The Role of JAK2 in Alveolar Macrophages (AM's) in Chronic Beryllium Disease (CBD)

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.)