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Progesterone plays a protective role in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Besides spinal cord neuropathology, MS patients present a dysfunctional hippocampus. In this work we studied the therapeutic effects of the progestin Nestorone in the brain of mice with chronic EAE. Nestorone decreased clinical grade and enhanced motor behavior. In addition, it increased cell proliferation and doublecortin positive neuroblasts in the hippocampus, increased GABAergic interneurons and attenuated the number of Iba1 + microglia/macrophages, events possibly linked to enhancement of neurogenesis. Therefore, Nestorone protected against hippocampus abnormalities and improved functional outcomes of EAE mice, suggesting its potential value for MS. (C) 2014 Elsevier B.V. All rights reserved.

Purpose: Primary cutaneous T-cell lymphomas (CTCL) are neoplastic disorders of skin-homing T cells. Affected skin areas show morphologic similarities with alterations in other T-cell-mediated dermatoses. Furthermore, as in atopic dermatitis but in contrast with psoriasis, patients with CTCL are frequently afflicted by cutaneous bacterial infections that support the survival of lymphoma cells. Our aim was to investigate the mechanisms of elevated susceptibility to cutaneous infections in patients with CTCL. Experimental Design: Skin samples from CTCL, psoriasis, and atopic dermatitis patients were used to illuminate the antibacterial competence status and the presence of its modulating cytokines. For substantiation of findings, 3-dimensional epidermis models, isolated and in vitro generated Th-subpopulations, were applied. Parameters were analyzed via qPCR and IHC. Results: CTCL lesions compared with psoriatic lesions presented an impaired upregulation of antibacterial proteins (ABPs), with levels even below those in atopic dermatitis. This was associated with a relative deficiency of the ABP-inducing cytokine IL-17 and a strong presence of the ABP-downregulating cytokine IL-13. The simultaneous presence of the Th17-cell cytokine IL-26 indicated that IL-17 deficiency in CTCL lesions results from functional deviation of Th17 cells. Accordingly, IL-17 but not IL-26 production by Th17 cells in vitro was inhibited by IL-4R alpha ligand. Levels of other ABP inducers were comparable between CTCL and psoriasis lesions. The same was true about IL-22/TNF-alpha targets, including the keratinocyte hyper-regeneration marker K16 and the matrix-degrading enzyme MMP1. Conclusion: Our results suggest that the cutaneous bacterial infections in CTCL are caused by impaired ABP induction as consequence of Th2-mediated biased Th17-cell function. (C) 2014 AACR.

Aldolase A deficiency has been reported as a rare cause of hemolytic anemia occasionally associated with myopathy. We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease.

SIGN-R1 is a principal receptor for microbial polysaccharides uptake and is responsible for C3 fixation via an unusual complement activation pathway on splenic marginal zone macrophages. In these macrophages, SIGN-R1 is also involved in anti-inflammatory activity of intravenous immunoglobulin by direct interaction with sialylated Fcs. The high-resolution crystal structures of SIGN-R1 carbohydrate recognition domain and its complexes with dextran sulfate or sialic acid, and of the sialylated Fc antibody provide insights into SIGN-R1's selective recognition of alpha-2,6-sialylated glycoproteins. Unexpectedly, an additional binding site has been found in the SIGN-R1 carbohydrate recognition domain, structurally separate from the calcium-dependent carbohydrate-binding site. This secondary binding site could bind repetitive molecular patterns, as observed in microbial polysaccharides, in a calcium-independent manner. These two binding sites may allow SIGN-R1 to simultaneously bind both immune glycoproteins and microbial polysaccharide components, accommodating SIGN-R1's ability to relate the recognition of microbes to the activation of the classical complement pathway.

Addiction to MOP-r agonists such as heroin (and also addiction to prescription opioids) has reemerged as an epidemic in the twenty first century, causing massive morbidity. Understanding the genetics contributing to susceptibility to this disease is crucial for the identification of novel therapeutic targets, and also for discovery of genetic markers which would indicate relative protection or vulnerability from addiction, and relative responsiveness to pharmacotherapy. This information could thus eventually inform clinical practice. In this review, we focus primarily on association studies of heroin and opiate addiction, and further describe the studies which have been replicated in this field, and are thus more likely to be useful for translational efforts.

The development and evaluation of effective therapies and vaccines for the hepatitis C virus (HCV) and the study of its interactions with the mammalian host have been hindered for a long time by the absence of suitable small animal models. Due to the narrow host tropism of HCV, the development of mice that can be robustly engrafted with human hepatocytes was a major breakthrough since they recapitulate the complete HCV life cycle. This model has been useful to investigate many aspects of the HCV life cycle, including antiviral interventions. However, studies of cellular immunity, immunopathogenesis and resulting liver diseases have been hampered by the lack of a small animal model with a functional immune system. In this review, we summarize the evolution of in vivo models for the study of HCV. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Interferon-gamma receptor 2 (IFN-gamma R2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-gamma R2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-gamma R2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of 5 years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-gamma R2 defect was autosomal recessive and partial. Autosomal recessive IFN-gamma R2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-gamma R2 deficiency associated with M. simiae infection to be described.

A search for excited quarks decaying into the gamma + jet final state is presented. The analysis is based on data corresponding to an integrated luminosity of 19.7 fb(-1) collected by the CMS experiment in proton-proton collisions at root s = 8 TeV at the LHC. Events with photons and jets with high transverse momenta are selected and the gamma + jet invariant mass distribution is studied to search for a resonance peak. The 95% confidence level upper limits on the product of cross section and branching fraction are evaluated as a function of the excited quark mass. Limits on excited quarks are presented as a function of their mass and coupling strength; masses below 3.5 TeV are excluded at 95% confidence level for unit couplings to their standard model partners. (C) 2014 The Authors. Published by Elsevier B.V.