PMID- 23940344
OWN - NLM
STAT- MEDLINE
DCOM- 20131122
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 35
DP  - 2013 Aug 27
TI  - Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of 
      Lyn kinase, causes severe autoimmunity and inflammation.
PG  - E3311-20
LID - 10.1073/pnas.1300617110 [doi]
AB  - Deletion of lyn, a Src-family tyrosine kinase expressed by B, myeloid, and 
      dendritic cells (DCs), triggers lupus-like disease in mice, characterized by 
      autoantibody production and renal immune complex deposition leading to chronic 
      glomerulonephritis. B cells from these mice are hyperactive to antigen-receptor 
      stimulation owing to a loss of inhibitory signaling mediated by Lyn kinase. The 
      hyperactive B-cell responses are thought to underlie the development of 
      autoimmunity in this model. Lyn-deficient mice also manifest significant 
      myeloexpansion. To test the contribution of different immune cell types to the 
      lupus-like disease in this model, we generated a lyn(flox/flox) transgenic mouse 
      strain. To our surprise, when we crossed these mice to Cd11c-cre animals, 
      generating DC-specific deletion of Lyn, the animals developed spontaneous B- and 
      T-cell activation and subsequent production of autoantibodies and severe 
      nephritis. Remarkably, the DC-specific Lyn-deficient mice also developed severe 
      tissue inflammatory disease, which was not present in the global lyn(-/-) strain. 
      Lyn-deficient DCs were hyperactivated and hyperresponsive to Toll-like receptor 
      agonists and IL-1beta. To test whether dysregulation of these signaling pathways in 
      DCs contributed to the inflammatory/autoimmune phenotype, we crossed the lyn(f/f) 
      Cd11c-cre(+) mice to myd88(f/f) animals, generating double-mutant mice lacking 
      both Lyn and the adaptor protein myeloid differentiation factor 88 (MyD88) in 
      DCs, specifically. Deletion of MyD88 in DCs alone completely reversed the 
      inflammatory autoimmunity in the DC-specific Lyn-mutant mice. Thus, we 
      demonstrate that hyperactivation of MyD88-dependent signaling in DCs is 
      sufficient to drive pathogenesis of lupus-like disease, illuminating the fact 
      that dysregulation in innate immune cells alone can lead to autoimmunity.
FAU - Lamagna, Chrystelle
AU  - Lamagna C
AD  - Department of Laboratory Medicine, University of California, San Francisco, CA 
      94143, USA.
FAU - Scapini, Patrizia
AU  - Scapini P
FAU - van Ziffle, Jessica A
AU  - van Ziffle JA
FAU - DeFranco, Anthony L
AU  - DeFranco AL
FAU - Lowell, Clifford A
AU  - Lowell CA
LA  - eng
GR  - P01 AI078869/AI/NIAID NIH HHS/United States
GR  - AI68150/AI/NIAID NIH HHS/United States
GR  - R01 AI068150/AI/NIAID NIH HHS/United States
GR  - AI078869/AI/NIAID NIH HHS/United States
GR  - T32 CA009043/CA/NCI NIH HHS/United States
GR  - R01 AI065495/AI/NIAID NIH HHS/United States
GR  - AI65495/AI/NIAID NIH HHS/United States
GR  - 5T32CA009043/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130812
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Autoantibodies)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - EC 2.7.10.2 (lyn protein-tyrosine kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Animals
MH  - Autoantibodies/biosynthesis
MH  - *Autoimmunity
MH  - Dendritic Cells/enzymology/immunology/*metabolism
MH  - Inflammation/*metabolism
MH  - Lymphatic Diseases/genetics/metabolism
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Knockout
MH  - Myeloid Differentiation Factor 88/*metabolism
MH  - *Signal Transduction
MH  - Splenomegaly/genetics/metabolism
MH  - src-Family Kinases/*genetics
PMC - PMC3761623
OTO - NOTNLM
OT  - Lyn tyrosine kinase
OT  - conditional dendritic cell mutants
OT  - interleukin 1 signaling
OT  - lipopolysacchride signaling
COIS- The authors declare no conflict of interest.
EDAT- 2013/08/14 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/02/27
CRDT- 2013/08/14 06:00
PHST- 2013/08/14 06:00 [entrez]
PHST- 2013/08/14 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/02/27 00:00 [pmc-release]
AID - 1300617110 [pii]
AID - 201300617 [pii]
AID - 10.1073/pnas.1300617110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):E3311-20. doi: 
      10.1073/pnas.1300617110. Epub 2013 Aug 12.