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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2013)

Dendritic cells are crucial for the development of the adaptive immune response and have also been implicated in a number of inflammatory diseases. Much of what we know about dendritic cell function is limited to mouse models of disease, as human DCs remain difficult to identify consistently and samples can be difficult to acquire. We undertook a study to identify the prevalence of BDCA1+ DCs in a panel of healthy and diseased lung donors by carefully and comprehensively identifying DCs in parenchymal lung tissue. We found a dramatic increase in the prevalence of BDCA1+ DCs in the fibrotic lung diseases idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (HP) by flow cytometry. We also saw a significant increase in BDCA1+ DCs in Th2-high asthma by using the high-affinity IgE receptor, FcERI and MHCII as identification markers of DCs in biopsy sections. These increased numbers of BDCA1+ DCs could potentially contribute to disease and may represent a novel therapeutic target. Because of the potential role of FcERI in promoting Th2-mediated allergy via DCs, we also investigated regulation of this receptor on human DCs. Surprisingly, we found that human DCs and monocytes constitutively endocytose FcERI and IgE in the absence of crosslinking stimulus. Transgenic mice expressing human FcERIa showed similar FcERI regulation, which resulted in rapid human IgE endocytosis in blood DCs and monocytes in vivo. Serum IgE catabolism was accelerated in FcERI-transgenic mice and was significantly influenced by DC and monocyte numbers. DCs and monocytes may therefore contribute to serum IgE control through constitutive IgE endocytosis and could represent a novel therapeutic strategy for allergic conditions. Further work on the trafficking mechanism of FcERI regulation may provide a significant novel strategy for control of IgE-mediated allergies.

    Cover page: Human dendritic cells accumulate in lung disease and contribute to serum IgE clearance via FcERI
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2014)
    The high-affinity IgE receptor FcεRI is constitutively expressed in mast cells and basophils and is required for transmitting stimulatory signals upon engagement of IgE-bound allergens. FcεRI is also constitutively expressed in dendritic cells (DCs) and monocytes in humans; however, the specific functions of the FcεRI expressed by these cells are not completely understood. Here, we found that FcεRI expressed by human blood DC antigen 1-positive (BDCA1+) DCs and monocytes, but not basophils, traffics to endolysosomal compartments under steady-state conditions. Furthermore, IgE bound to FcεRI on BDCA1+ DCs was rapidly endocytosed, transported to the lysosomes, and degraded in vitro. IgE injected into mice expressing human FcεRIα (FCER1A-Tg mice) was endocytosed by conventional DCs and monocytes, and endocytosis was associated with rapid clearance of circulating IgE from these mice. Importantly, this rapid IgE clearance was dependent on monocytes or DCs but not basophils. These findings strongly suggest that constitutive internalization of human FcεRI by DCs and monocytes distinctively contributes to serum IgE clearance.
      Cover page: Serum IgE clearance is facilitated by human FcεRI internalization
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2014)
      The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aires targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aires interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
        Cover page: The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2014)
        Dendritic cells (DCs) significantly contribute to the pathology of several mouse lung disease models. However, little is known of the contribution of DCs to human lung diseases. In this study, we examined infiltration with BDCA1⁺ DCs of human lungs in patients with interstitial lung diseases or asthma. Using flow cytometry, we found that these DCs increased by 5∼6 fold in the lungs of patients with idiopathic pulmonary fibrosis or hypersensitivity pneumonitis, which are both characterized by extensive fibrosis in parenchyma. The same DC subset also significantly increased in the lung parenchyma of patients with chronic obstructive pulmonary disease, although the degree of increase was relatively modest. By employing immunofluorescence microscopy using FcεRI and MHCII as the specific markers for BDCA1⁺ DCs, we found that the numbers of BDCA1⁺ DCs also significantly increased in the airway epithelium of Th2 inflammation-associated asthma. These findings suggest a potential contribution of BDCA1⁺ DCs in human lung diseases associated with interstitial fibrosis or Th2 airway inflammation.
          Cover page: Accumulation of BDCA1+ Dendritic Cells in Interstitial Fibrotic Lung Diseases and Th2-High Asthma
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