CNS Demyelination with TNF-α Blockers

Kemanetzoglou, Elissavet; Andreadou, Elisabeth

doi:10.1007/s11910-017-0742-1

Cited by 261 publications

(229 citation statements)

References 104 publications

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“…Inhibits disease (Klinkert et al, 1997) Exacerbates disease (Kemanetzoglou and Andreadou 2017) IL-12 (p40/−35) and IL-23 (p40/p19) Abs Ameliorated by anti-IL-23 not IL-12 Abs (Cua et al, 2003;Grifka-Walk et al, 2015) No efficacy (Segal et al, 2008) IL-17Ab (secukinumab) Inhibits disease (Komiyama et al, 2006) Nonsignificant lesion reduction (effective in psoriasis and RA) (Havrdova et al, 2016) IL-27 Abs + (inhibits GM-CSF) (Casella et al, 2017) n/a GM-CSFR blockade Prevents relapses (Nissen et al, 2018) Ameliorates progression (Ifergan et al, 2017) No alteration of initial clinical course; limits extent of chronic CNS injury (Duncker et al, 2018) Abbreviations: Abs, antibodies; EAE, experimental autoimmune encephalomyelitis; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; MS, multiple sclerosis; RA, rheumatoid arthritis. gadolinium enhanced MRI lesions or clinical measures of disease activity in relapsing remitting MS (RRMS) (Khoury et al, 2017).…”

Section: Glia As Immune-therapeutic Targetsmentioning

confidence: 99%

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Healy

Yaqubi

Ludwin

et al. 2019

Glia

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Cells of the adaptive and innate immune systems in the brain parenchyma and in the meningeal spaces contribute to physiologic functions and disease states in the central nervous system (CNS). Animal studies have demonstrated the involvement of immune constituents, along with major histocompatibility complex (MHC) molecules, in neural development and rare genetic disorders (e.g., colony stimulating factor 1 receptor [CSF1R] deficiency). Genome wide association studies suggest a comparable role of the immune system in humans. Although the CNS can be the target of primary autoimmune disorders, no current experimental model captures all of the features of the most common human disorder placed in this category, multiple sclerosis (MS). Such features include spontaneous onset, environmental contributions, and a recurrent/progressive disease course in a genetically predisposed host. Numerous therapeutic interventions related to antigen and cytokine specific therapies have demonstrated effectiveness in experimental autoimmune encephalomyelitis (EAE), the animal model used to define principles underlying immune‐mediated mechanisms in MS. Despite the similarities in the two diseases, most treatments used to ameliorate EAE have failed to translate to the human disease. As directly demonstrated in animal models and implicated by correlative studies in humans, adaptive and innate immune constituents within the systemic compartment and resident in the CNS contribute to the disease course of neurodegenerative and neurobehavioral disorders. The expanding knowledge of the molecular properties of glial cells provides increasing insights into species related variables. These variables affect glial bidirectional interactions with the immune system as well as their own production of “immune molecules” that mediate tissue injury and repair.

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Section: Glia As Immune-therapeutic Targetsmentioning

confidence: 99%

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Healy

Yaqubi

Ludwin

et al. 2019

Glia

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“…4A, B). CYP27B1 expression is regulated by a complex network of cytokines (4); we therefore assessed the impact of proinflammatory cytokines known to play a role in MS pathology (TNF-α and IL-1β) on CYP27B1 expression, 25OHD metabolism, and MerTK expression (30). We observed that the addition of TNF-α, and to a lesser degree IL-1β, enhanced the expression of CYP27B1 in MØ GMcsf cells but not MØ 0 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells

Clarke

Yaqubi

Futhey

et al. 2020

Preprint

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Vitamin D deficiency is a major environmental risk factor for the development of multiple 1 sclerosis (MS). The major circulating metabolite of vitamin D (25OHD) is converted to the 2 active form (calcitriol) by the hydroxylase enzyme CYP27B1. In MS lesions the tyrosine kinase 3MerTK expressed by microglia and macrophages regulates phagocytosis of myelin debris and 4 apoptotic cells that can accumulate and inhibit tissue repair and remyelination. We show that 5 calcitriol downregulates MerTK mRNA and protein expression in adult human microglia and 6 monocyte-derived macrophages, thereby inhibiting myelin phagocytosis and apoptotic cell 7 clearance. Proinflammatory myeloid cells express high levels of CYP27B1 compared to 8 homeostatic (TGFβ-treated) myeloid cells. Only proinflammatory cells in the presence of TNF-α 9 generate calcitriol from 25OHD, resulting in repression of MerTK expression and function. The 10 selective production of calcitriol in proinflammatory myeloid cells leading to downregulation of 11 MerTK-mediated phagocytosis has the potential to reduce the risk for auto-antigen presentation 12 while retaining the phagocytic ability of homeostatic myeloid cells, thereby contributing to 13 inflammation reduction and enhanced tissue repair. 14 cuprizone model of demyelination (7). MDMs derived from MS patients show impaired ability 38 to phagocytose myelin, a defect linked to a reduction in MerTK expression (8). In addition to 39 clearing myelin debris, MerTK mediates the process of efferocytosis, the removal of dead/dying 40 cells, which is important for autoreactive T-cell fate determination in MS (9). The functions of 41 myeloid cells are dependent on their state of activation. TGFβ, a key cytokine involved in CNS 42 homeostasis, has been shown to maintain cells in a homeostatic state characterized by high 43 expression of MerTK, TREM2, CSF1R and Mafb (10). In contrast, MerTK expression is 44 comparatively lower in proinflammatory myeloid cells, a population shown to contribute to MS 45 pathogenesis (6). Genome-wide association studies (GWAS) have explained much of MS 46 heritability. Single nucleotide polymorphisms (SNPs) in CYP24A1 and CYP27B1, which tightly 47 Methods 61Monocyte-derived macrophages -Human peripheral blood mononuclear cells (PBMCs) were 62 isolated from healthy donors by Ficoll-Hypaque density gradient centrifugation (GE healthcare). 63Monocytes were isolated from PBMCs using magnetic CD14+ isolation beads (Miltenyi). 64Proinflammatory (MØ GMcsf ) and alternative (M2) macrophages were generated by differentiating 65 monocytes for 6 days in the presence of 25ng/mL GM-CSF and M-CSF respectively. To 66 generate CNS homeostatic (MØ 0 ) macrophages, TGFβ (50ng/mL) was added to the M-CSF 67 culture conditions on days 3 and 6. 10 -7 M calcitriol (Selleckchem) was added to designated 68 macrophages on day 1 of culture and maintained throughout differentiation. Culture media was 69 replenished every 2-3 days. 70Microglia & astrocytes -Human adult microglia were isolated from brain tissue of ...

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“…These comorbidities are also relevant due to their possible influence in treatment decisions; for example, the use of natalizumab in patients with previous immunosuppression or the risk of possible exacerbation of MS with certain drugs, such as tumor necrosis factor inhibitors, that should be avoided in this population. 19 Other studies have found that family members of patients with MS have an increased risk of AID other than MS. 4,5,16 Nevertheless, these studies were compared with healthy controls, so they cannot be compared with the present findings. We have not found evidence that family members of MS patients with other concomitant AID have an added risk of AID (compared with the known risk in MS first relatives).…”

Section: Discussionmentioning

confidence: 98%

“Multiple sclerosis plus”: Does it influence the disease course?

Seabra

Abreu

Mendonça

et al. 2020

Clinical & Exp Neuroim

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Objectives:To study the association between multiple sclerosis (MS) and other autoimmune diseases (AID).Methods: From a cohort of 635 patients with MS, 66 patients with an history of AID were selected. Controls, matched 1:1, were chosen from the population of patients with MS without autoimmune comorbidities. Further analysis aimed to compare these groups. Results:The prevalence of comorbid AID in our population was 10.4%. The mean age was 43 ± 13 years; 77% were women. A total of 15 different types of AID were identified, the predominant one was autoimmune thyroiditis (18/66; 27%). In 46% of patients, the AID was diagnosed before, and in 49%, it was diagnosed after the diagnosis of MS. The presence of family history of AID was not associated with the risk of developing AID. Our analysis found no association between the presence of AID and disease activity (new lesions, gadolinium enhancement, mean of annual relapse rate, initiation of a second-line treatment), either when considering each variable individually or within a composite score. The median Extended Disability Status Scale and Multiple Sclerosis Severity Score was 1.5 (interquartile range [IQR] 3.0) and 1.0 (IQR 3.0), respectively, in the AID group, and 1.5 (IQR 3.0) and 2.0 (IQR 3.0), respectively, in the control group, and the difference was not statistically significant. The presence of a concomitant AID influenced therapeutic choice in nine patients. Conclusions:The present study underlines the varied range of AID that might coexist with MS. This common ground does not seem to have a negative effect on the disease course. K E Y W O R D Sautoimmune diseases, demyelinating diseases, immune system diseases, immunomodulation, multiple sclerosis

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CNS Demyelination with TNF-α Blockers

Cited by 261 publications

References 104 publications

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells

“Multiple sclerosis plus”: Does it influence the disease course?

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