The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH) 2 D 3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG 35–55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8 + T cells was analyzed by microarray ( n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8 + T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy. Electronic supplementary material The online version of this article (10.1007/s00401-019-02018-8) contains supplementary material, which is available to authorized users.

Multiple sclerosis (MS) is characterized as an autoimmune disease affecting the central nervous system. It is one of the most common neurological disorders in young adults. Over the past decades, increasing evidence suggested that hypovitaminosis D is a contributing factor to the risk of developing MS. From different risk factors contributing to the development of MS, vitamin D status is of particular interest since it is not only a modifiable risk factor but is also associated with MS disease activity. MS patients with lower serum vitamin D concentrations were shown to have higher disease activity. However, this finding does not demonstrate causality. In this regard, prospective vitamin D supplementation studies missed statistical significance in its primary endpoints but showed promising results in secondary outcome measures or post hoc analyses. An explanation for missed primary endpoints may be underpowered trials. Besides vitamin D supplementation as a potential add-on to long-term immunotherapeutic treatment, a recent laboratory study of our group pointed toward a beneficial effect of vitamin D to improve the efficacy of glucocorticoids in relapse therapy. In the following article, we will briefly review the effects of vitamin D on MS by outlining its effects on the immune and nervous system and by reviewing the association between vitamin D and MS risk as well as MS disease activity. We will also review the effects of vitamin D supplementation on MS risk and MS disease activity.

Background: In multiple sclerosis (MS), the frequency of hypogammaglobulinemia is unknown. We aimed to evaluate the frequency of reduced immunoglobulin (Ig) concentrations and its association with immunotherapy and disease course in two independent MS cohorts. Methods: In our retrospective cross-sectional study, MS patients and control patients with head or neck pain from Bern University Hospital (Bern, Switzerland) and Eginition University Hospital (Athens, Greece) were included. The lower limits of normal (LLN) for serum Ig concentration were IgG < 700 mg/dl, IgM < 40 mg/dl, and IgA < 70 mg/dl. Mann–Whitney U test, analysis of variance test, and multiple linear regression analysis were employed. Results: In total, 327 MS patients were retrospectively identified (Bern/Athens: n = 226/101). Serum IgG concentrations were frequently under LLN in both MS cohorts (Bern/Athens: 15.5%/14.9%), even when considering only untreated patients (Bern/Athens: 7.9%/8.6%). MS patients ( n = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls ( n = 58) ( p = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [ n (MS patients/controls): IgA 203/30, IgM 224/24]. Independently of age, secondary progressive MS patients had lower IgG concentrations than relapsing–remitting and primary progressive patients (both: p ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab ( p = 0.001; n = 42/327), intravenous corticosteroids ( p < 0.001; n = 16/327), natalizumab ( p < 0.001; n = 48/327), and fingolimod ( p = 0.003; n = 6/327). Conclusion: Our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments. The significance of lower IgG concentrations at the levels noted is unclear considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl. However, the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400 mg/dl.