The Role of JAK2 in Alveolar Macrophages (AM's) in Chronic Beryllium Disease (CBD)
Condition: Chronic Beryllium Disease (CBD); Beryllium Sensitization (BeS)
MeSH terms: Berylliosis
Study type: Observational

Summary: 
      Current studies suggest that alveolar macrophages (AM) act as silencers of most immune
      responses in the lung. However, in pathological conditions, such as asthma, hypersensitivity
      pneumonitis, and sarcoidosis, AMs become involved in the maintenance and further expansion of
      the immune response in the target organ. The Investigator has preliminary data demonstrating
      that CBD AMs at the site of disease involvement (bronchoalveolar lavage, BAL) display an
      activated cell surface phenotype compared to AMs from healthy controls. Furthermore, exciting
      data from our group demonstrates significant differences in gene expression profiles between
      CBD and Beryllium Sensitivity (BeS) bronchial alveolar lavage (BAL) cells, in pivotal immune
      response genes and networks. Specifically, the Investigator has found the JAK/STAT pathway
      and the JAK2 gene was dramatically overexpressed in CBD BAL cells. In addition,
      constitutively phosphorylated JAK2 (pJAK2) was found in AMs from Chronic Beryllium Disease
      (CBD) patients by Westernblot and was increased after beryllium (Be) stimulation for 30 min.
      Moreover, the JAK2 inhibitor TG101348 significantly inhibited Be-induced CBD AMs TNFa and
      IFNy production. Meanwhile, overexpression of the JAK2 inhibitor SOCS 1 (suppressors of
      cytokine signaling) protein decreased Be-induced TNFa production from AMs. Based on this
      information, the Investigator hypothesizes that CBD AMs overexpress JAK2, which augments the
      immune response to Be and development of CBD but not BeS.

      The investigators believe that these studies are highly innovative since they will
      undoubtedly shed light on exposure-mediated immune dysregulation in Alveolar Macrophages
      (AMs) that lead to disease development and likely progression and with additional study of
      this pathway will reveal potential biomarkers for clinical prognosis and diagnosis. The
      results obtained from this study will improve the investigators understanding of factors
      involved in the development of Chronic Beryllium disease (CBD), as well as define targets for
      therapy, and will serve as a model of other exposure-related immune responses and
      environmentally-induced chronic diseases. Most importantly, these studies will provide the
      investigator with preliminary data to submit a high quality R01, allowing the Investigator to
      apply similar approaches to other genes, define a potential target for this and other similar
      immune-mediated diseases and continue research efforts at National Jewish Health (NJH.)
    


Intervention name(s): Blood draw; bronchoscopy
Intervention type(s): Procedure; Procedure
Intervention description(s): We will draw 4 heparin tubes for peripheral blood mononuclear cells (PBMC); CBD subjects will undergo a bronchoscopy with lavage. This is the passage of a think flexible tube through the nose into the windpipe then into the bronchial tubes. Sterile saltwater solution is through the flexible tube then immediately removed.
Other intervention name(s): BAL
Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Those diagnosed with Beryllium Sensitization. Those diagnosed with Chronic beryllium
        disease
      
Biospecimen description: 
      Bronchoalveolar lavage fluid 4 heparin tubes for PBMC