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SAT0262 BCL2-associated athanogene 3 protein is associated with B-cell hyperactivity including lymphoma in primary sjÖgren's syndrome
  1. A Alunno1,
  2. F Carubbi2,3,
  3. A Falco4,
  4. O Bistoni1,
  5. V Valentini1,
  6. G Cafaro1,
  7. R Giacomelli2,
  8. M Pascale4,
  9. R Gerli1
  1. 1Department of Medicine, Rheumatology Unit, University of Perugia, Perugia
  2. 2Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila
  3. 3Department of Medicine, ASL 1 Avezzano-L'Aquila-Sulmona, L'Aquila
  4. 4Department of Pharmacy, University of Salerno, Salerno, Italy

Abstract

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.

References

  1. Rosati A et al. Cell Death Dis 2011;2:e141.

References

Disclosure of Interest None declared

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