Human Cytomegalovirus - A possible activator of the immune system in Polymyositis and Dermatomyositis - OP0057
Authors: A.E.R. Fasth 1, A. Rahbar 2, M. Dastmalchi 3, C. Söderberg-Nauclér 2, C. Trollmo 3, I.E. Lundberg 3, V. Malmström 3. 1Rheumatology Unit, Dept of Medicine, Karolinska University Hospital, 2Center for Molecular Medicine, Dept of Medicine, Karolinska University Hospital, 3Rheumatology Unit, Dept Medicine, Karolinska University Hospital, Stockholm, Sweden
Background:
This group has previously shown increased frequencies of hyper-responsive and perforin-expressing CD4+ CD28null and CD8+ CD28null T cells in the circulation of patients with polymyositis (PM) and dermatomyositis (DM). CD28null T cells also constituted the major cell type infiltrating muscle tissue in these patients. Increased frequencies of CD4+ CD28null and CD8+ CD28null T cells have previously been reported in patients with chronic viral infections. In this experiment, they investigate the association of human cytomegalovirus infection (HCMV) to the frequency of circulating CD28null T cells in patients with DM and PM.
Methods:
Serum samples from 65 patients diagnosed with DM (n = 23) or PM (n = 42) were investigated for IgM and IgG reactivity against HCMV by ELISA. The frequencies of CD4+ and CD8+ CD28null T cells were analyzed by flow cytometry. HCMV reactivity of CD28null T cells from 5 patients positive for HCMV-IgG and 4 patients negative for HCMV-IgG was tested by in vitro-stimulation with HCMV-derived peptides, HCMV-pp65 and HCMV-IEA. Upregulated levels of intracellular IFN-gamma was used as readout for activated T cells and analyzed by flow cytometry.
Results:
ELISA results indicated that 72% of the DM and PM patients are IgG seropositive for HCMV to the same frequency (72%) as the average population. 17% were HCMV-IgM positive. However, increased CD4+ and CD8+ CD28null T cell populations were mainly found in individuals seropositive for HCMV IgG, indicating a latent virus infection. Results from the in vitro reactivity assays confirmed the associations to HCMV since the CD28null T cells produced IFN-gamma following activation by HCMV-derived peptides. Interestingly, increased CD4+ and CD8+ CD28null T cell populations were already present at disease onset.
Conclusion:
This study demonstrated that the increase of CD4+ and CD8+ CD28null T cells in patients with DM and PM is strongly associated with chronic HCMV infection. Hence one may suggest a role for HCMV infection in the pathogenesis in subsets of DM and PM and that the effector T cells are of CD28null phenotype.
Comment:
The pathogenesis of dermatomyositis and polymyositis remains poorly understood. This study suggests that human cytomegalovrus infection may play a direct role in the pathogenesis of these diseases. It seems that it is not the seropositivity, but rather the increase in CD4+ and CD8+ CD28null T cell population of those who were seropositive for CMV that conferred the association. This is a provocative study but challenges many prior studies that have attempted to demonstrate that a viral etiology was responsible for the initiation of the disease process of autoimmune myopathies.