Adenosine A receptors are putative therapeutic targets for neurological disorders. The adenosine A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A receptor blockers might help counteract memory problems in patients with Alzheimer's disease.
The structural determination of peptide:HLA (human leucocyte antigen) class I complexes by X-ray crystallography has provided valuable information for understanding how peptides bind to individual HLA class I molecules and how this may influence the immune response. We compared 101 crystal structures of 9-mer peptide:HLA class I complexes available in the protein data bank (PDB) by performing a contact analysis using the Contact Map Analysis webserver http://ligin.weizmann.ac.il/cma. An InterSystems Caché 'post-relational' database containing residue position, amino acid (AA) and buried surface that contact a particular peptide position was then created allowing data comparison for all the structures (Pocketcheck). The analysis illustrates that the HLA class I residues 24, 45, 63 and 67 show high contact frequencies to both the p1 and/or p2 position of bound peptides, indicating that they might influence the nature of a peptide anchor. To determine the influence of these residues we utilized soluble HLA technology and mass spectrometry to analyze peptides derived from HLA-B*44:06 since it differs from the previously described allele B*44:02 by seven AA exchanges located in the alpha 1 domain (residues 24, 32, 41, 45, 63, 67 and 80). HLA-B*44:06 features an anchor motif of P or A at p2 and Y or W at the C-terminal. Additionally B*44:06-derived peptides feature an auxiliary anchor motif at p1, comprising D or E. Our results illustrate that structural analysis can provide valuable information to understand allogenicity and provides a further step towards intelligent HLA mismatching.
BackgroundIn 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient.Case presentationA 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies.ConclusionsThis case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected.Electronic supplementary materialThe online version of this article (10.1186/s12883-019-1269-7) contains supplementary material, which is available to authorized users.
Position 45 represents a highly polymorphic residue within HLA class I alleles, which contacts the p2 position of bound peptides in 85% of the peptide-HLA structures analyzed, while the neighboring residues 41 and 46 are not involved in peptide binding. To investigate the influence of residue 45 at the functional level, we sequenced peptides eluted from recombinant HLA-B*44:08(41Ala/45Met/46Ala) molecules and compared their features with known peptides from B*44:02(41Thr/45Lys/46Glu). While HLA-B*44:02 has an anchor motif of E at the p2 anchor position, HLA-B*44:08 exhibits Q and L as anchor motif. The 45(Met/Lys) polymorphism contributes to the alteration in the peptide-binding motif and provides further evidence that mismatches at position 45 should be considered as nonpermissive in a transplantation setting.
Tumor necrosis factor-α is assumed to be an important mediator in thyroid autoimmunity. In the present study we have shown that human thyrocytes possess a single specific binding site for recombinant tumor necrosis factor-α with an average of 9,300 receptors/cell (Kd = 1.9 · 10−10 mol). The effects of the cytokine on thyroid cell proliferation were assessed by 3H-thymidine uptake as well as by the protein and DNA content of cell monolayers. Low dose tumor necrosis factor-α resulted in a moderate stimulation of cell proliferation with an increase of 3H-thymidine incorporation from 44,613±7,989 cpm under basal conditions to 63,326±6,822 cpm after 100 U/l tumor necrosis factor-α (p <0.01). Higher doses of the cytokine were less effective. On average, bTSH stimulated cAMP production of human thyrocytes was significantly augmented after preincubation with recombinant tumor necrosis factor-α. The maximum effect was observed after 1,000 U/l tumor necrosis factor-α (281.5±107.0 vs 114.5±33.6 fmol cAMP/μg protein under basal conditions; p<0.05), whereas higher doses of the cytokine were again less effective. This phenomenon could at least partly be explained by a cytokine-mediated downregulation of tumor necrosis factor-α binding. We conclude that in vitro tumor necrosis factor-α modulates in addition to its well known synergistic effect on interferon-γ induced HLA class II expression the function and proliferation of human thyroid follicular cells as well. These effects are mediated via specific cell surface receptors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.