H syndrome treated with Tocilizumab: two case reports and literature review.

H syndrome is a rare autosomal recessive genetic disorder characterized by the following clinical features: cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, hyperglycemia, fixed flexion contractures of the toe joints, and the proximal interphalangeal joints. In rare cases, autoinflammatory and lymphoproliferative manifestations have also been reported. This disorder is due to loss-of-function mutations in SLC29A3 gene, which encode the equilibrative nucleoside transporter ENT3. This deficiency leads to abnormal function and proliferation of histiocytes. H syndrome is part of the R-group of histiocytosis. We report two different cases, one was diagnosed in adulthood and the other in childhood. The first case reported is a 37-year-old woman suffering from H syndrome with an autoinflammatory systemic disease that begins in adulthood (fever and diffuse organ's infiltration) and with cutaneous, articular, auditory, and endocrinological manifestations since childhood. The second case reported is a 2-year-old girl with autoinflammatory, endocrine, and cutaneous symptoms (fever, lymphadenopathy, organomegaly, growth delay, and cutaneous hyperpigmentation). Homozygous mutations in SLC29A3 confirmed the diagnosis of H syndrome in both cases. Each patient was treated with Tocilizumab with a significant improvement for lymphoproliferative, autoinflammatory, and cutaneous manifestations. Both cases were reported to show the multiple characteristics of this rare syndrome, which can be diagnosed either in childhood or in adulthood. In addition, an overview of the literature suggested Tocilizumab efficiency.

Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes.

Monocytes and macrophages may either promote or down-regulate inflammatory reactions depending on their state of activation. The effects of glucocorticoids (GCs), the most widely used immunosuppressive drugs, on monocytes are currently not well defined. By analyzing the GC-induced expression pattern in human monocytes by microarray technology, we identified for the first time GC-dependent regulation of 133 genes, including anti-inflammatory molecules such as adenosine A3 receptor, CD1d, and IL-1 receptor II. The results were independently confirmed by real-time polymerase chain reaction (PCR) and flow cytometry. Functional clustering of GC-regulated genes indicated induction of monocytic properties such as phagocytosis and motility as well as repression of adhesion, apoptosis, and oxidative burst. These predictions were confirmed by independent functional assays. GCs up-regulate fMLP receptors and specifically promote chemotaxis to this chemoattractant. Furthermore, GCs promote survival of an anti-inflammatory monocytic phenotype in inflammatory reactions, probably by inhibition of apoptosis because of oxidative stress. GCs limit tissue damage because of induction of antioxidative properties and high capacity for phagocytosis of proinflammatory agents. Thus, GC treatment did not cause a global suppression of monocytic effector functions but results in differentiation of a specific anti-inflammatory phenotype which seems to be actively involved in resolution of inflammatory reactions.

Regulation of gene transcription by a constitutively active mutant of activating transcription factor 2 (ATF2).

Activating transcription factor 2 (ATF2) belongs to the family of basic region leucine zipper (bZIP) proteins that are characterized by the presence of a basic domain that functions as the DNA-binding domain and a leucine zipper domain that is required for dimerization. Together with bZIP proteins of the Fos and Jun families, ATF2 constitutes the AP-1 transcription factor complex. The biological activity of ATF2 is controlled by phosphorylation of two threonine residues within the N-terminal activation domain. Unphosphorylated ATF2 is trancriptionally silent, excluding simple overexpression studies to identify transcriptional targets of ATF2. We therefore decided to construct a constitutively active ATF2 mutant that would allow us to uncouple the investigation of transcriptional targets and biological functions of ATF2 from the variety of signaling pathways that lead to an activation of ATF2. We exchanged the phosphorylation-dependent activation domain of ATF2 with the constitutively active transcriptional activation domain of the transcription factor CREB2. In transient transfection experiments, this constitutively active ATF2 mutant stimulated c-jun, tumor necrosis factor alpha, and Fas ligand promoter activities. The transcriptional activity of the constitutively active ATF2 mutant could be impaired by dominant-negative forms of ATF2 or c-Jun, indicating that ATF2 and c-Jun utilize a similar dimerization code. In contrast, a dominant-negative CREB2 mutant did not impair ATF2-mediated transcriptional activation, suggesting that CREB2 exhibits a different dimerization specificity than ATF2 or c-Jun.

Role of c-Jun concentration in neuronal cell death.

A dimer of the basic region leucine zipper proteins c-Jun and c-Fos constitutes the classical activator protein-1 (AP-1) transcription factor. c-Jun is thought to play essential roles in many important cellular pathways, including the control of proliferation and cell death. To investigate the roles of c-Jun and c-Fos concentrations in the regulation of neuronal cell death, we generated conditional alleles by fusing c-Jun and c-Fos to the ligand binding domain of the murine estrogen receptor (ER), with the aim of controlling the biological activities of c-Jun and c-Fos by the synthetic ligand 4-hydroxytamoxifen (4OHT). Transient transfection experiments revealed an increase in AP-1 activity following transfection of an expression vector encoding a c-Jun/estrogen receptor fusion protein (c-JunER) and stimulation with 4OHT. In contrast, a c-Fos/estrogen receptor fusion protein (c-FosER) was only weakly active in HT22 immortalized hippocampal cells and in PC12 pheochromocytoma cells. Highest levels of AP-1 activity were obtained by cotransfection of c-FosER and c-JunER and stimulation with 4OHT. Using retroviral gene transfer, we generated HT22 and PC12 cells expressing either c-JunER or c-FosER. The AP-1 activity was moderately increased in 4OHT-treated HT22 and PC12 cells expressing c-JunER, whereas no biological activity was observed in cells expressing c-FosER. We tested the influence of 4OHT-activated c-JunER or c-FosER upon cell survival and cell death by quantification of mitochondrial reduction capacity of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to formazan dye crystals. We did not observe any 4OHT-dependent decrease in cell survival in cells expressing c-JunER or c-FosER. Likewise, the number of pycnic nuclei did not increase in HT22 or PC12 cells expressing c-JunER or c-FosER. We conclude that an increase in the c-Jun concentration is not sufficient to trigger neuronal cell death. We propose that it is not the concentration of c-Jun that is critical for cell survival but rather the concentration of active, i.e., phosphorylated c-Jun.