Fatty acid amide hydrolase regulates peripheral B cell receptor revision, polyreactivity, and B1 cells in lupus

Simanta Pathak, Kirthi Raman Kumar, Hasna Kanta, Ferdicia Carr-Johnson, Jie Han, Anna Bashmakov, Lionel Faure, Huihua Ding, Kamala Vanarsa, Shaheen Khan, Quan Zhen Li, Kent Chapman, Edward K. Wakeland, Chandra Mohan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1507-1516
Number of pages10
JournalJournal of Immunology
Volume196
Issue number4
DOIs
StatePublished - Feb 15 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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