Publications by authors named "An Goris"

75 Publications

Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis.

Front Immunol 2021 26;12:676619. Epub 2021 May 26.

Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.

Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10), decrease in switched B cells (P = 3.29 x 10), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.
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http://dx.doi.org/10.3389/fimmu.2021.676619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187869PMC
May 2021

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis.

Ann Neurol 2021 05 24;89(5):884-894. Epub 2021 Mar 24.

Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.

Objective: Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date.

Methods: We performed a genomewide association study (GWAS) in a discovery cohort and investigated the genomewide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2,231 relapses occurring before the start of any immunomodulatory treatment in 991 patients. For assessing time to relapse, we applied a survival analysis utilizing Cox proportional hazards models. We also investigated the association between MS genetic risk scores and relapse hazard and performed a gene ontology pathway analysis.

Results: The low-frequency genetic variant rs11871306 within WNT9B reached genomewide significance in predicting relapse hazard and replicated (meta-analysis hazard ratio (HR) = 2.15, 95% confidence interval (CI) = 1.70-2.78, p = 2.07 × 10 ). A pathway analysis identified an association of the pathway "response to vitamin D" with relapse hazard (p = 4.33 × 10 ). The MS genetic risk scores, however, were not associated with relapse hazard.

Interpretation: Genetic factors underlying disease heterogeneity differ from variants associated with MS susceptibility. Our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence. The present study highlights these cross-talking pathways as potential modulators of MS disease activity. ANN NEUROL 2021;89:884-894.
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http://dx.doi.org/10.1002/ana.26061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252032PMC
May 2021

Quantitative MRI phenotypes capture biological heterogeneity in multiple sclerosis patients.

Sci Rep 2021 Jan 15;11(1):1573. Epub 2021 Jan 15.

Laboratory for Neuroimmunology, Department of Neurosciences, KU Leuven, Herestraat 49, Box 1022, 3000, Leuven, Belgium.

Magnetization transfer ratio (MTR) and brain volumetric imaging are (semi-)quantitative MRI markers capturing demyelination, axonal degeneration and/or inflammation. However, factors shaping variation in these traits are largely unknown. In this study, we collected a longitudinal cohort of 33 multiple sclerosis (MS) patients and extended it cross-sectionally to 213. We measured MTR in lesions, normal-appearing white matter (NAWM), normal-appearing grey matter (NAGM) and total brain, grey matter, white matter and lesion volume. We also calculated the polygenic MS risk score. Longitudinally, inter-patient differences at inclusion and intra-patient changes during follow-up together explained > 70% of variance in MRI, with inter-patient differences at inclusion being the predominant source of variance. Cross-sectionally, we observed a moderate correlation of MTR between NAGM and NAWM and, less pronounced, with lesions. Age and gender explained about 30% of variance in total brain and grey matter volume. However, they contributed less than 10% to variance in MTR measures. There were no significant associations between MRI traits and the genetic risk score. In conclusion, (semi-)quantitative MRI traits change with ongoing disease activity but this change is modest in comparison to pre-existing inter-patient differences. These traits reflect individual variation in biological processes, which appear different from those involved in genetic MS susceptibility.
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http://dx.doi.org/10.1038/s41598-021-81035-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811013PMC
January 2021

Smoking and multiple sclerosis risk: a Mendelian randomization study.

J Neurol 2020 Oct 11;267(10):3083-3091. Epub 2020 Jun 11.

Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Herestraat 49 bus 1022, 3000, Leuven, Belgium.

Background: Striking changes in the demographic pattern of multiple sclerosis (MS) strongly indicate an influence of modifiable exposures, which lend themselves well to intervention. It is important to pinpoint which of the many environmental, lifestyle, and sociodemographic changes that have occurred over the past decades, such as higher smoking and obesity rates, are responsible. Mendelian randomization (MR) is an elegant tool to overcome limitations inherent to observational studies and leverage human genetics to inform prevention strategies in MS.

Methods: We use genetic variants from the largest genome-wide association study for smoking phenotypes (initiation: N = 378, heaviness: N = 55, lifetime smoking: N = 126) and body mass index (BMI, N = 656) and apply these as instrumental variables in a two-sample MR analysis to the most recent meta-analysis for MS. We adjust for the genetic correlation between smoking and BMI in a multivariable MR.

Results: In univariable and multivariable MR, smoking does not have an effect on MS risk nor explains part of the association between BMI and MS risk. In contrast, in both analyses each standard deviation increase in BMI, corresponding to roughly 5 kg/m units, confers a 30% increase in MS risk.

Conclusion: Despite observational studies repeatedly reporting an association between smoking and increased risk for MS, MR analyses on smoking phenotypes and MS risk could not confirm a causal relationship. This is in contrast with BMI, where observational studies and MR agree on a causal contribution. The reasons for the discrepancy between observational studies and our MR study concerning smoking and MS require further investigation.
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http://dx.doi.org/10.1007/s00415-020-09980-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501136PMC
October 2020

Transcript-specific regulation in T-cells in multiple sclerosis susceptibility.

Eur J Hum Genet 2020 07 2;28(7):849-850. Epub 2020 Apr 2.

KU Leuven - Department of Neurosciences, Laboratory for Neuroimmunology, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1038/s41431-020-0615-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316710PMC
July 2020

CHIT1 at Diagnosis Reflects Long-Term Multiple Sclerosis Disease Activity.

Ann Neurol 2020 04 8;87(4):633-645. Epub 2020 Feb 8.

KU Leuven - Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium.

Objective: Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.

Methods: In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia-related proteins, chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1 or YKL-40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme-linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia-related markers in publicly available RNA expression data from postmortem brain tissue.

Results: CHIT1 levels at diagnostic LP correlated with 2 aspects of long-term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E-04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E-04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.

Interpretation: CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633-645.
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http://dx.doi.org/10.1002/ana.25691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187166PMC
April 2020

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions.

Nat Commun 2019 03 27;10(1):1396. Epub 2019 Mar 27.

Department of Neurology, University Hospitals Leuven, Leuven, 2333, Belgium.

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.
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http://dx.doi.org/10.1038/s41467-019-09111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437160PMC
March 2019

Leveraging human genetics to inform intervention strategies for multiple sclerosis.

Neurology 2019 04 20;92(16):735-736. Epub 2019 Mar 20.

From the Department of Neurosciences (A.G., B.D.), Laboratory for Neuroimmunology, KU Leuven; Leuven Brain Institute (A.G., B.D.); and Department of Neurology (B.D.), University Hospitals Leuven, Belgium.

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http://dx.doi.org/10.1212/WNL.0000000000007298DOI Listing
April 2019

Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes.

Ann Rheum Dis 2019 05 12;78(5):617-628. Epub 2019 Mar 12.

VIB Center for Brain and Disease Research, Leuven, Belgium

Objectives: Juvenile idiopathic arthritis (JIA) is the most common class of childhood rheumatic diseases, with distinct disease subsets that may have diverging pathophysiological origins. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed.

Methods: Here we profiled the adaptive immune system of 85 patients with JIA and 43 age-matched controls with indepth flow cytometry and machine learning approaches.

Results: Immune profiling identified immunological changes in patients with JIA. This immune signature was shared across a broad spectrum of childhood inflammatory diseases. The immune signature was identified in clinically distinct subsets of JIA, but was accentuated in patients with systemic JIA and those patients with active disease. Despite the extensive overlap in the immunological spectrum exhibited by healthy children and patients with JIA, machine learning analysis of the data set proved capable of discriminating patients with JIA from healthy controls with ~90% accuracy.

Conclusions: These results pave the way for large-scale immune phenotyping longitudinal studies of JIA. The ability to discriminate between patients with JIA and healthy individuals provides proof of principle for the use of machine learning to identify immune signatures that are predictive to treatment response group.
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http://dx.doi.org/10.1136/annrheumdis-2018-214354DOI Listing
May 2019

A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease.

Hum Mol Genet 2019 04;28(8):1369-1380

KU Leuven, Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium.

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of >55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.
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http://dx.doi.org/10.1093/hmg/ddy425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452186PMC
April 2019

Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.

Cell Rep 2018 10;25(3):798-810.e6

KU Leuven Department of Neurosciences, Laboratory for Neuroimmunology, 3000 Leuven, Belgium; Leuven Brain Institute (LBI), Leuven, Belgium. Electronic address:

The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives.
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http://dx.doi.org/10.1016/j.celrep.2018.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205839PMC
October 2018

LncRNAs expression profile in peripheral blood mononuclear cells from multiple sclerosis patients.

J Neuroimmunol 2018 11 27;324:129-135. Epub 2018 Aug 27.

University of Milan, Dino Ferrari Center, Milan, Italy; Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address:

LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression.
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http://dx.doi.org/10.1016/j.jneuroim.2018.08.008DOI Listing
November 2018

IFN-γ stimulates CpG-induced IL-10 production in B cells via p38 and JNK signalling pathways.

Eur J Immunol 2018 09 1;48(9):1506-1521. Epub 2018 Aug 1.

KU Leuven, Rega Institute, Laboratory of Immunobiology, Leuven, Belgium.

The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production.
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http://dx.doi.org/10.1002/eji.201847578DOI Listing
September 2018

The origins of diversity in human immunity.

Nat Immunol 2018 03;19(3):209-210

Department of Neurosciences, KU Leuven-University of Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1038/s41590-018-0047-9DOI Listing
March 2018

Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells.

Brain 2018 03;141(3):786-796

University of Cambridge, Department of Clinical Neurosciences, Box 165, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.

The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells. Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10-5 in patients and ≤4.09 × 10-6 in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10-5 in controls). In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10-7). Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40. Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awx372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837558PMC
March 2018

Genetic basis for relapse rate in multiple sclerosis: Association with LRP2 genetic variation.

Mult Scler 2018 11 5;24(13):1773-1775. Epub 2018 Jan 5.

Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

Background: In contrast to successes for multiple sclerosis (MS) susceptibility, the genetic basis for clinical heterogeneity remains largely unresolved.

Objectives: We investigate the first reported genetic association with relapse rate.

Methods: We genotyped variant rs12988804 in LRP2 in a homogeneous study population of 527 Belgian MS patients with 970 documented relapses.

Results: The rs12988804*T allele is associated with a 1.16-fold increased hazard rate for a relapse occurring ( P = 0.0078) and a higher baseline relapse rate prior to immunomodulatory treatment ( P = 0.044).

Conclusion: Variant rs12988804 in LRP2, the first example of a genome-wide significant association with relapse rate in MS, is replicated in an independent study.
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http://dx.doi.org/10.1177/1352458517749894DOI Listing
November 2018

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia.

Nat Commun 2017 03 21;8:14774. Epub 2017 Mar 21.

Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
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http://dx.doi.org/10.1038/ncomms14774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364411PMC
March 2017

Inflammatory Gene Expression Profile and Defective Interferon-γ and Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis Patients.

Arthritis Rheumatol 2017 01;69(1):213-224

University of Leuven, Leuven, Belgium.

Objective: Systemic juvenile idiopathic arthritis (JIA) is an immunoinflammatory disease characterized by arthritis and systemic manifestations. The role of natural killer (NK) cells in the pathogenesis of systemic JIA remains unclear. The purpose of this study was to perform a comprehensive analysis of NK cell phenotype and functionality in patients with systemic JIA.

Methods: Transcriptional alterations specific to NK cells were investigated by RNA sequencing of highly purified NK cells from 6 patients with active systemic JIA and 6 age-matched healthy controls. Cytokines (NK cell-stimulating and others) were quantified in plasma samples (n = 18). NK cell phenotype and cytotoxic activity against tumor cells were determined (n = 10), together with their interferon-γ (IFNγ)-producing function (n = 8).

Results: NK cells from the systemic JIA patients showed an altered gene expression profile compared to cells from the healthy controls, with enrichment of immunoinflammatory pathways, increased expression of innate genes including TLR4 and S100A9, and decreased expression of immune-regulating genes such as IL10RA and GZMK. In the patients' plasma, interleukin-18 (IL-18) levels were increased, and a decreased ratio of IFNγ to IL-18 was observed. NK cells from the patients exhibited specific alterations in the balance of inhibitory and activating receptors, with decreased killer cell lectin-like receptor G1 and increased NKp44 expression. Although NK cells from the patients showed increased granzyme B expression, consistent with intact cytotoxicity and degranulation against a tumor cell line, decreased granzyme K expression in CD56 NK cells and defective IL-18-induced IFNγ production and signaling were demonstrated.

Conclusion: NK cells are active players in the inflammatory environment typical of systemic JIA. Although their cytotoxic function is globally intact, subtle defects in NK-related pathways, such as granzyme K expression and IL-18-driven IFNγ production, may contribute to the immunoinflammatory dysregulation in this disease.
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http://dx.doi.org/10.1002/art.39933DOI Listing
January 2017

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1043-8. Epub 2016 Jul 25.

Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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http://dx.doi.org/10.1038/ng.3622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556360PMC
September 2016

Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice.

Hum Mol Genet 2016 08 4;25(16):3491-3499. Epub 2016 Jul 4.

KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND)

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by the selective death of motor neurons. Disease pathophysiology is complex and not yet fully understood. Higher gene expression of the inositol 1,4,5-trisphosphate receptor 2 gene (ITPR2), encoding the IP receptor 2 (IPR2), was detected in sporadic ALS patients. Here, we demonstrate that IPR2 gene expression was also increased in spinal cords of ALS mice. Moreover, an increase of IPR2 expression was observed in other models of chronic and acute neurodegeneration. Upregulation of IPR2 gene expression could be induced by lipopolysaccharide (LPS) in murine astrocytes, murine macrophages and human fibroblasts indicating that it may be a compensatory response to inflammation. Preventing this response by genetic deletion of ITPR2 from SOD1 mice had a dose-dependent effect on disease duration, resulting in a significantly shorter lifespan of these mice. In addition, the absence of IPR2 led to increased innate immunity, which may contribute to the decreased survival of the SOD1 mice. Besides systemic inflammation, IPR2 knockout mice also had increased IFNγ, IL-6 and IL1α expression. Altogether, our data indicate that IPR2 protects against the negative effects of inflammation, suggesting that the increase in IPR2 expression in ALS patients is a protective response.
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http://dx.doi.org/10.1093/hmg/ddw190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179944PMC
August 2016

Immunologic profiles of multiple sclerosis treatments reveal shared early B cell alterations.

Neurol Neuroimmunol Neuroinflamm 2016 Aug 10;3(4):e240. Epub 2016 May 10.

Department of Immunology and Microbiology (J.D., D.F., J.E.G.-P., D.D.-A., A.T.L.N., A.L.), Laboratory for Neuroimmunology, Department of Neurosciences (I.P., I.S., K.H., B. Dubois, A.G.), Laboratory for Neurobiology, Department of Neurosciences (L.D.M.), Laboratory for Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine (B. Decallonne), and Department of Neurology, University Hospitals Leuven (I.S., J.T., B. Dubois), KU Leuven-University of Leuven; and Center for the Biology of Disease (J.D., D.F., J.E.G.-P., D.D.-A., A.T.L.N., A.L.), VIB (L.D.M.), Leuven, Belgium.

Objective: We undertook a systems immunology approach of the adaptive immune system in multiple sclerosis (MS), overcoming tradeoffs between scale and level of detail, in order to identify the immunologic signature of MS and the changes wrought by current immunomodulatory treatments.

Methods: We developed a comprehensive flow cytometry platform measuring 38 immunologic cell types in the peripheral blood of 245 individuals in a routine clinical setting. These include patients with MS, untreated or receiving any of 4 current immunomodulatory treatments (interferon-β, glatiramer acetate, natalizumab, or fingolimod), patients with autoimmune thyroid disease, and healthy controls.

Results: An increase in memory CD8(+) T cells and B cells was observed in untreated patients with MS. Interferon-β and fingolimod induce significant changes upon multiple aspects of the peripheral immune system, with an unexpectedly prominent alteration of B cells. Overall, both treatments push the immune system in different directions, with only 2 significant effects shared across these treatments-an increase in transitional B cells and a decrease in class-switched B cells. We further identified heightened B cell-activating factor (BAFF) levels as regulating this shared B cell pathway.

Conclusions: A systems immunology approach established different immunologic profiles induced by current immunomodulatory MS treatments, offering perspectives for personalized medicine. Pathways shared between the immunologic architecture of existing efficacious treatments identify targets for future treatment design.
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http://dx.doi.org/10.1212/NXI.0000000000000240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872020PMC
August 2016

Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

G3 (Bethesda) 2016 07 7;6(7):2073-9. Epub 2016 Jul 7.

Institute for Clinical Neuroimmunology, Ludwig Maximilian University, 80539 Munich, Germany.

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
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http://dx.doi.org/10.1534/g3.116.030841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938660PMC
July 2016

Power estimation for non-standardized multisite studies.

Neuroimage 2016 07 1;134:281-294. Epub 2016 Apr 1.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA. Electronic address:

A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions.
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http://dx.doi.org/10.1016/j.neuroimage.2016.03.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656257PMC
July 2016

Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.

Sci Transl Med 2016 Mar;8(332):332ra45

INSERM, UMR S933, Paris F-75012, France. Université Pierre et Marie Curie-Paris, UMR S933, Paris F-75012, France. Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.
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http://dx.doi.org/10.1126/scitranslmed.aaf1471DOI Listing
March 2016

The cellular composition of the human immune system is shaped by age and cohabitation.

Nat Immunol 2016 Apr 15;17(4):461-468. Epub 2016 Feb 15.

Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.

Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.
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http://dx.doi.org/10.1038/ni.3371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890679PMC
April 2016

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Nat Genet 2015 Oct 7;47(10):1107-1113. Epub 2015 Sep 7.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
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http://dx.doi.org/10.1038/ng.3395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874245PMC
October 2015

Genetic burden mirrors epidemiology of multiple sclerosis.

Mult Scler 2015 Oct 21;21(11):1353-4. Epub 2015 Jul 21.

Laboratory for Neuroimmunology, Department of Neurosciences, KU Leuven - University of Leuven, Belgium

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http://dx.doi.org/10.1177/1352458515596603DOI Listing
October 2015

Burden of risk variants correlates with phenotype of multiple sclerosis.

Mult Scler 2015 Nov 6;21(13):1670-80. Epub 2015 May 6.

Laboratory for Neuroimmunology, Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Belgium

Background: More than 100 common variants underlying multiple sclerosis (MS) susceptibility have been identified, but their effect on disease phenotype is still largely unknown.

Objective: The objective of this paper is to assess whether the cumulative genetic risk score of currently known susceptibility variants affects clinical presentation.

Methods: A cumulative genetic risk score was based on four human leukocyte antigen (HLA) and 106 non-HLA risk loci genotyped or imputed in 842 Belgian MS patients and 321 controls. Non-parametric analyses were applied.

Results: An increased genetic risk is observed for MS patients, including subsets such as oligoclonal band-negative and primary progressive MS patients, compared to controls. Within the patient group, a stronger association between HLA risk variants and the presence of oligoclonal bands, an increased immunoglobulin G (IgG) index and female gender was apparent. Results suggest an association between a higher accumulation of non-HLA risk variants and increased relapse rate as well as shorter relapse-free intervals after disease onset.

Conclusion: MS patients display a significantly increased genetic risk compared to controls, irrespective of disease course or presence of oligoclonal bands. Whereas the cumulative burden of non-HLA risk variants appears to be reflected in the relapses of MS patients, the HLA region influences intrathecal IgG levels.
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http://dx.doi.org/10.1177/1352458514568174DOI Listing
November 2015

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Brain 2015 Mar 22;138(Pt 3):632-43. Epub 2015 Jan 22.

18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
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http://dx.doi.org/10.1093/brain/awu405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408440PMC
March 2015