Functional genomics in sarcoidosis - reduced or increased apoptosis?

Background: A variety Of Studies have stressed the importance of the contro l of inflammatory cell longevity and the balance of pro-survival and pro-ap optotic signaling pathways. The aim of the study was to investigate the sys temic activation of apoptosis pathways using cDNA array technology in patie nts with acute onset sarcoidosis. Method: We have performed a comprehensive genomic analysis, applying high-d ensity human GeneChip((R)) probe arrays (HGU95A, Affymetrix) for RNA expres sion profiling from peripheral blood mononuclear cells from patients with a cute pulmonary sarcoidosis and matched healthy controls. Twelve patients an d 12 controls were assessed, mean age 36 +/- 12 and 33 +/- 10 years respect ively. Results focus on apoptosis-related gene products. Group differences were assessed with the Mann-Whitney U-test. Results: Seven patients had self-limited disease (all type I sarcoidosis) a nd 5 progressive disease requiring immunosuppression (all type II or III sa rcoidosis). We found 53 of 112 (47%) apoptosis-related gene products dysreg ulated in sarcoidosis compared to controls. Particular growth factors, espe cially heparin-binding EGF-like GF, EGF, PDEGF, SISPDGF2 and VEGF, were upr egulated in patients consistent vith a pro-survival profile. The Bcl-2 fami ly of genes also showed a net pro-survival profile in sarcoidosis patients. In contrast, alterations in the TNF-pathway were compatible with increased apoptosis signals in both, type I and type II/III sarcoidosis patients. Ot her cell death receptors were equally expressed, as were caspases and p53-a ssociated genes. In contrast to patients with type I-sarcoidosis, patients with progressive type II or III disease showed an upregulation of NFKB and a leak of downregulation of inhibitor of apoptosis 1. Conclusion: Significant differences in the expression of apoptosis-related genes were found in peripheral blood of patients with acute onset sarcoidos is. Gene expression did not show, a definite pattern that was suggestive of pro-survival or pro-apoptosis. However, the number of genes whose altered expression would be predicted to favour increased survival exceeded that of genes likely to reduce survival. Protein-based confirmation of the differe nces in the activity, of apoptosis-pathways needs to be done in further Stu dies.