CD40L demethylation in CD4+ T cells from women with rheumatoid arthritis
Highlights
► CD40L expression is increased in CD4+ T cells from female but not in male RA patients. ► DNA demethylation contributes to CD40L overexpression in RA CD4+ T cells. ► These results may help explain the higher incidence of RA in females.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease primarily characterized by chronic polyarthritis and joint deformity [1]. Women are three times more susceptible to RA than men. Although the etiology of RA remains unknown, recent studies suggest that the X-linked gene CD40L is involved in the pathogenesis of the disorder [2].
CD40L is expressed mainly at the surface of activated CD4+ T cells where it interacts with the CD40 receptor on B cells. The CD40–CD40L co-stimulatory pathway plays a pivotal role in controlling autoimmune responses and inflammation [3], [4]. CD40L expression is significantly higher in the serum of RA patients [5]; however, the mechanism underlying this overexpression remains to be elucidated.
Maintenance of DNA methylation patterns contributes to the proper regulation of gene transcriptional activity. Increased methylation levels on cytosine bases in CG pairs, particularly within gene regulatory elements, represses transcription by recruiting methylation-dependent repressor complexes. In a number of autoimmune disorders such as systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and systemic sclerosis (SSc), the CD40L gene locus in T cells of female patients has been found to be demethylated. This demethylation is thought to contribute to the onset of autoreactive immune responses [6], [7], [8]. In the present study, we tested the hypothesis that a similar pattern of CD40L hypomethylation can be found in T cells of female RA patients and also speculate that the CD40L promoter demethylation is a common cause of immune hyperactivity in human autoimmune disorders.
Section snippets
Subjects
Twenty-one patients (12 females, mean age 40.5 ± 9.2 years; 9 males, mean age 41.2 ± 7.4 years) with RA were recruited from outpatient clinics at the Xiangya Hospital and Second Xiangya Hospital, Central South University. All of the patients satisfied the American College of Rheumatology Diagnostic Criteria for RA [9]. Clinical profiles of the patients included in the study are summarized in Table 1. Nineteen healthy controls (10 females, mean age 36.5 ± 13.2 years; 9 males, mean age 37.7 ± 12.0 years)
CD40L is increased in CD4+ T cells of female patients with RA
Data from real-time quantitative RT-PCR analysis showed that CD40L mRNA expression relative to that of β-actin was significantly higher in female RA patients than in female controls (7.4 ± 2.0 vs 4.5 ± 1.5, p < 0.05) (Fig. 1A). However, the difference between male patients and controls was not statistically significant (4.8 ± 1.2 vs 3.7 ± 1.0, p > 0.05). Data from two-color flow cytometry experiments showed that the percentage of CD4+CD40L+ T cells was also significantly higher in female RA patients
Discussion
The CD40–CD40L pathway mediates immune response and down-stream inflammatory processes [10], and CD40L mRNA expression is abnormally high in the T cells of RA patients [11]. The interaction between T cells and monocytes/macrophages through CD40L–CD40 also induces the production of elevated levels of matrix metalloproteinases (MMps), which are involved in inflammation and joint destruction in RA [12]. Blocking the CD40–CD40L interaction with anti-CD40L allows the deletion of rheumatoid factor
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by the National Basic Research Program of China (973 Plan, grant 2009CB825605) and the National Science Foundation of China (Nos: 30972745, 81101194 and 30901300).
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2020, Trends in GeneticsCitation Excerpt :Loss of DNA methylation at sex-differentially expressed genes has been involved in the pathogenesis of immune-related diseases. DNA demethylation has been observed at the promoter of the X-linked gene CD40L in large cohorts of patients affected by various autoimmune diseases (e.g., systemic sclerosis, RA, SLE) and is associated with CD40L overexpression in female T cells [74–76]. Notably, this is consistent with a role for Xi gene reactivation in the pathogenesis of autoimmune diseases (Figure 1B and Box 3).
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