Abstract
BackgroundParkinson's disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)-containing dopaminergic cells and a profound reduction in striatal dopamine. It has been shown recently that anti-melanin antibodies are increased in sera of Parkinson patients, suggesting that NM may act as an autoantigen. In this study we tested whether NM is being recognized by dendritic cells (DCs), the major cell type for inducing T- and B-cell responses in vivo. This recognition of NM by DCs is a prerequisite to trigger an adaptive autoimmune response directed against NM-associated structures.ResultsMurine DCs were treated with NM of substantia nigra (SN) from human subjects or with synthetic dopamine melanin (DAM). DCs effectively phagocytized NM and subsequently developed a mature phenotype (CD86high/MHCIIhigh). NM-activated DCs secreted the proinflammatory cytokines IL-6 and TNF-α. In addition, they potently triggered T cell proliferation in a mixed lymphocyte reaction, showing that DC activation was functional to induce a primary T cell response. In contrast, DAM, which lacks the protein and lipid components of NM but mimics the dopamine-melanin backbone of NM, had only very little effect on DC phenotype and function.ConclusionsNM is recognized by DCs in vitro and triggers their maturation. If operative in vivo, this would allow the DC-mediated transport and presentation of SN antigens to the adaptive immune system, leading to autoimmmunity in susceptible individuals. Our data provide a rationale for an autoimmune-based pathomechanism of PD with NM as the initial trigger.
Highlights
Parkinson’s disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)containing dopaminergic cells and a profound reduction in striatal dopamine
Dendritic cells phagocytose NM and dopamine melanin (DAM) In order to assess whether dendritic cells (DCs) recognize NM as a potential antigen we coincubated DCs with NM and studied phagocytosis by differential interference contrast microscopy
DCs mature in response to NM Phagocytosis of NM resulted within 48 h in maturation of DCs measured by the upregulation of the cell surface molecules MHCII and CD86
Summary
Parkinson’s disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)containing dopaminergic cells and a profound reduction in striatal dopamine. In this study we tested whether NM is being recognized by dendritic cells (DCs), the major cell type for inducing Tand B-cell responses in vivo. This recognition of NM by DCs is a prerequisite to trigger an adaptive autoimmune response directed against NM-associated structures. Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized at the cellular level by a destruction especially of neuromelanin (NM)-containing dopaminergic cells and a profound reduction in striatal dopamine. Both protective and toxic effects have been reported
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