Reassessing the Role of the Active TGF-<i>β</i>1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Dantas, Andréa Tavares; Gonçalves, Sayonara Maria Calado; Almeida, Anderson Rodrigues de; Gonçalves, Rafaela Silva Guimarães; Sampaio, Maria Clara Pinheiro Duarte; Vilar, Kamila de Melo; Pereira, Michelly Cristiny; Rêgo, Moacyr Jesus Barreto de Melo; Pitta, Ivan da Rocha; Marques, Cláudia Diniz Lopes; Duarte, Ângela Luzia Branco Pinto; Pitta, Maíra Galdino da Rocha

doi:10.1155/2016/6064830

Cited by 29 publications

(20 citation statements)

References 27 publications

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“…This finding is in keeping with the results of in-vitro experiments in which the production of TGF-b1 by myelomonocytic cells was increased strongly after incubation with recombinant soluble HLA-G molecules [57]. Moreover, this observation supports the hypothesis that sHLA-G may contribute to the immunopathogenesis of systemic sclerosis because TGF-b has been identified as a major activator of fibroblasts in both mouse models and human disease [58][59][60][61].…”

Section: Discussionsupporting

confidence: 87%

Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis

Contini

Negrini

Murdaca

et al. 2018

Clinical and Experimental Immunology

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Systemic sclerosis (SSc) is a complex disease characterized by immune dysregulation, extensive vascular damage and widespread fibrosis. Human leucocyte antigen-G (HLA-G) is a non-classic class I major histocompatibility complex (MHC) molecule characterized by complex immunomodulating properties. HLA-G is expressed on the membrane of different cell lineages in both physiological and pathological conditions. HLA-G is also detectable in soluble form (sHLA-G) deriving from the shedding of surface isoforms (sHLA-G1) or the secretion of soluble isoforms (HLA-G5). Several immunosuppressive functions have been attributed to both membrane-bound and soluble HLA-G molecules. The plasma levels of sHLA-G were higher in SSc patients (444·27 ± 304·84 U/ml) compared to controls (16·74 ± 20·58 U/ml) (P < 0·0001). The plasma levels of transforming growth factor (TGF)-β were higher in SSc patients (18 937 ± 15 217 pg/ml) compared to controls (11 099 ± 6081 pg/ml; P = 0·003), and a significant correlation was found between TGF-β and the plasma levels of total sHLA-G (r = 0·65; P < 0·01), sHLA-G1 (r = 0·60; P = 0·003) and HLA-G5 (r = 0·47; P = 0·02). The percentage of HLA-G-positive monocytes (0·98 ± 1·72), CD4 (0·37 ± 0·68), CD8 (2·05 ± 3·74) and CD4 CD8 double-positive cells (14·53 ± 16·88) was higher in SSc patients than in controls (0·11 ± 0·08, 0·01 ± 0·01, 0·01 ± 0·01 and 0·39 ± 0·40, respectively) (P < 0·0001). These data indicate that in SSc the secretion and/or shedding of soluble HLA-G molecules and the membrane expression of HLA-G by peripheral blood mononuclear cells (PBMC) is clearly elevated, suggesting an involvement of HLA-G molecules in the immune dysregulation of SSc.

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Section: Discussionsupporting

confidence: 87%

Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis

Contini

Negrini

Murdaca

et al. 2018

Clinical and Experimental Immunology

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“…Furthermore, we observed that expression of these integrin subunits was regulated by TGFβ, as demonstrated by the use of the TGFBR1 (ALK5) kinase inhibitor SB-505124 and exogenously added hTGFβ1. Although TGFβ is widely regarded as an important driver of SSc pathophysiology [1], e.g., because it stimulates the excessive production of collagen type I by skin fibroblasts and enhances the contractile properties of these cells [10], its plasma and serum levels have been a controversial topic for many years; studies have reported increased [11][12][13], equal, and, similarly to our study, decreased levels [14,15] of TGFβ in serum and plasma of the SSc patients. Possibly, these differences can be attributed to the heterogeneity of disease course in SSc or to the heterogeneity of disease duration in our cohort.…”

Section: Discussionsupporting

confidence: 84%

“…With the use of a bioassay, biological activity can be determined. Of course, with the use of an ELISA also, active levels of TGFβ can be measured [11], but it should be realized that the activity of TGFβ measured in our bioassay not only reflects the presence of active TGFβ in serum, but also how well skin fibroblasts can activate (part of) the latent pool of TGFβ in the course of the experiment (16 h). Furthermore, TGFβ signaling is known to be cellular context dependent, and for example, pro-inflammatory factors present in serum can alter TGFβ signaling.…”

Section: Discussionmentioning

confidence: 99%

TGFβ-mediated expression of TGFβ-activating integrins in SSc monocytes: disturbed activation of latent TGFβ?

Caam

Aarts

et al. 2020

Arthritis Res Ther

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Introduction: The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGFβ signaling. TGFβ is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGFβ in serum of SSc patients and investigated if this correlates with integrin expression on monocytes.Methods: A TGFβ/SMAD3-or BMP/SMAD1/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGFβ and BMP levels respectively. A pan-specific TGFβ1/2/3 neutralizing antibody was used to confirm TGFβ signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGFβ1 or a small molecule inhibitor of TGFBR1: SB-505124.Results: SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGFβ levels were not different. Addition of a pan-specific TGFβ1/2/3 neutralizing antibody fully inhibited SMAD3reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits ITGA5 and ITGAV was significantly reduced in monocytes obtained from SSc patients. Furthermore, ITGB3, ITGB5, and ITGB8 expression was also reduced in SSc monocytes. Stimulation of monocytes with TGFβ1 induced ITGA5 and ITGAV but lowered ITGB8 expression, whereas the use of the TGFβ receptor inhibitor SB-505124 had the opposite effect.Conclusion: Total TGFβ serum levels are not different between SSc patients and controls, but TGFβ activity is. This coincides with a reduced expression of TGFβ-activating integrins in monocytes of SSc patients. Because TGFβ regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.

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“…On the other hand, a relatively recent study showed that serum TGF-β1 is increased in SSc patients and positively correlates with severe digital ulcers and extensive skin fibrosis. However, presence of this cytokine in serum did not correlate with lung involvement or disease severity [ 44 ]. Further studies will be needed to determine the significance of circulating TGF-β in SSc.…”

Section: Growth Factorsmentioning

confidence: 99%

Potential Biomarkers in Systemic Sclerosis: A Literature Review and Update

Utsunomiya

Oyama

Hasegawa

2020

JCM

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Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by dysregulation of the immune system, vascular damage, and fibrosis of the skin and internal organs. Patients with SSc show a heterogeneous phenotype and a range of clinical courses. Therefore, biomarkers that are helpful for precise diagnosis, prediction of clinical course, and evaluation of the therapeutic responsiveness of disease are required in clinical practice. SSc-specific autoantibodies are currently used for diagnosis and prediction of clinical features, as other biomarkers have not yet been fully vetted. Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and CCL18 have been considered as serum biomarkers of SSc-related interstitial lung disease. Moreover, levels of circulating brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) can provide diagnostic information and indicate the severity of pulmonary arterial hypertension. Assessment of several serum/plasma cytokines, chemokines, growth factors, adhesion molecules, and other molecules may also reflect the activity or progression of fibrosis and vascular involvement in affected organs. Recently, microRNAs have also been implicated as possible circulating indicators of SSc. In this review, we focus on several potential SSc biomarkers and discuss their clinical utility.

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Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Cited by 29 publications

References 27 publications

Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis

Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis

TGFβ-mediated expression of TGFβ-activating integrins in SSc monocytes: disturbed activation of latent TGFβ?

Potential Biomarkers in Systemic Sclerosis: A Literature Review and Update

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