Summary
Naturally occurring CD4+ CD25 + regulatory T cells (nTreg) play a major role in controlling autoimmunity by suppressing self-reactive T cells. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS), where T cells play a key role in orchestrating tissue damage. While CD4 + CD25 + nTreg have been investigated in peripheral blood from MS patients, little is known about their presence and possible function within the target organ, the CNS. In order to study whether these cells are present in the cerebrospinal fluid (CSF) under pathological conditions, we have analysed the frequency of CD4 + CD25 + nTreg in peripheral blood and CSF from MS patients (n = 14), patients with other neurological disorders (OND; n = 9) and compared peripheral levels with healthy controls (n = 40). We found that the frequency of CD4 + CD25 + forkhead transcription factor 3 (FOXP3) + nTreg was significantly elevated in the CSF from MS patients (mean CSF = 4·05 Ϯ 1·54% versus mean peripheral blood = 2·93 Ϯ 0·94%) but not from patients with other neurological disorders (mean CSF = 3·78 Ϯ 1·26% versus mean peripheral blood = 3·74 Ϯ 1·4%). The frequency of nTreg in the periphery did not differ between MS patients and healthy donors; however, nTreg from MS patients showed reduced suppressive capacity.
FOXP3-expressing naturally occurring CD4+CD25high T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4+ T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4+ T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.
SummaryThe serine protease cathepsin (Cat) G dominates the proteolytic processing of the multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) in lysosomes from primary human B cells and dendritic cells. This is in contrast to B-lymphoblastoid cell lines, where the asparagine endopeptidase (AEP) is responsible for this task. We have analysed microglia-derived lysosomal proteases for their ability to process MBP in vitro. In lysosomes derived from primary murine microglia, CatD, CatS, AEP and CatG were involved in the processing of MBP. Interestingly, when microglia were treated with interferon-c to mimic a T helper type 1-biased cytokine milieu in MS, CatG was drastically down-regulated, in contrast to CatS, CatB, CatL, CatD or AEP. This resulted in significantly increased stability of MBP and a selective lack of CatG-derived proteolytic fragments; however, it did not affect the gross pattern of MBP processing. Inhibition of serine proteases eliminated the processing differences between lysosomal extracts from resting microglia compared to interferon-stimulated microglia. Thus, the cytokine environment modulates lysosomal proteases in microglia by a selective down-regulation of CatG, leading to decreased MBP-processing by microglia-derived lysosomal proteases in vitro.
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