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 journalArticle

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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

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B-Lymphocytes
Autoantibodies
Central Tolerance
Tissue Array Analysis
Chromosomes, Human, Pair 4
Autoimmunity
Inbred C57BL Mouse
Systemic Lupus Erythematosus
Genes
Up-Regulation
Western Blotting
Pharmacology
fatty-acid amide hydrolase

ASJC Scopus subject areas

  • Immunology

Cite this

Fatty acid amide hydrolase regulates peripheral B cell receptor revision, polyreactivity, and B1 cells in lupus. / Pathak, Simanta; Kumar, Kirthi Raman; Kanta, Hasna; Carr-Johnson, Ferdicia; Han, Jie; Bashmakov, Anna; Faure, Lionel; Ding, Huihua; Vanarsa, Kamala; Khan, Shaheen; Li, Quan Zhen; Chapman, Kent; Wakeland, Edward K.; Mohan, Chandra.

In: Journal of Immunology, Vol. 196, No. 4, 15.02.2016, p. 1507-1516.

Research output: Contribution to journalArticle

Pathak, S, Kumar, KR, Kanta, H, Carr-Johnson, F, Han, J, Bashmakov, A, Faure, L, Ding, H, Vanarsa, K, Khan, S, Li, QZ, Chapman, K, Wakeland, EK & Mohan, C 2016, 'Fatty acid amide hydrolase regulates peripheral B cell receptor revision, polyreactivity, and B1 cells in lupus', Journal of Immunology, vol. 196, no. 4, pp. 1507-1516. https://doi.org/10.4049/jimmunol.1500291
Pathak, Simanta ; Kumar, Kirthi Raman ; Kanta, Hasna ; Carr-Johnson, Ferdicia ; Han, Jie ; Bashmakov, Anna ; Faure, Lionel ; Ding, Huihua ; Vanarsa, Kamala ; Khan, Shaheen ; Li, Quan Zhen ; Chapman, Kent ; Wakeland, Edward K. ; Mohan, Chandra. / Fatty acid amide hydrolase regulates peripheral B cell receptor revision, polyreactivity, and B1 cells in lupus. In: Journal of Immunology. 2016 ; Vol. 196, No. 4. pp. 1507-1516.
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