Disabled-2 (DAB2) Overexpression Inhibits Monocyte-Derived Dendritic Cells' Function in Vogt-Koyanagi-Harada Disease

Abstract

PURPOSE. Recent studies reported that the tumor suppressor disabled-2 (DAB2) is a negative regulator of immune function. In this study, we investigated the role of DAB2 in monocytederived dendritic cells (DCs) from Vogt-Koyanagi-Harada disease (VKH) patients. METHODS. The mRNA and protein levels of DAB2 were quantified by quantitative real-time PCR and Western blot. The Sequenom MassARRAY system was used to detect the promoter methylation level. An adenovirus carrying the DAB2 gene was transduced into immature DCs, isolated, and induced from active VKH patients. The surface markers of DCs, the frequency of T helper (Th) type 1 (Th1) and Th17 cells in CD4 þ T cells, which were cocultured with DCs, were tested by flow cytometry. ELISA was used to analyze the inflammatory cytokines produced by DC and CD4 þ T cell cocultures. RESULTS. The mRNA and protein expression levels of DAB2 in DCs obtained from active VKH patients were decreased, while the DAB2 promoter methylation level was marginally increased when compared with inactive VKH patients and normal controls. The expression of CD86 on DCs was significantly downregulated by DAB2 overexpression. The DC-related inflammatory factors IL-6 and TNF-a were also decreased. The frequency of Th1 and Th17 cells and their related cytokines were reduced significantly after coculture with DAB2 overexpressing DCs. DAB2 overexpression did not affect autophagy in DCs from VKH patients. CONCLUSIONS. These results suggest that the decreased expression of DAB2 in DCs plays a role in the pathogenesis of VKH disease. DAB2 overexpression inhibits DC function, but this is not mediated via autophagy.

Disabled‐2 overexpression mediates immune suppression in systemic lupus erythematosus by modulating Treg/Th17 cell differentiation

“…The influence of DAB2 has been documented earlier in autoimmune diseases including encephalomyelitis and Vogt‐Koyanagi‐Harada disease 15,20,21 . DAB2 can exert critical roles in maintaining immune cell function and regulating inflammatory response 22 .…”

“…In the immune system, DAB2, a target gene of the transcription factor forkhead box P3 (Foxp3), can maintain the function of Treg cells 13 . DAB2 deficiency contributes to the transformation of colonic dendritic cells to inflammatory Th1/Th17 phenotype and promotes the release of inflammatory factors tumour necrosis factor alpha (TNF‐α), interleukin (IL)‐6 and IL‐17A, whereas overexpression of DAB2 contributes to the opposite effects 14,15 . These findings suggest that DAB2 may play key roles in regulating Treg/Th17 cell differentiation.…”

Emerging Roles of Disabled Homolog 2 (DAB2) in Immune Regulation

“…The DAB2 has been studied in humans DCs in the context of systemic autoimmunity directed against tissues expressing melanosome-associated tissues called Vogt-Koyanagi-Haranda (VKH) ( 36 ). The reported findings suggest that DAB2 repression in DCs may indeed contribute to pathogenesis of autoimmune diseases.…”

“…The reported findings suggest that DAB2 repression in DCs may indeed contribute to pathogenesis of autoimmune diseases. Dab2 mRNA and protein were found decreased in monocyte-derived DCs from patients with active VKH, and restored to normal levels after immunosuppressive therapy ( 36 ). Epigenetic modifications in Dab2 gene were found in DCs from VKH patients and may contribute to its repression during this disease.…”

“…Epigenetic modifications in Dab2 gene were found in DCs from VKH patients and may contribute to its repression during this disease. Additionally, Dab2 overexpression in DCs from active VKH patients led to decreased expression of activation markers CD83, CD40 and CD86, as well as production of TNFα and IL12p70 after LPS challenge, which ultimately rendered DCs less efficient in inducing differentiation of naïve CD4 + T cells into Th1 and Th17 effector cells ( 36 ). In effects, this observation showed that restoration of DAB2 expression in DCs counter-regulated their inflammatory phenotype.…”