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The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes.

Radstake TR, van Bon L, Broen J, Hussiani A, Hesselstrand R, Wuttge DM, Deng Y, Simms R, Lubberts E, Lafyatis R - PLoS ONE (2009)

Bottom Line: In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well.The combination of IL-17, IFNgamma and TGFbeta levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc.Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. tradstake73@gmail.com

ABSTRACT

Background: Systemic sclerosis (SSc) is an autoimmune disease where controversy on Th1/Th2 balance dominates. We investigated whether the recently discovered Th17 pattern was present in SSc.

Methodology and principal findings: Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 12) or diffuse cutaneous SSc (dcSSc, n = 24). A further arbitrary subdivision was made between early dcSSc (n = 11) and late dcSSc (n = 13) based upon the duration of disease. As a comparator group 14 healthy controls were studied. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, CD45Ro, CD45Ra, IL-23, GITR, CD69 and intracellular expression of IL-17, TGFbeta and IFNgamma using flow cytometry. Levels of IL-17, IL-6, IL-1alpha and IL-23 were measured using Bioplex assays. SSc patients had more and more activated CD4+ cells. In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well. In contrast, IFNgamma and TGFbeta were selectively up regulated in SSc subsets. In line with these observation, circulating levels of IL-17 inducing cytokines IL-6, IL-23 and IL-1alpha were increased in all or subsets of SSc patients.

Conclusion and significance: The combination of IL-17, IFNgamma and TGFbeta levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc. Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc.

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Increased level of Th17 inducing cytokines in the circulation of SSc patients.Panel A depicts the presence of IL-17 in the circulation of SSc patients and healthy controls. Panel B, C and D represents the levels of IL-6, IL-1α and IL-23, respectively. The circulating levels of IL-17, IL-1α and IL-23 was measured by ELISA whereas IL-6 was studied by Bioplex assays.
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pone-0005903-g003: Increased level of Th17 inducing cytokines in the circulation of SSc patients.Panel A depicts the presence of IL-17 in the circulation of SSc patients and healthy controls. Panel B, C and D represents the levels of IL-6, IL-1α and IL-23, respectively. The circulating levels of IL-17, IL-1α and IL-23 was measured by ELISA whereas IL-6 was studied by Bioplex assays.

Mentions: It has previously been reported that IL-17 levels are increased in the circulation in SSc patients [15]. A major limitation of these studies was the small sample size. This, together with our experience that circulating IL-17 is very difficult to detect in other autoimmune disorders such as rheumatoid arthritis, we investigated the levels of IL-17 and IL-17 promoting cytokines in a large cohort of SSc patients (n = 177) consisting out of 110 patients with LSSc, 34 with ldSSc and 33 with the edSSc phenotype. As a comparator group we used 28 healthy controls. When comparing the level of IL-17 in SSc patients and healthy controls, IL-17 could only be detected in a minority of the samples (9 of 177; Table 3, Figure 3a) and was not detected more frequently in SSc patients compared to controls. In contrast, the levels of IL-6 (53.6±9.7 vs. 5.4±3.4, P<0.0001), IL-1α (83.2±11.2 vs. 1.2±1.1, P<0.002) and IL-23 (49.1±7.3 vs. 5.3±0.6, P = 0.003) were significantly higher in SSc as a whole compared with controls (Figure 3b–d). Subgroup analysis revealed that IL-6 and IL-23 levels were equally distributed among SSc phenotypes whereas IL-1α was significantly increased in lSSc patients (P<0.001) only. An association between clinical characteristics including the presence of autoantibodies, disease duration and/or pulmonary involvement was not observed (data not shown).


The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes.

Radstake TR, van Bon L, Broen J, Hussiani A, Hesselstrand R, Wuttge DM, Deng Y, Simms R, Lubberts E, Lafyatis R - PLoS ONE (2009)

Increased level of Th17 inducing cytokines in the circulation of SSc patients.Panel A depicts the presence of IL-17 in the circulation of SSc patients and healthy controls. Panel B, C and D represents the levels of IL-6, IL-1α and IL-23, respectively. The circulating levels of IL-17, IL-1α and IL-23 was measured by ELISA whereas IL-6 was studied by Bioplex assays.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2691991&req=5

pone-0005903-g003: Increased level of Th17 inducing cytokines in the circulation of SSc patients.Panel A depicts the presence of IL-17 in the circulation of SSc patients and healthy controls. Panel B, C and D represents the levels of IL-6, IL-1α and IL-23, respectively. The circulating levels of IL-17, IL-1α and IL-23 was measured by ELISA whereas IL-6 was studied by Bioplex assays.
Mentions: It has previously been reported that IL-17 levels are increased in the circulation in SSc patients [15]. A major limitation of these studies was the small sample size. This, together with our experience that circulating IL-17 is very difficult to detect in other autoimmune disorders such as rheumatoid arthritis, we investigated the levels of IL-17 and IL-17 promoting cytokines in a large cohort of SSc patients (n = 177) consisting out of 110 patients with LSSc, 34 with ldSSc and 33 with the edSSc phenotype. As a comparator group we used 28 healthy controls. When comparing the level of IL-17 in SSc patients and healthy controls, IL-17 could only be detected in a minority of the samples (9 of 177; Table 3, Figure 3a) and was not detected more frequently in SSc patients compared to controls. In contrast, the levels of IL-6 (53.6±9.7 vs. 5.4±3.4, P<0.0001), IL-1α (83.2±11.2 vs. 1.2±1.1, P<0.002) and IL-23 (49.1±7.3 vs. 5.3±0.6, P = 0.003) were significantly higher in SSc as a whole compared with controls (Figure 3b–d). Subgroup analysis revealed that IL-6 and IL-23 levels were equally distributed among SSc phenotypes whereas IL-1α was significantly increased in lSSc patients (P<0.001) only. An association between clinical characteristics including the presence of autoantibodies, disease duration and/or pulmonary involvement was not observed (data not shown).

Bottom Line: In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well.The combination of IL-17, IFNgamma and TGFbeta levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc.Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. tradstake73@gmail.com

ABSTRACT

Background: Systemic sclerosis (SSc) is an autoimmune disease where controversy on Th1/Th2 balance dominates. We investigated whether the recently discovered Th17 pattern was present in SSc.

Methodology and principal findings: Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 12) or diffuse cutaneous SSc (dcSSc, n = 24). A further arbitrary subdivision was made between early dcSSc (n = 11) and late dcSSc (n = 13) based upon the duration of disease. As a comparator group 14 healthy controls were studied. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, CD45Ro, CD45Ra, IL-23, GITR, CD69 and intracellular expression of IL-17, TGFbeta and IFNgamma using flow cytometry. Levels of IL-17, IL-6, IL-1alpha and IL-23 were measured using Bioplex assays. SSc patients had more and more activated CD4+ cells. In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well. In contrast, IFNgamma and TGFbeta were selectively up regulated in SSc subsets. In line with these observation, circulating levels of IL-17 inducing cytokines IL-6, IL-23 and IL-1alpha were increased in all or subsets of SSc patients.

Conclusion and significance: The combination of IL-17, IFNgamma and TGFbeta levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc. Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc.

Show MeSH
Related in: MedlinePlus