Corticotropin-releasing hormone (CRH), CRH-related peptides, and CRH receptors play major roles in coordinating the behavioral, endocrine, autonomic, and immune responses to stress. The wide influence of the CRH system on physiological processes in both brain and periphery implicates the respective peptides in the pathophysiology of numerous disorders characterized by dysregulated stress responses. The potential use of CRH antagonists is presently under intense investigation. Selective antagonists have been used experimentally to elucidate the role of CRH-related peptides in disease processes, such as anxiety and depression, sleep disorders, addictive behavior, inflammatory disorders, acute and chronic neurodegeneration, and preterm labor.
Luteinizing hormone (LH) plays its effects on ovarian and testicular cells through binding to a specific cell surface receptor. We recently described two kindreds with LH resistance due to abnormalities of the LH receptor (LH-R) gene. Affected XY members presented with severe or mild fetal undermasculinization (female external genitalia or micropenis) and primary hypogonadism, while an XX affected member showed normal pubertal development, increased plasma concentrations of LH, and amenorrhea. The first kindred included three XY phenotypic female siblings with Leydig cell hypoplasia and primary hypogonadism and a fully developed XX sister with elevated plasma concentrations of LH and amenorrhea. PCR amplification of genomic DNA and direct sequencing of the entire exon 11 of the LH-R revealed that all four affected individuals had a homozygous mutation (Arg554-->Stop codon) in the third cytosolic loop of the LH-R, which resulted in a truncated LH-R unable to transduce the hormonal signal. The second kindred included a 6-year-old XY boy with a micropenis and bilaterally descended testes, who demonstrated no response to exogenous human chorionic gonadotrophin postnatally. This patient had a nonconservative homozygous amino acid substitution (Ser616-->Tyr616) in the seventh transmembrane domain of his LH-R gene that was inherited from his heterozygous parents. The mutant receptor expressed in heterologous cells in vitro demonstrated no appreciable binding of 125I-labeled hLH, nor did it confer cAMP responsiveness to LH. Homozygous inactivating mutations of the LH-R cause complete or mild testicular failure in genetic males, resulting in female external genitalia or micropenis and primary hypogonadism. Similar mutations in genetic females may cause failure of ovulation and corpus luteum formation, resulting in amenorrhea. Follicular growth and development are apparently sufficient to allow feminization at puberty.
Abstract The potential existence and roles of the meningeal lymphatic system in normal and pathological brain function have been a long-standing enigma. Recent evidence suggests that meningeal lymphatic vessels are present in both the mouse and human brain; in mice, they seem to play a role in clearing toxic amyloid-beta peptides, which have been connected with Alzheimer disease (AD). Here, we review the evidence linking the meningeal lymphatic system with human AD. Novel findings suggest that the recently described meningeal lymphatic vessels could be linked to, and possibly drain, the efferent paravascular glial lymphatic (glymphatic) system carrying cerebrospinal fluid, after solute and immune cell exchange with brain interstitial fluid. In so doing, the glymphatic system could contribute to the export of toxic solutes and immune cells from the brain (an exported fluid we wish to describe as glymph, similarly to lymph) to the meningeal lymphatic system; the latter, by being connected with downstream anatomic regions, carries the glymph to the conventional cervical lymphatic vessels and nodes. Thus, abnormal function in the meningeal lymphatic system could, in theory, lead to the accumulation, in the brain, of amyloid-beta, cellular debris, and inflammatory mediators, as well as immune cells, resulting in damage of the brain parenchyma and, in turn, cognitive and other neurologic dysfunctions. In addition, we provide novel insights into APOE4—the leading genetic risk factor for AD—and its relation to the meningeal lymphatic system. In this regard, we have reanalyzed previously published RNA-Seq data to show that induced pluripotent stem cells (iPSCs) carrying the APOE4 allele (either as APOE4 knock-in or stemming from APOE4 patients) express lower levels of (a) genes associated with lymphatic markers, and (b) genes for which well-characterized missense mutations have been linked to peripheral lymphedema. Taking into account this evidence, we propose a new conceptual framework, according to which APOE4 could play a novel role in the premature shrinkage of meningeal lymphatic vessels (meningeal lymphosclerosis), leading to abnormal meningeal lymphatic functions (meningeal lymphedema), and, in turn, reduction in the clearance of amyloid-beta and other macromolecules and inflammatory mediators, as well as immune cells, from the brain, exacerbation of AD manifestations, and progression of the disease. Altogether, these findings and their potential interpretations may herald novel diagnostic tools and therapeutic approaches in patients with AD.
Abstract The human microbiome plays an integral role in health. In particular, it is important for the development, differentiation, and maturation of the immune system, 70% of which resides in the intestinal mucosa. Microbiome studies conducted to date have revealed an association between disturbances in the microbiota (dysbiosis) and various pathological disorders, including changes in host immune status. Autoimmune thyroid diseases are one of the most common organ-specific autoimmune disorders, with a worldwide prevalence higher than 5%. The predominant autoimmune thyroid diseases are Hashimoto’s thyroiditis and Grave’s disease. Several factors, such as genetic and environmental ones, have been studied. In accordance with recent studies, it is assumed that the gut microbiome might play a significant role in triggering autoimmune diseases of the thyroid gland. However, the exact etiology has not yet been elucidated. The present review aims to describe the work carried out so far regarding the role of gut microflora in the pathogenesis of autoimmune thyroid diseases and its involvement in the appearance of benign nodules and papillary thyroid cancer. It appears that future work is needed to elucidate more precisely the mechanism for gut microbiota involvement in the development of autoimmune thyroid diseases.
Stress is defined as a state of threatened homeostasis. The principal effectors of the stress system include corticotropin-releasing hormone, arginine vasopressin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Activation of the stress system leads to adaptive behavioral and physical changes. The principal stress hormones glucocorticoids and catecholamines affect major immune functions such as antigen presentation, leukocyte proliferation and traffic, secretion of cytokines and antibodies, and selection of the T helper (Th) 1 versus Th2 responses. A fully fledged systemic inflammatory reaction results in stimulation of the stress response, which in turn, through induction of a Th2 shift protects the organism from systemic overshooting with Th1/pro-inflammatory cytokines. Stress is often regarded as immunosuppressive, but recent evidence indicates that stress hormones influence the immune response in a less monochromatic way – systemically they inhibit Th1/pro-inflammatory responses and induce a Th2 shift, whereas in certain local responses they promote pro-inflammatory cytokine production and activation of the corticotropin-releasing hormone-mast cell-histamine axis. Through this mechanism a hyper- or hypoactive stress system associated with abnormalities of the systemic anti-inflammatory feedback and/or hyperactivity of the local pro-inflammatory factors may play a role in the pathogenesis of chronic inflammation and immune-related diseases.
