| 1. |
- Ekici, Rifat, et al.
(författare)
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Enhanced capture of extramembranous IgM and IgG on B cells in the NOD mouse : implications for immune complex trapping
- 2009
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 21:5, s. 533-541
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Tidskriftsartikel (refereegranskat)abstract
- Binding of various antibody isotypes to B cells through either FcgammaRs or complement receptors has been attributed to play several roles, e.g. in immune complex (IC) transportation and regulation of B cell receptor signaling. We have revealed a novel B cell intrinsic receptor for IgM and IgG which is present in C57BL/6 (B6) mice and is more abundant in non-obese diabetic (NOD) mice. As a consequence, the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared with B6 mice. The effect of this aberration was that all B cells in peripheral blood of (NOD.IgH(a) x B6(IgH(b)))F(1) mice carried both IgM allotypes on their surface. In addition, analysis of IC binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with B6. We hypothesize that this novel Ig-binding receptor is part of the normal immune system function. The aberrant function in the NOD mouse could contribute to the development of Type 1 diabetes by altering normal B cell functions such as activation, IC transportation and B cell homeostasis.
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| 2. |
- Haraldsson, Katarina, 1958-
(författare)
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Defining the genetics of systemic autoimmunity in mouse models of lupus
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic Lupus Erythematosus (SLE) is a chronic multi-organ autoimmune disease considered a prototype for autoantibody and immune complex-mediated tissue injury. Although autoantibodies against a wide diversity of self-antigens are characteristically found in this disease, an important hallmark is the presence of autoantibodies to nuclear antigens. Despite this common clinical feature, individual patients vary widely in the organ systems afflicted, disease severity, disease course, and response to treatment. These characteristics make clinical management of SLE challenging and highlight the need for effective and less toxic therapeutic interventions. Susceptibility to lupus has been shown in both human studies and mouse models to be dependent on genetic predisposition. Therefore, it is likely that knowledge of the genetic basis of SLE will be required before full understanding of SLE pathogenesis can be achieved. In this thesis, studies to define the genetic basis of lupus in an induced and two spontaneous models of the disease are presented. These studies encompass mapping, characterization of interval congenic mice, and cloning of the Lmb3 locus gene. In the first study, a genomewide mapping study was performed to define the genetic basis for resistance of the DBA/2 mice to mercury-induced autoimmunity. On chromosome 1, a single quantitative trait was linked with resistance to HgIA. These results linked the locus Hmr1 to a late stage of lupus with GN. Interval congenic mice are important tools to define and characterize the roles of different loci in lupus-like diseases. The second paper identifies the effect of NZB and NZW Lbw2 alleles on lupus susceptibility by using BWF1 mice with none, one or two copies of the lupus-predisposing NZB.Lbw2 locus. The lack of the NZB locus significantly reduced mortality, GN and B cell activation. IgM anti-chromatin levels in genome-wide mapping was linked only to Lmb2 and none of the known B cell hyperactivity-promoting genes were present in this location, which might indicate a novel B cell activation gene. The third study used reciprocal single locus interval-specific congenic mice to characterize the contribution of Lmb1-4 on the MRL-Faslpr and B6-Faslpr backgrounds. The Lmb3 locus on chromosome 7 was found to have the most prominent phenotype with clear effects on lymphoproliferation, GN and mortality. In the fourth paper the Lmb3 was cloned and shown to be a spontaneous nonsense mutation in the Coro1a gene that encodes an actin-binding and -regulatory protein. Upon further characterization, this genetic alteration was discovered to be a new lupus suppressing mutation that reduced T cell migration, activation, and survival. Our findings highlight the complexity of the genetics of lupus, and further suggest that genes involved in controlling the actin cytoskeleton might be potential targets for autoimmune therapeutics.
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| 3. |
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| 4. |
- Lind, Lisbet K, et al.
(författare)
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EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families
- 2006
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Ingår i: BMC Medical Genetics. - : BioMed Central. - 1471-2350. ; 7, s. 80-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR) protein that plays an important role during embryogenesis.METHODS: The coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED.RESULTS: A non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X), thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene.CONCLUSION: The finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.
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| 5. |
- Motta, Vinicius, et al.
(författare)
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The NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells.
- 2007
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 28:4, s. 216-223
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Tidskriftsartikel (refereegranskat)abstract
- Recent data have suggested that non-obese diabetic (NOD) mice display a defect in negative thymic selection. Using mixed bone marrow chimeras, we demonstrate that the NOD allele of the diabetes susceptibility region 5 (Idd5) locus on chromosome 1, confers defective negative selection in response to endogenous superantigens (SAg) Mtv8 and Mtv9. We generated mixed bone marrow (BM) chimeras in which the donor cells of NOD and C3H or NOD.Idd5(b10) and C3H coexist and are similarly exposed to the Mtv8 and Mtv9 SAg. Under these conditions, SAg-mediated deletion of Vbeta11+ T cells is less efficient in chimeric mice reconstituted with NOD+C3H BM, compared with chimeras reconstituted with NOD.Idd5(b10)+C3H BM. Interestingly, the observed discrepancy was not T cell autonomous but was found to be mediated by a BM derived cellular subset, and under control of a gene(s) in the Idd5 region.
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| 6. |
- Persson-Sjögren, Solveig, et al.
(författare)
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Expression of the NK-1 receptor on islet cells and invading immune cells in the non-obese diabetic mouse
- 2005
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411. ; 24:4, s. 269-279
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Tidskriftsartikel (refereegranskat)abstract
- The underlying mechanistic causes of immune cell infiltration in the islets of Langerhans and beta cell failure in the non-obese diabetic (NOD) mouse is still to be completely revealed. Substance P (SP) is a substance known to have pro-inflammatory, endocrine, neuromodulatory and trophic effects, and its preferred receptor, the neurokinin receptor 1 (NK-1 R), is reported to be involved in extravasation of granulocytes and in inflammation and tissue derangement. Therefore, we have investigated the expression of NK-1 R during development of insulitis in the NOD mouse. We show that the magnitude of immunoreactivity scoring NK-1 R expression in the islets was increased in the 12-week-old NOD mouse. Expression of NK-1 R co-localized with expression of glucagon. In line with this expression pattern, we did not detect any effect of SP on glucose-induced insulin release. NK-1 R expression was particularly observed in islet cells in association with the clusters of immune cells. Expression of NK-1 R was also demonstrated in a fraction of the infiltrating B and T lymphocytes, as well as on infiltrating macrophages and dendritic cells. The observations show that the level of NK-1 R expression is increased in 12-week-old NOD mice, being correlated with the occurrence of islet mononuclear infiltration. Our data suggest that SP may act as a chemoattractant, contributing to the pathogenic mononuclear infiltration process in the NOD mouse. On the whole, the observations suggest that SP and the NK-1 R to certain extents are involved in the changes that occur during the development of insulitis in the NOD mouse.
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| 7. |
- Sundström, Mia, 1980-, et al.
(författare)
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Idd-linked genetic regulation of TACIhigh expressing B cells in NOD mice
- 2007
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 29:2-3, s. 116-124
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Tidskriftsartikel (refereegranskat)abstract
- In NOD mice, B cells play a key role in the initiation of type 1 diabetes pathogenesis. We have identified a novel NOD-specific B cell-related trait, i.e. the increased percentage of TACI(high)-expressing splenic B cells, by comparing NOD mice with non-autoimmune C57BL/6 mice. Using athymic NOD mice, we determined that this trait was T cell independent. We mapped the loci contributing to the increased proportion of TACI(high) expressing splenic B cells and found that the control of TACI expression was strongly linked to chromosome 1, in a region which includes the insulin-dependent diabetes (Idd) 5 loci. Moreover, another locus potentially involved was detected in the vicinity of Idd22 on chromosome 8. Interestingly, when analyzing age-dependent contribution to the obtained LOD scores we observed that the linkage to chromosome 8 was explained solely by mice > or =61 days of age, suggesting a temporal genetic regulation of TACI expression. In addition, analysis of genetic interaction between chromosome 1 and chromosome 8 indicated that the two loci acted in an additive fashion. Our findings corroborate the notion that B cell deviations contribute to type 1 diabetes development, and suggest a temporal regulation of TACI(high) expression, possibly influenced by the ongoing autoimmune process.
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| 8. |
- Våbenø, Jon, et al.
(författare)
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Benzyl-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenylhexanoate
- 2005
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Ingår i: Acta Crystallographica Section E-Structure Reports Online. ; 61
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Tidskriftsartikel (refereegranskat)abstract
- The title compound, C24H29NO5, the benzyl ester of the Phe-Gly dipeptidomimetic containing a ketomethylene motif, was synthesized from the readily available α,β-unsaturated γ-ketoester. The methylene group in the benzyl part of the molecule is disordered. There is an intermolecular N-H••• O hydrogen bond linking the molecules in the crystal structure.
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| 9. |
- Våbenø, Jon, et al.
(författare)
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Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter: implications for design of hPEPT1 targeted prodrugs.
- 2005
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Ingår i: Bioorganic & medicinal chemistry. - : Elsevier BV. - 0968-0896. ; 13:6, s. 1977-88
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to develop a computational method aiding the design of dipeptidomimetic pro-moieties targeting the human intestinal di-/tripeptide transporter hPEPT1. First, the conformation in which substrates bind to hPEPT1 (the bioactive conformation) was identified by conformational analysis and 2D dihedral driving analysis of 15 hPEPT1 substrates, which suggested that psi(1) approximately 165 degrees , omega(1) approximately 180 degrees , and phi(2) approximately 280 degrees were descriptive of the bioactive conformation. Subsequently, the conformational energy required to change the peptide backbone conformation (DeltaE(bbone)) from the global energy minimum conformation to the identified bioactive conformation was calculated for 20 hPEPT1 targeted model prodrugs with known K(i) values. Quantitatively, an inverse linear relationship (r(2)=0.81, q(2)=0.80) was obtained between DeltaE(bbone) and log1/K(i), showing that DeltaE(bbone) contributes significantly to the experimentally observed affinity for hPEPT1 ligands. Qualitatively, the results revealed that compounds classified as high affinity ligands (K(i)<0.5 mM) all have a calculated DeltaE(bbone)<1 kcal/mol, whereas medium and low-affinity compounds (0.5 mM
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