Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS

Zastepa, Evelyn; Fitz-Gerald, Leslie; Hallett, Michael; Antel, Jack P.; Bar‐Or, Amit; Baranzini, Sergio E.; Lapierre, Yves; Haegert, David G.

doi:10.1212/wnl.0000000000000146

Cited by 25 publications

(19 citation statements)

References 32 publications

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“…It has been reported that there is enhanced cellular expression of TLR2 in MS patients, e.g. on neutrophils , T cells and in the central nervous system (CNS) . However, in the present study we did not find an enhanced expression of TLR2 on CD14 + monocytes in patients with MS.…”

Section: Discussioncontrasting

confidence: 99%

Enhanced TLR2 responses in multiple sclerosis

Fujiwara

Anstadt

Flynn

et al. 2018

Clinical and Experimental Immunology

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SummaryThe roles of the microbiome and innate immunity in the pathogenesis of multiple sclerosis (MS) remain unclear. We have previously documented abnormally low levels of a microbiome‐derived Toll‐like receptor (TLR)2‐stimulating bacterial lipid in the blood of MS patients and postulated that this is indicative of a deficiency in the innate immune regulating function of the microbiome in MS. We postulated further that the resulting enhanced TLR2 responsiveness plays a critical role in the pathogenesis of MS. As proof‐of‐concept, we reported that decreasing systemic TLR2 responsiveness by administering very low‐dose TLR2 ligands attenuated significantly the mouse model of MS, experimental autoimmune encephalomyelitis. Studies of Toll‐like receptor responses in patients with MS have been conflicting. Importantly, most of these investigations have focused on the response to TLR4 ligation and few have characterized TLR2 responses in MS. In the present study, our goal was to characterize TLR2 responses of MS patients using multiple approaches. Studying a total of 26 MS patients and 32 healthy controls, we now document for the first time that a large fraction of MS patients (50%) demonstrate enhanced responsiveness to TLR2 stimulation. Interestingly, the enhanced TLR2 responders include a significant fraction of those with progressive forms of MS, a subset of patients considered unresponsive to adaptive immune system‐targeting therapies. Our results suggest the presence of a pathologically relevant TLR2 related innate immune abnormality in patients with both relapsing–remitting and progressive MS. These findings may have significant implications for understanding the role of innate immunity in the pathogenesis of MS.

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Section: Discussioncontrasting

confidence: 99%

Enhanced TLR2 responses in multiple sclerosis

Fujiwara

Anstadt

Flynn

et al. 2018

Clinical and Experimental Immunology

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“…Indeed, primary progressive (PP) patients and (SP) secondary progressive patients were shown to exhibit a sustained increase in the number of Th1 and T cytotoxic type 1 cells in peripheral blood, suggesting that the progressive phase of the disease is characterized by a permanent peripheral type 1 immune activation . Differences in naive CD4+ T cell biology identify patients with MS having different rates of development of secondary progression ; higher percentages of circulating CD4+ and CD8+ T‐bet T cells were found in SP and PP patients, and these values were correlated with the severity of the disease . Moreover, studies have shown that SP patients display low IFN‐γ, IL‐17 and IL‐10 production, while Th17 activation dominates the immunologic milieu of PP patients .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients

et al. 2019

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Patients with primary progressive (PP) and secondary progressive (SP) forms of multiple sclerosis (MS) exhibit a sustained increase in the number of Th1, T cytotoxic type-1 and Th17 cells in peripheral blood, suggesting that the progressive phase is characterized by a permanent peripheral immune activation. As T cell functionality and activation are strictly connected to their metabolic profile, we investigated the mitochondrial functionality and metabolic changes of T cell subpopulations in a cohort of progressive MS patients. T cells from progressive patients were characterized by low proliferation and increase of terminally differentiated/exhausted cells. T cells from PP patients showed lower Oxygen Consumption Rate and Extracellular Acidification Rate, lower mitochondrial mass, membrane potential and respiration than those of SP patients, a downregulation of transcription factors supporting respiration and higher tendency to shift towards glycolysis upon stimulation. Furthermore, PP effector memory T cells were characterized by higherGlucose transporter -1 levels and a higher expression of glycolytic-supporting genes if compared to SP patients. Overall, our data suggest that profound differences exist in the phenotypic and metabolic features of T cells from PP and SP patients, even though the two clinical phenotypes are considered part of the same disease spectrum.Keywords: flow cytometry r metabolism r mitochondria r multiple sclerosis r T cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

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“…These authors hypothesize that differential TLRs expression may modulate inflammation and may be associated with MS clinical courses. Increased expression of TLR4 and TLR2 and relative signaling pathways has been described in naïve CD4+ T lymphocytes isolated from secondary progressive MS (SP MS) 21. These authors conclude that SP MS CD4+ T lymphocytes are biologically different from HD in terms of cell activation and this functional disregulation is associated with a subgroup of SP MS patients characterized by a strong response to anti-inflammatory therapies.…”

Section: Discussionmentioning

confidence: 92%

Increased CXCL10 expression in MS MSCs and monocytes is unaffected by AHSCT

Bonechi

Aldinucci

Mazzanti

et al. 2014

Ann Clin Transl Neurol

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ObjectiveTo confirm CXCL10 over production in bone marrow mesenchymal stem cells (MSCs) and circulating monocytes isolated from multiple sclerosis patients (MS) and identify predate cell molecular signature; to extend this analysis after autologous hematopoietic stem cell transplantation (AHSCT) to test if therapy has modifying effects on MSCs and circulating monocytes.MethodsMSCs and monocytes were isolated from 19 MS patients who undergone AHSCT before and seven of them at least 3 years after transplant. CXCL10 production was detected after LPS/IFN-γ stimulation. TLR4 signaling pathways were investigated by means of transcription factors phosphorylation/activation level. RT-PCR of activated transcription factors was performed to quantify their expression. All experiments were conducted in parallel with 24 matched healthy donors (HD).ResultsCXCL10 expression was significantly increased in both peripheral circulating monocytes and BM MSCs compared to HD. We showed that CXCL10 production is determined by an altered signaling pathway downstream TLR4, with the involvement of STAT-1, NF-κB, p38, JNK, and CREB. All upregulated transcription factors are more phosphorylated in MS patient sample. These features are not modified after AHSCT.InterpretationWe demonstrated that in MS two different cell lineages are characterized by significantly increased production of CXCL10, due to altered signaling pathways of innate immune reaction mediated by TLR4, probably associated with disease phenotype. This characteristic is not modified by AHSCT, suggesting that when T and B lymphocytes are reset, other possible components of MS pathology, such as CXCL10 over production, do not determine therapy outcome.

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Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS

Cited by 25 publications

References 32 publications

Enhanced TLR2 responses in multiple sclerosis

Enhanced TLR2 responses in multiple sclerosis

Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients

Increased CXCL10 expression in MS MSCs and monocytes is unaffected by AHSCT

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