Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns.

Narcolepsy is a chronic sleep disorder, likely with an autoimmune component. During 2009 and 2010, a link between A(H1N1)pdm09 Pandemrix vaccination and onset of narcolepsy was suggested in Scandinavia. In this study, we searched for autoantibodies related to narcolepsy using a neuroanatomical array: rat brain sections were processed for immunohistochemistry/double labeling using patient sera/cerebrospinal fluid as primary antibodies. Sera from 89 narcoleptic patients, 52 patients with other sleep-related disorders (OSRDs), and 137 healthy controls were examined. Three distinct patterns of immunoreactivity were of particular interest: pattern A, hypothalamic melanin-concentrating hormone and proopiomelanocortin but not hypocretin/orexin neurons; pattern B, GABAergic cortical interneurons; and pattern C, mainly globus pallidus neurons. Altogether, 24 of 89 (27%) narcoleptics exhibited pattern A or B or C. None of the patterns were exclusive for narcolepsy but were also detected in the OSRD group at significantly lower numbers. Also, some healthy controls exhibited these patterns. The antigen of pattern A autoantibodies was identified as the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/alpha-melanocyte-stimulating hormone (NEI/alphaMSH) peptides. Passive transfer experiments on rat showed significant effects of pattern A human IgGs on rapid eye movement and slow-wave sleep time parameters in the inactive phase and EEG theta-power in the active phase. We suggest that NEI/alphaMSH autoantibodies may interfere with the fine regulation of sleep, contributing to the complex pathogenesis of narcolepsy and OSRDs. Also, patterns B and C are potentially interesting, because recent data suggest a relevance of those brain regions/neuron populations in the regulation of sleep/arousal

Human Th2 cells selectively express the orexigenic peptide, pro-melanin-concentrating hormone

Th1 and Th2 cells represent the two main functional subsets of CD4+ T helper cell, and are defined by their cytokine expression. Human Th1 cells express IFNγ, whilst Th2 cells express IL-4, IL-5, and IL-13. Th1 and Th2 cells have distinct immunological functions, and can drive different immunopathologies. Here, we show that in vitro-differentiated human Th2 cells highly selectively express the gene for pro-melanin-concentrating hormone (PMCH), using real-time RT-PCR, enzyme immunoassay, and Western blot analysis. PMCH encodes the prohormone, promelanin-concentrating hormone (PMCH), which is proteolytically processed to produce several peptides, including the orexigenic hormone melanin-concentrating hormone (MCH). PMCH expression by Th2 cells was activation responsive and increased throughout the 28-day differentiation in parallel with the expression of the Th2 cytokine genes. MCH immunoreactivity was detected in the differentiated Th2 but not Th1 cell culture supernatants after activation, and contained the entire PMCH protein, in addition to several smaller peptides. Human Th1 and Th2 cells were isolated by their expression of IFNγ and CRTH2, respectively, and the ex vivo Th2 cells expressed PMCH upon activation, in contrast to the Th1 cells. Because Th2 cells are central to the pathogenesis of allergic diseases including asthma, expression of PMCH by activated Th2 cells in vivo may directly link allergic inflammation to energy homeostasis and may contribute to the association between asthma and obesity

New aspects of melanocortin signaling: a role for PRCP in α-MSH degradation

The role of the central melanocortin system in the regulation of energy metabolism has received much attention during the past decade since gene mutations of key components in melanocortin signaling cause monogenic forms of obesity in animals and humans. In the arcuate nucleus of the hypothalamus the prohormone proopiomelanocortin (POMC) is posttranslationally cleaved to produce α-melanocyte stimulating hormone (α-MSH), a peptide with anorexigenic effects upon activation of the melanocortin receptors (MCRs). α-MSH undergoes extensive post-translational processing and its in vivo activity is short lived due to rapid degradation. The enzymatic process that controls α-MSH inactivation is incompletely understood. Recent evidence suggests that prolyl carboxypeptidase (PRCP) is an enzyme responsible for α-MSH degradation. As for many key melanocortin peptides, gene mutation of PRCP causes a change in the metabolic phenotype of rodents. This review summarizes the current knowledge on the melanocortin system with particular focus on PRCP, a newly discovered component of the melanocortin system