Transcription of Several Genes Associated with Antigen-Induced Anergy are Regulated by Rheumatoid Arthritis Synovial T-Cells
The pathogenesis of rheumatoid arthritis (RA) has been classically thought to involve T-cell dependent autoimmune mechanisms. Anergy is a state of T-cell nonresponsiveness characterized by downregulated IL-2 production. Paradoxically, rheumatoid synovial, T-cells share some characteristics of anergic T-cells such as hyporesponsiveness and poor proliferation in response to antigens and mitogens. Using differential display RT-PCR, Ali et al (J Clin Inv 107:519,2001) examined the levels of differentially expressed transcripts in RA and as a control, T-cells compared to an anergic T-cell clone and to T-cells from reactive arthritis (ReA) patients in which no activation defect is known.
Transcription of anergy-related transcripts was compared in synovial tissue from patients in the early stages of RA and ReA. Three anergy-associated genes were downregulated in RA compared to ReA. These were cellular apoptosis susceptibility protein (CAS), Calmodulin, and BF626661. The CAS transcript plays a role in apoptosis susceptibility. Anergic T-cells upregulate CAS and are unusually susceptible to apoptosis. Conversely, apoptosis in RA T-cells is defective and CAS downregulation may explain this phenomenon. In this study, CAS transcription in RA T cells was 5% of that of anergic T-cells and 25% of that of ReA T-cells. Calmodulin is a calcium-binding protein that binds free intracellular calcium and regulates other calcium-dependent proteins involved in signal transduction. Transcription of calmodulin in RA was found to be less than 1% of that in ReA or anergic T-cells. Reduced calmodulin transcription may explain, in part, the hyporesponsiveness of RA T-cells. BF626661 is an expressed sequence tag and was transcribed tenfold lower in RA. The significance of downregulation of BF626661 is not clear.
Calmodulin transcription was found to increase three to ten times, 2 weeks after a single infusion of 3 mg/kg Infliximab. Calmodulin blockage inhibited the proliferation of T cells to PPD in a dose dependent manner in control individuals. Transcription of CAS bore no relationship to Infliximab therapy.
These data suggest that downregulation of Calmodulin and CAS could explain, in part, the hyporesponsiveness and apoptotic defect of RA T cells. These data may also shed light on the immunosuppression involved in RA.
Editorial Comment: RA is considered to be an autoimmune disease yet the hyporesponsiveness of RA synovial T-cells to antigen stimulation and their resistance to apoptosis are in apparent conflict with the autoimmune concept. The current study advances our understanding of the defects in RA T-cells by comparing them to anergic T-cells, and indentifies important differences in the transcription units of several key genes involved with these biological processes.