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Inflammation aggravates disease severity in Marfan syndrome patients.

Radonic T, de Witte P, Groenink M, de Waard V, Lutter R, van Eijk M, Jansen M, Timmermans J, Kempers M, Scholte AJ, Hilhorst-Hofstee Y, van den Berg MP, van Tintelen JP, Pals G, Baars MJ, Mulder BJ, Zwinderman AH - PLoS ONE (2012)

Bottom Line: Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml).When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.In conclusion, our results imply a modifying role of inflammation in MFS.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.

ABSTRACT

Background: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.

Methodology/principal findings: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.

Conclusion/significance: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

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Related in: MedlinePlus

Six inflammatory genes differentially expressed in patients with pectus deformities, of which five are down-regulated.The CD molecules are cell surface molecules participating in inflammatory cell interactions. SOD3 encodes for extracellular superoxide dismutase, which is an enzyme that protects against oxidative stress caused by inflammatory cells. (FC = 0.6, 0.8; 0.6; 1.6; 0.6; 0.6respectively; FDR = 0%).
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pone-0032963-g007: Six inflammatory genes differentially expressed in patients with pectus deformities, of which five are down-regulated.The CD molecules are cell surface molecules participating in inflammatory cell interactions. SOD3 encodes for extracellular superoxide dismutase, which is an enzyme that protects against oxidative stress caused by inflammatory cells. (FC = 0.6, 0.8; 0.6; 1.6; 0.6; 0.6respectively; FDR = 0%).

Mentions: Interestingly, in patients with chest deformities resulting from the over-growth of ribs, we found a predominant up-regulation of growth-related genes. Expression profiles of patients carrying pectus deformities (severe pectus excavatum and pectus carinatum) were compared with patients without these features. Multiclass analysis of these deformities revealed 40 differentially expressed genes with FDR = 0% between the groups. (Table S3 for up-regulated genes and Table S4 for down-regulated genes). Some of these genes are known TGF-β related genes (FLRT3, WISP2, CLK1, ACVRL1 and IGFBP4). In addition, six inflammatory genes were present in the list of differentially expressed genes, namely CD68, CD13, CD248, CD24, CD81 and SOD3 (Figure 7). The CD molecules are cell surface molecules participating in pro-inflammatory cell interactions. SOD3 encodes for extracellular superoxide dismutase, which is an enzyme that protects against oxidative stress caused by inflammatory cells. (FC = 0.6, 0.8; 0.6; 0.6; 1.6; 0.6 respectively; FDR = 0%). Five of these inflammatory genes were down-regulated in patients with chest deformities when compared to patients without these features. Only CD24 was increased in this subpopulation of MFS patients. CD24 is known to selectively repress tissue damage-induced immune responses [17] and in that light high CD24 is anti-inflammatory.


Inflammation aggravates disease severity in Marfan syndrome patients.

Radonic T, de Witte P, Groenink M, de Waard V, Lutter R, van Eijk M, Jansen M, Timmermans J, Kempers M, Scholte AJ, Hilhorst-Hofstee Y, van den Berg MP, van Tintelen JP, Pals G, Baars MJ, Mulder BJ, Zwinderman AH - PLoS ONE (2012)

Six inflammatory genes differentially expressed in patients with pectus deformities, of which five are down-regulated.The CD molecules are cell surface molecules participating in inflammatory cell interactions. SOD3 encodes for extracellular superoxide dismutase, which is an enzyme that protects against oxidative stress caused by inflammatory cells. (FC = 0.6, 0.8; 0.6; 1.6; 0.6; 0.6respectively; FDR = 0%).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316543&req=5

pone-0032963-g007: Six inflammatory genes differentially expressed in patients with pectus deformities, of which five are down-regulated.The CD molecules are cell surface molecules participating in inflammatory cell interactions. SOD3 encodes for extracellular superoxide dismutase, which is an enzyme that protects against oxidative stress caused by inflammatory cells. (FC = 0.6, 0.8; 0.6; 1.6; 0.6; 0.6respectively; FDR = 0%).
Mentions: Interestingly, in patients with chest deformities resulting from the over-growth of ribs, we found a predominant up-regulation of growth-related genes. Expression profiles of patients carrying pectus deformities (severe pectus excavatum and pectus carinatum) were compared with patients without these features. Multiclass analysis of these deformities revealed 40 differentially expressed genes with FDR = 0% between the groups. (Table S3 for up-regulated genes and Table S4 for down-regulated genes). Some of these genes are known TGF-β related genes (FLRT3, WISP2, CLK1, ACVRL1 and IGFBP4). In addition, six inflammatory genes were present in the list of differentially expressed genes, namely CD68, CD13, CD248, CD24, CD81 and SOD3 (Figure 7). The CD molecules are cell surface molecules participating in pro-inflammatory cell interactions. SOD3 encodes for extracellular superoxide dismutase, which is an enzyme that protects against oxidative stress caused by inflammatory cells. (FC = 0.6, 0.8; 0.6; 0.6; 1.6; 0.6 respectively; FDR = 0%). Five of these inflammatory genes were down-regulated in patients with chest deformities when compared to patients without these features. Only CD24 was increased in this subpopulation of MFS patients. CD24 is known to selectively repress tissue damage-induced immune responses [17] and in that light high CD24 is anti-inflammatory.

Bottom Line: Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml).When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.In conclusion, our results imply a modifying role of inflammation in MFS.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.

ABSTRACT

Background: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.

Methodology/principal findings: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.

Conclusion/significance: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Show MeSH
Related in: MedlinePlus