Dysregulation of the IL-23/IL-17 axis and myeloid factors in secondary progressive MS

Huber, Amanda K.; Wang, Lu; Han, Peisong; Zhang, Xu; Ekholm, Sven; Srinivasan, Ashok; Irani, David N.; Segal, Benjamin M.

doi:10.1212/wnl.0000000000000908

Cited by 62 publications

(43 citation statements)

References 42 publications

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“…6A). Cerebral MRI scans were obtained from each subject and analyzed as previously described [17]. Average MRI T2 lesion load was similar across the three groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…PBMCs were isolated using CPT Vacutainer tubes (Fisher Scientific), suspended in fetal bovine serum with 20% dimethyl sulfoxide, and stored in liquid nitrogen until thawed for analysis. ELISPOT assays were performed to enumerate the frequencies of MBP-specific IFNγ and IL-17 producers, using a protocol that we previously described [17]. Subjects were classified as IFNγ-skewed if the frequency of MBP-specific IFNγ producers in their PBMC exceeded that of IL-17 producers by two-fold or more in at least two thirds of samples.…”

Section: Methodsmentioning

confidence: 99%

“…Brain parenchymal and T1 and T2 lesion volumes were measured using commercial software developed by VirtualScopics (Rochester, NY) as previously described [17]. …”

Section: Methodsmentioning

confidence: 99%

“…( B, C ) Each subject underwent cerebral MRI scanning. T1- and T2-weighted lesion volume and brain parenchymal volume (BPV) were measured using a semi-automated approach [17]. The figures show average T1 and T2 lesion volumes normalized to total BPV.…”

Section: Figurementioning

confidence: 99%

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Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Carbajal

Mironova

Ulrich-Lewis

et al. 2015

The Journal of Immunology

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Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4+ Th cells. IL-12 polarized Th1 cells, IL-23 polarized Th17 cells, and exTh17 cells (Th17 cells that acquire Th1 characteristics) have each been implicated in autoimmune pathogenesis. It is currently debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study we assess the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (EAE, widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFNγ- or IL-17- skewed responses to myelin basic protein (MBP) over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFNγ and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of EAE. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS.

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“…6A). Cerebral MRI scans were obtained from each subject and analyzed as previously described [17]. Average MRI T2 lesion load was similar across the three groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Brain parenchymal and T1 and T2 lesion volumes were measured using commercial software developed by VirtualScopics (Rochester, NY) as previously described [17]. …”

Section: Methodsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Carbajal

Mironova

Ulrich-Lewis

et al. 2015

The Journal of Immunology

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“…Many previous studies reported increased activation of peripheral blood immune cells from progressive patients, while pathology studies indicate that in SP and PP the inflammation is abundant, widespread and diffuse in CNS, and correlates with axonal damage and disease progression (42). A crucial role of IL-17 and of dysregulation of the IL-23/IL-17 axis in the blood of SP patients, and a correlation between the levels of these pro-inflammatory factors, the lesion load at MRI and brain atrophy have been recently documented (43, 44). Studies in experimental autoimmune encephalitis animal models showed that myelin-reactive Th17 cells induces ectopic follicles in the CNS (45), and this seems particularly intriguing in light of the discovery of lymphoid follicle-like structures in the meninges and in the large perivascular space of CNS of SP patients’ brain specimens, supporting the hypothesis of a compartmentalization of, and sustained inflammation in the CNS of progressive stages of MS (46, 47).…”

Section: Discussionmentioning

confidence: 99%

iNKT Cells in Secondary Progressive Multiple Sclerosis Patients Display Pro-inflammatory Profiles

et al. 2016

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BackgroundMultiple sclerosis (MS), an autoimmune disease with neurodegeneration and inflammation is characterized by several alterations of different T cell subsets. However, few data exist on the role of iNKT lymphocytes.ObjectiveTo identify possible changes in the phenotype of iNKT cells in patients with different clinical forms of MS and find alterations in their polyfunctionality [i.e., ability to produce simultaneously up to four cytokines such as IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-4].MethodsWe studied a total of 165 patients, 91 with a relapsing–remitting form [RR; 31 were treated with interferon (IFN)1a-β, 25 with natalizumab (NAT), 29 with glatiramer acetate; 17 were newly diagnosed RR without treatment, 19 not-active RR without treatment]. Forty-four patients had a progressive MS: 20 primary progressive (PP) and 24 secondary progressive (SP). A total of 55 age- and sex-matched subjects represented healthy controls (CTR). Among fresh peripheral blood mononuclear cells, iNKT cells were identified by flow cytometry. Moreover, the capability of iNKT cells to produce different cytokines (IL-17, TNF-α, IFN-γ, and IL-4) after in vitro stimulation were evaluated in 18 RR (11 treated with NAT and 7 with IFN), 4 PP, 6 SP, and 16 CTR.ResultsNo main differences were found in iNKT cell phenotype among MS patients with different MS forms or during different treatments. However, the polyfunctional response of iNKT cells showed Th1 and Th17 profiles. This was well evident in patients with SP form, who are characterized by high levels of inflammation and neurodegeneration, and exhibited a sustained increase in the production of Th17 cytokines. Patients treated with NAT displayed lower levels of iNKT cells producing IL-17, TNF-α, and IFN-γ.ConclusionOur data suggest that the progressive phase of the disease is characterized by permanent iNKT activation and a skewing towards an inflammatory phenotype. Compared to other treatments, NAT was able to modulate iNKT cell function.

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Myeloid cell plasticity in the evolution of central nervous system autoimmunity

Giles

Washnock-Schmid

Duncker

et al. 2018

Annals of Neurology

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These observations demonstrate the heterogeneity of CNS myeloid cells, their evolution during the course of autoimmune demyelinating disease, and their plasticity on the single cell level. Future therapeutic strategies for disease modification in individuals with MS may be focused on accelerating the transition of CNS myeloid cells from a proinflammatory to a noninflammatory phenotype. Ann Neurol 2018;83:131-141.

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Dysregulation of the IL-23/IL-17 axis and myeloid factors in secondary progressive MS

Cited by 62 publications

References 42 publications

Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

iNKT Cells in Secondary Progressive Multiple Sclerosis Patients Display Pro-inflammatory Profiles

Myeloid cell plasticity in the evolution of central nervous system autoimmunity

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