MyD88-dependent autoimmune disease in Lyn-deficient mice.
Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyn-deficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cell-independent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis.
Silver
Karlee L
KL
Henry Wellcome Building of Molecular Physiology, University of Oxford, Oxford, UK.
Crockford
Tanya L
TL
Bouriez-Jones
Tiphaine
T
Milling
Simon
S
Lambe
Teresa
T
Cornall
Richard J
RJ
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics*
D001323:Autoantibodies; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases