The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY.

OBJECTIVES: Many autoimmune diseases are characterised by a female predominance. This may be caused by sex hormones, sex chromosomes or both. This report uses a transgenic mouse model to investigate how sex chromosome complement, not confounded by differences in gonadal type, might contribute to lupus pathogenesis. METHODS: Transgenic NZM2328 mice were created by deletion of the Sry gene from the Y chromosome, thereby separating genetic from gonadal sex. Survival, renal histopathology and markers of immune activation were compared in mice carrying the XX versus the XY(-) sex chromosome complement, with each genotype being ovary bearing. RESULTS: Mice with XX sex chromosome complement compared with XY(-) exhibited poorer survival rates and increased kidney pathology. Splenic T lymphocytes from XX mice demonstrated upregulated X-linked CD40 ligand expression and higher levels of activation markers ex vivo. Increased MMP, TGF and IL-13 production was found, while IL-2 was lower in XX mice. An accumulation of splenic follicular B cells and peritoneal marginal zone B cells was observed, coupled with upregulated costimulatory marker expression on B cells in XX mice. CONCLUSION: These data show that the XX sex chromosome complement, compared with XY(-), is associated with accelerated spontaneous lupus.

Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha).

Matrix metalloproteinases (MMPs) have a crucial function in migration of inflammatory cells into the central nervous system (CNS). Levels of MMP-9 are elevated in multiple sclerosis (MS) and predict the occurrence of new active lesions on magnetic resonance imaging (MRI). This translational study aims to determine whether in vivo treatment with the pregnancy hormone estriol affects MMP-9 levels from immune cells in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). Peripheral blood mononuclear cells (PBMCs) collected from three female MS patients treated with estriol and splenocytes from EAE mice treated with estriol, estrogen receptor (ER) alpha ligand, ERbeta ligand or vehicle were stimulated ex vivo and analyzed for levels of MMP-9. Markers of CNS infiltration were assessed using MRI in patients and immunohistochemistry in mice. Supernatants from PBMCs obtained during estriol treatment in female MS patients showed significantly decreased MMP-9 compared with pretreatment. Decreases in MMP-9 coincided with a decrease in enhancing lesion volume on MRI. Estriol treatment of mice with EAE reduced MMP-9 in supernatants from autoantigen-stimulated splenocytes, coinciding with decreased CNS infiltration by T cells and monocytes. Experiments with selective ER ligands showed that this effect was mediated through ERalpha. In conclusion, estriol acting through ERalpha to reduce MMP-9 from immune cells is one mechanism potentially underlying the estriol-mediated reduction in enhancing lesions in MS and inflammatory lesions in EAE.

Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

CD147 is an activation induced glycoprotein that promotes the secretion and activation of matrix metalloproteinases (MMPs) and is upregulated during the differentiation of macrophages. Interestingly, some of the molecular functions of CD147 rely on its glycosylation status: the highly glycosylated forms of CD147 induce MMPs whereas the lowly glycosylated forms inhibit MMP activation. Statins are hydroxy-methylglutaryl coenzyme A reductase inhibitors that block the synthesis of mevalonate, thereby inhibiting all mevalonate-dependent pathways, including isoprenylation, N-glycosylation and cholesterol synthesis. In this study, we investigated the role of statins in the inhibition of macrophage differentiation and the associated process of MMP secretion through modulation of CD147. We observed that differentiation of the human monocytic cell line THP-1 to a macrophage phenotype led to upregulation of CD147 and CD14 and that this effect was inhibited by statins. At the molecular level, statins altered CD147 expression, structure and function by inhibiting isoprenylation and N-glycosylation. In addition, statins induced a shift of CD147 from its highly glycosylated form to its lowly glycosylated form. This shift in N-glycosylation status was accompanied by a decrease in the production and functional activity of MMP-2 and MMP-9. In conclusion, these findings describe a novel molecular mechanism of immune regulation by statins, making them interesting candidates for autoimmune disease therapy.

Genetics of coronary artery disease - a clinician's perspective.

Coronary artery disease (CAD) is the major cause of fatality and disability among all cardiovascular diseases (CVD). Intricate interactions of genes and environment dictate the outcomes of CAD. Technological advances in the different fields of genetics including linkage studies (LS), candidate gene studies (CGS) and genome-wide association studies (GWA studies) have augmented the knowledge of pathogenesis of CAD. LS were more successful in identifying genetic variants among monogenic disease. GWA studies were relatively popular in identification of variation in polygenic disease. Until now, GWA studies recognized about 50 loci determining around 6% of the heritability in CAD. Clinical utility of the above knowledge would result in better CAD management, but validation of the variants in native population is warranted for active adoption into the clinic. The major aim of this review is to provide an adequate perspective of our current understanding and advances of genetics in CAD.

Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones.

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.

Dynamic development of glucocorticoid resistance during autoimmune neuroinflammation.

CONTEXT: Glucocorticoids (GC) are powerful endogenous and therapeutic modulators of inflammation and play a critical role for controlling autoimmunity. GC resistance can be seen in patients with cell-mediated autoimmune disorders, but it is unknown whether this represents a stable trait or a state. OBJECTIVE: The objective of the study was to determine whether GC resistance of T cell responses is dynamically regulated in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). DESIGN: This was a translational observational study. PATIENTS AND ANIMALS: EAE was induced in C57BL/6 mice. A cross-sectional sample of 25 patients with relapsing-remitting MS was included as well as four MS patients during pregnancy and postpartum. MAIN OUTCOME MEASURES: Outcome measures included GC sensitivity of T cell proliferation and GC-mediated apoptosis. RESULTS: GC resistance was seen in both autoantigen-specific and nonspecific responses of T cells obtained from mice with EAE. GC resistance preceded clinical symptoms and central nervous system infiltration of immune cells. T cells obtained during EAE were resistant to GC-induced apoptosis, and this was linked to down-regulation of GC receptor-α expression. GC resistance in T cells was also seen in MS patients with radiological evidence for ongoing inflammation. GC resistance was absent in the MS patients during pregnancy, when relapse risk is decreased, but recurred postpartum, a time of increased relapse risk. CONCLUSIONS: These data demonstrate that GC resistance during autoimmune neuroinflammation is dynamically regulated. This has implications for the timing of steroid treatments and provides a putative pathway to explain the observed association between psychological stress and exacerbation of autoimmune diseases.