An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state.

Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. Although it is well established that many of the age-induced changes are intrinsic to HSCs, less is known regarding the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations.

Cartilage oligomeric matrix protein specific antibodies are pathogenic.

Introduction: Cartilage oligomeric matrix protein (COMP) is a major non-collagenous component of cartilage. Earlier, we developed a new mouse model for rheumatoid arthritis using COMP. This study was undertaken to investigate the epitope specificity and immunopathogenicity of COMP-specific monoclonal antibodies (mAbs).

Cystatin C influences the autoimmune but not inflammatory response to cartilage type II collagen leading to chronic arthritis development.

Introduction: Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis (RA) and is induced after immunization with type II collagen (CII). CIA, like RA, is an autoimmune disease leading to destruction of cartilage and joints, and both the priming and inflammatory phases have been suggested to be dependent on proteases. In particular, the cysteine proteases have been proposed to be detrimental to the arthritic process and even immunomodulatory.

CD68-expressing cells can prime T cells and initiate autoimmune arthritis in the absence of reactive oxygen species.

It is widely believed that DC, but not macrophages, prime naïve T cells in vivo. Here, we investigated the ability of CD68-expressing cells (commonly defined as macrophages) in priming autoreactive T cells and initiating collagen-induced arthritis (CIA) in the mouse. For this purpose, a transgenic mouse was developed (MBQ mouse) where macrophages exclusively expressed the MHC class II H2-A(q) (A(q)) on an H2-A(p) (A(p)) background.

Increased litter size and super-ovulation rate in congenic C57BL mice carrying a polymorphic fragment of NFR/N origin at the Fecq4 locus of chromosome 9.

By analysing N2 mice from a cross between the inbred C57BL strain B10.Q and the NMRI-related NFR/N strain, we recently identified a quantitative trait locus (QTL) influencing litter size. This locus is now denoted Fecq4, and it is present on the murine chromosome 9.

Cartilage oligomeric matrix protein deficiency promotes early onset and the chronic development of collagen-induced arthritis.

Introduction: Cartilage oligomeric matrix protein (COMP) is a homopentameric protein in cartilage. 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.

Increased susceptibility to collagen-induced arthritis in female mice carrying congenic Cia40/Pregq2 fragments.

Introduction: Collagen-induced arthritis (CIA) in mice is a commonly used experimental model for rheumatoid arthritis (RA). We have previously identified a significant quantitative trait locus denoted Cia40 on chromosome 11 that affects CIA in older female mice. This locus colocalizes with another locus, denoted Pregq2, known to affect reproductive success.

Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species.

Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages.

Identification of genetic regions of importance for reproductive performance in female mice.

Both environmental and genetic factors can dramatically affect reproductive performance in mice. In this study we have focused on the identification of genetic regions, quantitative trait loci (QTL), which affect the breeding capacity of female mice. We have identified polymorphic microsatellite markers for the mouse strains used and performed a genomewide scan on 237 females from a gene-segregating backcross between a high breeder and a relatively poor breeder.

Identification of collagen-induced arthritis loci in aged multiparous female mice.

Collagen-induced arthritis in mice is one of the most commonly used autoimmune experimental models, with many similarities to rheumatoid arthritis. Since collagen-induced arthritis is a complex polygenic disease there is a need for identification of several major disease-controlling genes. Because rheumatoid arthritis particularly affects aged women, we have in the present study identified new genetic regions critical for collagen-induced arthritis by studying aged female mice of a cross between NFR/N and B10.

IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.

Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-beta knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-gamma in response to recall Ag.

Timing the doxycycline yields different patterns of genomic recombination in brain neurons with a new inducible Cre transgene.

We have developed a transgenic mouse expressing the Cre recombinase under control of a tetracycline-responsive promoter. Using a CamKIIalpha-driven tTA transgenic strain and a lacZ reporter mouse, we obtained the expected neuronal pattern of recombination in the olfactory lobe, cortex, striatum, hippocampus and Purkinje cells. Moreover, recombination can be completely abolished by feeding the mice doxycycline in their drinking water.

Insulin-like growth factor II plays a central role in atherosclerosis in a mouse model.

Insulin-like growth factor II is a fetal promoter of cell proliferation that is involved in some forms of cancer and overgrowth syndromes in humans. Here, we provide two sources of genetic evidence for a novel, pivotal role of locally produced insulin-like growth factor II in the development of atherosclerosis. First, we show that homozygosity for a disrupted insulin-like growth factor II allele in mice lacking apolipoprotein E, a widely used animal model of atherosclerosis, results in aortic lesions that are approximately 80% smaller and contain approximately 50% less proliferating cells compared with mice lacking only apolipoprotein E.