Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors

2013 ◽  
Vol 20 (5) ◽  
pp. 548-557 ◽  
Author(s):  
Kristof Thewissen ◽  
Amber H Nuyts ◽  
Nathalie Deckx ◽  
Bart Van Wijmeersch ◽  
Guy Nagels ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Genetic Risk ◽  
Ex Vivo ◽  
Study Groups ◽  
Genetic Risk Factors ◽  
Healthy Controls ◽  
Multiple Sclerosis Patients

Background: The role of the adaptive immune system and more specifically T cells in the pathogenesis of multiple sclerosis (MS) has been studied extensively. Emerging evidence suggests that dendritic cells (DCs), which are innate immune cells, also contribute to MS. Objectives: This study aimed to characterize circulating DC populations in MS and to investigate the contribution of MS-associated genetic risk factors to DCs. Methods: Ex vivo analysis of conventional (cDCs) and plasmacytoid DCs (pDCs) was carried out on peripheral blood of MS patients ( n = 110) and age- and gender-matched healthy controls ( n = 112). Results: Circulating pDCs were significantly decreased in patients with chronic progressive MS compared to relapsing–remitting MS and healthy controls. While no differences in cDCs frequency were found between the different study groups, HLA-DRB1*1501+ MS patients and patients not carrying the protective IL-7Rα haplotype 2 have reduced frequencies of circulating cDCs and pDCs, respectively. MS-derived DCs showed enhanced IL-12p70 production upon TLR ligation and had an increased expression of the migratory molecules CCR5 and CCR7 as well as an enhanced in vitro chemotaxis. Conclusion: DCs in MS are in a pro-inflammatory state, have a migratory phenotype and are affected by genetic risk factors, thereby contributing to pathogenic responses.

scholarly journals The expression profile of virus-recognizing toll-like receptors in natural killer cells of Cypriot multiple sclerosis patients

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Elie Deeba ◽  
Anastasia Lambrianides ◽  
Marios Pantzaris ◽  
George Krashias ◽  
Christina Christodoulou
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Nk Cells ◽  
Expression Profile ◽  
Genetic Risk ◽  
Viral Infections ◽  
Healthy Controls ◽  
Functional Differences ◽  
Multiple Sclerosis Patients ◽  
And Control

Abstract Objective The exact aetiology of multiple sclerosis (MS) remains elusive, although several environmental and genetic risk factors have been implicated to varying degrees. Among the environmental risk factors, viral infections have been suggested as strong candidates contributing to MS pathology/progression. Viral recognition and control are largely tasked to the NK cells via TLR recognition and various cytotoxic and immunoregulatory functions. Additionally, the complex roles of different TLRs in MS pathology are highlighted in multiple, often contradictory, studies. The present work aims to analyse the TLR expression profile of NK cells isolated from MS patients. Highly purified CD56+CD3− NK cells isolated from peripheral blood of MS patients (n = 19) and healthy controls (n = 20) were analysed via flow cytometry for their expression of viral antigen-recognizing TLRs (TLR2, TLR3, TLR7, and TLR9). Results No difference was noted in TLR expression between MS patients and healthy controls. These results aim to supplement previous findings which study expressional or functional differences in TLRs present in various subsets of the immune system in MS, thus aiding in a better understanding of MS as a complex multifaceted disease.

scholarly journals Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Till F. M. Andlauer ◽  
◽  
Jenny Link ◽  
Dorothea Martin ◽  
Malin Ryner ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Prediction Models ◽  
Genetic Risk Factors ◽  
Genome Wide Association ◽  
Risk Haplotype ◽  
Interferon Β ◽  
Genome Wide ◽  
Multiple Sclerosis Patients

Abstract Background Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations. Methods We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis. Results Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81–4.48), p = 2.1 × 10−26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69–4.72), p = 6.6 × 10−19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29–3.61), p = 7.4 × 10−20) while DR3-DQ2 was protective (OR = 0.37 (0.27–0.52), p = 3.7 × 10−09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33–12.47), p = 1.5 × 10−13). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85–0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8–463.6, p = 4.4 × 10−6) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71–0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0–63.3, p = 7.5 × 10−4). Conclusions We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.

scholarly journals Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta

2020 ◽  
Author(s):  
Till F. M. Andlauer ◽  
Jenny Link ◽  
Dorothea Martin ◽  
Malin Ryner ◽  
Christina Hermanrud ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Prediction Models ◽  
Genetic Risk Factors ◽  
Genome Wide Association ◽  
Risk Haplotype ◽  
Interferon Β ◽  
Genome Wide ◽  
Multiple Sclerosis Patients

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations. Methods: We analyzed a large sample of 2,757 genotyped and imputed patients from two cohorts, split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis. Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR)=3.55 (95% confidence interval=2.81-4.48), p=2.1x10-26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR=3.56 (2.69-4.72), p=6.6x10-19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR=2.88 (2.29-3.61), p=7.4x10-20) while DR3-DQ2 was protective (OR=0.37 (0.27-0.52), p=3.7x10-09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR=7.35 (4.33-12.47), p=1.5x10-13). These haplotypes exhibit large population-specific frequency differences. In a cohort of IFNβ-1a s.c.-treated patients, prediction models for nADA reached an AUC of 0.91 (0.85-0.95), a sensitivity of 0.78, and a specificity of 0.90. Patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR of 73.9 (11.8 463.6, p=4.4x10-06) of developing nADA. Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.

CRYAB modulates the activation of CD4+ T cells from relapsing–remitting multiple sclerosis patients

2013 ◽  
Vol 19 (14) ◽  
pp. 1867-1877 ◽  
Author(s):  
Que Lan Quach ◽  
Luanne M Metz ◽  
Jenna C Thomas ◽  
Jonathan B Rothbard ◽  
Lawrence Steinman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cytokine Production ◽  
Clinical Signs ◽  
Healthy Controls ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Background: Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. Objective: We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. Methods: CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. Results: The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8+ T cells, in CD4+ T cells of MS patients that displayed suppressed cytokine production (responders). Conclusion: CRYAB may be capable of suppressing the activation of CD4+ T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

2015 ◽  
Vol 21 (14) ◽  
pp. 1811-1822 ◽  
Author(s):  
Felix Luessi ◽  
Stefan Kraus ◽  
Bettina Trinschek ◽  
Steffen Lerch ◽  
Robert Ploen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Healthy Subjects ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Direct Effects ◽  
Quantitative Analyses ◽  
Ifn Γ ◽  
Multiple Sclerosis Patients ◽  
Antigen Presenting

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. Conclusions: Our data indicate that fingolimod – apart from trapping lymphocytes in lymph nodes – exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

scholarly journals HERV-K18 Env Expression and the Potential Association With TGF-β and Epstein–Barr Virus Infection in the Presence and the Absence of Vitamin D in Multiple Sclerosis Patients

2021 ◽  
Author(s):  
Tayebeh Latifi ◽  
Majid Teymoori-Rad ◽  
Ahmad Nejati ◽  
Shohreh Shahmahmoodi ◽  
Farhad Rezaei ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Real Time ◽  
Real Time Pcr ◽  
Epstein Barr Virus Infection ◽  
Healthy Controls ◽  
Increased Risk ◽  
Multiple Sclerosis Patients ◽  
Vitro Effect

Abstract Previous studies have reported that Human endogenous retroviruses (HERVs) such as HERV-K18 is associated with an increased risk of multiple sclerosis (MS). The present study aimed to evaluate the association between the expression of HERV-K18 env, TGF-β, and in vitro effect of EBV infection on the expression level of HERV-K18 env in PBMC of MS patients in both presence and absence of vitamin D (1,25-OHD). The levels of HERV-K18 env was measured in peripheral blood mononuclear cells (PBMCs) from 20 MS patients and 20 healthy controls by quantitative real-time PCR. PBMCs were further treated with EBV in the presence or the absence of vitamin D. After 72 hours, cells were collected for measurement of HERV-K18 env expression using Real-time PCR. While the expression of HERV-K18 env was significantly higher in MS patients than healthy controls, the expression of TGF–β was found to be significantly lower in MS patients compare to healthy controls. Interestingly, an inverse correlation was found between HERV-K18 env expression and TGF-β expression in MS patients but not for healthy controls. Although in vitro stimulated PBMCs with EBV showed no significant differences in terms of HERV-K18 expression, EBV infected cells revealed different patterns in the presence and the absence of vitamin D treatment. These findings not only support the important role of HERV-K18 env expression but also highlight the plausible interactions with different risk factors in MS.

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