Management of progressive multifocal leukoencephalopathy associated with natalizumab--possibilities and responsibility.
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Antibodies, Monoclonal↗
Biomedical subjects
F Vartdal
Publications and source records attributed to F Vartdal.
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↗
Physical separation of HLA-A alleles by denaturing high-performance liquid chromatography.
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 lambda-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.
Alleles↗
T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid.
Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immunoglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous CSF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the CSF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to CSF IgG from other MS patients and that the CSF may contain T cells responding to autologous CSF IgG. This suggests that CSF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.
Adult↗
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↗
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↗
Genetic background for immune-mediated diseases.
Gene variants (alleles) involved in the immune response are most likely selected during evolution. The allelic polymorphisms that may be advantageous in fighting harmful agents may be susceptibility genes in immune-mediated diseases. Identification of susceptibility genes is important because these genes encode proteins, which are most probably involved in the disease process. Hence, the identification of susceptibility genes may lead to an improved understanding of the pathogenesis and may therefore help the development of preventive and therapeutic measures. Susceptibility genes may be identified by analyzing genes known to be involved in immune responses (candidate gene search) or by analyzing gene markers evenly distributed over the genome (genome-wide scan). However, since several genes jointly contribute to disease susceptibility, the frequencies of single susceptibility genes may be quite high in the normal population. Moreover, different set of genes may predispose to the same clinical disease. It may therefore be very difficult to identify susceptibility genes, apart from the major histocompatibility complex (MHC) genes, which have now been shown to predispose to several immune-mediated diseases.
Genetic Markers↗
Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis.
The HLA-DR2, DQ6 (i.e., HLA-DRB1*1501, DQA1*0102, DQB1*0602) haplotype contributes to the risk of developing multiple sclerosis (MS) in Caucasoids of Northern European heritage. A correlation between the clinical expression of MS and the presence of HLA-DR2, DQ6 has, however, not convincingly been shown. In this study conventional bivariate analysis and logistic regression analysis were used to study the relationship between HLA-DR2, DQ6 and four disease variables in a cohort of 286 Norwegian MS patients from the Oslo area. Logistic regression analysis showed that HLA-DR2, DQ6 was significantly more frequent among female than male patients (P=0. 0251), and was negatively correlated with age at diagnosis regardless of sex (P=0.0254). No significant correlation was observed between HLA-DR2, DQ6 and type of disease (relapsing-remitting versus primary chronic progressive MS) or presence/absence of oligoclonal bands in the cerebrospinal fluid.
Adolescent↗
[Immunologic reactions in transplantation].
Transplantation is the therapy of choice for an increasing number of patients. Organ transplantation is used to treat irreversible kidney, heart, lung and liver failure. Stem cell transplantation (previously called bone marrow transplantation) is used to treat leukaemia, bone marrow failure, severe combined immunodeficiencies and various congenital metabolic disorders. After organ transplantation, the recipient's immune system will recognise and reject the transplanted organ. T-lymphocytes transferred along with the stem cells in stem cell transplantation will attack the recipient. This paper describes how immunocompetent cells (T- and B-lymphocytes) recognise and destroy foreign cells. Strategies for the induction of specific immunologic tolerance are briefly explained.
B-Lymphocytes↗
Transplantation immunology--the role of human leucocyte antigen in allorecognition.
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Antigen-Antibody Reactions↗
CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis.
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.
Abatacept↗
The role of HLA matching in renal transplantation: experience from one center.
The influence of serology-based HLA matching on the risk of acute rejection episodes and of graft loss was analyzed in a material of 678 living donor (LD) and 997 cadaveric donor (CD) renal transplantations performed in our center in the period 1989-97. In LD transplantation, recipients of HLA-identical sibling grafts had the lowest rejection risk and the best graft survival, with a half-life estimate of 30 years. One-HLA-haplotype mismatched grafts did better than two-haplotype mismatched related or unrelated donor grafts. Matching for HLA-DR significantly reduced the rejection risk of one-haplotype mismatched grafts. In CD first transplants, HLA-DR matched grafts had a lower incidence of rejection and better survival than HLA-DR mismatched grafts. Expected half-life for HLA-DR matched grafts was 12 years compared to less than 7 years for HLA-DR mismatched grafts. The effects of matching for HLA-A and -B did not reach statistical significance. In CD regrafts, a two-antigen mismatch for HLA-A or -DR led to a significantly poorer graft survival, but the panel-reactive antibody (PRA) status of the recipient was the most influential factor. In CD renal transplantation, we conclude that organ allocation based on matching for HLA-DR 1-14 is effective and not too difficult to obtain even in centers with a short patient waiting list.
Adolescent↗
[The medical prize of Anders Jahre 1998].
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Awards and Prizes↗
A strong impact of matching for a limited number of HLA-DR antigens on graft survival and rejection episodes: a single-center study of first cadaveric kidneys to nonsensitized recipients.
BACKGROUND: A single-center study of 655 nonsensitized recipients of primary cadaveric kidney grafts is presented. RESULTS: Graft survival in serologically HLA-DR 1-10 antigen-matched grafts to nonsensitized recipients at 1 year was 90%, compared with 82% (P=0.004) and 73% (P=0.001) in one and two DR antigen-mismatched grafts. The corresponding figures at 5 years were 76%, 62%, and 56%, respectively. Matching for the DR antigens 11-14, or for some DR alleles only detectable by genomic typing, further improved graft survival, but the differences did not reach statistical significance. Matching also for the serologically defined HLA-A and -B antigens did not significantly further improve overall graft survival, but some effects for grafts surviving at least 1 year were observed. Among recipients of grafts mismatched for zero, one, or two HLA-DR antigens, acute rejection episodes were experienced in 48%, 64% (P<0.001), and 82% (P<0.001), respectively, within the first 3 months. HLA-A and -B mismatches showed no significant correlation to acute rejection episodes. CONCLUSION: Matching for the DR antigens 1-10 significantly secures and prolongs the survival of first cadaveric renal grafts. Our results also show that DR 1-10 antigen-matched combinations can often be obtained even in rather small recipient pools, when actively sought for.
Adolescent↗
Molecular cloning of a T cell-specific adapter protein (TSAd) containing an Src homology (SH) 2 domain and putative SH3 and phosphotyrosine binding sites.
Adapter proteins link catalytic signaling proteins to cell surface receptors or downstream effector proteins. In this paper, we present the cDNA sequence F2771, isolated from an activated CD8+ T cell cDNA library. The F2771 cDNA encodes a novel putative adapter protein. The predicted amino acid sequence includes an SH2 domain as well as putative SH3 and phosphotyrosine binding interaction motifs, but lacks any known catalytic domains. The expression of the gene is limited to tissues of the immune system and, in particular, activated T cells. The protein expressed by F2771 cDNA in transfected COS cells is localized in the cytoplasm. A polyclonal antiserum raised against an F2771-encoded peptide reacts with a tyrosine-phosphorylated 52-kDa protein expressed in phytohemagglutinin-stimulated peripheral blood mononuclear cells. The gene is localized to chromosome 1q21, a region often found to be aberrant in lymphomas. The T cell-specific expression and the rapid induction of mRNA expression upon receptor binding, as well as the lack of catalytic domains in the presence of protein interaction domains, indicate that the F2771 gene encodes a novel T cell-specific adapter protein (TSAd) involved in the control of T cell activation.
Adaptor Proteins, Signal Transducing↗
A peptide-binding assay for the disease-associated HLA-DQ8 molecule.
The study of peptide binding to HLA class II molecules has mostly concentrated on DR molecules. Since many autoimmune diseases show a primary association to particular DQ molecules rather than DR molecules, it is also important to study the peptide-binding properties of DQ molecules. Here we report a biochemical peptide-binding assay for the type I diabetes-associated DQ8, i.e. DQ (alpha1*0301, beta1*0302), molecule. Affinity-purified DQ8 molecules were tested in peptide-binding assays using a radiolabelled influenza haemagglutinin (Ha) peptide encompassing positions 255-271(Y) as an indicator peptide. The Ha 255-271(Y) peptide bound to DQ8 in a pH-dependent fashion showing optimal binding around pH 5. The association kinetics were relatively slow and the resulting complexes were heat labile. The specificity of peptide binding to DQ8 was investigated in competitive inhibition experiments with a panel of 43 peptides of different lengths and sequences. The DQ8 molecules showed a different pattern of peptide binding compared to a previously studied DQ2 molecule. Peptides derived from thyroid peroxidase, HLA-DQ(alpha1*0301), HLA-DQ(alpha1*0302), retinol receptor and p21ras were among the high-affinity binders, whereas peptides derived from myelin basic protein were among the low-affinity binders. The sequence of the high-affinity peptides conformed with a previously published peptide-binding motif of DQ8.
Amino Acid Sequence↗
Erik Thorsby is 60.
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History, 20th Century↗
The HLA-DQ(alpha 1*0102, beta 1*0602) heterodimer may confer susceptibility to multiple sclerosis in the absence of the HLA-DR(alpha 1*01, beta 1*1501) heterodimer.
The frequencies of DR2, DQ6-related DRB1, DQA1, DQB1 haplotypes were compared in 181 multiple sclerosis patients and 294 controls in Norway. All individuals carried either DR2 or DQ6, i.e., the DQ(alpha 1*0102, beta 1*0602) heterodimer. The DR(alpha 1*01, beta 1*1501) and the DQ(alpha 1*0102, beta 1*0602) heterodimers were carried by 171 of the patients (94%) and 289 (98%) of the controls. Seven of the patients and one of the controls carried the DQ(alpha 1*0102, beta 1*0603) heterodimer together with the DR(alpha 1*01, beta 1*1501) heterodimer. Two patients carried the DQ(alpha 1*0102, beta 1*0602) heterodimer in the absence of the DR( alpha 1*01, beta 1*1501) heterodimer. The DR(alpha 1*01, beta 1*1501) heterodimer was not observed in the absence of the DQ(alpha 1*0102, beta 1*0602) heterodimer or the DQ(alpha 1*0102, beta 1*0603) heterodimer, neither in the patients nor in the controls. Our findings indicate that the genes encoding the DQ(alpha 1*0102, beta 1*0602) heterodimer may confer susceptibility to developing multiple sclerosis in the absence of the DRB1*1501 allele.
Alleles↗