Impact of glucocorticoid receptor density on ligand-independent dimerization, cooperative ligand-binding and basal priming of transactivation: a cell culture model

Glucocorticoid receptor (GR) levels vary between tissues and individuals and are altered by physiological and pharmacological effectors. However, the effects and implications of differences in GR concentration have not been fully elucidated. Using three statistically different GR concentrations in transiently transfected COS-1 cells, we demonstrate, using co-immunoprecipitation (CoIP) and fluorescent resonance energy transfer (FRET), that high levels of wild type GR (wtGR), but not of dimerization deficient GR (GRdim), display ligand-independent dimerization. Whole-cell saturation ligand-binding experiments furthermore establish that positive cooperative ligand-binding, with a concomitant increased ligand-binding affinity, is facilitated by ligand-independent dimerization at high concentrations of wtGR, but not GRdim. The down-stream consequences of ligand-independent dimerization at high concentrations of wtGR, but not GRdim, are shown to include basal priming of the system as witnessed by ligand-independent transactivation of both a GRE-containing promoter-reporter and the endogenous glucocorticoid (GC)-responsive gene, GILZ, as well as ligand-independent loading of GR onto the GILZ promoter. Pursuant to the basal priming of the system, addition of ligand results in a significantly greater modulation of transactivation potency than would be expected solely from the increase in ligand-binding affinity. Thus ligand-independent dimerization of the GR at high concentrations primes the system, through ligand-independent DNA loading and transactivation, which together with positive cooperative ligand-binding increases the potency of GR agonists and shifts the bio-character of partial GR agonists. Clearly GR-levels are a major factor in determining the sensitivity to GCs and a critical factor regulating transcriptional programs

Sleep and immune function

Sleep and the circadian system exert a strong regulatory influence on immune functions. Investigations of the normal sleep–wake cycle showed that immune parameters like numbers of undifferentiated naïve T cells and the production of pro-inflammatory cytokines exhibit peaks during early nocturnal sleep whereas circulating numbers of immune cells with immediate effector functions, like cytotoxic natural killer cells, as well as anti-inflammatory cytokine activity peak during daytime wakefulness. Although it is difficult to entirely dissect the influence of sleep from that of the circadian rhythm, comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes. Moreover, such studies revealed a selectively enhancing influence of sleep on cytokines promoting the interaction between antigen presenting cells and T helper cells, like interleukin-12. Sleep on the night after experimental vaccinations against hepatitis A produced a strong and persistent increase in the number of antigen-specific Th cells and antibody titres. Together these findings indicate a specific role of sleep in the formation of immunological memory. This role appears to be associated in particular with the stage of slow wave sleep and the accompanying pro-inflammatory endocrine milieu that is hallmarked by high growth hormone and prolactin levels and low cortisol and catecholamine concentrations

Adult onset polyarticular pigmented villonodular synovitis

Pigmented Villonodular Synovitis (PVNS), typically, presents as a chronic monoarthritis affecting medium to large joints or tendon sheaths. Polyarticular presentation of PVNS is extremely rare, mostly reported in children and has not yet been reported in adults. We report a case of polyarticular PVNS, presenting in adulthood. We made the diagnosis based on characteristic MRI findings and typical histopathological changes. Patient was successfully managed with synovectomies and was not subject to inappropriate DMARDs. We suggest, that PVNS should be considered in the differential diagnosis of seronegative polyarthropathy, to avoid a delay in diagnosis and consequent delay in appropriate treatment. To our knowledge, this is the first case report of PPVNS presenting in adulthood, and serves as an example of atypical presentation of a rare condition

Systemic sclerosis: From pathogenesis towards targeted immunotherapies

Systemic sclerosis (SSc), a chronic disease with widespread collagen deposition, has three pathogenetic facets: immune activation, microvasculopathy and fibroblast activation. Immune activation and microvasculopathy occur very early in the disease process, and inflammatory infiltrates in the skin are restricted in early-phase disease. There is good evidence that fibroblast activation with collagen production may be triggered by the immune system. In early-phase disease, we slowly move from general immunosuppression to therapeutically targeting specific molecules involved in immune activation, such as T cell-directed targets, B cell-directed targets, cytokine targets, and tyrosine kinases targets. © 2012 Bentham Science Publishers

Spontaneous resolution of a case of anti-retroviral treatmentnaïve HIV-associated polymyositis

Autoimmune Rheumatic Diseases (ARD) have been described in individuals with Human Immunodeficiency Virus (HIV) infection. However, the incidence of ARD in individuals with HIV has evolved since the introduction of Highly Active Anti Retroviral Therapy (HAART) for the treatment of HIV. Clinicians face a therapeutic dilemma regarding the use of potent immunosuppressants when managing ARD in individuals with HIV infection. The disease activity of ARD varies during the natural course of HIV infection and its treatment with HAART. The outcomes of some ARDs may be better in individuals with HIV when compared with individuals without HIV. Here we report the first case of spontaneous resolution of HIV-Associated Polymyositis (HAM) presenting with profound proximal muscle weakness occurring in a treatment-naïve patient with HIV and discuss the possible treatment options of HAM based on evidence from the literature. Keywords: HIV, Polymyositis, HIVassociated myositis, HAART, Highly Active Antiretroviral Treatment and antiretroviral drug

Early systemic sclerosis-opportunities for treatment

Systemic sclerosis (SSc) is characterized by microvasculopathy (Raynaud's phenomenon and fibrointimal proliferation), presence of autoantibodies and collagen deposition in skin (scleroderma) and internal organs. Microvasculopathy, detected by nailfold capillaroscopy, and disease-specific autoantibodies (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III antibodies) usually appear earlier, even years before scleroderma. At that stage of the disease, immune activation with T cells and B cells promote fibrosis. Diagnosis of SSc has been relied on scleroderma, and by this time, internal organs may have developed fibrosis, a lethal feature with no available treatment. The new EULAR/ACR 2013 criteria for the classification of SSc will help identify SSc patients before fibrosis of internal organs. The early diagnosis of SSc, before the development of fibrosis in internal organs, will allow the introduction of immunosuppressive medications in these patients in a controlled setting (randomized trials). It is anticipated that this approach will change the hitherto grim prognosis of SSc for the better