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2016 ; 14
(ä): 98
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Fn14-Fc suppresses germinal center formation and pathogenic B cells in a lupus
mouse model via inhibition of the TWEAK/Fn14 Pathway
#MMPMID27098560
Min HK
; Kim SM
; Park JS
; Byun JK
; Lee J
; Kwok SK
; Park YW
; Cho ML
; Park SH
J Transl Med
2016[Apr]; 14
(ä): 98
PMID27098560
show ga
BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune-mediated chronic
inflammatory disease. Half of patients with SLE suffer from lupus nephritis,
which is major cause of death in SLE. TNF-like weak inducer of apoptosis
(TWEAK)/fibroblast growth factor-inducible 14 (Fn14) interactions mediate
inflammatory responses that are linked to the pathogenesis of lupus nephritis.
Blocking of the TWEAK/Fn14 pathway by Fn14-Fc was performed in a SLE mouse model
and the likely therapeutic mechanisms were investigated. METHODS: To investigate
the impact of TWEAK on B cell differentiation in SLE, the levels of AID, Blimp-1,
and IRF4 messenger RNA were measured in CD19(+) B cells extracted from the
spleens of sanroque mice and cultured with TWEAK. To identify the therapeutic
effects of Fn14-Fc in SLE, sanroque mice were treated with Fn14-Fc or a
control-Fc for 3 weeks. Immunoglobulin (Ig) G, IgG1, IgG2a, and anti-dsDNA
antibody (Ab) levels were measured in the sera of each group. Spleens from each
group were stained with antibodies against CD4, B220, GL-7, CD138, and PD-1.
Kidneys were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff
(PAS). RESULTS: Administration of TWEAK increased the mRNA levels of AID,
Blimp-1, and IRF4. Treatment with Fn14-Fc suppressed levels of IgG, IgG1, IgG2a,
and anti-dsDNA Ab in sera and reduced numbers of B, plasma, and follicular helper
T (Tfh) cells in spleens of sanroque mice. In addition, renal protective effects
of Fn14-Fc were shown. CONCLUSION: Fn14-Fc had beneficial effects in a SLE mouse
model by repressing B cells, plasma cells, Tfh, and renal damage. This suggested
that Fn14-Fc represents a potential therapeutic agent for SLE.