R Holmdahl

..The aim of this study was to use gene-expression profiling to understand the protective effect against arthritis of activation of NADPH oxidase in the immune system...

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..The development of arthritis, like collagen-induced arthritis (CIA), involves cartilage as a target tissue. We have investigated the development of CIA in COMP-deficient mice...

..This study indicates that several gene loci control arthritis in aged multiparous females, and that at least one of these loci coincides with pregnancy failure...

..The aim of the present study was to investigate whether genes within Eae39, in addition to EAE, control development of collagen-induced arthritis (CIA)...

..These findings accentuate the importance of cartilage stability; cartilage disrupted as a result of genetic disorders could be more accessible and vulnerable to an autoimmune attack by pathogenic antibodies...

..We conclude that G6PI has the ability to induce a chronic arthritis, which is MHC associated and B-cell dependent. Thus, there are striking similarities between this and the collagen-induced arthritis model...

..The present study was performed to evaluate the role of the Cia40 locus in congenic B10.Q mice and to identify possible polymorphic candidate genes, which may also be relevant in the context of RA...

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..The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes...

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..In this review I will argue for the usefulness of animal models as a tool to identify genes and pathways associated with disease. The examples to be discussed are genes controlling the oxidative burst pathways and MHC class II genes...

..The genetic variability of autoantigen expression in the thymus thus seems to determine the variable predisposition to autoimmunity...

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..Taken together, these results represent a novel model for RP: matrilin-1-induced RP. Our findings also suggest that different cartilage proteins are involved in pathogenic models of RP and RA...

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..We conclude that this glycopeptide is immunodominant in CIA and that posttranslational modifications of CII create new T cell determinants that generate a diverse TCR repertoire...

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..The definition of genetic interactions was a prerequisite to dissect the Cia5 QTL and we suggest the partial advanced intercross strategy to be helpful also for dissecting other QTL controlling complex phenotypes...

..These data emphasize the importance of studying IL-10 in a defined genetic context in vivo, to understand its role in a complex disease like arthritis...

..We suggest that lack of endogenous IFN-beta in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits...

..In this study we aimed to evaluate Rabeximod as a treatment for autoimmune diseases, using animal models...

..However, a combined treatment with anti-CII monoclonal antibodies and CII-reactive T cells enhanced the progression of severe arthritis...

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..We conclude the QTL-chip strategy to be valuable in the selection of candidate genes to be prioritized for further investigation...

..These findings demonstrate for the first time that different phases of a chronic self-perpetuative disease which mimics RA are associated with distinct sets of genes...

..Our results show that different phases of EAE are controlled by different sets of genes and that common genes are likely to be involved in different autoimmune diseases...

..We conclude that B cells play a crucial role in the development of CIA...

..We conclude that IL-4 plays different roles depending on the type of adjuvant used and the phase (acute or chronic) of the clinical disease...

..Therefore, the LEW/Mol should be regarded as a recombinant inbred strain...

..yaa mice a reduced number of T cells were found to produce interferon-gamma after in vitro stimulation with CII. Thus, although autoreactive B cells are important in both diseases they play different roles in murine lupus and in CIA...

..We further conclude that B cells have the potential to play an important role as APC in the development of CIA...

..We conclude that alphabeta T cells are necessary for CIA development and for an IgG response towards CII, whereas gammadelta T cells are neither necessary nor sufficient for development of CIA...

..In conclusion, this study shows that the APLEC locus is a major locus regulating the severity of experimentally induced arthritis in rats...

..These data open the possibility that outoimmune disease may be caused by the creation of new epitopes by posttranslational modification of proteins under circumstances such as trauma, inflammation or ageing...

..Q compared to NOD. Consequently, we show that different haplotypes of MHC are instrumental in directing the specificity of the spontaneous autoimmune inflammation...

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..Therefore, we conclude that the transient post-translationally modified form of cartilage CII does not induce T cell tolerance. This lack of T cell tolerance could increase the risk of developing autoimmune arthritis...

..The genetic control of sialadenitis seemed to be unique in comparison to diabetes and arthritis, as no loci associated with these diseases have been identified at the same location...

..To investigate the genetic regulation of rheumatoid factor (RF) in a rat model of rheumatoid arthritis, in order to gain understanding of the enigmatic role of RF in the disease...

..We investigated the genetic control of the acute-phase protein response in pristane-induced arthritis (PIA), which is a chronic erosive arthritis model in rats...

..In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis...

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..These data highlight the usefulness of the statistical power obtained in a backcross of a complex disease like arthritis...

..Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders...

..We conclude that pristane-induced arthritis is a joint-specific model whereas collagen-induced arthritis affect joints as well as extra-articular cartilage. Furthermore, collagen immunization induces an antibody response to matrilin-1...

..This new model will be useful for further analyses of the different pathways involved in rheumatoid arthritis...

..In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans...

..CONCLUSION: The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage-specific antigen (type II collagen) to induce CIA but not PIA...

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..This is important as we, for the first time, can follow the effect of ROS on molecular mechanisms where T cells are responsible for either protection or promotion of arthritis depending on the level of oxygen species produced...

..Taken together, C(XI)IA is a chronic relapsing and erosive polyarthritis that is MHC associated, which in fact fulfills the criteria for diagnosis of RA. Thus the C(XI)IA model will be useful as a novel and relevant animal model for RA...

..Again, a strong vaccination potential of the glycopeptide was seen. Hence CII-glycopeptides may be the optimal choice of vaccination target in RA, since humans share the same epitope as the MMC mouse...

..To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis...

..However, the V genes used for recognition of the closely related collagen structures differed considerably between mouse and rat, indicating an influence of the species-specific variation in the V gene repertoire...

..We investigated the response to matrilin 1 and other cartilage proteins in sera from patients with RP, 4 additional groups of patients with other major connective tissue diseases, and healthy control subjects...

..A second putative locus was identified on chromosome 13 (lod 3.13). The present finding identifies new loci outside the MHC controlling CIA and provides evidence that mouse CIA is controlled by polymorphic genes...

..As the introduction of Pia4 heterozygosity results in a lower level of arthritis severity we regard this as an additive interaction with a severity threshold-lowering effect...

..To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP-induced arthritis (COMPIA)...

..These new congenic fragments, on both chromosome 10 and 17, provide new mouse strains suitable for studies aiming at positional cloning of new genes associated with arthritis...

..These findings provide clues to how genetic factors by themselves, and in interaction with each other, regulate the development of a disease, which displays many similarities to RA...

..Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view...

..These results demonstrate that the insufficient production of ROS promotes the breakdown of immune tolerance and development of autoimmune and adjuvant-free arthritis through an IL-5- and IL33R-dependent T cell activation pathway...

..Thus, a complex between MHC class II molecules and a posttranslationally modified peptide offers a new possibility for treatment of chronically active autoimmune inflammation such as rheumatoid arthritis...

..These data show that not only arthritis but also C5-dependent complement activity is dominantly suppressed, confirming that C5 is one of the major genes explaining the Cia2 effect...

..Hence, Ncf1 is associated with a new autoimmune mechanism leading to severe destructive arthritis, notably similar to rheumatoid arthritis in humans...

..We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states...

..PIA can be diagnosed by biochemical analyzes in plasma that reflects systemic inflammation (alpha1-acid glycoprotein (AGP) and IL-6) and cartilage erosion (COMP)...

..The genetic control of arthritis is unique in comparison to diabetes, since none of these loci have been identified in analysis of diabetes susceptibility...

..These results demonstrate that single IgG anti-CII mAb can induce erosive arthritis and that IgG anti-CII Ab mediate arthritis by engagement of FcgammaR...

..These data suggest that the in vivo administration of a non-antigenic adjuvant, like pristane, activates CD4+ alphabetaT cells that are MHC class II restricted and arthritogenic...

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..We conclude that CAIA is an acute arthritis triggered by antibody binding and neutrophils bypassing immune activation but with many characteristics in common with collagen-induced arthritis...

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..e., another epitope within the CII molecule is recognized. 4) There is a sharing of certain V genes in B cell clones specific for different epitopes, indicating structural similarities of the different CII epitopes...

..In this review, we outline the methods used to identify Ncf1 as one single susceptibility gene in a complex puzzle of inherited factors that render susceptibility to a complex autoimmune disorder like arthritis...

..Animal models are therefore valuable tools for identifying genes and determining their pathogenic role in the disease. This is probably the fastest route towards unravelling the pathogenesisis of RA and developing new therapies...

..In addition, the mechanisms of estrogen and anti-estrogens are discussed in relation to their possible use as future therapeutic anti-inflammatory agents...

..Both Tcr loci were within CIA loci making them candidate susceptibility genes. The results demonstrate the importance of breaking up genetic regions in smaller fragments to identify the underlying complex set of loci...

..CONCLUSION: These findings show that estrogen-induced suppression of CIA is mediated via the nuclear ERs and is operating at physiologic, possibly even subphysiologic, levels of estrogens...

..The induction of arthritis in rats with CXI or COMP provides an arthritis models with a distinct pathogenesis as compared with other induced arthritis models...

..Nevertheless, we conclude that DA substrains show distinct genetic differences and caution should be taken when comparing arthritis data from different DA substrains...

..To investigate whether IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a bacterial cysteine endopeptidase that cleaves human IgG in the hinge region, can be used for blocking the development of arthritis...

..Genes of the cytochrome P450 family (1, 11 and 19), such as Cyp19a1, are assumed to be particularly interesting, since they are known to exhibit female-associated reproductive phenotypes, affecting the ovulation rate, if mutated...

..The rheumatoid factor like reactivity of CIIC1 antibody together with its collagen type II specificity may explain the pathogenicity of this antibody...

..Hence, the asparagine-linked glycan on IgG plays a crucial role in the development of arthritis...

..We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future...

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..Our results indicate that F(2) crosses do not reveal the full complexity of identified QTLs, and that detection is more dependent on the genetic context of a QTL than the potential effect of the underlying gene...

..To our knowledge, this is the first description of an eosinophilic disease form of destructive arthritis...

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..IL-1R- and IL-1RTNFR-deficient mice were completely resistant to CAIA. Thus, IL-4 promotes an antibody-mediated and TNF-alpha/IL-1beta-dependent inflammation in vivo...

..It is well known that reproductive performance is polygenically controlled, and the identification of the major loci in this complex process opens the possibility of investigating the natural genetic control of reproduction...

..Thus, this method is recommended as a new protocol for the induction of CAIA...

..Both of these genes are associated with T cell activation and arthritis severity...

..Clinical trials using interferon-beta (IFNbeta) in the treatment of rheumatoid arthritis have shown conflicting results. We undertook this study to understand the mechanisms of IFNbeta in arthritis at a physiologic level...