A. Spurkland - Academia.edu (original) (raw)
Papers by A. Spurkland
Arthritis Research & Therapy, 2001
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with define... more We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA). An indirect immunofluorescence test and rat oesophagus substrate was used for the detection and quantification of AKA antibodies in patients´ sera. Overall 33/60 patients with JIA had sera positive for AKA (55 %, P = 0,0001) ranging from 1:10 to 1:160 dilutions. Following idiopathic arthritis of childhood classification criteria AKA occurred in 2/7 patients with systemic disease (28,6 %), in 13/30 patients with RF negative polyarthritis (43,3 %, P = 0,008) and in 15/18 RF positive polyarthritis (83,3 %, P = 0,000002). AKA were also found in a small cohort of patients with oligoarthritis (1/3) and psoriatic arthritis (2/2). AKA positivity occurred in 3/26 healthy controls at a 1:20 dilution. The presence of AKA was correlated as well as with the severity of the disease. Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, however this did not reach statistical significance (P = 0,18). We also observed that AKA remained positive regardless of disease activity. AKA were detectable in 55,6 % patients with active JIA and in 48,6 % patients in the complete or near remission. Acknowledgement: This research was supported by a European Commission (Acronym: EUROBANK, contract no: QOL-2000-14.1), web site http://www.ncl.ac.uk and by grant of 2nd Medical Faculty, Charles University in Prague, VZ no. 111300003. P2 The significance of antibodies to cyclic citrullinated peptide, antikeratin antibodies, antiperinuclear factor, rheumatoid factor isotypes and HLA shared epitope in prediction of erosive disease in early rheumatoid arthritis patients
BACKGROUND AND AIMSPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of... more BACKGROUND AND AIMSPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association
Genes and Immunity, 2016
Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system ... more Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes.
Science signaling, Jan 9, 2014
The substrate specificity of Src family kinases (SFKs) is partly determined by their Src homology... more The substrate specificity of Src family kinases (SFKs) is partly determined by their Src homology 2 (SH2) domains. Thus, transient alterations in the SH2 domain of SFKs might change their binding partners and affect intracellular signaling pathways. Lck is an SFK that is central to the initiation of T cell activation in response to ligand binding to the T cell receptor (TCR) and is also critical for later signaling processes. The kinase activity of Lck requires both the phosphorylation of an activating tyrosine residue and the dephosphorylation of an inhibitory tyrosine residue. We found that a third conserved tyrosine phosphorylation site (Tyr(192)) within the SH2 domain of Lck was required for proper T cell activation and formation of cell-cell conjugates between T cells and antigen-presenting cells. Through phosphopeptide arrays and biochemical assays, we identified several regulators of the actin cytoskeleton that preferentially bound to Lck phosphorylated at Tyr(192) compared t...
Transplantation proceedings, 1993
British journal of cancer, 1994
DNA from 251 primary tumours obtained from 123 male and 125 female Norwegian patients with colore... more DNA from 251 primary tumours obtained from 123 male and 125 female Norwegian patients with colorectal carcinoma was analysed for the presence of K-ras point mutations at codons 12 and 13. Mutations were found in 99 (39%) of the samples. The frequency of K-ras mutations was significantly related to age and sex of the patients, and to the location of the tumours (overall: P = 0.008). K-ras mutations were much less frequent in colonic tumours from male than female patients at younger ages (< 40 years, odds ratio < 0.014). The low frequency might indicate that a different, ras-independent, pathway to neoplasia is dominating in the colon of younger males. In contrast, older men had more mutations than older women (e.g. 90 years, odds ratio = 5.8). An inverse but less pronounced relationship was seen for rectal tumours. The type of mutation was found to be associated to sex of patient and location of tumour. G-->C transversions accounted for 35% of the mutations in rectal tumours...
Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, Jan 30, 1994
HLA molecules play a central role in the initiation and perpetuation of immune responses. Our kno... more HLA molecules play a central role in the initiation and perpetuation of immune responses. Our knowledge about the structure and function of these molecules has increased considerably in the last few years. This has opened up for new therapeutic options in auto-immune diseases and cancer, and has greatly improved the outcome of organ transplantation. In this review, the author presents some of the new possibilities of manipulating immune responses via the HLA molecules.
Scandinavian Journal of Immunology, 2014
T cell-specific adapter protein (TSAd) encoded by the SH2D2A gene is expressed in activated T cel... more T cell-specific adapter protein (TSAd) encoded by the SH2D2A gene is expressed in activated T cells, NK cells and endothelial cells, but its tissue expression has not yet been mapped. Here, we have defined the specificity of two commercially available anti-TSAd monoclonal reagents using peptide arrays. We found them to bind separate epitopes in the C-terminal part of TSAd. We then used immunohistochemistry to examine TSAd expression in various human lymphoid and non-lymphoid tissues. Immunostaining of adjacent tissue sections revealed that a substantial fraction of CD3-positive cells in normal lymphoid and non-lymphoid tissues expressed TSAd. In particular, essentially all intra-epithelial T cells appeared to coexpress TSAd. In addition, TSAd expression was observed in endothelial cells of dermal microvessels, while it was not detected in endothelial cells of the other tested tissues. This work provides insight into the expression pattern of TSAd in various healthy human tissues.
Tissue Antigens, 1999
The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comp... more The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).
Tissue Antigens, 2004
In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribu... more 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.
Tissue Antigens, 2003
Genomic typing of polymorphic loci may be hampered by ambiguous typing results. Moreover, robust ... more Genomic typing of polymorphic loci may be hampered by ambiguous typing results. Moreover, robust methods for simultaneous sequencing of two alleles present in a given sample may be difficult to establish. We used denaturing high-performance liquid chromatography (DHPLC) for physical separation of HLA-A alleles before sequence-based genomic typing (SBT). Physical separation was achieved by resolution of heteroduplexes between the sample alleles and a modified reference probe by DHPLC followed by selective reamplification of the sample alleles present in heteroduplexes. Complementary strands of the reference probe and sample alleles for heteroduplex induction were obtained by l-exonuclease digestion. HLA-A genotyping of 101 individuals using DHPLC-SBT yielded better typing resolution compared with serological typing and genotyping by the sequence-specific primer-polymerase chain reaction (SSP-PCR) method. Physical separation of alleles using a modified reference probe allows for development of fully automated methods for genomic typing of highly polymorphic loci such as HLA. High-resolution typing of alleles at a polymorphic locus requires the determination of the nucleotide sequences of the alleles. Some methods that are routinely applied for genomic HLA-A typing are only able to detect previously defined alleles and may miss new polymorphisms, which may induce graft-vs-host disease after transplantation of stem cells from unrelated donors. Ideally, HLA-alleles should be sequenced before stem-cell transplantation between unrelated individuals. Sequencing of heterozygous samples without prior separation of the alleles by cloning is limited in that eventual deletions and insertions in one of the alleles may hamper interpretation of the sequence. For highly polymorphic loci, like HLA, the same polymorphisms may occur on different alleles, thus making it sometimes impossible to distinguish between certain heterozygous combinations of alleles. Furthermore, reliable identification of heterozygous positions in a nucleotide sequence may be difficult using automated sequencing where all four bases are analyzed in the same lane. Physical separation
Tissue Antigens, 2007
Most archaeological and linguistic evidence suggest a Polynesian origin of the population of East... more Most archaeological and linguistic evidence suggest a Polynesian origin of the population of Easter Island (Rapanui), and this view has been supported by the identification of Polynesian mitochondrial DNA (mtDNA) polymorphisms in prehistoric skeletal remains. However, some evidence of an early South American contact also exists (the sweet potato, bottle gourd etc.), but genetic studies have so far failed to show an early Amerindian contribution to the gene pool on Easter Island. To address this issue, we analyzed mtDNA and Y chromosome markers and performed high-resolution human leukocyte antigen (HLA) genotyping of DNA harvested from previously collected sera of 48 reputedly nonadmixed native Easter Islanders. All individuals carried mtDNA types and HLA alleles previously found in Polynesia, and most men carried Y chromosome markers of Polynesian origin, providing further evidence of a Polynesian origin of the population of Easter Island. A few individuals carried HLA alleles and/or Y chromosome markers of European origin. More interestingly, some individuals carried the HLA alleles A*0212 and B*3905, which are of typical Amerindian origin. The genealogy of some of the individuals carrying these non-Polynesian HLA alleles and their haplotypic backgrounds suggest an introduction into Easter Island in the early 1800s, or earlier. Thus, there may have been an early European and Amerindian contribution to the Polynesian gene pool of Easter Island.
Tissue Antigens, 2002
HLA class II alleles were determined by PCR-SSO and PCR-SSP typing of DNA samples from 55 Nentsy,... more HLA class II alleles were determined by PCR-SSO and PCR-SSP typing of DNA samples from 55 Nentsy, 81 Saami and 73 Pomor individuals from the North-European part of Russia. The results were compared with similar data from Russians. A high frequency of the DRB1*04-DQA1*0301-DQB1*0302 haplotype and a low frequency of the DRB1*11-DQA1*0501-DQB1*0301 haplotype, observed in all three ethnic groups, may indicate a common aboriginal component in their ancestry. Saami and Pomors displayed a similar pattern of allele and haplotype distribution, with the exception of the DRB1*04-DQA1*0304-DQB1*0301 haplotype, which was significantly higher among Saami compared Nentsy, Pomors and Russians. Nentsy individuals had a particularly high frequency of the DRB1*09-DQA1*0301-DQB1*0303 and the DRB1*12-DQA1*0501-DQB1*0301 haplotypes. Genetic distances and correspondence analysis show that Pomors have a close relationship with Norwegians and Finns, whereas Nentsy and Saami are more closely related to Oriental populations.
Tissue Antigens, 1997
... Vilches C, de Pablo R, Moreno ME, Solis R, Kreisler M. Characterization of an HLA-DR 15 DQ5 h... more ... Vilches C, de Pablo R, Moreno ME, Solis R, Kreisler M. Characterization of an HLA-DR 15 DQ5 haplotype found in the Spanish Caucasoid population. ... Roushdy J, Santoso S, Kalb R, Meier-Ewert K, Albert ED, Mueller-Eckhardt G. A deletion in the second exon of an HLA-DRBI ...
Tissue Antigens, 1991
patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HL... more patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HLA associations.
Tissue Antigens, 1993
Thorsby. HLA matching of unrelated bone marrow transplant pairs: Direct sequencing of in vitro am... more Thorsby. HLA matching of unrelated bone marrow transplant pairs: Direct sequencing of in vitro amplified HLA-DRB 1 and-DQB I genes using magnetic beads as solid support.
Tissue Antigens, 2007
Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*03... more Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.
Tissue Antigens, 1991
bution of HLA-DRB1,-DQA1 and-DQBl alleles and DQA1-DQB1 genotypes among Norwegian patients with i... more bution of HLA-DRB1,-DQA1 and-DQBl alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus.
Tissue Antigens, 1999
The human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene may be a candidate susceptibil... more The human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene may be a candidate susceptibility gene in multiple sclerosis (MS). In this study the distribution of the dimorphisms of exon 1 (+49 A/G) and promoter (-318 C/T) regions of the CTLA4 gene was analysed in 296 unrelated Norwegian MS patients and 271 matched controls by polymerase chain reaction and restriction fragment length polymorphism. The frequency of the exon 1 (+49) A-G genotype was increased in patients (57%) compared with controls (44%) (Pcorrected=0.01), and even more increased in patients with relapsing remitting MS (59%) (Pcorrected=0.006). No other significant differences were found between clinical subgroups of patients or between HLA-DRB1*1501, DQB1*0602-positive and negative patients and controls.
Science Translational Medicine, 2009
Multiple sclerosis, the most common cause of progressive neurological disability in young adults,... more Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-gamma expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.
Arthritis Research & Therapy, 2001
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with define... more We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA). An indirect immunofluorescence test and rat oesophagus substrate was used for the detection and quantification of AKA antibodies in patients´ sera. Overall 33/60 patients with JIA had sera positive for AKA (55 %, P = 0,0001) ranging from 1:10 to 1:160 dilutions. Following idiopathic arthritis of childhood classification criteria AKA occurred in 2/7 patients with systemic disease (28,6 %), in 13/30 patients with RF negative polyarthritis (43,3 %, P = 0,008) and in 15/18 RF positive polyarthritis (83,3 %, P = 0,000002). AKA were also found in a small cohort of patients with oligoarthritis (1/3) and psoriatic arthritis (2/2). AKA positivity occurred in 3/26 healthy controls at a 1:20 dilution. The presence of AKA was correlated as well as with the severity of the disease. Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, however this did not reach statistical significance (P = 0,18). We also observed that AKA remained positive regardless of disease activity. AKA were detectable in 55,6 % patients with active JIA and in 48,6 % patients in the complete or near remission. Acknowledgement: This research was supported by a European Commission (Acronym: EUROBANK, contract no: QOL-2000-14.1), web site http://www.ncl.ac.uk and by grant of 2nd Medical Faculty, Charles University in Prague, VZ no. 111300003. P2 The significance of antibodies to cyclic citrullinated peptide, antikeratin antibodies, antiperinuclear factor, rheumatoid factor isotypes and HLA shared epitope in prediction of erosive disease in early rheumatoid arthritis patients
BACKGROUND AND AIMSPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of... more BACKGROUND AND AIMSPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association
Genes and Immunity, 2016
Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system ... more Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes.
Science signaling, Jan 9, 2014
The substrate specificity of Src family kinases (SFKs) is partly determined by their Src homology... more The substrate specificity of Src family kinases (SFKs) is partly determined by their Src homology 2 (SH2) domains. Thus, transient alterations in the SH2 domain of SFKs might change their binding partners and affect intracellular signaling pathways. Lck is an SFK that is central to the initiation of T cell activation in response to ligand binding to the T cell receptor (TCR) and is also critical for later signaling processes. The kinase activity of Lck requires both the phosphorylation of an activating tyrosine residue and the dephosphorylation of an inhibitory tyrosine residue. We found that a third conserved tyrosine phosphorylation site (Tyr(192)) within the SH2 domain of Lck was required for proper T cell activation and formation of cell-cell conjugates between T cells and antigen-presenting cells. Through phosphopeptide arrays and biochemical assays, we identified several regulators of the actin cytoskeleton that preferentially bound to Lck phosphorylated at Tyr(192) compared t...
Transplantation proceedings, 1993
British journal of cancer, 1994
DNA from 251 primary tumours obtained from 123 male and 125 female Norwegian patients with colore... more DNA from 251 primary tumours obtained from 123 male and 125 female Norwegian patients with colorectal carcinoma was analysed for the presence of K-ras point mutations at codons 12 and 13. Mutations were found in 99 (39%) of the samples. The frequency of K-ras mutations was significantly related to age and sex of the patients, and to the location of the tumours (overall: P = 0.008). K-ras mutations were much less frequent in colonic tumours from male than female patients at younger ages (< 40 years, odds ratio < 0.014). The low frequency might indicate that a different, ras-independent, pathway to neoplasia is dominating in the colon of younger males. In contrast, older men had more mutations than older women (e.g. 90 years, odds ratio = 5.8). An inverse but less pronounced relationship was seen for rectal tumours. The type of mutation was found to be associated to sex of patient and location of tumour. G-->C transversions accounted for 35% of the mutations in rectal tumours...
Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, Jan 30, 1994
HLA molecules play a central role in the initiation and perpetuation of immune responses. Our kno... more HLA molecules play a central role in the initiation and perpetuation of immune responses. Our knowledge about the structure and function of these molecules has increased considerably in the last few years. This has opened up for new therapeutic options in auto-immune diseases and cancer, and has greatly improved the outcome of organ transplantation. In this review, the author presents some of the new possibilities of manipulating immune responses via the HLA molecules.
Scandinavian Journal of Immunology, 2014
T cell-specific adapter protein (TSAd) encoded by the SH2D2A gene is expressed in activated T cel... more T cell-specific adapter protein (TSAd) encoded by the SH2D2A gene is expressed in activated T cells, NK cells and endothelial cells, but its tissue expression has not yet been mapped. Here, we have defined the specificity of two commercially available anti-TSAd monoclonal reagents using peptide arrays. We found them to bind separate epitopes in the C-terminal part of TSAd. We then used immunohistochemistry to examine TSAd expression in various human lymphoid and non-lymphoid tissues. Immunostaining of adjacent tissue sections revealed that a substantial fraction of CD3-positive cells in normal lymphoid and non-lymphoid tissues expressed TSAd. In particular, essentially all intra-epithelial T cells appeared to coexpress TSAd. In addition, TSAd expression was observed in endothelial cells of dermal microvessels, while it was not detected in endothelial cells of the other tested tissues. This work provides insight into the expression pattern of TSAd in various healthy human tissues.
Tissue Antigens, 1999
The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comp... more The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).
Tissue Antigens, 2004
In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribu... more 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.
Tissue Antigens, 2003
Genomic typing of polymorphic loci may be hampered by ambiguous typing results. Moreover, robust ... more Genomic typing of polymorphic loci may be hampered by ambiguous typing results. Moreover, robust methods for simultaneous sequencing of two alleles present in a given sample may be difficult to establish. We used denaturing high-performance liquid chromatography (DHPLC) for physical separation of HLA-A alleles before sequence-based genomic typing (SBT). Physical separation was achieved by resolution of heteroduplexes between the sample alleles and a modified reference probe by DHPLC followed by selective reamplification of the sample alleles present in heteroduplexes. Complementary strands of the reference probe and sample alleles for heteroduplex induction were obtained by l-exonuclease digestion. HLA-A genotyping of 101 individuals using DHPLC-SBT yielded better typing resolution compared with serological typing and genotyping by the sequence-specific primer-polymerase chain reaction (SSP-PCR) method. Physical separation of alleles using a modified reference probe allows for development of fully automated methods for genomic typing of highly polymorphic loci such as HLA. High-resolution typing of alleles at a polymorphic locus requires the determination of the nucleotide sequences of the alleles. Some methods that are routinely applied for genomic HLA-A typing are only able to detect previously defined alleles and may miss new polymorphisms, which may induce graft-vs-host disease after transplantation of stem cells from unrelated donors. Ideally, HLA-alleles should be sequenced before stem-cell transplantation between unrelated individuals. Sequencing of heterozygous samples without prior separation of the alleles by cloning is limited in that eventual deletions and insertions in one of the alleles may hamper interpretation of the sequence. For highly polymorphic loci, like HLA, the same polymorphisms may occur on different alleles, thus making it sometimes impossible to distinguish between certain heterozygous combinations of alleles. Furthermore, reliable identification of heterozygous positions in a nucleotide sequence may be difficult using automated sequencing where all four bases are analyzed in the same lane. Physical separation
Tissue Antigens, 2007
Most archaeological and linguistic evidence suggest a Polynesian origin of the population of East... more Most archaeological and linguistic evidence suggest a Polynesian origin of the population of Easter Island (Rapanui), and this view has been supported by the identification of Polynesian mitochondrial DNA (mtDNA) polymorphisms in prehistoric skeletal remains. However, some evidence of an early South American contact also exists (the sweet potato, bottle gourd etc.), but genetic studies have so far failed to show an early Amerindian contribution to the gene pool on Easter Island. To address this issue, we analyzed mtDNA and Y chromosome markers and performed high-resolution human leukocyte antigen (HLA) genotyping of DNA harvested from previously collected sera of 48 reputedly nonadmixed native Easter Islanders. All individuals carried mtDNA types and HLA alleles previously found in Polynesia, and most men carried Y chromosome markers of Polynesian origin, providing further evidence of a Polynesian origin of the population of Easter Island. A few individuals carried HLA alleles and/or Y chromosome markers of European origin. More interestingly, some individuals carried the HLA alleles A*0212 and B*3905, which are of typical Amerindian origin. The genealogy of some of the individuals carrying these non-Polynesian HLA alleles and their haplotypic backgrounds suggest an introduction into Easter Island in the early 1800s, or earlier. Thus, there may have been an early European and Amerindian contribution to the Polynesian gene pool of Easter Island.
Tissue Antigens, 2002
HLA class II alleles were determined by PCR-SSO and PCR-SSP typing of DNA samples from 55 Nentsy,... more HLA class II alleles were determined by PCR-SSO and PCR-SSP typing of DNA samples from 55 Nentsy, 81 Saami and 73 Pomor individuals from the North-European part of Russia. The results were compared with similar data from Russians. A high frequency of the DRB1*04-DQA1*0301-DQB1*0302 haplotype and a low frequency of the DRB1*11-DQA1*0501-DQB1*0301 haplotype, observed in all three ethnic groups, may indicate a common aboriginal component in their ancestry. Saami and Pomors displayed a similar pattern of allele and haplotype distribution, with the exception of the DRB1*04-DQA1*0304-DQB1*0301 haplotype, which was significantly higher among Saami compared Nentsy, Pomors and Russians. Nentsy individuals had a particularly high frequency of the DRB1*09-DQA1*0301-DQB1*0303 and the DRB1*12-DQA1*0501-DQB1*0301 haplotypes. Genetic distances and correspondence analysis show that Pomors have a close relationship with Norwegians and Finns, whereas Nentsy and Saami are more closely related to Oriental populations.
Tissue Antigens, 1997
... Vilches C, de Pablo R, Moreno ME, Solis R, Kreisler M. Characterization of an HLA-DR 15 DQ5 h... more ... Vilches C, de Pablo R, Moreno ME, Solis R, Kreisler M. Characterization of an HLA-DR 15 DQ5 haplotype found in the Spanish Caucasoid population. ... Roushdy J, Santoso S, Kalb R, Meier-Ewert K, Albert ED, Mueller-Eckhardt G. A deletion in the second exon of an HLA-DRBI ...
Tissue Antigens, 1991
patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HL... more patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HLA associations.
Tissue Antigens, 1993
Thorsby. HLA matching of unrelated bone marrow transplant pairs: Direct sequencing of in vitro am... more Thorsby. HLA matching of unrelated bone marrow transplant pairs: Direct sequencing of in vitro amplified HLA-DRB 1 and-DQB I genes using magnetic beads as solid support.
Tissue Antigens, 2007
Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*03... more Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.
Tissue Antigens, 1991
bution of HLA-DRB1,-DQA1 and-DQBl alleles and DQA1-DQB1 genotypes among Norwegian patients with i... more bution of HLA-DRB1,-DQA1 and-DQBl alleles and DQA1-DQB1 genotypes among Norwegian patients with insulin-dependent diabetes mellitus.
Tissue Antigens, 1999
The human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene may be a candidate susceptibil... more The human cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene may be a candidate susceptibility gene in multiple sclerosis (MS). In this study the distribution of the dimorphisms of exon 1 (+49 A/G) and promoter (-318 C/T) regions of the CTLA4 gene was analysed in 296 unrelated Norwegian MS patients and 271 matched controls by polymerase chain reaction and restriction fragment length polymorphism. The frequency of the exon 1 (+49) A-G genotype was increased in patients (57%) compared with controls (44%) (Pcorrected=0.01), and even more increased in patients with relapsing remitting MS (59%) (Pcorrected=0.006). No other significant differences were found between clinical subgroups of patients or between HLA-DRB1*1501, DQB1*0602-positive and negative patients and controls.
Science Translational Medicine, 2009
Multiple sclerosis, the most common cause of progressive neurological disability in young adults,... more Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-gamma expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.