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A Svejgaard

Publications and source records attributed to A Svejgaard.

At least 19 recordsLinked to original sources
PubMed2006

Genetic polymorphisms in the genes encoding human interleukin-7 receptor-alpha: prognostic significance in allogeneic stem cell transplantation.

Interleukin-7 (IL-7) is essential for T-cell development in the thymus and for the maintenance of peripheral T cells. IL-7 signals through IL-7R, that consists of the gammac-chain and an alpha-chain. Sequencing of IL-7Ralpha has revealed the existence of four single nucleotide polymorphisms (SNPs) (+510C/T, +1237 A/G, 2087T/C and +3110A/G), which all give rise to amino-acid substitutions. The aim of the present investigation was to evaluate the significance of IL-7Ralpha SNPs for the outcome in allogeneic stem cell transplantation (SCT). IL-7Ralpha polymorphisms were determined in 195 recipient and donor pairs from either matched sibling donors or matched unrelated donors (MUD). Genotyping of 173 normal controls was performed in parallel. In MUD transplants, the +1237 genotype of the donor was associated with survival after SCT, the mortality being highest and intermediate for the GG and AG genotypes, respectively (P = 0.023). This pattern was more pronounced with respect to treatment-related mortality (P = 0.003), while IL-7Ralpha genotypes were unrelated to the risk of relapse of leukaemia. The IL-7Ralpha +1237 genotype of the recipient and the genotypes of the other three polymorphisms, were not significantly associated with the outcome of SCT. These findings suggest that the IL-7Ralpha polymorphisms may be of importance for treatment-related mortality after SCT.

Case-Control Studies↗
PubMed2005

Normal ICOS, ICOSL and AID alleles in Danish patients with common variable immunodeficiency.

Common variable immunodeficiency, CVID, is a primary antibody deficiency characterized by decreased levels of serum immunoglobulin G (IgG), decreased IgA and/or IgM and recurrent infections. It is assumed to be heterogeneous group of disorders caused by different genetic defects. Some patients have decreased levels of class switched memory B cells and/or decreased levels of somatic hypermutation which points to defects in the germinal centre (GC) reactions as cause of the disease in these patients. The inducible costimulator, ICOS, and its' ligand, ICOSL, are both involved in and necessary for the GC reaction and so is activation-induced cytidine deaminase, AID. Therefore, we sequenced the ICOS, ICOSL and AID genes in a cohort of 34 Danish CVID patients. We found 13 new single nucleotide polymorphisms (SNP) in the intron regions of the ICOSL gene as well as one SNP in exon 3. However, none of these polymorphisms were associated with CVID. We did not find a previously reported CVID-causing ICOS gene deletion or any other unique mutations in the ICOS or AID genes.

Adolescent↗
PubMed2004

Chimerism studies in HLA-identical nonmyeloablative hematopoietic stem cell transplantation point to the donor CD8(+) T-cell count on day + 14 as a predictor of acute graft-versus-host disease.

Chimerism analysis of hematopoietic cells has emerged as an essential tool in nonmyeloablative hematopoietic stem cell transplantation. We have investigated the development of donor chimerism in granulocytes and CD4(+) and CD8(+) T cells in blood and bone marrow of 24 patients with hematologic malignancies who received HLA-identical sibling peripheral blood stem cell grafts after conditioning with fludarabine and 2 Gy of total body irradiation. The T-cell chimerism of blood and bone marrow was tightly correlated. Complete donor chimerism was reached earlier in the granulocytes than in the T cells. Mixed T-cell chimerism was common at the time of onset of acute graft-versus-host disease (aGVHD), and both CD4(+) and CD8(+) donor T-cell chimerism increased with the occurrence of aGVHD grades II to IV (P =.0002 and P =.019, respectively). The rate of disappearance of recipient CD8(+) T cells was faster in patients with aGVHD grades II to IV than in patients without clinically significant aGVHD (P =.016). This observation indicates a role of graft-versus-lymphohematopoietic tissue reactions in creating complete donor T-cell chimerism. A donor CD8(+) T-cell count above the median on day +14 increased the risk of subsequent development of aGVHD grades II to IV (P =.003).

Acute Disease↗
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↗
PubMed2003

Three new alleles of IGHG2 and their prevalence in Danish Caucasians, Mozambican Blacks and Japanese.

The human IGHG2 gene locus is polymorphic, encoding two known allotypes of IgG2: G2m(n-) and G2m(n+). The allele prevalence varies greatly between different ethnic groups and individual genotypes correlate with the level of plasma IgG2 and with antibody responses to certain polysaccharide antigens. In this study, we present three new alleles of IGHG2 (IGHG2*03, 04, and 05), and a complete sequence specific PCR typing system allowing discrimination between the different allotypes of IgG2. A hitherto unknown allotype, which we name G2m(ny), is encoded by IGHG2*04 and differs from G2m(n-) by asparagine rather than serine in CH1 residue 75 and by phenylalanine rather than leucine in CH1 residue 76 (EU numbering 192 and 193). The polymorphic residues are probably surface exposed near the hinge region. The same residues are also found in IgG1, IgG3, and IgG4, and G2m(ny) is therefore an isoallotype that probably arises by gene conversion within the heavy chain locus. The IGHG2*04 allele is present among Danish Caucasians with a low prevalence (2.5%), but was not found in Japanese or Mozambicans. The two other new alleles (IGHG2*03 and IGHG2*05) both encode the G2m(n-) allotype. The IGHG2*03 allele encodes most of the IgG2 of the G2m(n-) allotype in Danish Caucasians.

Alleles↗
PubMed2003

Association between an interleukin-13 promoter polymorphism and atopy.

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)-13 has been mapped to the cytokine cluster on chromosome 5q31-33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL-13 gene (C to T exchange) at position -1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case-control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position -1111. In the present study, we established that this polymorphism is located at position -1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL-13 -1024TT genoype and inhalation allergy (P = 2.4E-02). By combining the data from the three studies, we demonstrated a strong association (P = 1.09E-05) between the IL-13 -1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis (P = 2.0E-02). No association with MS was found.

Base Sequence↗
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

Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRB1*1501, CCR5 deletion mutation, apolipoprotein E).

As the understanding of the autoimmune inflammatory response in multiple sclerosis (MS) expands, polymorphic genes involved in this process become possible candidates that may determine the severity of disease. Therefore, three candidate genes DRB1*1501, CCR5 and apolipoprotein E (APOE) were examined in a population-based patient sample (n = 70) to assess an association between disease progression measured by clinical disability and MRI parameters. The total lesion area (TLA) on T2-weighted images was measured with a semi-automated threshold technique. Patients with the CCR5delta32 allele showed a non-significant trend towards a smaller lesion burden (TLA/years duration), but were not associated to a milder EDSS/years duration. Our data support previous assumptions of a modulation of severity in MS by the CCR5delta32 genotype, which may convey less inflammation and tissue destruction. Carriers of the DRB1*1501 and APOE-epsilon4 allels did not reveal more severe disease progression, neither by the EDSS/years of duration nor by the TLA/years duration. This study was performed on a population-based sample in a genetically homogeneous Danish population but, due to the limited number of patients examined, weak associations between candidate genes and disease variables cannot be excluded.

Adult↗
PubMed2001

CXCR3 expression on CD34(+) hemopoietic progenitors induced by granulocyte-macrophage colony-stimulating factor: II. Signaling pathways involved.

CXCR3, known to have four ligands (IFN-gamma inducible protein 10 (gamma IP-10), monokine induced by IFN-gamma (Mig), I-TAC, and 6Ckine), is predominantly expressed on memory/activated T lymphocytes. We recently reported that GM-CSF induces CXCR3 expression on CD34(+) hemopoietic progenitors, in which gamma IP-10 and Mig induce chemotaxis and adhesion. Here we further report that stimulation with GM-CSF causes phosphorylation of Syk protein kinase, but neither Casitas B-lineage lymphoma (Cbl) nor Cbl-b in CD34(+) hemopoietic progenitors can be blocked by anti-CD116 mAb. Specific Syk blocking generated by PNA antisense completely inhibits GM-CSF-induced CXCR3 expression in CD34(+) progenitors at both mRNA and protein as well as at functional levels (chemotaxis and adhesion). Cbl and Cbl-b blocking have no such effects. Thus, GM-CSF binds to its receptor CD116, and consequently activates Syk phosphorylation, which leads to induce CXCR3 expression. gamma IP-10 and Mig can induce Syk, Cbl, and Cbl-b phosphorylation in CD34(+) progenitors by means of CXCR3. gamma IP-10 or Mig has induced neither chemotaxis nor adhesion in GM-CSF-stimulated Cbl-b-blocked CD34(+) hemopoietic progenitors, whereas SDF-1alpha induces both chemotaxis and adhesion in these cells. Interestingly, gamma IP-10 and Mig can induce chemotaxis and adhesion in GM-CSF-stimulated Syk- or Cbl-blocked CD34(+) hemopoietic progenitors. Thus, Cbl-b, but not Syk and Cbl phosphorylation, is essential for gamma IP-10- and Mig-induced chemotaxis and adhesion in CD34(+) hemopoietic progenitors. This study provides a useful insight into novel signaling transduction pathways of the functions of CXCR3/gamma IP-10 and Mig, which may be especially important in the cytokine/chemokine environment for mobilization, homing, and recruitment during proliferation, differentiation, and maturation of hemopoietic progenitor cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

No linkage or association of the nitric oxide synthase genes to multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown etiology. Nitric oxide (NO) is a free radical that participates in a variety of biological processes. It is an important mediator in the immune response. Several studies indicate involvement of NO in the pathogenesis of MS. We studied five markers within the three NO synthase genes with regards to susceptibility and disease course in 156 affected sib-pairs and in 96 "benign" and 96 "severe" definite MS patients and 148 controls. We found no significant association or evidence for linkage in our data sets.

Case-Control Studies↗
PubMed2001

The first constant-domain (CH1) exon of human IGHG2 is polymorphic and in strong linkage disequilibrium with the CH2 exon polymorphism encoding the G2m(n+) allotype in Caucasians.

Here we describe a hitherto unknown proline/threonine polymorphism at residue 72 of the human IgG2 CH1 domain (EU numbering 189) and show that it is linked to the known valine/methionine polymorphism at residue 52 of CH2 (EU numbering 282) defining the G2m(n+)/G2m(n-) allotypes. We sequenced the entire constant region of the heavy-chain gene for secreted IgG2 in five IGHG2*02 homozygous individuals covering CH1, hinge, CH2, and CH3 regions (approximately 2 kb). Proline 72 in CH1 of G2m(n-) is changed to threonine in the G2m(n+) [G2m(23)] allotype. Based on the crystal structure of human IgG1, this amino acid position is expected to be surface exposed in IgG2. Besides this structural difference, we identified two silent nucleotide polymorphisms in the CH1 region and seven in the introns. Finally, we developed a sequence-specific PCR typing system detecting the polymorphisms in the CH1 and CH2 regions. We typed 64 Danish Caucasians and found that the CH1 and CH2 region polymorphisms are in complete linkage disequilibrium in this population.

Alleles↗
PubMed2001

The T cell regulator gene SH2D2A contributes to the genetic susceptibility of multiple sclerosis.

The T cell specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the control of T cell activation. The gene is located in the 1q21 region, which has been implicated in susceptibility to experimental allergic encephalomyelitis in the mouse. We therefore evaluated whether a polymorphic GA repeat (GA(13)-GA(33)) within the promoter region of the SH2D2A gene shows association to multiple sclerosis (MS). The frequency of the short alleles GA(13-16) was increased among 313 Norwegian MS patients compared to 277 healthy controls (0.332 vs 0.249, OR 1.5, Pc = 0.03). Transmission disequilibrium analysis in 146 Scandinavian families with at least two affected sibs showed increased transmission of GA(16) to MS patients. No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed. After activation of naive CD4(+) T cells, T cells homozygous for MS associated short alleles displayed lower level of TSAd ex vivo than T cells carrying at least one long allele, which were not associated to MS. Since the SH2D2A protein modulates T cell activation, this may be a mechanism for how short SH2D2A alleles confer susceptibility to develop MS.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Linkage analysis suggests a region of importance for multiple sclerosis in 3p14-13.

Four genomic screens for linkage in multiple sclerosis (MS) have been reported. They confirmed the established role of the human leucocyte antigen (HLA) complex genes in MS and, in addition, suggested the importance of a few other chromosomal segments. Here we report evidence for the importance of 3p14-13 region identified by suggestive linkage in genomic screens from Canada and the United Kingdom. When studying 146 Nordic MS multiplex families, mostly affected sib-pairs, with eight microsatellite markers, spanning a 36-cM region, we observed a two-point non-parametric linkage (NPL) score of 2.39 (P = 0.007) by the GENEHUNTER package for marker D3S1285 and a multipoint NPL score of 1.20 in the same region. Association studies in Swedish MS patients revealed modest allelic associations of uncertain significance not supported by transmission analysis. Analysis of the trinucleotide repeat sequence of the SCA7 gene in Swedish index cases did not reveal expansions. We conclude that support was obtained for the location of a gene or genes with importance for MS susceptibility in 3p14-13 region.

Alleles↗