TY - JOUR
T1 - Fatty acid amide hydrolase regulates peripheral B cell receptor revision, polyreactivity, and B1 cells in lupus
AU - Pathak, Simanta
AU - Kumar, Kirthi Raman
AU - Kanta, Hasna
AU - Carr-Johnson, Ferdicia
AU - Han, Jie
AU - Bashmakov, Anna
AU - Faure, Lionel
AU - Ding, Huihua
AU - Vanarsa, Kamala
AU - Khan, Shaheen
AU - Li, Quan Zhen
AU - Chapman, Kent
AU - Wakeland, Edward K.
AU - Mohan, Chandra
N1 - Funding Information:
This work was supported by National Institutes of Health Grant AR055600 (to C.M.), U.S. Department of Energy Grant DE-FG02-05ER15647 (to K.C.), and an Arthritis Foundation fellowship (to S.P.). We thank Anne Satterthwaite for critical reading of the manuscript.
Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - C57BL/6 mice bearing the Sle2z lupus-susceptibility congenic interval on chromosome 4 display high titers of polyclonal autoantibodies with generalized B cell hyperactivity, hallmarks of systemic lupus erythematosus. In B6.Sle2zHELIg.sHEL BCRtransgenic mice, Sle2z did not breach central tolerance, but it led to heightened expression of endogenous Ig H and L chains in splenic B cells, upregulation of RAG, and serological polyreactivity, suggestive of excessive receptor revision. Fatty acid amide hydrolase (FAAH), a gene in the minimal subcongenic interval generated through recombinant mapping, was found to be upregulated in Sle2z B cells by microarray analysis, Western blot, and functional assays. Pharmacological inhibition of FAAH reversed the increase in receptor revision, RAG expression, and polyreactive autoantibodies in lupus-prone mice. These studies indicate that increased peripheral BCR revision, or selective peripheral expansion of BCR-revised B cells, may lead to systemic autoimmunity and that FAAH is a lupus-susceptibility gene that might regulate this process.
AB - C57BL/6 mice bearing the Sle2z lupus-susceptibility congenic interval on chromosome 4 display high titers of polyclonal autoantibodies with generalized B cell hyperactivity, hallmarks of systemic lupus erythematosus. In B6.Sle2zHELIg.sHEL BCRtransgenic mice, Sle2z did not breach central tolerance, but it led to heightened expression of endogenous Ig H and L chains in splenic B cells, upregulation of RAG, and serological polyreactivity, suggestive of excessive receptor revision. Fatty acid amide hydrolase (FAAH), a gene in the minimal subcongenic interval generated through recombinant mapping, was found to be upregulated in Sle2z B cells by microarray analysis, Western blot, and functional assays. Pharmacological inhibition of FAAH reversed the increase in receptor revision, RAG expression, and polyreactive autoantibodies in lupus-prone mice. These studies indicate that increased peripheral BCR revision, or selective peripheral expansion of BCR-revised B cells, may lead to systemic autoimmunity and that FAAH is a lupus-susceptibility gene that might regulate this process.
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U2 - 10.4049/jimmunol.1500291
DO - 10.4049/jimmunol.1500291
M3 - Article
C2 - 26773143
AN - SCOPUS:84958576337
SN - 0022-1767
VL - 196
SP - 1507
EP - 1516
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -