B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease

Z. Xu, S. Ramachandran, M. Gunasekaran, D. Nayak, N. Benshoff, R. Hachem, A. Gelman, T. Mohanakumar

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell-activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2Kb was administered intrabronchially into Batf -/- and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf -/- mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction. There was lack of Abs to SAgs, reduction of Sag-specific interleukin (IL)-17 T cells, IL-6, IL-23, IL-17, IL-1β, fibroblast growth factor-6, and CXCL12 and decreased Janus kinase 2, signal transducer and activator of transcription 3 (STAT3), and retinoid-related orphan receptor γT. Further, micro-RNA (miR)-301a, a regulator of Th17, was reduced in Batf -/- mice in contrast to upregulation of miR-301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) in anti-MHC-induced OAD animals. We also demonstrate an increase in miR-301a in the bronchoalveolar lavage cells from lung transplant recipients with Abs to human leukocyte antigen. This was accompanied by reduction in PIAS3 mRNA. Therefore, we conclude that BATF plays a critical role in the immune responses to SAgs and pathogenesis of anti-MHC-induced rejection. Targeting BATF should be considered for preventing chronic rejection after human lung transplantation.

Original languageEnglish (US)
Pages (from-to)1173-1182
Number of pages10
JournalAmerican Journal of Transplantation
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank Billie Glasscock for her assistance in preparing this manuscript. This work is supported by National Institutes of Health grants HL092514 and HL056643.and the BJC foundation (TM).

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