Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar. 1 Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs 2 and also in the action of mood stabilizing agents, particularly lithium carbonate. 3 Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain, 4 are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser), 5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this interpopulation variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD ( 2 = 7.34, df 1, P = 0.006) and BP ( 2 = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder. Molecular Psychiatry (2001) 6, 579-585.It is widely accepted that the genetic basis of affective disorders, both unipolar (recurrent major depression) and bipolar (manic depressive illness) is complex and is likely to involve several genes and also environmental factors. 6,7 A principal aim of the European Collaborative Project on Affective Disorders (ECPAD) is to harness the statistical power potentially provided by the large numbers of subjects who can be recruited by the participating centers in order to elucidate the role of candidate genes and environmental factors in the pathogenesis of affective illness. 8 In the course of the project a very large sample has been recruited and clinically evaluated, with blood samples obtained for DNA extraction. The method of recruitment of patients has been described in detail by Souery et al 8 and is summarized below in the Methods section. Subjects were genotyped for the HT2CR cys23ser polymorphism in the participating laboratories according to a standardized protocol (see below). Clinical and genotype data were centralized in the ECPAD database in Brussels and were electronically transferred to BL and FM for statistical analysis. After removal of subjects whose geographical origin was unclear, whose genotype data were ambiguous or contrad...
This article shows that liver and kidney damage in a lupus-prone mouse line occurs by different mechanisms and that only drugs targeting core components of signaling pathway, such as IRAK4, are able to suppress all facets of the disease.
Type 2 Innate lymphoid cells (ILC2s) are implicated in helminth infections and asthma where they play a role in the production of Th2-type cytokines. ILC2s express the IL-33 receptor and are a major cell type thought to mediate the effects of this cytokine in vivo. To study the signalling pathways that mediate IL-33 induced cytokine production, a culture system was set up to obtain pure populations of ILC2s from mice. Inhibitors of the p38α/β and ERK1/2 MAPK pathways reduced the production of IL-5, IL-6, IL-9, IL-13 and GM-CSF by ILC2 in response to IL-33, with inhibition of p38 having the greatest effect. MK2 and 3 are kinases activated by p38α; MK2/3 inhibitors or knockout of MK2/3 in mice reduced the production of IL-6 and IL-13 (two cytokines implicated in asthma) but not IL-5, IL-9 or GM-CSF in response to IL-33. MK2/3 inhibition also suppressed IL-6 and IL-13 production by human ILC2s. MK2/3 were required for maximal S6 phosphorylation, suggesting an input from the p38α-MK2/3 pathway to mTOR1 activation in ILC2s. The mTORC1 inhibitor rapamycin also reduced IL-6 and IL-13 production, which would be consistent with a model in which MK2/3 regulate IL-6 and IL-13 via mTORC1 activation in ILC2s.Innate lymphoid cells (ILCs) are a recently identified group of lymphocytes acting within the innate immune system. ILCs lack antigen specific receptors, however in terms of the cytokines they produce they mimic various Th cell subsets. ILCs are found in both lymphoid and non-lymphoid tissues, particularly at the barrier sites including skin, respiratory and gastrointestinal systems 1-4 . Based on their effector function, cell surface markers and the transcription factors required for their development, ILCs can be subdivided into several distinct groups 1,2 . Group 1 includes NK cells and ILC1 cells, which are involved in protective immunity to viral infections and antimicrobial responses. The second group comprises of type 2 innate lymphoid cells (ILC2). ILC2 cells secrete type two cytokines and are implicated in responses to helminth infection, asthma and atopic diseases. The third group includes the lymphoid tissue inducer cells and ILC3. In 2017, a potential new group of ILC with regulatory functions was discovered. ILCreg are found in human and mouse gut and limit the activity of ILC1 and ILC3 by secreting the anti-inflammatory cytokine IL-10 5 .The first evidence for the existence of ILC2 cells was found in 2006 when Fallon et al. showed that during infection with the helminth Nippostrongylus brasilienis a population of non-T and non-B cells secrete IL-4, IL-5 and IL-13 and promote helminth expulsion 6 . In 2010, several labs reported the characterisation of ILC2s as a distinct population of cells, which were initially referred to as either neuocytes, innate helper 2 cells or natural helper cells 7-9 . ILC2s are found in the lymphoid tissues such as spleen and mesenteric lymph nodes, as well as in some non-lymphoid organs including fat associated lymphoid clusters, lungs, skin and liver. In mice, ILC2 are character...
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