Abstract
Autoimmune hepatitis (AIH) is a necroinflammatory disease associated with interactive cell populations of the innate and adaptive immune systems. The contribution of conventional dendritic cells (cDCs) to AIH and the underlying mechanism remain poorly understood. The frequency of peripheral mature cDCs increased in AIH patients and was positively correlated with disease severity. In experimental autoimmune hepatitis (EAH), hepatic accumulation of mature cDCs was observed, along with an increase in the periphery. Sequentially, bone marrow-derived dendritic cells (BMDC) from EAH mice exhibit more proinflammatory function than those from control mice. In vitro, ConA treatment promotes the maturation of BMDCs, which are characterized by higher expression of MHC-II, costimulatory molecules and cytokine secretion. ConA also induced the expression of autophagy-related protein and the formation of autophagosomes in DCs. To further investigate whether ConA-induced DC activation is associated with autophagy, we utilized 3-MA and bafilomycin A1 to block autophagy flux and accessed the maturation and function of DCs induced by ConA. 3-MA and bafilomycin A1 inhibited the mature status and proinflammatory cytokine secretion and diminished the proliferation and differentiation of CD4+ T cells when ConA-induced BMDCs cocultured CD4+ T cells. We demonstrated that cDCs contribute to the pathogenesis of AIH through excessive maturation. Aberrant autophagy flux plays a vital role in the immunogenic maturation of cDCs in AIH, and tolerogenic cDCs by inhibition of autophagy flux can be exploited as a new therapeutic approach for AIH.
Highlights
Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver that is characterized by histological interface hepatitis, hypergammaglobulinemia and the production of autoantibodies and could rapidly lead to cirrhosis and end-stage-liver disease if left untreated[1]
The quantitative expression of this molecule can affect the initiation of immune responses. An increase in this molecule might lead to the overreaction of Conventional dendritic cells (DCs) (cDCs), which results in systematic immune imbalance
Using the fresh peripheral blood and liver section of AIH patients and healthy controls, we demonstrated that mature cDCs played a detrimental role in promoting AIH, and a mouse experimental autoimmune hepatitis (EAH) model was used to validate the phenomenon
Summary
Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver that is characterized by histological interface hepatitis, hypergammaglobulinemia and the production of autoantibodies and could rapidly lead to cirrhosis and end-stage-liver disease if left untreated[1]. During AIH, self-tolerance ( termed homeostatic processes) is impaired, resulting in Kupffer. DCs are heterogeneous, differing in origin, location, function and migratory pathways[5]. Infections or inflammatory stimuli can affect their function and generation. Conventional DCs (cDCs) are a DC subsets with a dendritic form that exhibit DC functions in a steady state. CDCs account for 1% of hepatic nonparenchymal cells (NPC).
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