Saleh Yusuf ibrahim - Academia.edu (original) (raw)

Papers by Saleh Yusuf ibrahim

Frontiers in immunology, 2018

IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and ... more IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variat...

Journal of autoimmunity, Jan 24, 2018

Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a ... more Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a diagnostic and pathogenic hallmark of granulomatosis with polyangiitis (GPA). It is, however, incompletely understood if inflamed tissue supports presence or emergence of PR3-ANCA B cells. In search of such cells in inflamed tissue of GPA, immunofluorescence staining for IgG and a common PR3-ANCA idiotype (5/7 Id) was undertaken. Few 5/7 Id/IgG B cells were detected in respiratory and kidney tissue of GPA. To gain more insight into surrogate markers possibly indicative of an anti-PR3-response, a meta-analysis comprising IGVH and IGVL genes derived from respiratory tract tissue of GPA (231 clones) was performed. Next generation sequencing-based IGHV genes derived from peripheral blood of healthy donors (244.353 clones) and previously published IGLV genes (148 clones) served as controls. Additionally, Ig genes of three murine and five known human monoclonal anti-PR3 antibodies were analyze...

Experimental dermatology, Apr 17, 2016

The genetic difference between C57Bl/6J and C57Bl/6N mice significantly impacts Aldara™-induced p... more The genetic difference between C57Bl/6J and C57Bl/6N mice significantly impacts Aldara™-induced psoriasiform dermatitis 1 | BACKGROUND Since its first description in 2009, 1 the Aldara™ (MEDA Pharma GmbH, Bad Homburg, Germany)-induced psoriasiform dermatitis (AIPD) model has become a most commonly used mouse model of plaque psoriasis. It is mostly conducted in the C57Bl/6 mouse strain. Two substrains of this mouse strain, C57Bl/6J and C57Bl/6N, are in parallel widely used for research purposes. The two substrains are phenotypically identical but genetically differ by 34 SNPs, two indels and 15 gene variants that overlap a gene. 2-4 Notably, gene knockout and transgenic mice on the C57Bl/6 background are often held on an intermediate genotype between the two substrains due to incomplete backcrossing after genetic manipulation. This issue has become even more common in recent years with the International Knockout Mouse Consortium's (IKMC) decision to preferentially generate genetic knockouts in C57Bl/6N embryonic stem cells, 4 while, in contrast, most investigators still preferably use C57Bl/6J mice.

Journal of Alzheimer's disease : JAD, Jan 19, 2018

Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer&... more Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer's disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amy...

Oncotarget, Jan 23, 2016

MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a mode... more MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a model to study the genetic, molecular and immunological basis of the disease. Here, we have addressed the question whether distinctive features of their dendritic cells (DCs) may predispose MRL/MpJ mice to the chronic inflammation. Pancreatic lesions were analyzed employing histological methods. Cohorts of young (healthy) MRL/MpJ mice, adult (sick) individuals, and AIP-resistant CAST/EiJ mice were used to establish cultures of bone marrow (BM)-derived conventional DCs (cDCs). The cells were subsequently characterized regarding the expression profile of CD markers and selected genes, proliferative activity as well as cytokine secretion. In pancreatic lesions, large numbers of cells expressing the murine DC marker CD11c were detected in close spatial proximity to CD3+ cells. A high percentage of BM-derived cDCs from adult MRL/MpJ mice expressed typical markers of DC maturation (such as CD83) a...

Molecular Neurobiology, 2015

Parkinson's disease and dementia with Lewy bodies are major challenges in research and clinical m... more Parkinson's disease and dementia with Lewy bodies are major challenges in research and clinical medicine worldwide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APPtransgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synucleintransgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNA Arg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.

Arthritis research & therapy, 2005

Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought t... more Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 +/- 3.6; DBA/1J-pfp-/-, 59 +/- 4.9 (mean +/- SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 +/- 1.1; DBA/1J-pfp-/-, 3.4 +/- 1.4 (mean +/- SEM); P < 0.05). Concomit...

Arthritis research & therapy, 2007

Quantitative traits such as complex diseases are controlled by many small-effect genes that are d... more Quantitative traits such as complex diseases are controlled by many small-effect genes that are difficult to identify. Here we present a novel strategy to identify the candidate genes for small-effect quantitative trait loci (QTL) in collagen induced arthritis (CIA) using global genome and transcriptome approaches. First, we performed genome linkage analysis in F2 progeny of the CIA susceptible and resistant strains to search for small-effect QTL. Second, we detected gene expression patterns of both strains during CIA. The candidate genes were identified using three criteria: they are located in a genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed regarding the two parental strains. Eight small-effect QTL controlling CIA severity were identified. Of 22,000 screened genes, 117 were both strain-specific and disease-specific differentially expressed during CIA. Of these 117 genes, 21 were lo...

Molecular Cancer, 2003

Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a... more Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor

Journal of Molecular Medicine, 2005

Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncoupl... more Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common −866G/A promoter polymorphism is associated with susceptibility to multiple sclerosis (MS) in the German population. We analysed altogether 1,097 MS patients and 462 control subjects from two cohorts and found that the common G allele is associated with disease susceptibility (p=0.0015). The UCP2 −866G allele is correlated with lower levels of UCP2 expression as shown here in vitro and in vivo. Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems.

The Journal of Immunology, 2006

The generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine... more The generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine mapping of quantitative trait loci (QTLs), because they accumulate much more recombination events compared with conventional F2 intercross and N2 backcross. However, the application of this approach is severely hampered by the requirements of excessive resources to maintain such crosses, i.e., in terms of animal care, space, and time. Therefore, in this study, we produced an AIL to fine map collagen-induced arthritis (CIA) QTLs using comparatively limited resources. We used only 308 (DBA/1 × FVB/N)F11/12 AIL mice to refine QTLs controlling the severity and onset of arthritis as well as the Ab response and T cell subset in CIA, namely Cia2, Cia27, and Trmq3. These QTLs were originally identified in (DBA/1 × FVB/N)F2 progeny. The confidence intervals of the three QTLs were refined from 40, 43, and 48 Mb to 12, 4.1, and 12 Mb, respectively. The data were complemented by the use of another ...

Genome Research, 2008

Previous reports have demonstrated that the mtDNA of mouse common inbred strains (CIS) originated... more Previous reports have demonstrated that the mtDNA of mouse common inbred strains (CIS) originated from a single female ancestor and that mtDNA mutations occurred during CIS establishment. This situation provides a unique opportunity to investigate the impact of individual mtDNA variations on complex traits in mammals. In this study, we compiled the complete mtDNA sequences of 52 mouse CIS. Phylogenetic analysis demonstrated that 50 of the 52 CIS descended from a single female Mus musculus domesticus mouse, and mtDNA mutations have accumulated in 26 of the CIS. We then generated conplastic strains on the C57BL/6J background for 12 mtDNA variants with one to three functional mtDNA mutations. We also generated conplastic strains for mtDNA variants of the four M. musculus subspecies, each of which contains hundreds of mtDNA variations. In total, a panel of conplastic strains was generated for 16 mtDNA variants. Phenotypic analysis of the conplastic strains demonstrated that mtDNA variat...

Genes & Immunity, 2009

We reported earlier that two mitochondrial gene polymorphisms, UCP2-866 G/A (rs659366) and mtDNA ... more We reported earlier that two mitochondrial gene polymorphisms, UCP2-866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2-866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2-866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR) ¼ 0.91, 95% confidence interval (95% CI): 0.86-0.96), P ¼ 0.0003) or genotypes (OR ¼ 0.88, (95% CI: 0.82-0.95), P ¼ 0.0008), with the-866A allele associated with a decreased risk to diseases. As the À866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.

Genes & Immunity, 2007

Advanced intercross line (AIL) is a powerful tool for high-resolution mapping of quantitative tra... more Advanced intercross line (AIL) is a powerful tool for high-resolution mapping of quantitative trait loci (QTLs). Several AILs have been generated to refine QTLs since the method was proposed about a decade ago. However, no AIL has been used for identifying novel QTLs. Here we used an AIL to test this possibility. We genotyped 308 (DBA/1 Â FVB/N) F 11/12 AIL mice with 109 informative markers covering four chromosomes, with an average intermarker distance of 5.5 Mb. Several normally distributed quantitative traits involved in the immune response during the course of collagen-induced arthritis (CIA), such as anti-collagen II antibodies, T-cell subset proportions and reactive oxygen species (ROS) production were taken as phenotypes. Four QTLs, namely Ciaa1, Lctlp1, Lctlp2 and Rosq1, controlling anti-collagen II IgG2a levels, lymph nodes CD8 þ T cell proportion and ROS production were identified with support intervals of 15, 14, 8 and 8 Mb, respectively. Alleles of Lctlp1 and Lctlp2 suppressing CD8 þ T cell proportion as well as the Rosq1 allele enhancing ROS production were correlated with higher CIA severity scores. Taken together, we successfully used an AIL to identify novel QTLs controlling immune responses during CIA with relatively small support intervals.

Current Opinion in Neurology, 2005

Purpose of review Multiple sclerosis (MS) is the most common chronic inflammatory neurological di... more Purpose of review Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. Despite major advances the aetiology of this disease it is still not completely understood. In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets. Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed. Recent findings The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS. The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale singlenucleotide-polymorphism association studies and novel cross-species synteny analysis. Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells. Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the nervous system in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field. Summary The complexity of MS is clearly reflected in the latest findings using global profiling methods. Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its polygenicity, the central role of neuroinflammation and the emerging neurodenegerative processes. These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Brain, 2001

Multiple sclerosis is thought to be a polygenic disease driven by dysregulation of the immune sys... more Multiple sclerosis is thought to be a polygenic disease driven by dysregulation of the immune system leading to an autoimmune response against one or several antigens of cerebral white matter tissue. Experimental autoimmune encephalomyelitis (EAE) is a mouse model that is used to study the aetiology and pathogenesis of multiple sclerosis and new therapeutic approaches. We used oligonucleotide microarrays to determine gene expression profiles of the inflamed spinal cords of EAE mice at the onset and at the peak of the disease. Of the~11 000 genes studied, 213 were regulated differentially and 100 showed

The American Journal of Pathology, 2006

Uncoupling protein 2 (UCP2) is a member of the mitochondrial transporter superfamily that is expr... more Uncoupling protein 2 (UCP2) is a member of the mitochondrial transporter superfamily that is expressed in many tissues, including immune cells. UCP2 prevents oxidative stress by reducing reactive oxygen species. Using UCP2-deficient mice, it was shown that UCP2 is involved in the regulation of insulin secretion, in the resistance to infection, and in atherosclerosis. Here, we investigated the role of UCP2 in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Immunized C57BL/6J UCP2-deficient mice showed a slightly delayed onset during experimental autoimmune encephalomyelitis (13.0 ؎ 0.6 versus 11.5 ؎ 0.8 in wild-type controls) and developed significantly higher disease scores than littermate controls (maximum disease score of 2.9 ؎ 0.2 versus 1.7 ؎ 0.2, P ‫؍‬ 0.001). Higher levels of infiltrating T cells into the spinal cord meninges and parenchyma were observed. The T-cell proliferative response to the specific antigen was increased in UCP2-deficient mice compared with littermate controls, and CD4 cells of UCP2 knockout mice produced significantly higher levels of pro-inflammatory cytokines, eg, tumor necrosis factor-␣ and interleukin-2, resulting from a Th1 response. Mice lacking UCP2 also developed a higher B-cell response. Concomitantly, CD4 and CD8 cells of the UCP2-deficient mice showed increased production of reactive oxygen species. These results suggest a protective function of UCP2 in chronic inflammatory diseases such as multiple sclerosis.

Frontiers in immunology, 2018

Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidas... more Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epi...

Frontiers in immunology, 2018

IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and ... more IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variat...

Journal of autoimmunity, Jan 24, 2018

Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a ... more Circulating anti-neutrophilic cytoplasmic autoantibodies targeting proteinase 3 (PR3-ANCA) are a diagnostic and pathogenic hallmark of granulomatosis with polyangiitis (GPA). It is, however, incompletely understood if inflamed tissue supports presence or emergence of PR3-ANCA B cells. In search of such cells in inflamed tissue of GPA, immunofluorescence staining for IgG and a common PR3-ANCA idiotype (5/7 Id) was undertaken. Few 5/7 Id/IgG B cells were detected in respiratory and kidney tissue of GPA. To gain more insight into surrogate markers possibly indicative of an anti-PR3-response, a meta-analysis comprising IGVH and IGVL genes derived from respiratory tract tissue of GPA (231 clones) was performed. Next generation sequencing-based IGHV genes derived from peripheral blood of healthy donors (244.353 clones) and previously published IGLV genes (148 clones) served as controls. Additionally, Ig genes of three murine and five known human monoclonal anti-PR3 antibodies were analyze...

Experimental dermatology, Apr 17, 2016

The genetic difference between C57Bl/6J and C57Bl/6N mice significantly impacts Aldara™-induced p... more The genetic difference between C57Bl/6J and C57Bl/6N mice significantly impacts Aldara™-induced psoriasiform dermatitis 1 | BACKGROUND Since its first description in 2009, 1 the Aldara™ (MEDA Pharma GmbH, Bad Homburg, Germany)-induced psoriasiform dermatitis (AIPD) model has become a most commonly used mouse model of plaque psoriasis. It is mostly conducted in the C57Bl/6 mouse strain. Two substrains of this mouse strain, C57Bl/6J and C57Bl/6N, are in parallel widely used for research purposes. The two substrains are phenotypically identical but genetically differ by 34 SNPs, two indels and 15 gene variants that overlap a gene. 2-4 Notably, gene knockout and transgenic mice on the C57Bl/6 background are often held on an intermediate genotype between the two substrains due to incomplete backcrossing after genetic manipulation. This issue has become even more common in recent years with the International Knockout Mouse Consortium's (IKMC) decision to preferentially generate genetic knockouts in C57Bl/6N embryonic stem cells, 4 while, in contrast, most investigators still preferably use C57Bl/6J mice.

Journal of Alzheimer's disease : JAD, Jan 19, 2018

Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer&... more Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer's disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amy...

Oncotarget, Jan 23, 2016

MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a mode... more MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a model to study the genetic, molecular and immunological basis of the disease. Here, we have addressed the question whether distinctive features of their dendritic cells (DCs) may predispose MRL/MpJ mice to the chronic inflammation. Pancreatic lesions were analyzed employing histological methods. Cohorts of young (healthy) MRL/MpJ mice, adult (sick) individuals, and AIP-resistant CAST/EiJ mice were used to establish cultures of bone marrow (BM)-derived conventional DCs (cDCs). The cells were subsequently characterized regarding the expression profile of CD markers and selected genes, proliferative activity as well as cytokine secretion. In pancreatic lesions, large numbers of cells expressing the murine DC marker CD11c were detected in close spatial proximity to CD3+ cells. A high percentage of BM-derived cDCs from adult MRL/MpJ mice expressed typical markers of DC maturation (such as CD83) a...

Molecular Neurobiology, 2015

Parkinson's disease and dementia with Lewy bodies are major challenges in research and clinical m... more Parkinson's disease and dementia with Lewy bodies are major challenges in research and clinical medicine worldwide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APPtransgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synucleintransgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNA Arg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.

Arthritis research & therapy, 2005

Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought t... more Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 +/- 3.6; DBA/1J-pfp-/-, 59 +/- 4.9 (mean +/- SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 +/- 1.1; DBA/1J-pfp-/-, 3.4 +/- 1.4 (mean +/- SEM); P < 0.05). Concomit...

Arthritis research & therapy, 2007

Quantitative traits such as complex diseases are controlled by many small-effect genes that are d... more Quantitative traits such as complex diseases are controlled by many small-effect genes that are difficult to identify. Here we present a novel strategy to identify the candidate genes for small-effect quantitative trait loci (QTL) in collagen induced arthritis (CIA) using global genome and transcriptome approaches. First, we performed genome linkage analysis in F2 progeny of the CIA susceptible and resistant strains to search for small-effect QTL. Second, we detected gene expression patterns of both strains during CIA. The candidate genes were identified using three criteria: they are located in a genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed regarding the two parental strains. Eight small-effect QTL controlling CIA severity were identified. Of 22,000 screened genes, 117 were both strain-specific and disease-specific differentially expressed during CIA. Of these 117 genes, 21 were lo...

Molecular Cancer, 2003

Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a... more Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor

Journal of Molecular Medicine, 2005

Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncoupl... more Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common −866G/A promoter polymorphism is associated with susceptibility to multiple sclerosis (MS) in the German population. We analysed altogether 1,097 MS patients and 462 control subjects from two cohorts and found that the common G allele is associated with disease susceptibility (p=0.0015). The UCP2 −866G allele is correlated with lower levels of UCP2 expression as shown here in vitro and in vivo. Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems.

The Journal of Immunology, 2006

The generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine... more The generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine mapping of quantitative trait loci (QTLs), because they accumulate much more recombination events compared with conventional F2 intercross and N2 backcross. However, the application of this approach is severely hampered by the requirements of excessive resources to maintain such crosses, i.e., in terms of animal care, space, and time. Therefore, in this study, we produced an AIL to fine map collagen-induced arthritis (CIA) QTLs using comparatively limited resources. We used only 308 (DBA/1 × FVB/N)F11/12 AIL mice to refine QTLs controlling the severity and onset of arthritis as well as the Ab response and T cell subset in CIA, namely Cia2, Cia27, and Trmq3. These QTLs were originally identified in (DBA/1 × FVB/N)F2 progeny. The confidence intervals of the three QTLs were refined from 40, 43, and 48 Mb to 12, 4.1, and 12 Mb, respectively. The data were complemented by the use of another ...

Genome Research, 2008

Previous reports have demonstrated that the mtDNA of mouse common inbred strains (CIS) originated... more Previous reports have demonstrated that the mtDNA of mouse common inbred strains (CIS) originated from a single female ancestor and that mtDNA mutations occurred during CIS establishment. This situation provides a unique opportunity to investigate the impact of individual mtDNA variations on complex traits in mammals. In this study, we compiled the complete mtDNA sequences of 52 mouse CIS. Phylogenetic analysis demonstrated that 50 of the 52 CIS descended from a single female Mus musculus domesticus mouse, and mtDNA mutations have accumulated in 26 of the CIS. We then generated conplastic strains on the C57BL/6J background for 12 mtDNA variants with one to three functional mtDNA mutations. We also generated conplastic strains for mtDNA variants of the four M. musculus subspecies, each of which contains hundreds of mtDNA variations. In total, a panel of conplastic strains was generated for 16 mtDNA variants. Phenotypic analysis of the conplastic strains demonstrated that mtDNA variat...

Genes & Immunity, 2009

We reported earlier that two mitochondrial gene polymorphisms, UCP2-866 G/A (rs659366) and mtDNA ... more We reported earlier that two mitochondrial gene polymorphisms, UCP2-866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2-866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2-866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR) ¼ 0.91, 95% confidence interval (95% CI): 0.86-0.96), P ¼ 0.0003) or genotypes (OR ¼ 0.88, (95% CI: 0.82-0.95), P ¼ 0.0008), with the-866A allele associated with a decreased risk to diseases. As the À866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.

Genes & Immunity, 2007

Advanced intercross line (AIL) is a powerful tool for high-resolution mapping of quantitative tra... more Advanced intercross line (AIL) is a powerful tool for high-resolution mapping of quantitative trait loci (QTLs). Several AILs have been generated to refine QTLs since the method was proposed about a decade ago. However, no AIL has been used for identifying novel QTLs. Here we used an AIL to test this possibility. We genotyped 308 (DBA/1 Â FVB/N) F 11/12 AIL mice with 109 informative markers covering four chromosomes, with an average intermarker distance of 5.5 Mb. Several normally distributed quantitative traits involved in the immune response during the course of collagen-induced arthritis (CIA), such as anti-collagen II antibodies, T-cell subset proportions and reactive oxygen species (ROS) production were taken as phenotypes. Four QTLs, namely Ciaa1, Lctlp1, Lctlp2 and Rosq1, controlling anti-collagen II IgG2a levels, lymph nodes CD8 þ T cell proportion and ROS production were identified with support intervals of 15, 14, 8 and 8 Mb, respectively. Alleles of Lctlp1 and Lctlp2 suppressing CD8 þ T cell proportion as well as the Rosq1 allele enhancing ROS production were correlated with higher CIA severity scores. Taken together, we successfully used an AIL to identify novel QTLs controlling immune responses during CIA with relatively small support intervals.

Current Opinion in Neurology, 2005

Purpose of review Multiple sclerosis (MS) is the most common chronic inflammatory neurological di... more Purpose of review Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. Despite major advances the aetiology of this disease it is still not completely understood. In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets. Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed. Recent findings The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS. The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale singlenucleotide-polymorphism association studies and novel cross-species synteny analysis. Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells. Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the nervous system in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field. Summary The complexity of MS is clearly reflected in the latest findings using global profiling methods. Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its polygenicity, the central role of neuroinflammation and the emerging neurodenegerative processes. These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Brain, 2001

Multiple sclerosis is thought to be a polygenic disease driven by dysregulation of the immune sys... more Multiple sclerosis is thought to be a polygenic disease driven by dysregulation of the immune system leading to an autoimmune response against one or several antigens of cerebral white matter tissue. Experimental autoimmune encephalomyelitis (EAE) is a mouse model that is used to study the aetiology and pathogenesis of multiple sclerosis and new therapeutic approaches. We used oligonucleotide microarrays to determine gene expression profiles of the inflamed spinal cords of EAE mice at the onset and at the peak of the disease. Of the~11 000 genes studied, 213 were regulated differentially and 100 showed

The American Journal of Pathology, 2006

Uncoupling protein 2 (UCP2) is a member of the mitochondrial transporter superfamily that is expr... more Uncoupling protein 2 (UCP2) is a member of the mitochondrial transporter superfamily that is expressed in many tissues, including immune cells. UCP2 prevents oxidative stress by reducing reactive oxygen species. Using UCP2-deficient mice, it was shown that UCP2 is involved in the regulation of insulin secretion, in the resistance to infection, and in atherosclerosis. Here, we investigated the role of UCP2 in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Immunized C57BL/6J UCP2-deficient mice showed a slightly delayed onset during experimental autoimmune encephalomyelitis (13.0 ؎ 0.6 versus 11.5 ؎ 0.8 in wild-type controls) and developed significantly higher disease scores than littermate controls (maximum disease score of 2.9 ؎ 0.2 versus 1.7 ؎ 0.2, P ‫؍‬ 0.001). Higher levels of infiltrating T cells into the spinal cord meninges and parenchyma were observed. The T-cell proliferative response to the specific antigen was increased in UCP2-deficient mice compared with littermate controls, and CD4 cells of UCP2 knockout mice produced significantly higher levels of pro-inflammatory cytokines, eg, tumor necrosis factor-␣ and interleukin-2, resulting from a Th1 response. Mice lacking UCP2 also developed a higher B-cell response. Concomitantly, CD4 and CD8 cells of the UCP2-deficient mice showed increased production of reactive oxygen species. These results suggest a protective function of UCP2 in chronic inflammatory diseases such as multiple sclerosis.

Frontiers in immunology, 2018

Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidas... more Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epi...