Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

2021 ◽  
pp. 135245852198909
Author(s):  
Mukanthu H Nyirenda ◽  
Giulia Fadda ◽  
Luke M Healy ◽  
Ina Mexhitaj ◽  
Laurence Poliquin-Lasnier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Disease Activity ◽  
Human Peripheral Blood ◽  
Enzyme Linked Immunosorbent Assay ◽  
Functional Responses ◽  
Human Microglia ◽  
Increased Risk ◽  
Normal Human Peripheral Blood ◽  
Pediatric Onset

Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. Conclusions: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

Gene–environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution

2022 ◽  
pp. 135245852110699
Author(s):  
Amin Ziaei ◽  
Amy M Lavery ◽  
Xiaorong MA Shao ◽  
Cameron Adams ◽  
T Charles Casper ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Air Pollutant ◽  
Ozone Exposure ◽  
County Level ◽  
Ozone Pollution ◽  
Ozone Level ◽  
Additive Interaction ◽  
Gene Environment ◽  
Increased Risk ◽  
Pediatric Onset

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA- DRB1*15, the strongest genetic variant associated with POMS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC’s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 ( DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother’s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

scholarly journals A Scoping Review of Modifiable Risk Factors in Pediatric Onset Multiple Sclerosis: Building for the Future

Children ◽  
2018 ◽  
Vol 5 (11) ◽  
pp. 146 ◽  
Author(s):  
Julie Pétrin ◽  
Max Fiander ◽  
Prenitha Doss ◽  
E. Yeh
Keyword(s):  
Physical Activity ◽  
Multiple Sclerosis ◽  
Vitamin D ◽  
Relapse Rate ◽  
Scoping Review ◽  
Full Text ◽  
Lifestyle Factors ◽  
Increased Risk ◽  
Modifiable Lifestyle Factors ◽  
Pediatric Onset

Knowledge of the effect of modifiable lifestyle factors in the pediatric multiple sclerosis (MS) population is limited. We therefore conducted a scoping review, following the framework provided by Arksey and O’Malley. Four databases were searched for pediatric MS and modifiable lifestyle factors using index terms and keywords, from inception to May 2018. All quantitative and qualitative primary articles were included and limited to English and full text. Of the 7202 articles identified and screened, 25 full-text articles were relevant to our objective and were included. These articles focused on diet obesity, physical activity, and sleep. In cross-sectional analyses, these lifestyle factors were associated with increased risk of pediatric onset MS (POMS), and increased disease activity. Diet, particularly vitamin D and vegetable intake, was associated with reduced relapse rate. Obesity was linked to increased risk of POMS, and physical activity was associated with reduced relapse rate and sleep/rest fatigue. Thus, available studies of lifestyle related outcomes in pediatric MS suggest specific lifestyle related factors, including obesity, higher vitamin D levels, and higher physical activity may associate with lower disease burden in POMS. Studies reviewed are limited by their observational designs. Future studies with longitudinal and experimental designs may further clarify the role of modifiable lifestyle factors in this population.

scholarly journals Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis

Cell Reports ◽  
2016 ◽  
Vol 16 (11) ◽  
pp. 2928-2939 ◽  
Author(s):  
Sandra Hellberg ◽  
Daniel Eklund ◽  
Danuta R. Gawel ◽  
Mattias Köpsén ◽  
Huan Zhang ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Dynamic Response ◽  
Disease Activity ◽  
Cd4 T Cells

Association of Th1/Th2-Related Chemokine Receptors in Peripheral T Cells with Disease Activity in Patients with Multiple Sclerosis and Neuromyelitis Optica

2011 ◽  
Vol 66 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Yuko Shimizu ◽  
Kohei Ota ◽  
Sachiko Kubo ◽  
Chiaki Kabasawa ◽  
Masaki Kobayashi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Disease Activity ◽  
Neuromyelitis Optica ◽  
Chemokine Receptors ◽  
Peripheral T Cells

scholarly journals Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis

2019 ◽  
Vol 12 ◽  
pp. 175628641983780 ◽  
Author(s):  
Luca Prosperini ◽  
Revere P. Kinkel ◽  
Augusto A. Miravalle ◽  
Pietro Iaffaldano ◽  
Simone Fantaccini
Keyword(s):  
Multiple Sclerosis ◽  
Systematic Review ◽  
Disease Activity ◽  
Meta Analysis ◽  
Random Effect ◽  
Patient Characteristics ◽  
Increased Risk ◽  
Disease Reactivation ◽  
Definition Of ◽  
High Level

Background: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity. Objective: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data. Methods: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing–remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients’ clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse. Results: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1–24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9–80% of patients and peaked at 4–7 months, whereas radiological disease activity was observed in 7–87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation ( p ⩽ 0.05). Conclusions: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.

CD26+CD4+T cell counts and attack risk in interferon-treated multiple sclerosis

2005 ◽  
Vol 11 (6) ◽  
pp. 641-645 ◽  
Author(s):  
F Sellebjerg ◽  
C Ross ◽  
N Koch-Henriksen ◽  
P Soelberg Sørensen ◽  
J L Frederiksen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Hazard Ratio ◽  
Cd4 T Cell ◽  
Immunomodulatory Treatment ◽  
Cell Counts ◽  
Increased Risk ◽  
Insufficient Response

Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-β-treated patients, we found that the hazard ratio for developing an attack was 2.8 in patients with CD26+CD4+T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-β antibodies. CD26+CD4+T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-β.

scholarly journals Relationship between Multiple Sclerosis-Associated IL2RA Risk Allele Variants and Circulating T Cell Phenotypes in Healthy Genotype-Selected Controls

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 634 ◽  
Author(s):  
Sophie Buhelt ◽  
Helle Bach Søndergaard ◽  
Annette Oturai ◽  
Henrik Ullum ◽  
Marina Rode von Essen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Multiparameter Flow Cytometry ◽  
Risk Genotype ◽  
Increased Risk ◽  
New Findings

Single nucleotide polymorphisms (SNPs) in or near the IL2RA gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with CD25 expression on T cells ex vivo by multiparameter flow cytometry in paired genotype-selected healthy controls. We observed that MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with expression of CD25 in CD4+ but not CD8+ T cells. In CD4+ T cells, carriers of the risk genotype had a reduced frequency of CD25+ TFH1 cells (p = 0.001) and an increased frequency of CD25+ recent thymic emigrant cells (p = 0.006). Furthermore, carriers of the risk genotype had a reduced surface expression of CD25 in post-thymic expanded CD4+ T cells (CD31−CD45RA+), CD39+ TReg cells and in several non-follicular memory subsets. Our study found novel associations of MS-associated IL2RA SNPs on expression of CD25 in CD4+ T cell subsets. Insight into the associations of MS-associated IL2RA SNPs, as these new findings provide, offers a better understanding of CD25 variation in the immune system and can lead to new insights into how MS-associated SNPs contribute to development of MS.

Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: relevance for biomarker development

2013 ◽  
Vol 20 (4) ◽  
pp. 438-444 ◽  
Author(s):  
Pia Kivisäkk ◽  
Brian C Healy ◽  
Katiana Francois ◽  
Roopali Gandhi ◽  
Taha Gholipour ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Clinical Setting ◽  
Plasma Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Concurrent Disorders ◽  
Radiological Criteria ◽  
Disease Subtype ◽  
Relapsing Remitting ◽  
Unselected Cohort

Background: Osteopontin (OPN) is a pleiotropic protein with important roles in inflammation and immunity that has been suggested as a candidate biomarker for disease activity in multiple sclerosis (MS). Objective: We evaluated plasma levels of OPN in an unselected cohort of MS patients, to determine its potential as a biomarker for disease subtype and/or disease activity in a regular clinical setting. Methods: We analyzed OPN plasma levels in 492 consecutive MS patients, using a commercial enzyme-linked immunosorbent assay (ELISA). Results: OPN levels were higher in relapsing–remitting and secondary progressive MS, compared to healthy controls. Treatment with natalizumab or glatiramer acetate was associated with lower OPN levels. There was no significant association between the OPN levels and disease activity, as measured by clinical or radiological criteria. One-third of patients with high OPN levels had concurrent disorders that may also be associated with increased OPN expression, and which may mask a modest effect of MS disease activity on OPN levels. Conclusion: Our data do not support a role for circulating OPN levels as a biomarker for disease activity in a heterogeneous clinical setting, but does not rule out a potential role in the cerebrospinal fluid, in a controlled setting such as a clinical trial, or in concert with other biomarkers.

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