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J Hillert

Publications and source records attributed to J Hillert.

At least 19 recordsLinked to original sources
PubMed2007

A proliferation-inducing ligand (APRIL) is expressed by astrocytes and is increased in multiple sclerosis.

A proliferation-inducing ligand (APRIL) is a newly described member of the tumour necrosis factor (TNF) superfamily that was first identified as a factor favouring tumorigenesis. APRIL is also important for several immune functions, including B-cell survival. Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that is commonly diagnosed in early adulthood. Several TNF superfamily members have been identified in brains of patients with MS, although their exact function within the CNS is presently unknown. To investigate whether APRIL is expressed in the CNS, we studied APRIL protein expression by immunohistochemistry in MS patients and controls. Morphologically, APRIL-positive cells appeared to be astrocytes. A two-colour immunohistochemistry revealed that APRIL expression was cytoplasmic, granular and restricted to GFAP-positive cells. Conversely, HLA class II-positive microglial cells were negative for APRIL expression. APRIL-positive cells were fewer in brains of controls compared with those with MS. We further corroborated our findings by studying APRIL protein expression in several glioblastoma cell lines, and found APRIL to be expressed by most cell lines analysed. APRIL's binding partner syndecan-1 (CD138) was detected in brains of neither MS nor control patients. Furthermore, B cells were detectable in the brain of one of five patients with MS. We conclude that APRIL is expressed by reactive astrocytes in MS and may be of relevance in gliotic scar formation.

Adult↗
PubMed2006

Blockade of chemokine signaling in patients with multiple sclerosis.

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.

Central Nervous System↗
PubMed2006

A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort.

OBJECTIVE: To investigate the molecular genetic basis of cluster headache (CH), using a genome-wide scan and candidate gene strategy. METHODS: Northern European CH families and a case-control cohort of Danish, Swedish, and British origin (total n = 259 sporadic CH patients), including 267 control subjects matched for ancestry, participated in the study. A genome-wide genetic screen using approximately 400 microsatellite markers was performed for five informative Danish CH families. Additional markers were typed for those loci generating statistical evidence suggestive of linkage, together with genotypes for 111 individuals from further Danish and Italian kindreds. Sporadic CH patients and controls were investigated by association analysis for variation in the candidate gene, HCRTR2. Finally, complete HCRTR2 sequencing was undertaken for eight independent probands. RESULTS: Potential linkage was identified at four possible disease loci in Danish kindreds, yet no single chromosome location generated a lod or NPL score of recognized significance. No deleterious sequence variants of the HCRTR2 gene were detected by comparison to wild-type sequence. Association of the HCRTR2 gene was not replicated in this large dataset, even when the data were stratified into distinct populations. CONCLUSIONS: Cluster headache is a complex genetic disorder, with possible phenotypic and genetic heterogeneity compounding attempts at gene identification.

Adolescent↗
PubMed2006

APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.

BACKGROUND: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. METHODS: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. RESULTS: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96-1.34 and OR 0.89, 95% CI 0.78-1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. CONCLUSION: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Alleles↗
PubMed2006

Increased soluble 4-1BB ligand (4-1BBL) levels in peripheral blood of patients with multiple sclerosis.

4-1BB ligand (4-1BBL; CD137L) is a member of the tumour necrosis factor superfamily expressed primarily on antigen presenting cells such as B cells, macrophages and dendritic cells. Its engagement with the receptor 4-1BB (CD137) has been shown to promote T-cell activation and regulate proliferation and survival of T cells. The role of the costimulatory molecule in multiple sclerosis (MS) remains unclear. In this study, the expression of 4-1BBL and soluble 4-1BBL (s4-1BBL) protein levels were analysed in peripheral blood of MS patients. Compared with healthy controls, MS patients had an increase in both plasma s4-1BBL protein levels and expression of 4-1BBL in CD14(+) monocytes. In contrast, myelin basic protein-reactive T-cell proliferation was not found to be inhibited by the use of an anti-4-1BBL antibody. The elevated s4-1BBL protein levels in the MS patients may function as a self-regulatory mechanism of 4-1BB/4-1BBL interaction and costimulation.

4-1BB Ligand↗
PubMed2005

Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.

BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Adult↗
PubMed2005

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this two-stage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (P<0.08) between patients and controls. After additional genotyping in stage two, two genes--each containing at least three significantly (P<0.05) associated SNPs--conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis--and, by extension, derangement of immune homeostasis--influence the risk of MS.

Antigens, CD↗
PubMed2005

Familial cluster headache. Is atypical cluster headache in family members part of the clinical spectrum?

Familial cluster headache (CH) was analysed in 21 Swedish families. Diagnosis was made according to The International Classification of Headache Disorders 2004. We identified 55 affected, of whom 42 had episodic or chronic CH, one had probable CH and 12 had atypical symptoms. The atypical cases did not fulfil the diagnostic criteria for CH, but had clinical symptoms with more resemblance to CH than to migraine or other trigeminal autonomic cephalgia syndromes. The overall male : female ratio was 1.8:1. The overall mean age at onset was significantly lower in the second/third generation than in the first generation (mean age at onset 22 vs. 31 years, SD +/- 7 vs. 13 years; P < 0.01). This may be anticipation or selection bias, since individuals with late age at onset from the second/third generation may not yet have symptoms. The prevalence of migraine was 24% (13/55), i.e. similar to the prevalence in the general population. The high incidence of atypical CH cases in the Swedish families with other members affected with CH may suggest that the spectrum of CH is broader than previously thought. We suggest that atypical CH in CH families may represent an expanded spectrum of the disease with a common aetiology, i.e. a common genetic background.

Adult↗
PubMed2004

Genes in the HLA class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis.

In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS.

Case-Control Studies↗
PubMed2004

A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with supposedly autoimmune features known to be associated with a specific HLA DR-DQ haplotype (DR15, DQ6, or HLDRB1*1501,DRB5*0101,DQA1*0102,DQB1*0602). We have previously reported that the associated haplotype extends to HLA-B and described an independent association with HLA-A alleles in MS. Owing to a complex situation with extensive linkage disequilibria, it is still unclear whether classical HLA genes are responsible or whether associations may be due to other genes in this region. Here, we analyzed an association in MS with the NOTCH4 and TNFalpha (tumor necrosis factor-alpha) genes, located between the HLA-DRB1 gene and the HLA-A gene. For NOTCH4, located 0.4 Mb telomeric to HLA-DRB1, an SNP at position -25 and a trinucleotide repeat were investigated in 181 MS patients, and 180 controls also typed P = 0.027 for HLA-DRB and HLA-A. A modest association was observed (OR = 3.44) with the C-25 allele. However, two-locus analysis revealed that this association was secondary to the classical association with HLA-DRB1. For TNF, located 0.7 Mb telomeric of NOTCH4, SNPs at positions -308 and -238 were studied in the same dataset. We found no association between these TNFalpha gene polymorphisms and MS in this dataset, although there was linkage disequilibrium (LD) between DRB1 and TNF and between HLA-A and TNF. We conclude that alleles of the NOTCH4 and TNFalpha genes are unlikely to be of importance for the susceptibility to MS, although specific alleles of these genes are often carried on the same haplotype as DR15, DQ6.

Alleles↗
PubMed2003

Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q.

Epidemiological studies show that susceptibility to multiple sclerosis (MS) has a strong genetic component, but apart from the HLA gene complex, additional genetic factors have proven difficult to map in the general population. Thus, localized populations, where MS patients are assumed to be more closely related, may offer a better opportunity to identify shared chromosomal regions. We have performed a genome-wide scan with 834 microsatellite markers in a data set consisting of 54 MS patients and 114 healthy family members. A group of families from a small village were possible to track back to common ancestors living in the 17th century. We used single marker- and haplotype-based transmission disequilibrium test (TDT) analysis and nonparametric linkage analysis to analyze genotyping data. Regions on chromosomes 2q23-31, 6p24-21, 6q25-27, 14q24-32, 16p13-12 and 17q12-24 were found to be in transmission disequilibrium with MS. Strong transmission disequilibrium was detected in 14q24-32, where several dimarker haplotypes were in transmission disequilibrium in affected individuals. Several regions showed modest evidence for linkage, but linkage and TDT were both clearly positive only for 17q12-24. All patients and controls were also typed for HLA class II genes; however, no evidence for a gene-gene interaction was observed.

Chromosomes, Human, Pair 14↗
PubMed2003

Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables.

Magnetic resonance imaging (MRI) remains the most valuable tool for monitoring disease activity and progression in patients with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS) with presumably autoimmune etiology. Chemokine receptors have been implicated in MS as key molecules directing inflammatory cells into the CNS. Regulatory (CD4+CD25+) T cells (Tr cells) are important in suppressing autoimmunity, and their absolute or functional deficit could be expected in MS. In the present study, venous blood was obtained from MS patients concurrent with MRI examination of the brain, and expression of chemokine receptors CCR1, CCR2, CCR5, CXCR3 and CXCR4 by CD4 T cells and monocytes, proportions of Tr cells, as well as expression of CD45RO, CD95, CTLA-4, HLA-DR and interleukin (IL)-10 by Tr cells and non-Tr (CD25-) CD4 T cells was analyzed by flow cytometry. Surface expression of CXCR3 by CD4 T cells was downregulated in the group of patients with high lesion load (LL) on T2-weighted images and gadolinium (Gd)-enhancing lesions on T1-weighted images, compared to the group with high LL and no Gd-enhancing lesions, and to the group with low LL, suggesting internalization of CXCR3 due to the release of its chemokine ligand (IP-10/CXCL10) from active MS lesions. Proportions of Tr cells amongst all CD4 T cells, and expression of IL-10 by Tr cells were increased in the patients with high LL and Gd-enhancing lesions. These results suggest that there is correlation between MRI parameters, chemokine receptor expression and the status of circulating Tr cells in MS, but further studies need to discriminate between pathogenetically relevant and bystander phenomena.

Adult↗
PubMed2003

Genome-wide linkage screen of a consanguineous multiple sclerosis kinship.

Multiple sclerosis (MS), like Alzheimer's disease (AD) and Parkinson's disease (PD), is a common neurological disorder thought to be caused by the interaction of several genes with unknown environmental factors. In both AD and PD the identification of disease forms inherited in a classic Mendelian fashion has helped investigators elucidate pathogenetic mechanisms. In this study a whole-genome screen, with an average of 608 successful genotypes per person, was performed on nine members of a consanguineous family: the index case, three of her siblings and her daughter, all of whom have been diagnosed with definite MS; as well as the parents of the index case (first cousins), one of her five healthy siblings and her husband (who is also her first cousin). Nonparametric linkage analysis was performed on genotyping data. Based on the presence of consanguinity, the a priori hypothesis was that the disease is transmitted in an autosomal recessive fashion in the pedigree. Linkage analysis revealed a suggestive logarithm of odds (LOD) score of 2.29 on the long arm of chromosome 9. Four of five affected family members were identically homozygous for a haplotype under this peak, spanning approximately 43 cM, while the fifth affected subject and all unaffected family members were heterozygous for the haplotype.

Adolescent↗
PubMed2002

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Denmark↗
PubMed2002

Analysis of a CD40 ligand dinucleotide microsatellite in multiple sclerosis.

In recent years, numerous reports have described the diverse roles of the CD40-CD40 ligand receptor-ligand pair. The interaction of these two cell-surface molecules regulates both humoral and cell-mediated immune functions. Because the CD40 ligand is known to be highly expressed on the peripheral blood mononuclear cells (PBMC) of multiple sclerosis (MS) patients, and because activated helper T cells expressing CD40 ligand have been found in the brain sections of MS patients, but not in those of normal controls, the protein is believed to be involved in MS development. We studied the influence of a polymorphic dinucleotide-repeat marker located in the 3' untranslated region of the X-linked gene encoding CD40 ligand (CD40LG) on susceptibility to and disease severity in MS. From a total cohort of 771 Nordic definite-MS patients, the most (n = 92) and least (n = 90) disabled octiles, as well as random samples of intermediately disabled males (n = 119) and females (n = 121), were genotyped; 135 ethnically matched healthy subjects were used as controls. In addition, the effect of the polymorphism on CD40 ligand mRNA expression was assessed using PBMC from 54 MS patients and 22 controls. The phenotype frequencies for the CD40LG marker did not differ significantly between gender-conditioned intermediate-MS subgroups and controls, or between gender-conditioned disability octiles. Nor did the polymorphism appear to exert any significant effect on mRNA expression in either patients or controls.

Alleles↗
PubMed2002

Analysis of nitric oxide synthase genes in cluster headache.

The aetiology of cluster headache is still not yet completely understood, but the potential relevance of genetic factors has been recognized during recent years. Nitric oxide (NO) plays a critical role in the regulation of vasodilation, neurotransmission, inflammation and many other events throughout the body. NO also appears to be an important mediator of vascular headache pathophysiology. In this study we have performed an association analysis of five polymorphic microsatellite markers in the three different NO synthase (NOS) genes; nNOS (NOS1), iNOS (NOS2A) and eNOS (NOS3). Ninety-one cluster headache patients diagnosed according to International Headache Society criteria and 111 matched controls were studied. Phenotype and allele frequencies were similarly distributed in patients and controls except for an iNOS (NOS2A) pentanucleotide repeat allele which was significantly more common in controls. We observed a higher phenotype frequency of this allele in our control group compared with rates in control groups of other studies, whereas the frequency in our patients was similar to that in controls from previous reports. Thus, we conclude that it is unlikely that genetic variations within the NOS genes contribute greatly to cluster headache susceptibility.

Adult↗
PubMed2002

APOE genotypes and disease severity in multiple sclerosis.

Apolipoprotein E (opoE) is involved in the transport of lipids necessary for membrane repair and is encoded by a gene on chromosome 19q13, a region positive for linkage in two multiple sclerosis (MS) genome-wide screens. The APOE epsilon4 allele confers susceptibility to both familial and sporadic Alzheimer's disease (AD). Carriage of epsilon4 is associated with defective dendritic remodeling in AD, and with unfavorable clinical outcome in head trauma and cerebrovascular disease. According to the results of previous studies, APOE epsilon4 does not increase the risk of developing MS, but it may influence disease progression and ultimate disability. From a total cohort of over 900 MS patients, we compared APOE epsilon2-4 genotypes in, roughly, the cohort's least disabled and most disabled septiles. 'Benign MS' (n=124) was defined as an Expanded Disability Status Scale (EDSS) score of 3.0 or less, despite at least 10 years of disease duration, and 'severe MS' (n=140) as the attainment of an EDSS score of 6.0 within 8 years of disease onset. We found no significant differences in genotype or phenotype frequencies between the benign-MS and severe-MS septiles; however, the risk conferred by epsilon4 rose progressively upon comparison of carriage rates in more narrowly defined anti-podal quantiles.

Adolescent↗