Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

Crouser, Elliott D.; Culver, Daniel A.; Knox, Kenneth S.; Julián, M; Shao, Guohong; Abraham, Susamma; Liyanarachchi, Sandya; Macre, Jennifer E.; Wewers, Mark D.; Gavrilin, Mikhail A.; Ross, Patrick; Abbas, Abbas; Eng, Charis

doi:10.1164/rccm.200803-490oc

Cited by 132 publications

(141 citation statements)

References 43 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…Our findings suggest that increased CXCL9 factor may identify those at risk for chronic disease, and warrant further study in validation cohorts. It is notable that our IFN signature was predominantly driven by STAT1 and STAT2 expression in sarcoidosis peripheral blood, as this finding supports prior studies showing that STAT1 may play an important role in disease pathogenesis [19,20]. Using microarray gene network analyses and immunohistochemical staining of granulomas, ROSENBAUM et al [20] previously demonstrated that STAT1 signalling is strongly upregulated in peripheral blood (n512), and lung and lymph node tissues.…”

Section: Discussionsupporting

confidence: 84%

“…Unexpectedly, the IFN-inducible chemokine CXCL9 gene (factor 7) was not intercorrelated with the other IFN-related genes in factor 1. We had particular interest in CXCL9 (factor 7), as CXCL9 is upregulated in gene network analyses of sarcoidosis organ tissues [19,20], and we and others have previously shown that serum protein levels of this chemokine are upregulated in sarcoidosis [15,21]. In summary, factor analysis of the qPCR results provided confirmation of the IFN, pattern recognition and TCR pathways in a separate replicate cohort, and additionally demonstrated a separate factor for CXCL9.…”

Section: Factor Analysis Demonstrates Distinct Clusters Of Intercorrementioning

confidence: 53%

See 1 more Smart Citation

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

Su¹,

Li²,

Bhakta³

et al. 2014

Eur Respir J

View full text Add to dashboard Cite

Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally.We applied Ingenuity Pathway Analysis to a cross-sectional derivation microarray dataset (n538) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n5103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity.In the cross-sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronic versus nonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9.These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally. @ERSpublications Blood gene transcript measurements predict sarcoidosis chronicity and severity longitudinally

show abstract

Section: Discussionsupporting

confidence: 84%

Section: Factor Analysis Demonstrates Distinct Clusters Of Intercorrementioning

confidence: 53%

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

Su¹,

Li²,

Bhakta³

et al. 2014

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…It is expressed during differentiation of dendritic cells and is constitutively expressed in macrophages (1,12). Until now, ADAMDEC1 has primarily been studied on a transcriptional level, where it has been found differently regulated in a number of pathologies (13)(14)(15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, expression is strongly induced by spontaneous as well as by CD40-or LPS-stimulated maturation of immature dendritic cells (1,12). ADAMDEC1 expression was found to be up-regulated in atherosclerotic plaques (13), pulmonary sarcoidosis (14), intestinal inflammation (15), intracranial tumor (craniopharyngioma) (16), and infection of lymphoblastoid cells by Epstein-Barr virus (17), whereas it is down-regulated in colorectal cancer (18). In addition, ADAMDEC1 is up-regulated during pregnancy (19).…”

mentioning

confidence: 99%

ADAMDEC1 Is a Metzincin Metalloprotease with Dampened Proteolytic Activity

Lund

Olsen

Sørensen

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: ADAMDEC1 is a putative ADAM-like metalloprotease with a short domain structure and a noncanonical active site. Results: Recombinant ADAMDEC1 cleaves ␣ 2 -macroglobulin and casein. The activity is significantly enhanced upon reconstituting the consensus zinc-binding site. Conclusion: ADAMDEC1 is secreted as a proteolytic active, glycosylated metalloprotease. Significance: The ADAMDEC1 has adapted a reduced catalytic activity, possibly compensating the loss of auxiliary specificity determining domains.

show abstract

“…[20][21][22] Macrophage activation is a multistep process and has been divided into proinflammatory/ M1 or regulatory/M2 polarization. 23,24 Although epithelioid cell formation in sarcoidosis and tuberculosis was shown to be associated with an M1 phenotype of macrophages, 25,26 tumor-associated macrophages were usually found to have an M2-like phenotype. 24,27 Data on macrophage polarization in HIV are contradictory, and a switch from M1 to M2 polarization of macrophages during the disease course has been proposed.…”

Section: Discussionmentioning

confidence: 99%

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

et al. 2013

View full text Add to dashboard Cite

Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDSdefining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin-and Reed-Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4 þ T-cells and a significantly increased number of CD163 þ macrophages in HIVrelated Hodgkin lymphoma. Cases exhibiting a 'sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the 'sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4 þ T-cells around Hodgkin-and Reed-Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.

show abstract

Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

Cited by 132 publications

References 43 publications

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

ADAMDEC1 Is a Metzincin Metalloprotease with Dampened Proteolytic Activity

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

Contact Info

Product

Resources

About