Mite Allergen Der-p2 Triggers Human B Lymphocyte Activation and Toll-Like Receptor-4 Induction

Abstract

BackgroundAllergic disease can be characterized as manifestations of an exaggerated inflammatory response to environmental allergens triggers. Mite allergen Der-p2 is one of the major allergens of the house dust mite, which contributes to TLR4 expression and function in B cells in allergic patients. However, the precise mechanisms of Der-p2 on B cells remain obscure.Methodology/Principal FindingsWe investigated the effects of Der-p2 on proinflammatory cytokines responses and Toll-like receptor-4 (TLR4)-related signaling in human B cells activation. We demonstrated that Der-p2 activates pro-inflammatory cytokines, TLR4 and its co-receptor MD2. ERK inhibitor PD98059 significantly enhanced TLR4/MD2 expression in Der-p2-treated B cells. Der-p2 markedly activated mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) and decreased p38 phosphorylation in B cells. MKP-1-siRNA downregulated TLR4/MD2 expression in Der-p2-treated B cells. In addition, Der-p2 significantly up-regulated expression of co-stimulatory molecules and increased B cell proliferation. Neutralizing Der-p2 antibody could effectively abrogate the Der-p2-induced B cell proliferation. Der-p2 could also markedly induce NF-κB activation in B cells, which could be counteracted by dexamethasone.Conclusions/SignificanceThese results strongly suggest that Der-p2 is capable of triggering B cell activation and MKP-1-activated p38/MAPK dephosphorylation-regulated TLR4 induction, which subsequently enhances host immune, defense responses and development of effective allergic disease therapeutics in B cells.

Dp2-Induce Autoantigen/Autoantibody Production from Patients with Systemic Lupus Erythematosus and Its Modulation by Cppecp

“…Purified B cells from the PBMCs were prepared as previously described [6]. B cell preparations were 95% positive for the CD19 marker as determined by FACS analysis.…”

“…Dp2 is able to both trigger human B lymphocyte activation, and induce B cell proliferation. Dp2 can induce expressionof IL-1β, TNF-α and IL-8, and up-regulate MD2, TLR4 induction in B cells, which enhance the host's immune response [6]. Dp2 can induce bystander activation of B cells derived from patients with SLE [7].…”

Innate Immune Responses in House Dust Mite Allergy

“…Recombinant Der p 2 was indeed able to stimulate airway smooth muscle cells in a TLR4-independent manner but triggered the MyD88 signaling pathway through TLR2 [54]. Der p 2 was also able to trigger human B-cell activation through NFkB-dependent IL-1 β , CXCL10, IL-8, and TNF- α as well as TLR4/MD-2 induction [55]. …”

Der p 2 can induce bystander activation of B cells derived from patients with systemic lupus erythematosus

“…Purified B cells from the PBMCs were prepared as previously described (Tsai et al 2011). B cell preparations were 95% positive for the CD19 marker as determined by FACS analysis.…”

“…Whole cell lysates were prepared as described previously (Liu et al 2010;Tsai et al 2011). After blocking, the blots were incubated with antibodies for anti-human PGK-1, TIM, enolase-1 (Santa Cruz Biotechnology), TRIM-21 (Bethyl) and ␤-actin (Millipore) in TBS with 0.1% Tween 20 for 1 h, followed by three 10-min washes in TBS with 0.1% Tween 20.…”