Dendritic cells activate autologous T cells and induce IL-4 and IL-10 production in myasthenia gravis

Dendritic cells (DC), as initiators and orchestrators of immune responses, control both naive and primed T cell responses. Depending on their maturation stage, DC promote immunity or tolerance. Here we investigated (1) the phenotype and cytokine secretion patterns of IL-10-modulated immature DC (IL-10-DC) and lipopolysaccharide (LPS)-driven mature DC (LPS-DC) in comparison with unmodulated immature DC (imDC) and (2) the effects of IL-10-DC, and of LPS-DC, vs. imDC on autologous T cell responses in patients with myasthenia gravis (MG) compared with healthy controls (HC). All three types of DC derived from MG significantly increased the levels of CD4+CD25+ T cells and of their subfraction expressing CD69, when compared to DC derived from HC. IL-10-DC induced production of IL-10 and IL-4 by T cells from MG patients, but only IL-10 production from HC. LPS-DC activated autologous T cells as reflected by augmented CD25, CD69 and CTLA-4 expression on CD4+ T cells, without differences between MG and HC. This was associated with increased production of both Th1 (IFN-gamma) and Th2 (IL-10 and IL-4) cytokines by T cells. These results indicate that DC-induced activation of autologous T cells is more pronounced in MG than in HC. In addition, DC-induced T cell responses in MG vs. HC are more Th2-prone.     

The expression of TNF-alpha receptors 1 and 2 on peripheral blood mononuclear cells in chronic inflammatory demyelinating polyneuropathy

The proportion of peripheral blood mononuclear cells (PBMCs) expressing TNF-alpha and its receptors (TNFR1, TNFR2) and the serum concentrations of its soluble forms were analyzed by FACS and ELISA in the patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and in controls. Elevated levels of TNFR2 were observed on blood T cells in CIDP and idiopathic polyneuropathy. Low levels of TNFR1 were detected on monocytes in the subgroup of patients with CIDP examined after treatment with intravenous immunoglobulin. However, the proliferative activity of PBMCs in CIDP was not influenced by soluble recombinant TNFR1. Our limited data suggested the exact role of TNF-alpha and its receptors need to study further in CIDP, as well as in idiopathic neuropathies.     

Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis

A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.     

Sex differences in the inflammatory response and inflammation-induced vascular dysfunction

Background

Premenopausal women have a lower incidence of cardiovascular disease, although the exact mechanism underlying this protection is unclear. Both systemic and localised inflammation have a crucial role in the progression of cardiovascular disease, and much preclinical and observational data in human beings suggest that differences in inflammation between the sexes exist. We investigated whether inflammation, and which components of the inflammatory response, might be altered in women compared with men.

Monocyte-derived dendritic cells express and secrete matrix-degrading metalloproteinases and their inhibitors and are imbalanced in multiple sclerosis

Dendritic cells (DC) are antigen-presenting cells (APC) that most efficiently initiate and control immune responses. Migration processes of blood DC are crucial to exert their professional antigen-presenting functions. Matrix-degrading metalloproteinases (MMP) are proteolytic enzymes, which are considered to be key enzymes in extracellular matrix (ECM) turnover and mediators of cell migration. Tissue inhibitors of metalloproteinases (TIMP) are important regulators of MMP activity. Here we investigate whether blood monocyte-derived immature DC (iDC) and mature DC (mDC) express, produce and secrete functionally active MMP-1, -2, -3 and -9 and their inhibitors TIMP-1 and -2, and examine their involvement in multiple sclerosis (MS). On mRNA level, we observed high numbers of MMP-2 and TIMP-2 mRNA expressing iDC in MS. On protein level, high percentages of MMP-1, -2 and -9 expressing iDC by flow cytometry, and high MMP-1 secretion by Western blot together with high MMP-2 and -9 activities in iDC supernatants as studied with zymography were observed. Similarly, MS is associated with high percentages of MMP-2 and -3 and of TIMP-1 expressing mDC by flow cytometry together with high MMP-3 secretion and high MMP-9 activity in culture supernatants. Spontaneous migratory capacity of both iDC and mDC over ECM-coated filters was higher in MS compared to healthy controls (HC).In conclusion, blood monocyte-derived iDC and mDC express, produce and secrete several MMP and TIMP. Alterations in these molecules as observed in MS may be functionally important for DC functioning.     

Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis

A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.     

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy

Introduction: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. Methods: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. Results: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. Discussion: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59 :354–357, 2019