Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming

Objectives: Major histocompatibility complex (MHC) class II-mediated priming of T and B lymphocytes is a central element of autoimmunity in systemic lupus erythematosus (SLE) and lupus nephritis. The cysteine protease cathepsin S degrades the invariant peptide chain during MHC II assembly with antigenic peptide in antigen-presenting cells; therefore, we hypothesised that cathepsin S inhibition would be therapeutic in SLE. Methods: We developed a highly specific small molecule, orally available, cathepsin S antagonist, RO5461111, with suitable pharmacodynamic and pharmacokinetic properties that efficiently suppressed antigen-specific T cell and B cell priming in vitro and in vivo. Results: When given to MRL-Fas(lpr) mice with SLE and lupus nephritis, RO5461111 significantly reduced the activation of spleen dendritic cells and the subsequent expansion and activation of CD4 T cells and CD4/CD8 double-negative T cells. Cathepsin S inhibition impaired the spatial organisation of germinal centres, suppressed follicular B cell maturation to plasma cells and Ig class switch. This reversed hypergammaglobulinemia and significantly suppressed the plasma levels of numerous IgG (but not IgM) autoantibodies below baseline, including anti-dsDNA. This effect was associated with less glomerular IgG deposits, which protected kidneys from lupus nephritis. Conclusions: Together, cathepsin S promotes SLE by driving MHC class II-mediated T and B cell priming, germinal centre formation and B cell maturation towards plasma cells. These afferent immune pathways can be specifically reversed with the cathepsin S antagonist RO5461111, which prevents lupus nephritis progression even when given after disease onset. This novel therapeutic strategy could correct a common pathomechanism of SLE and other immune complex-related autoimmune diseases

Altered Serum IgG Levels to a-Synuclein in Dementia with Lewy Bodies and Alzheimer’s Disease.

Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against asynuclein is not well known. We explored serum IgG levels to monomeric a-synuclein in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-asynuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against a-synuclein in DLB and AD, which may relate to a disturbed a-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target a-synuclein in neurodegenerative disease.Fil: Koehler, Niklas. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Stransky, Elke. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Shing, Mona. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Gaertner, Susanne. Department of Psychiatry and Psychotherapy, EBERHARD-KARLS-UNIVERSITY;Fil: Meyer, Mirjam. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Schreitmueller, Brigitte. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Leyhe, Thomas. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Laske, Cristoph. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Maetzler, Walter. Department of Neurodegeneration. HERTIE INSTITUTE FOR CLINICAL BRAIN RESEARCH;Fil: Kahle, Philipp. FUNCTIONAL NEUROGENETICS. HERTIE INSTITUTE FOR CLINICAL;Fil: Celej, Maria Soleda. MAX-PLANCK-INSTITUTE FOR BIOPHYSICAL CHEMISTRY; Consejo Nacional de Invest.cientif.y Tecnicas. Centro Cientifico Tecnol.conicet - Cordoba. Centro de Invest.en Qca.biol.de Cordoba (p);Fil: Jovin, Thomas M.. MAX-PLANCK-INSTITUTE FOR BIOPHYSICAL CHEMISTRY;Fil: Fallgatter, Andreas. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Batra, Anil. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Buchkremer, Gherard. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Schott, Klauss. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Richartz-Salzburger, Elke. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements