Case Report: Drug-Induced (Neuro) Sarcoidosis-Like Lesion Under IL4 Receptor Blockade With Dupilumab.

Dupilumab is a new monoclonal antibody inhibiting IL-4 and IL-13 signaling transduction through the blockage of the α-subunit of the IL-4 receptor. It is used to treat type 2 inflammatory disorders including atopic dermatitis, asthma, and chronic rhinosinusitis. Here we describe the case of a 79-year-old male presenting with visual hallucinations, disorientation, cognitive decline, and behavioral changes, evolving over 3 weeks. He had been under treatment with dupilumab for atopic dermatitis for the previous 4 months. Radiology and CSF analysis showed a granulomatous meningoencephalitis suspicious of sarcoidosis. Underlying infectious and antibody-mediated causes for meningoencephalitis were ruled out. Pausing Dupilumab and steroids (i.v. and oral) led to rapid clinical improvement. Inhibition of IL-4 and IL-13, key players in the differentiation and activation of Th2 cells, may shift the Th1/Th2- ratio toward an excessive Th1-mediated response, granuloma formation, and drug-induced (neuro)sarcoidosis reaction. Attention should be raised to this side effect.

Pubertal timing after neonatal diethylstilbestrol exposure in female rats: neuroendocrine vs peripheral effects and additive role of prenatal food restriction.

We studied the effects of neonatal exposure to diethylstilbestrol (DES) on pubertal timing in female rats. We examined associated neuroendocrine changes and effects of prenatal food restriction. Age at vaginal opening was advanced after exposure to 10 µg/kg/d of DES and delayed after 1 µg/kg/d (subcutaneous injections). Using this lower dose, pulsatile GnRH secretion was slower at 25 days of age. Both doses reduced KiSS1 mRNA levels at 15 days of age. Using functional Kisspeptin promoter assay, 1 or 10 µM DES reduced or increased KISS1 transcription, respectively. Leptin stimulatory effect on GnRH secretion in vitro (15 days of age) was reduced after prenatal food restriction and neonatal DES exposure (higher dose), both effects being cumulative. Thus, alterations in pubertal timing by DES neonatally are not unequivocally toward precocity, the level of exposure being critical. We provide evidence of neuroendocrine disruption and interaction with prenatal food availability.

Endocrine disrupting chemicals affect the gonadotropin releasing hormone neuronal network.

Endocrine disrupting chemicals have been shown to alter the pubertal process. The controlling levels of the Gonadotropin releasing hormone (GnRH) network involve GnRH itself, KiSS1, and the transcriptional regulators enhanced at puberty 1 (EAP1), Thyroid Transcription Factor 1 (TTF1), and Yin Yang 1 (YY1). While Genistein and Bisphenol A (BPA) have been shown to advance the advent of puberty, exposure to Dioxin delayed pubertal onset. Utilizing in vitro approaches, we observed that Genistein and BPA suppress inhibitory and activate stimulatory components of the GnRH network, while Dioxin exhibit an inhibitory effect at all regulatory hierarchical levels of the GnRH network. It repressed KiSS1, Gnrh, Ttf1 and Yy1 transcription via the xenobiotic response element (XRE), while EAP1 was not affected. Therefore, EDCs alter the neuroendocrine GnRH regulatory network at all hierarchical levels.

Transcription of the human EAP1 gene is regulated by upstream components of a puberty-controlling Tumor Suppressor Gene network.

Mammalian puberty is initiated by an increased pulsatile release of gonadotropin-releasing hormone (GnRH) from specialized neurons located in the hypothalamus. GnRH secretion is controlled by neuronal and glial networks, whose activity appears to be coordinated via transcriptional regulation. One of the transcription factors involved in this process is thought to be the recently described gene Enhanced at Puberty 1 (EAP1), which encodes a protein with dual transcriptional activity. In this study we used gene reporter and chromatin immunoprecipitation (ChIP) assays to examine the hypothesis that EAP1 expression is controlled by transcriptional regulators earlier postulated to serve as central nodes of a gene network involved in the neuroendocrine control of puberty. These regulators include Thyroid Transcription Factor 1 (TTF1), Yin Yang 1 (YY1), and CUX1, in addition to EAP1 itself. While TTF1 has been shown to facilitate the advent of puberty, YY1 (a zinc finger protein component of the Polycomb silencing complex) may play a repressive role. The precise role of CUX1 in this context is not known, but like EAP1, CUX1 can either activate or repress gene transcription. We observed that DNA segments of two different lengths (998 and 2744bp) derived from the 5'-flanking region of the human EAP1 gene display similar transcriptional activity. TTF1 stimulates transcription from both DNA segments with equal potency, whereas YY1, CUX1, and EAP1 itself, behave as transcriptional repressors. All four proteins are recruited in vivo to the EAP1 5'-flanking region. These observations suggest that EAP1 gene expression is under dual transcriptional regulation imposed by a trans-activator (TTF1) and two repressors (YY1 and CUX1) previously postulated to be upstream components of a puberty-controlling gene network. In addition, EAP1 itself appears to control its own expression via a negative auto-feedback loop mechanism. Further studies are needed to determine if the occupancy of the EAP1 promoter by these regulatory factors changes at the time of puberty.

Transcriptional regulation of the human KiSS1 gene.

Kisspeptin, the product of the KiSS1 gene, has emerged as a key component of the mechanism by which the hypothalamus controls puberty and reproductive development. It does so by stimulating the secretion of gonadotropin releasing hormone (GnRH). Little is known about the transcriptional control of the KiSS1 gene. Here we show that a set of proteins postulated to be upstream components of a hypothalamic network involved in controlling female puberty regulates KiSS1 transcriptional activity. Using RACE-PCR we determined that transcription of KiSS1 mRNA is initiated at a single transcription start site (TSS) located 153-156bp upstream of the ATG translation initiation codon. Promoter assays performed using 293 MSR cells showed that the KiSS1 promoter is activated by TTF1 and CUX1-p200, and repressed by EAP1, YY1, and CUX1-p110. EAP1 and CUX-110 were also repressive in GT1-7 cells. All four TFs are recruited in vivo to the KiSS1 promoter and are expressed in kisspeptin neurons. These results suggest that expression of the KiSS1 gene is regulated by trans-activators and repressors involved in the system-wide control of mammalian puberty.