Background Bcl2-associated athanogene 3 (BAG-3) is a co-chaperone protein that interacts with the ATPase domain on heat-shock protein 70. BAG-3 is involved is several biologic processes including apoptosis, cytoskeleton organization and autophagy and, therefore, it has been extensively investigated in the field of tumorigenesis (1). In particular, BAG-3 expression is constitutive in human primary tumors including leukemias and lymphomas and it is induced in different normal cell types, including leukocytes, by a variety of stimuli. BAG-3 is able to induce and maintain cell proliferation, resistance to therapy and cell motility, namely metastatization. On this basis, a role of BAG-3 in chronic inflammatory diseases may be postulated, but data on this topic are not available.
Objectives The purpose of our study was to investigate the expression of BAG-3 in primary Sjogren's syndrome (pSS) and the relationship with clinical and serological features.
Methods BAG-3 concentration was assessed in the serum of 103 patients with pSS according to the 2002 American-European classification criteria and in 40 sex and age matched healthy donors (HD). Clinical and serological records were collected and statistical analysis was performed with SPSS 21.0.
Results Twenty-six pSS patients were positive for BAG-3 (BAG-3+), with serum levels ranging from 32.1 to 950 pg/ml. When setting the cut-off value according to the highest value found in HD (300 pg/ml), we identified 13 pSS patients displaying a peculiar clinical serological phenotype. In detail, in this subgroup of pSS patients the prevalence of purpura, low C4, both anti-Ro and anti-La autontibodies, rheumatoid factor and lymphoma was higher, when compared to pSS patients with BAG-3 levels <300 pg/ml or BAG-3- (all p<0.05). Furthermore, they displayed less frequently sicca symptoms such as xerostomia and xerophtalmia (both p<0.05). Binary logistic regression analysis revealed that pSS patients with BAG-3 levels >300 pg/ml had on odds ratio (OR) of 12 (95% CI 1.9–86, p=0.009) for lymphoma and this association was independent of the presence of purpura, a well know marker of lymphoma in pSS. When including low complement, another feature associated with lymphoma, in the multivariable analysis, both low C4 and BAG-3 levels >300 pg/ml resulted independently associated to lymphoma (OR=24 and 12.4 respectively).
Conclusions Our study assessed for the first time serum BAG-3 levels in a large cohort of pSS patients. The results showed that the highest levels of BAG-3 identify a peculiar clinical and serological pSS phenotype, as consequence of a B-cell hyperactivity. Since it is known that BAG-3 is an anti-apoptotic protein playing a pivotal role in cell survival, and that B-cell hyperactivity in pSS is the consequence of coordinated and integrated actions of several stimuli and appropriate cytokines, our results may suggest that BAG-3 overexpression is involved in B-cell proliferation and activity, as well as in oligoclonal and monoclonal expansion in pSS.
Rosati A et al. Cell Death Dis 2011;2:e141.
Disclosure of Interest None declared