Autoimmune rheumatologic diseases
PPP2R2B encodes B55β, a regulatory subunit of the phosphatase PP2A that controls apoptosis of activated T cells. Impaired expression of B55β in patients with systemic lupus erythematosus (SLE) is associated with T cell resistance to cytokine withdrawal-induced death (CWID).
We analyzed the transcriptional regulation of PPP2R2B in T cells from patients with systemic autoimmune diseases (AID: SLE, rheumatoid arthritis [RA], Sjögren’s syndrome, n=86) and healthy donors (HD, n=25), to identify hereditary and acquired factors that could decrease its expression. Failed transcription of B55β was not confined to SLE and was documented in ~50% of patients. This was not associated with expansion or contraction of a CAG repeat that has been linked to altered B55β expression in patients with hereditary neurodegenerative diseases. Methylation-sensitive PCR indicated that a CpG island in the promoter of PPP2R2B was hypermethylated in patients. Pyrosequencing identified the cytosines whose methylation affected PPP2R2B transcription.
To determine whether PPP2R2B hypermethylation could be acquired during chronic inflammation, we analyzed the effects of cytokines on PPP2R2B methylation and transcription, and on T cell CWID. Healthy T cells exposed to TNF-α became resistant to CWID. This was linked to increased PPP2R2B methylation and decreased B55β expression. PPP2R2B methylation correlated with erythrocyte sedimentation rate (r=0.76, P=0.01). Moreover, disease activity (DAS28) was significantly higher in patients with RA who displayed PPP2R2B hypermethylation (P<0.0001).
These results identify a gene whose expression is affected by inflammation through an epigenetic mechanism. By decreasing the expression of B55β, inflammation may perpetuate itself.