Abstract: The spontaneous improvement of rheumatic disease duringpregnancy: do regulatory T cells play a role?
Background: Pregnancy is one of the few natural disease modifiers of rheumatic disease activity. During pregnancy, rheumatoid arthritis (RA) improves early whereas ankylosing spondylitis (AS) remains often active and improves first in the third trimester. The factors responsible for improvement/remission remain elusive. Recent research in animals and humans has shown that regulatory T cells may be involved in the suppression of autoimmune disease. Several subsets of regulatory T cells exist including CD4+CD25+ T cells. They are able to suppress autoreactive T effector cells and thereby prevent or mitigate autoimmune disease.Impairment in regard to proportion and function of regulatory T cells are present in RA and AS. Pregnancy restores normal proportions and functions of regulatory T cells.
Patients and methods: Sequential samples of peripheral blood mononuclear cells (PBMC) from each trimester of pregnancy and at regular intervals post partum from patients with RA, with AS, and healthy pregnant women are studied. The frequency of CD4+CD25+ T cells is analysed after staining with monoclonal antibodies by FACS analysis. The function of CD4+CD25+ T cells is analysed on the gene expression level and the protein level.Cytokines are crucial for the function of regulatory T cells. ThereforeTh1 and Th2 type cytokines are analysed on the mRNA level by RT-PCR, and on the protein level by measuring intracellular cytokines as well as cytokine secretion after stimulation of isolated T cell populations. The regulatory proportion of CD4+CD25+ T cells is identified by isolation of the CD4+CD25bright+ subset by FACS sorting, by measurement of Foxp3 by RT-PCR and by co-culture studies with responder T cells. Factors possible inducing an increase of regulatory T cells during pregnancy are studied by exposing PBMC to 10% 3rd trimester serum or to pregnancy concentrations of estriol, progesterone and cortisol and analyzing the proportion of of the CD4+CD25bright+ subset. Hormonal influences on the function of regulatory T cell subsets are studied by isolating CD4+CD25+ T cells from patients with active RA or AS and investigating suppressor function after incubation in pregnancy hormones.
Conclusion: By assessing proportions and functions of regulatory T cells in pregnant patients with RA and AS, the proposed study will investigate cellular processes underlying pregnancy related changes of disease activity in rheumatic disease. Insight into spontaneous remission opens for new therapeutic approaches in these chronic diseases.