgM MOG Ab levels over that seen in WT mice, along with a modest increase in the mRNA levels of complement C5 and its receptor, C5aR, in the spinal cord. Transfer of serum from MOG-immunized lyn(-/-) mice worsened EAE in WT mice, suggesting a pathogenic role for anti-MOG IgM Abs in EAE. These observations underscore the potential role of lyn in regulation of Th1-mediated disease and the role of autoantibodies and complement in the development of EAE.
Du
Caigan
C
Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
Sriram
Subramaniam
S
D000595:Amino Acid Sequence; D000818:Animals; D003165:Complement System Proteins / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics*
D016207:Cytokines; D006023:Glycoproteins; D007075:Immunoglobulin M; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D003165:Complement System Proteins; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases