Endogenous and Recombinant Type I Interferons and Disease Activity in Multiple Sclerosis

Sellebjerg, Finn; Krakauer, Martin; Limborg, Signe; Hesse, Dan; Lund, Henrik Hautop; Langkilde, Annika Reynberg; Søndergaard, Helle Bach; Sørensen, Per Soelberg

doi:10.1371/journal.pone.0035927

Cited by 15 publications

(14 citation statements)

References 38 publications

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“…Stronger CD134 expression on CD26 HIGH than on CD26 NEG and CD26 INT CD4 + T-cells suggests that the expression of these molecules may be associated. In a study of IFN-β treatment effects in RRMS, we found that treatment with IFN- β reduced the expression of CD134 on CD26 HIGH CD4+ T cells [36], in accordance with what we found in natalizumab-treated patients in our study. Thus decreased CD134 expression on CD26 HIGH CD4 + T-cells may reflect a decrease in T-cell activation.…”

Section: Discussionsupporting

confidence: 92%

Effect of Natalizumab on Circulating CD4+ T-Cells in Multiple Sclerosis

et al. 2012

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In multiple sclerosis (MS), treatment with the monoclonal antibody natalizumab effectively reduces the formation of acute lesions in the central nervous system (CNS). Natalizumab binds the integrin very late antigen (VLA)-4, expressed on the surface of immune cells, and inhibits VLA-4 dependent transmigration of circulating immune-cells across the vascular endothelium into the CNS. Recent studies suggested that natalizumab treated MS patients have an increased T-cell pool in the blood compartment which may be selectively enriched in activated T-cells. Proposed causes are sequestration of activated T-cells due to reduced extravasation of activated and pro-inflammatory T-cells or due to induction of VLA-4 mediated co-stimulatory signals by natalizumab. In this study we examined how natalizumab treatment altered the distribution of effector and memory T-cell subsets in the blood compartment and if T-cells in general or myelin-reactive T-cells in particular showed signs of increased immune activation. Furthermore we examined the effects of natalizumab on CD4+ T-cell responses to myelin in vitro. Natalizumab-treated MS patients had significantly increased numbers of effector-memory T-cells in the blood. In T-cells from natalizumab-treated MS patients, the expression of TNF-α mRNA was increased whereas the expression of fourteen other effector cytokines or transcription factors was unchanged. Natalizumab-treated MS patients had significantly decreased expression of the co-stimulatory molecule CD134 on CD4+CD26HIGH T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26HIGHCD4+ T-cells in vitro. Otherwise CD4+ T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. In conclusion natalizumab treatment selectively increased the effector memory T-cell pool but not the activation state of T-cells in the blood compartment. Myelin-reactive T-cells were not selectively increased in natalizumab treated MS.

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Section: Discussionsupporting

confidence: 92%

Effect of Natalizumab on Circulating CD4+ T-Cells in Multiple Sclerosis

et al. 2012

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“…high T cells in MS [15,[26][27][28]. We hypothesized that FOXP3, CBLB and CBLB gene expression could be lower in untreated MS patients and increase upon treatment with IFN-b, and therefore compared FOXP3 mRNA expression with expression of CBLB, ITCH mRNA and with the activation status of CD4 +…”

Section: Cd25mentioning

confidence: 99%

“…Treatment of MS with interferon (IFN)-b decreases disease activity, and treatment with IFN-b was reported recently to improve the functional activity and modulate the phenotype of CD4 + CD25 high T cells in MS [15,[26][27][28]. We hypothesized that FOXP3, CBLB and CBLB gene expression could be lower in untreated MS patients and increase upon treatment with IFN-b, and therefore compared FOXP3 mRNA expression with expression of CBLB, ITCH mRNA and with the activation status of CD4 + CD25 high T cells in healthy controls and MS patients before and during treatment with IFN-b 1a.…”

Section: Introductionmentioning

confidence: 99%

FOXP3, CBLBandITCHgene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis

Sellebjerg

Krakauer

Khademi

et al. 2012

Clinical and Experimental Immunology

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“…An enhanced type I IFN signature in a subset of MS patients has repeatedly been shown in the following studies, and increased IFN‐β bioactivity in the serum of these patients has been confirmed . Intriguingly, higher expression of MxA, a type I IFN‐inducible gene, in the peripheral blood of untreated MS patients is reported to be associated with lower disease activity . In addition, Börnsen et al .…”

Section: Endogenous Type I Ifn In Msmentioning

confidence: 64%

“…9 Intriguingly, higher expression of MxA, a type I IFN-inducible gene, in the peripheral blood of untreated MS patients is reported to be associated with lower disease activity. 10,12,13 In addition, B€ ornsen et al 14 showed that CD4+T cells from patients with a high type I IFN signature show decreased proliferation against myelin basic protein In contrast to these studies, which suggest enhanced type I IFN responses in MS, Tao et al 15 reported reduced type I IFN activity in the serum of MS patients compared with healthy participants. They additionally showed that this decrease in type I IFN activity is associated with enhanced T helper (Th)17 responses in MS. 15 Taken together, these reports all point to the protective role of endogenous type I IFN in MS.…”

Section: Endogenous Type I Ifn In Msmentioning

confidence: 99%

Endogenous type I interferons and their regulators in multiple sclerosis

Miyazaki

Niino

2017

Clinical & Exp Neuroim

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. In the past few decades, several disease-modifying drugs including interferon (IFN)-b have become available for treating MS. IFN-b belongs to the type I IFN family, and thus is an endogenous molecule whose primary role is thought to be host defense against viruses. In addition, type I IFN are constitutively produced at low amounts and involved in the homeostasis of various tissues. In contrast, it is suggested that type I IFN play a pathogenic role in other autoimmune diseases, such as lupus. Several lines of evidence from studies using MS samples and animal models suggest the protective role of endogenous type I IFN in MS. Correspondingly, MS patients with a higher endogenous type I IFN signature show lower disease activity. Paradoxically, these patients have been shown to respond poorly to IFN-b therapy. In addition, an animal model with a defective regulatory mechanism in type I IFN signaling has been shown to develop augmented central nervous system autoimmunity, suggesting that type I IFN responses need to be appropriately regulated in MS. Multiple endogenous molecules participate in the regulation of type I IFN responses, but their roles in MS have not been studied extensively. Further study delineating the role of endogenous type I IFN and their regulatory mechanisms in MS should enhance our understanding of the disease, and could lead to improvements in the therapeutic effects of IFN-b in MS.

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Endogenous and Recombinant Type I Interferons and Disease Activity in Multiple Sclerosis

Cited by 15 publications

References 38 publications

Effect of Natalizumab on Circulating CD4+ T-Cells in Multiple Sclerosis

Effect of Natalizumab on Circulating CD4+ T-Cells in Multiple Sclerosis

FOXP3, CBLBandITCHgene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis

Endogenous type I interferons and their regulators in multiple sclerosis

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