Premature senescence of the immune system in rheumatoid arthritis and multiple sclerosis patients.

Abstract

The decline in immunocompetence with age is accompanied by a steadily increasing incidence of autoimmune diseases. A reduced thymic output, which is an important aspect of immunosenescence will induce compensatory auto-proliferation. This process can lead to a premature senescence of T cells and contribute to the immune abnormalities associated with autoimmunity and aging. In this stud we tested whether the immune system of patients with rheumatoid arthritis(RA), multiple sclerosis (MS), and ankylosing spondylitis (AS) shows signs of an age-indepedent aging. Therefore, we measured two indicators of aging, the number of T cell receptor excision circles (TRECs) and the percentage of CD4+CD28null T cells, in peripheral blood mononuclear cells (PBMC). In addition, characteristics of senescent CD4+CD28null T cells were analyzed. PBMC were isolated from blood of 60 RA, 30 MS and 20 AS patients as well as 40 healthy controls (HC). The percentage of CD4+CD28null T cells was measured by flow cytometry. The number of TRECs in 100 ng of gDNA was determined by real-time PCR analysis. Intracellular FACS analysis and CDR3 fragment length analysis were used to determine the cytokine profile and the clonal origin of the CD4+CD28null T cells, respectively. In RA and MS patients, TREC numbers were significantly decreased compared to age-matched HC. TREC numbers were comparable between AS patients and HC. Furthermore, an increased percentage of CD4+CD28null T cells was detected in 40% of RA patients, 32% of MS patients and 12% of AS patients versus 10% of HC. In HC and RA patients, the presence of the HLA-DR4 haplotype, a genetic risk factor for developing RA, was found to be linked with the percentage of CD4+CD28null T cells. CD4+CD28null T cells were also detected in the synovial tissue of RA patients. Analysis of the CD4+CD28null T cells revealed clonal expansions and pro-inflammatory properties. This study provides indications for a premature senescence of the immune system in both RA and MS patients. Premature aing associated thymic involution and compensatory auto-proliferation might play an important role in the pathogenesis of autoimmunity. CD4+CD28null T cells have tissue damaging properties, are prematurely increased in both RA and MS patients and might therefore play an active role in the pathogenesis of these autoimmune diseases. Further study will be necessary to reveal the exact role of an aged immune system and more particular the role of an aged immune system and more particular the role of CD4+CD28null T cells in the pathogenesis of autoimmunity.