AB1169 BAG3 (BCL2-ASSOCIATED ATHANOGENE 3) IS OVEREXPRESSED IN SERUM AND SKIN OF PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: N. Del Papa, A. Minniti, M. De Marco, G. Armentaro, C. Iannone, M. R. Pellico, L. Marzullo, A. Rosati, C. Vitali, R. F. Caporali, M. C. Turco
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by an abnormal remodelling of tissue matrix, leading to fibrosis of skin and internal organs. Although progresses have been made in terms of knowledge of pathogenic mechanisms, disease biomarkers and therapeutic options are still limited. Lymphocytes, TGF-ß, PDGF- ß play a key role on fibroblast differentiation into activated apoptosis-resistant myofibroblast in SSc patients. Alpha smooth muscle actin (α-SMA) positive (+) myofibroblasts are the key effectors in the disease, being responsible for excessive synthesis, deposition, and remodelling of extracellular matrix proteins. Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that is constitutionally present in a few normal cell types and some tumors with large stromal component (i.e. pancreatic ductal adenocarcinoma), and may be induced by stressful stimuli in a wide variety of cells. Recent studies have demonstrated that BAG3 is a key player in fibrosis regulation; indeed, it is able to induce the transformation of cancer-associated fibroblasts to α -SMA+ myofibroblasts. These cells enhance the intra-tumoral deposition of collagen matrix making cancer more aggressive and drug-resistant. <h3>Objectives:</h3> To investigate BAG3 role in the pathogenesis of SSc and its contribution in the fibrotic processes. <h3>Methods:</h3> 106 patients with SSc [59 diffuse (dc) and 47 limited (lc) SSc subset, according to the criteria of Le Roy et al.] and an equal number of age- and sex-matched healthy controls were enrolled. BAG3 serum levels measured by a sandwich ELISA assay were compared in three subgroups of SSc patients divided according to their clinical subset, nailfold videocapillaroscopic (NVC) patterns, presence and degree of interstitial lung disease (ILD). Mann-Whitney non-parametric test was used to compare the levels of serum BAG3 in the normal population and in the three subset of SSc patients. Correlations of BAG3 serum levels with modified Rodnan skin score (mRSS) and EUSTAR disease activity score (2017) have been evaluated through Spearman rank correlation test. Moreover, BAG3 expression in skin biopsies of 8 patients with dcSSc was investigated with immunohistochemistry and immunofluorescence. The unpaired t-test was used to compare the mean intensity of BAG3 between groups in the immunohistochemistry studies. <h3>Results:</h3> BAG3 serum levels were significantly higher in patients with SSc than in healthy controls, finding limited to dSSc subset (Figure 1 A). BAG3 serum levels were significantly higher in patients with scleroderma pattern late at NVC and ILD presence and extent but were not correlated with mRSS and global disease activity score (Figure 1 B-C). Finally, BAG3 was strongly expressed in the skin biopsies of patients with dSSc (Figure 2 A-B-C). <h3>Conclusion:</h3> To our knowledge, this is the first study showing BAG3 expression in SSc patients' serum and skin. BAG3 levels are significantly higher in dcSSc, a clinical subset with a prevalent fibrotic signature. This finding was confirmed by BAG3 correlation with scleroderma pattern late and ILD extent. Unsurprisingly, no correlation was observed between BAG3 serum levels and EUSTAR disease activity score, an instrument expression of disease progression rather than fibrosis. The close correlation between serum BAG3 levels and major fibrotic manifestations of SSc suggests that BAG3 pathway may significantly contribute to the fibrotic process that involves both skin tissue and internal organs of SSc patients. Therefore, these promising data support our group to conduct further researches to promote BAG3 as a disease biomarker and therapeutic target in SSc. <h3>Acknowledgements:</h3> Next Generation EU (PNRR-MAD-2022-12376202 project). <h3>Disclosure of Interests:</h3> <b>None declared.</b>