Maturation, reactivity and therapy induced changes of memory T-cells in rheumatic autoimmune diseases

This thesis covers different aspects of CD4+T-cells (maturational pathway, auto-reactive potential and differential reaction to glucocorticoid-therapy) in two auto-immune diseases: systemic lupus erythematosus (SLE) and Rheumatoid arthritis (RA). Immunological memory is important for an adequate response to pathogens. CD4+(memory) T-cells constitutes one pillar of this immunological memory. We could elucidate the maturational pathway of memory T-cells in healthy persons by expanding the model of central and effector memory cells, distinct in their expression of CCR7, with the use of the co-stimulatory protein CD27 as phenotypic marker. We could establish that CD4+ T-cells mature from naïve à CCR7+/CD27+ à CCR7-/CD27+ à CCR7-/CD27-. The CCR7- subsets show a lower proliferative capacity, are more prone to undergo apoptosis, and show distinct cytokine production. This maturational pathway was also seen in SLE-patients; however, although the pathway was identical, the distribution was different with an accumulation of more mature CCR7- subsets in SLE. Additionally, significant deficiencies in cell survival and proliferation (only) of the CCR7- subsets compared with their “healthy” counterparts were apparent. Altogether these studies give more insight into the maturational pathway of CD4+T-cells in general and the disturbances therein in SLE-patients. We could furthermore identify 2 important (CD4+T-)cellular auto-antigens in SLE, namely Histone H1 and hnRNP-A2, a spliceosomal protein. The frequency and strength of T-cell reactivity in SLE patients was significantly higher than in healthy controls for both antigens, displaying predominantly a Th1 type response. As incubation of Histone H1 with H1-specific T-cells could induce an antibody response in SLE (in contrast to healthy controls), this histone possibly drives the humoral response to chromatin. Additionally, we discovered a T-cell subset, reactive for hnRNP-A2, with high IL-10 secretion and a CD8+CD28- phenotype, which was unique to SLE-patients. Together these findings provide more information of the pathogenesis of SLE enabling a better understanding of this disease. Moreover, we could establish the importance of hnRNP-A2 as cellular auto-antigen in RA, eliciting a Th1 response. In contrast, we could not detect a cellular response to citrullinated filaggrin, implying that the role of filaggrin is not central in the reactivity to citrullinated peptides in RA. As CD4+T-cells are a driving force in the pathogenesis of several auto-immune diseases, they also constitute a therapeutical target. Glucocorticoids (GC), the mainstay of therapy for auto-immune diseases, deploy their action - among others - by influencing CD4+T-cells. However, approximately one third of RA-patients do not respond adequately to GC. Searching for a prognostic factor to predict the clinical response to GC, we identified an increased expression of ERAP2 before therapy in CD4+T-cells and monocytes of GC-responsive RA-patients. After this finding is confirmed in bigger cohorts, it could be used as a prognostic marker for GC-therapy. We also found a difference in working mechanism of GC in responsive versus non-responsive RA-patients, as the gene expression profile of CD4+T-cells and monocytes revealed a more strongly down-regulated interferon signature by GC in non-responsive RA-patients. These findings could ultimately lead to a more tailor made (combination-) therapy in RA-patients, preventing unnecessary side effects.