Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis.

INTRODUCTION: A poor 25-hydroxyvitamin D (25(OH)D) status is a much replicated risk factor for developing multiple sclerosis (MS), and several vitamin D-associated single nucleotide polymorphisms (SNPs) have been associated with a higher risk of MS. However, studies on the benefit of vitamin D supplementation in MS show inconclusive results. Here, we explore whether vitamin D-associated SNPs and MS risk alleles confound serological response to vitamin D supplementation. METHODS: 34 participants from the SOLARIUM study consented to genotyping, of which 26 had vitamin D data available. The SOLARIUM study randomised relapsing-remitting MS patients to placebo or 14,000 IU vitamin D3 for 48 weeks. Participants were categorised as either 'carriers' or 'non-carriers' of the risk allele for 4 SNPs: two related to D binding protein (DBP) and associated with lower 25(OH)D levels (rs4588 and rs7041), and two related to vitamin D metabolism enzymes CYP27B1 and CYP24A1 and associated with a higher risk of MS (rs12368653; rs2248359, respectively). 25(OH)D levels were determined at baseline and after 48 weeks. RESULTS: The DBP-related SNPs showed no difference in 25(OH)D status at baseline, but carriers of the rs7041 risk allele showed lower 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 224.2 vs. 332.0 nmol/L, p = 0.013). For CYP related SNPs, neither showed a difference at baseline, but carriers of the rs12368653 risk allele showed higher 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 304.1 vs. 152.0 nmol/L, p = 0.014). DISCUSSION: Vitamin D-related SNPs affect the serological response to high-dose vitamin D supplementation. The effects on more common doses of vitamin D, as well as the clinical consequence of this altered response, need to be investigated further.

Proportions of circulating transitional B cells associate with MRI activity in interferon beta-treated multiple sclerosis patients.

B-cells contribute to MS pathogenesis. The association of circulating B-cell phenotypes with combined unique active lesions (CUA) on MRI at 48 weeks follow-up was investigated in 50 interferon beta-treated MS patients. Transitional B-cell proportions were lower in participants with CUA at week 0 and 48 [p = 0.004, p = 0.002]. A decrease in circulating anti-EBNA-1 IgG levels between week 0 and 48 associated with absence of CUA [p = 0.047], but not with B-cell profiles. In a multi-factor model for CUA-risk, transitional B-cell proportions contributed independent from NK/T-cell ratio, change in anti-EBNA-1 IgG, and vitamin D supplementation. Transitional B-cells may predict treatment response in MS.

NK/T cell ratios associate with interleukin-2 receptor alpha chain expression and shedding in multiple sclerosis.

NK/T-cell ratios predict disease activity in relapsing remitting multiple sclerosis (RRMS). We investigated in 50 RRMS patients whether interleukin-2 receptor alpha-chain (IL-2Rα) expression and shedding associates with NK/T-cell balance, as suggested by daclizumab-trials in RRMS. A subsample (N = 31) was genotyped for IL2RA-associated MS risk SNPs. CD56bright NK-cell/IL-17A+CD4+ T-cell ratios correlated negatively with plasma and PBMC-culture supernatant sIL-2Rα-levels [R = -0.209; p = 0.038 and R = -0.254; p = 0.012, resp.], and with CD4+ T-cell CD25 MFI [R = -0.341; p = 0.001]. Carriers of the rs3118470 risk-allele showed higher sIL-2Rα-levels (P = 0.031) and a lower CD56bright NK-cell/IL-17A+CD4+ T-cell ratio (P = 0.038). Therefore, IL-2Rα may be involved in the interplay between NK-cells and T-cells.

The IL-2 - IL-2 receptor pathway: Key to understanding multiple sclerosis.

The development, progression, diagnosis and treatment of autoimmune diseases, such as multiple sclerosis (MS), are convoluted processes which remain incompletely understood. Multiple studies demonstrated that the interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway plays a pivotal role within these processes. The most striking functions of the IL-2 - IL-2R pathway are the differential induction of autoimmune responses and tolerance. This paradoxical function of the IL-2 - IL-2R pathway may be an attractive therapeutic target for autoimmune diseases such as MS. However, the exact mechanisms that lead to autoimmunity or tolerance remain to be elucidated. Furthermore, another factor of this pathway, the soluble form of the IL-2R (sIL-2R), further complicates understanding the role of the IL-2 - IL-2R pathway in MS. The challenge is to unravel these mechanisms to prevent, diagnose and recover MS. In this review, first, the current knowledge of MS and the IL-2 - IL-2R pathway are summarized. Second, the key findings of the relation between the IL-2 - IL-2R pathway and MS have been highlighted. Eventually, this review may launch broad interest in the IL-2 - IL-2R pathway propelling further research in autoimmune diseases, including MS.

Prognostic value of natural killer cell/T cell ratios for disease activity in multiple sclerosis.

BACKGROUND AND PURPOSE: Natural killer (NK) cells may play a role in multiple sclerosis (MS). Ratios of NK cells to CD4+ T cells have been proposed as a biomarker for the therapeutic effect of stem cell transplantation in MS. The objectives here were to explore the relevance of this ratio in MS patients by analysing NK and T cell subsets, as well as their prognostic value for disease activity. METHODS: Baseline peripheral blood mononuclear cells of 50 relapsing-remitting MS patients, participating in our vitamin D supplementation study (SOLARIUM), were analysed with flow cytometry. Disease activity was measured as new magnetic resonance imaging lesions, relapses and mean plasma neurofilament light chain levels after 48 weeks of follow-up. RESULTS: The proportion of NK cells correlated negatively with CD4+ T cells (R = -0.335, p = 0.001) and interleukin 17A (IL-17A+ ) CD4+ T cells (R = -0.203, p = 0.043). Participants with magnetic resonance imaging activity or relapses displayed lower NK/IL-17A+  CD4+ T cell ratios (p =0.025 and p = 0.006, respectively). The NK/IL-17A+  CD4+ T cell ratio correlated negatively with neurofilament light chain levels (R = -0.320, p = 0.050). Vitamin D supplementation did not affect these ratios. CONCLUSIONS: Our data suggest a protective role of an expanded NK cell compartment compared to the CD4+ T cell subset fractions in relapsing-remitting MS patients. NK/CD4+ T cell ratios may be a prognostic biomarker for disease activity in MS.

Natural killer cells in multiple sclerosis: A review.

As the most common non-traumatic disabling disease among adolescents, multiple sclerosis (MS) is a devastating neurological inflammatory disease of the central nervous system. Research has not yet fully elucidated its pathogenesis, but it has shown MS to be a complex, multifactorial disease with many interplaying factors. One of these factors, natural killer (NK) cells, lymphocytes of the innate immune system, have recently gained attention due to the effects of daclizumab therapy, causing an expansion of the immunoregulatory subset of NK cells. Since then, NK cells and their relation to MS have been the focus of research, with many new findings being published in the last decade. In this review, NK cells are pictured as potent cytotoxic killers, as well as unique immune-regulators. Additionally, an overview of our current knowledge regarding NK cells in MS is given. The role of NK cells in MS is reviewed in the context of well-established environmental factors and current disease modifying therapies to gain further understanding of the pathogenesis and treatment options in MS.

Vitamin D3 supplementation and neurofilament light chain in multiple sclerosis.

OBJECTIVES: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D3 supplements were associated with lower circulating NfL levels. MATERIALS & METHODS: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D3 and N = 16 with placebo. Twenty-five hydroxyvitamin D3 (25(OH)D3 ) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. RESULTS: Serum 25(OH)D3 levels at 48 weeks were increased in the vitamin D3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P < .01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). CONCLUSIONS: Supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D3 on this biomarker of neuro-axonal injury.