Biomedical subjects

Tomas Olsson

Publications and source records attributed to Tomas Olsson.

At least 37 records · Page 2Linked to original sources

PubMed2005

Resolution of a 16.8-Mb autoimmunity-regulating rat chromosome 4 region into multiple encephalomyelitis quantitative trait loci and evidence for epistasis.

To investigate effects of a 16.8-Mb region on rat chromosome 4q42-43 on encephalomyelitis, we performed a high-resolution mapping using a 10th generation advanced intercross line between the susceptible DA strain and the MHC identical but resistant PVG.1AV1 strain. Clinical signs of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) developed in 29% of 772 F(10) rats. Three regions controlling disease, Eae20, Eae21, and Eae22, were mapped using 15 microsatellite markers spanning 16.8 Mb. Eae20 was a major genetic determinant within the region whereas Eae21 modified disease severity. Eae22 was identified as an epistatic region because it only displayed an effect together with Piebald Virol Glaxo (PVG) alleles on Eae20. Disease down-regulation by PVG alleles in the telomeric part of Eae20 was also demonstrated in DA rats made congenic for a approximately 1.44-Mb chromosomal region from PVG. As the region containing Eae20-Eae22 also regulates arthritis, together with the fact that the syntenic mouse 6F(2)-F(3) region regulates experimental lupus and diabetes, and the syntenic human 12p13.31-13.2 region regulates multiple sclerosis and rheumatoid arthritis, the present data point to genes that control several inflammatory diseases. The pairscan analyses of interaction, which here identified Eae22, are novel in the encephalomyelitis field and of importance in the design of further studies of this region in other diseases and species. The limited number of genes identified in Eae20, Eae21, and Eae22 enables focused examination of their relevance in mechanistic animal studies and screening of their association to human diseases.

Animals↗

PubMed2005

Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block.

Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200-239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.

Amino Acid Sequence↗

PubMed2005

Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems.

Expression of T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) can be used as T helper (Th) differentiation markers in the human and mouse. We examined the expression of TIM-1 and -3 mRNAs in rat MBP(63-88)-induced experimental autoimmune encephalomyelitis (EAE). TIM-3 expression was upregulated in the spinal cord during EAE and following antigen restimulation of the encephalitogenic TCRBV8S2+ population. Interestingly, TIM-3 expression was also detected by in situ hybridization in resident cells of the nervous system. TIM-1 was expressed in B cells but not in resident CNS cells and TIM-1 mRNA levels in spinal cord were unchanged throughout the course of EAE. These results support the notion that TIM-3 can also be used as a Th1 differentiation marker in the rat. However, expression of TIM-1 and -3 is not restricted solely to T cells and the presence of TIM-3 in resident CNS cells may indicate a role for this molecule in the interaction between the nervous and immune systems.

Animals↗

PubMed2005

Immunological patterns identifying disease course and evolution in multiple sclerosis patients.

Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking. We applied a multivariate statistical analysis on results obtained by measuring-by real-time RT-PCR-mRNA levels of 25 immunological relevant molecules in PBMCs from 198 MS patients. The combined measurement of mRNA levels of IL-1beta, TNF-alpha, TGF-beta, CCL20 and CCR3 was able to distinguish MS patients from healthy individuals. CXCR5, CCL5, and CCR3 combined mRNA levels identify primary progressive MS patients while TNF-alpha, IL-10, CXCL10 and CCR3 differentiate relapsing MS patients. Our results indicate that multi-parametric analysis of mRNA levels of immunological relevant molecules in PBMCs may represent a successful strategy for the identification of putative peripheral markers of disease state and disease activity in MS patients.

Adult↗

PubMed2005

CDR3 sequence preference of TCRBV8S2+ T cells within the CNS does not reflect single amino acid dependent avidity expansion.

To investigate the influence of antigen and restricting MHC class II molecule on the T cell repertoire, we varied the peptide source by immunizing either with myelin basic protein (MBP) (rat)63-88 or MBP(GUINEA PIG (GP))63-88, which differ in the core region of the peptide binding site at position 79 by a single exchange of threonine (T) to serine (S) and by altering the MHC by immunizing MHC congenic LEW (RT1(1)) and LEW.1W (RT1u) rats. In both MHC haplotypes both peptides lead to oligoclonal dominance of TCRBV8S2 expressing T cells within the central nervous system (CNS) as assessed by complementary determining region 3 (CDR3) spectratyping. In contrast cytofluorometric analysis indicated that only MBP(GP)63-88 in context with the RT1(l) haplotype of the LEW rat lead to strong expansions of TCRBV8S2 expressing T cells within the CNS. Importantly, the small conservative change from S to T at position 79 within MBP63-88 had a strong influence both on the encephalitogenic potential of the peptide and on the number of TCRBV8S2+ T cells infiltrating the CNS. These results demonstrate that even minor changes in only one side chain of an amino acid within an (auto)antigen can dramatically alter TCR avidity for certain MHC class II/peptide complexes.

Amino Acid Sequence↗

PubMed2004

MHC class II isotype- and allele-specific attenuation of experimental autoimmune encephalomyelitis.

Most autoimmune diseases are associated with certain MHC class II haplotypes. Autoantigen-based specific immune therapy can lead either to beneficial or, in the context of inflammatory conditions, detrimental outcomes. Therefore, we designed a platform of peptides by combinatorial chemistry selected in a nonbiased Ag-independent approach for strong binding to the rat MHC class II isotype RT1.D(n) allelic product of the RT1(n) haplotype that is presenting autoantigen in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LEW.1N rats. Peptide p17 (Ac-FWFLDNAPL-NH(2)) was capable of suppressing the induction of and also ameliorated established experimental autoimmune encephalomyelitis. MHC class II isotype and allele specificity of the therapeutic principle were demonstrated in myelin basic protein-induced experimental autoimmune encephalomyelitis in LEW rats bearing the RT1(l) haplotype. A general immunosuppressive effect of the treatment was excluded by allogeneic heart transplantation studies. In vitro studies demonstrated the blocking effect of p17 on autoantigenic T cell responses. We thus demonstrate a rational design of strong MHC class II-binding peptides with absolute isotype and allele specificity able to compete for autoantigenic sequences presented on disease-associated MHC class II molecules.

Alleles↗

PubMed2004

An advanced intercross line resolves Eae18 into two narrow quantitative trait loci syntenic to multiple sclerosis candidate loci.

Identification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms. Initial steps to map such genes using linkage analysis in F(2) intercross or backcross populations, however, result in broad quantitative trait loci (QTLs) containing hundreds of genes. In this study, an advanced intercross line in combination with congenic strains, was used to fine-map Eae18 on rat chromosome 10 in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein-induced EAE is a chronic relapsing disease that closely mimics key features of multiple sclerosis. Congenic DA.ACI rat strains localized Eae18 to an approximately 30-Mb large region. Fine-mapping was then performed in an advanced intercross line consisting of a (DA x PVG.1AV1)F(7) intercross, resulting in two adjacent EAE-regulating QTLs designated Eae18a and Eae18b. The two QTLs span 5.5 and 3 Mb, respectively, and the 3-Mb Eae18b contains as few as 10 genes, including a cluster of chemokine genes (CCL1, CCL2, CCL7, and CCL11). Eae18a and Eae18b are syntenic to human chromosome 17p13 and 17q11, respectively, which both display linkage to multiple sclerosis. Thus, Eae18 consists of at least two EAE-regulating genes, providing additional evidence that clustering of disease-regulating genes in QTLs is an important phenomenon. The overlap between Eae18a and Eae18b with previously identified QTLs in humans and mice further supports the notion that susceptibility alleles in inflammatory disease are evolutionary conserved between species.

Animals↗

PubMed2004

T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis.

T cell Ig- and mucin-domain-containing molecules (TIMs) comprise a recently described family of molecules expressed on T cells. TIM-3 has been shown to be expressed on murine Th1 cell clones and has been implicated in the pathogenesis of Th1-driven experimental autoimmune encephalomyelitis. In contrast, association of TIM-1 polymorphisms to Th2-related airway hyperreactivity has been suggested in mice. The TIM molecules have not been investigated in human Th1- or Th2-mediated diseases. Using real-time (TaqMan) RT-PCR, we show that human Th1 lines expressed higher TIM-3 mRNA levels, while Th2 lines demonstrated a higher expression of TIM-1. Analysis of cerebrospinal fluid mononuclear cells obtained from patients with multiple sclerosis revealed significantly higher mRNA expression of TIM-1 compared with controls. Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-gamma mRNA in cerebrospinal fluid mononuclear cells. In contrast, expression of TIM-3 correlated well with high expression of IFN-gamma and TNF-alpha. These data imply the differential expression of human TIM molecules by Th1 and Th2 cells and may suggest their differential involvement in different phases of a human autoimmune disease.

Adolescent↗

PubMed2004

Immunogenicity of Torpedo acetylcholine receptor in the context of different rat MHC class II haplotypes and non-MHC genomes.

The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG), a T-cell-dependent B-cell-mediated autoimmune disease. The nAChR is a pentameric transmembrane receptor comprising alpha alpha beta gamma delta chains. During early postnatal development the nAChR gamma chain is replaced by the nAChR epsilon chain. We tested the myasthenogenicity in experimental autoimmune myasthenia gravis (EAMG) of the native nAChR derived from the electric ray Torpedo californica (T-nAChR) in various inbred and MHC -congenic rat strains. Differences in the disease course emerged dependent on the MHC haplotype and non-MHC genes. Interestingly, no tested rat strain was completely resistant to EAMG, but there were strong differences in disease severity mainly depending on the MHC haplotype. In the LEW non-MHC genome, the B-cell response and the severity of EAMG were dependent on the expressed MHC haplotype. This study underscores the influence of genetic factors on disease severity, disease course and on the degree of the emerging antibody responses in EAMG.

Animals↗

PubMed2004

Different responses of myocardial and cerebral blood flow to cord occlusion in exteriorized fetal sheep.

Type and duration of fetal asphyxial insult affect the distribution of blood flow to the heart and brain. The purpose of this study was to describe dynamic and quantitative changes in regional myocardial and cerebral blood flow (CBF) during fetal asphyxia induced by total occlusion of the umbilical cord. Eleven exteriorized fetal sheep were subjected to total umbilical cord occlusion and five fetal sheep served as sham controls. Regional blood flow (BF) to the brain and heart was quantified using radioactive microspheres before and after 5 min of occlusion and finally when fetal mean arterial blood pressure had decreased below 25 mm Hg, 9.8 (0.8) [mean (SD)] min after occlusion. Right coronary arterial (RCA) blood flow velocity and carotid BF were registered continuously. Mean values of arterial pH and oxygen content (mL O(2)/100 mL) were 7.08 (0.11) and 4.4 (2.9) before cord occlusion and decreased to 6.83 (0.05) and 1.4 (0.9) at 5 min after occlusion (p < 0.01, respectively). Carotid BF was significantly below preocclusion values by 2.5 min (p < 0.05), whereas RCA velocity time integral per minute remained above preocclusion values for 9 min. CBF decreased from 316 (24) before cord occlusion to 156 (30) mL/min/100 g at 5 min (p < 0.01), whereas right myocardial BF was maintained at 792 (125) and 751 (183) mL/min/100 g, respectively. CBF decreased rapidly after total cord occlusion whereas myocardial BF increased and was maintained until shortly before cardiac arrest, suggesting the myocardium to be better preserved during this type of insult in already partially asphyxiated fetuses.

Animals↗

PubMed2004

Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis.

The etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode of action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal domain of the bovine milk protein butyrophilin (BTN). Analysis of paired samples of MS sera and cerebrospinal fluid (CSF) identified a BTN-specific Ab response in the CNS that differed in its epitope specificity from that in the periphery. This effect was statistically significant for the Ab response to BTN(76-100) (p = 0.0026), which cosequestered in the CSF compartment with Ab to the homologous MOG peptide MOG(76-100) in 34% of MS patients (n = 35). These observations suggested that intratheccal synthesis of Ab recognizing BTN peptide epitopes in the CNS was sustained by molecular mimicry with MOG. Formal evidence of molecular mimicry between the two proteins was obtained by analyzing MOG-specific autoantibodies immunopurified from MS sera. The MOG-specific Ab repertoire cross-reacts with multiple BTN peptide epitopes including a MOG/BTN(76-100)-specific component that occurred at a higher frequency in MS patients than in seropositive healthy controls, as well as responses to epitopes within MOG/BTN(1-39) that occur at similar frequencies in both groups. The demonstration of molecular mimicry between MOG and BTN, along with sequestration of BTN-reactive Ab in CSF suggests that exposure to this common dietary Ag may influence the composition and function of the MOG-specific autoimmune repertoire during the course of MS.

Adolescent↗

PubMed2004

Prior poliomyelitis-IVIg treatment reduces proinflammatory cytokine production.

The postpolio syndrome (PPS) is characterized by progressive disabilities decades after recovery from the acute paralytic disease. There are reports on intrathecal inflammatory reactions in PPS, including increased expression of cytokines by cerebrospinal fluid (CSF) mononuclear cells (CSF-MC). This is potentially of relevance for the clinical condition. We here explored if cytokine expression in the CSF of PPS patients could be modulated by high-dose intravenous immunoglobulins (IvIg). The expression of TNF-alpha, IFN-gamma, IL-10 and IL-4 mRNAs was measured by real-time RT-PCR in CSF and peripheral blood mononuclear cells (PBMC) of 16 PPS patients before, and 6-8 weeks after IvIg treatment, and in 26 patients with noninflammatory other neurological diseases (OND). TNF-alpha, IFN-gamma and IL-10 CSF mRNA levels were elevated in samples from untreated persons with PPS compared to OND. Upon IvIg treatment, IFN-gamma and TNF-alpha mRNA levels were dramatically reduced, while IL-10 remained unchanged. Placebo-controlled studies are now warranted to evaluate if IvIg treatment also has any effects on the clinical manifestations of PPS.

Adult↗

PubMed2004

MHC and non-MHC gene regulation of disease susceptibility and disease course in experimental inflammatory peripheral neuropathy.

With a panel of rat strains, we demonstrate a strong impact of the MHC genotype on susceptibility and disease course in experimental autoimmune neuritis induced with peripheral nerve myelin or the P2 peptide 58-81 (KNTEISFKLGQEFEETTADNRKTK). Beside the MHC genotype, non-MHC genes determined disease susceptibility and resistance. The type of disease induced with P2 58-81 was strongly correlated to the strength of the MHC class II isotype interaction with P2 58-81. These findings suggest a link between susceptibility and acute versus chronic disease courses on one hand and the strength of the MHC class II molecule/peptide affinity on the other hand.

Animals↗

PubMed2004

Parental age, family size, and risk of multiple sclerosis.

BACKGROUND: Family structure, such as having siblings, provides proxy measures for a variety of characteristics relevant to disease risk. The etiology of multiple sclerosis (MS) is not well defined and analysis of family structure may provide etiologic clues. We conducted a case-control study to examine possible associations. METHODS: Using the Swedish Inpatient Register, we identified 4443 patients with a diagnosis of MS. From the general Swedish population, using birth and death registers, we selected 24,194 controls with similar characteristics for year, county of birth, and survival until at least age at diagnosis of the matched cases. The Multi-Generation Register linked data on siblings and parents. The Census provided father's social class based on occupation. RESULTS: Having 3 or more younger siblings, compared with none, produced an adjusted odds ratio (OR) for MS (with 95% confidence interval) of 0.80 (0.70-0.92) (adjusting for number of siblings, twins, maternal and paternal age, parental MS, sex, father's social class, county and year of birth). With 3 or more older siblings, the adjusted OR was 0.83 (0.72-0.96). Different-sex twin pairs compared with singletons had an OR of 0.59 (0.37-0.95) for MS. The risk of MS increased steadily with father's age but not mother's age, up to 2.00 (1.35-2.96) for 51- to 55-year-old fathers (compared with 21- to 25-year-old fathers). CONCLUSIONS: Parents who have offspring with MS may have subtly impaired fertility. The unexpected association with paternal age may be the result of an increased risk of accumulating germ cell mutations among older men.

Adult↗

PubMed2004

Deletion of the adenosine A1 receptor gene does not alter neuronal damage following ischaemia in vivo or in vitro.

Extracellular adenosine is dramatically increased during cerebral ischaemia and is considered to be neuroprotective due to its inhibitory effect on synaptic transmission mediated by the adenosine A1 receptor (A1R). We investigated the importance of the A1R in a mouse model of global ischaemia and in a murine hippocampal slice culture model of in vitro ischaemia, using mice with the A1R gene deleted. In brains from mice lacking the A1R, damage induced by global ischaemia was similar to that in wild-type animals. In contrast, treatment with a selective A1R antagonist [8-cyclo-pentyl theophylline (8-CPT)], administered before the ischaemic insult in naive wild-type mice, exacerbated the neuronal damage following global ischaemia. Although the inhibitory action of adenosine on excitatory neurotransmission in hippocampal slices was lost in A1R knockout mice, there was no difference in damage between slices from wild-type and knockout mice after in vitro ischaemia. The results suggest that some effects of the A1R are compensated for in knockout animals.

Adenosine A1 Receptor Antagonists↗

PubMed2003

Myelin oligodendrocyte glycoprotein is expressed in the peripheral nervous system of rodents and primates.

The myelin oligodendrocyte glycoprotein (MOG) is a minor CNS myelin-specific protein that is an important candidate autoantigen in multiple sclerosis. We now report that MOG mRNA transcripts are present in the peripheral nervous system of rodents and primates at levels approximately ten-fold lower than in brain as demonstrated by real time PCR. A major source of this signal are Schwann cells which are also shown to express MOG protein within their cytoplasm in vitro by immunohistochemistry. Expression of MOG by Schwann cells associated with tissue innervation may account for the widespread distribution of low levels of MOG mRNA transcripts, and potentially may provide a source of antigen that can influence the composition and function of the MOG-specific immune repertoire.

Animals↗

PubMed2003

Discrete gene loci regulate neurodegeneration, lymphocyte infiltration, and major histocompatibility complex class II expression in the CNS.

Neurodegeneration and inflammation are fundamental aspects of many neurological diseases. A genome-wide scan of the response to ventral root avulsion (VRA) in a rat F2 cross discloses specific gene regions that regulate these processes. Two gene loci displayed linkage to neurodegeneration and T cell infiltration, respectively, and a single locus displayed extreme linkage to VRA-induced major histocompatibility complex class II expression on microglia. The demonstration that polymorphic genes in different loci control neurodegeneration and CNS inflammation has implications for various experimental rodent nervous system paradigms and potentially for genetically regulated susceptibility to a variety of human CNS diseases.

Animals↗

PubMed2003

Lack of neuroprotection by heat shock protein 70 overexpression in a mouse model of global cerebral ischemia.

Heat shock protein 70 (Hsp70) is induced in cells by a variety of stress conditions, is known to be cytoprotective, and has been proposed to be neuroprotective during brain ischemia. A recently developed mouse model of 12-min global cerebral ischemia by bilateral common carotid artery occlusion with artificial ventilation and bilateral monitoring of regional cerebral blood flow by laser Doppler was applied. We examined the expression and possible neuroprotective role of the inducible form of Hsp70 in the mouse brain following global cerebral ischemia. Ischemia induced a marked expression of Hsp70 in the ischemia vulnerable CA1-CA3 region of the hippocampus. Intraischemic hypothermia (33 degrees C) prevented cell damage without noticeable expression of Hsp70. A transgenic mouse overexpressing Hsp70 was subjected to 12 min of global cerebral ischemia, and the brain damage was evaluated after 4 days. No neuroprotection of ischemia-induced brain damage in hippocampus, striatum, cortex or thalamus was found in Hsp70 transgenic animals compared with wild-type littermate mice. We suggest that overexpression of Hsp70 following cerebral ischemia is an indicator of cell stress. Also, constitutively overexpression of Hsp70 is insufficient to effectively influence cell death after global cerebral ischemia in the mouse.

Animals↗