B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis
of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease
#MMPMID26844425
Xu Z
; Ramachandran S
; Gunasekaran M
; Nayak D
; Benshoff N
; Hachem R
; Gelman A
; Mohanakumar T
Am J Transplant
2016[Apr]; 16
(4
): 1173-82
PMID26844425
show ga
Antibodies (Abs) against major histocompatibility complex (MHC) results in T
helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-?1
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-H2K(b) 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-1?, fibroblast growth factor-6, and CXCL12 and decreased
Janus kinase 2, signal transducer and activator of transcription 3 (STAT3), and
retinoid-related orphan receptor ?T. 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.
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