Objective. The endogenous steroid dehydroepiandrosterone (DHEA) has been reported to play a role in rheumatoid arthritis (RA). DHEA is metabolized by the P450 enzyme CYP7B into 7␣-OH-DHEA, which has immunostimulating properties. This study was undertaken to investigate the putative role of CYP7B in arthritis using murine collagen-induced arthritis (CIA), an interleukin-1␤ (IL-1␤)-dependent model.Methods. DBA/1J mice were immunized and administered a booster with type II collagen. The presence of 7␣-OH-DHEA was determined in both arthritic and nonarthritic joints and the serum of CIA mice by radioimmunoassay. CYP7B messenger RNA (mRNA) expression was analyzed in synovial biopsy samples, and in fibroblast-like synoviocytes (FLS) isolated from these synovial biopsy samples, by reverse transcriptasepolymerase chain reaction (RT-PCR). In addition, the regulatory role of IL-1␤ on CYP7B activity in FLS was determined using RT-PCR, Western blotting, and highperformance liquid chromatography.Results. In knee joint synovial biopsy samples from arthritic mice, 7␣-OH-DHEA levels were 5-fold higher than in nonarthritic mice. Elevated levels of 7␣-OH-DHEA were accompanied by an increase in CYP7B mRNA expression and were positively correlated with disease severity. In serum, no differences in 7␣-OH-DHEA levels were observed between arthritic and nonarthritic mice. Incubation of FLS with IL-1␤ resulted in a dose-dependent increase in 7␣-OH-DHEA formation. In addition, IL-1␤ enhanced CYP7B mRNA and CYP7B protein levels in FLS.Conclusion. Disease progression in CIA is correlated with enhanced CYP7B activity, which leads to locally enhanced 7␣-OH-DHEA levels. Elevated IL-1␤ levels within the arthritic joint may regulate this increase in CYP7B activity.

Third trimester amelioration is not related to the fluctuation of circulating Th17 cells. Furthermore, a paradoxical decrease of immunosuppressive circulating Tregs can be observed during this phase, both in MS patients and controls.

The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Rα+ CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Rα+CD8+ and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8+IL-7Rα+ in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα+ lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-a (IL-7Ra)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Ra leads to increased soluble IL-7Ra production. Given the functional interaction between sIL-7Ra, membrane-bound IL-7Ra and IL-7, we assessed IL-7, mIL-7Ra and sIL-7Ra levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Ra levels compared with 73 HCs. The levels of sIL-7Ra increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Ra could result in a higher mIL-7Ra to soluble IL-7Ra ratio. Indeed, 52 MS patients had significantly increased mIL-7Ra to sIL-7Ra ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Ra influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Ra ratio. The soluble IL-7Ra levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Ra level may influence responsiveness of IL-7Ra þ cells.