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1.
Article in English | MEDLINE | ID: mdl-33589541

ABSTRACT

OBJECTIVE: To identify an MS-specific immune cell population by deep immune phenotyping and relate it to soluble signaling molecules in CSF. METHODS: We analyzed surface expression of 22 markers in paired blood/CSF samples from 39 patients using mass cytometry (cytometry by time of flight). We also measured the concentrations of 296 signaling molecules in CSF using proximity extension assay. Results were analyzed using highly automated unsupervised algorithmic informatics. RESULTS: Mass cytometry objectively identified a B-cell population characterized by the expression of CD49d, CD69, CD27, CXCR3, and human leukocyte antigen (HLA)-DR as clearly associated with MS. Concentrations of the B cell-related factors, notably FCRL2, were increased in MS CSF, especially in early stages of the disease. The B-cell trophic factor B cell activating factor (BAFF) was decreased in MS. Proteins involved in neural plasticity were also reduced in MS. CONCLUSION: When analyzed without a priori assumptions, both the soluble and the cellular compartments of the CSF in MS were characterized by markers related to B cells, and the strongest candidate for an MS-specific cell type has a B-cell phenotype.


Subject(s)
B-Cell Activating Factor/cerebrospinal fluid , B-Lymphocytes/cytology , Biomarkers/cerebrospinal fluid , Multiple Sclerosis/immunology , Adult , B-Lymphocytes/immunology , Biomarkers/analysis , Female , Humans , Male , Middle Aged , Phenotype
2.
Front Immunol ; 11: 472, 2020.
Article in English | MEDLINE | ID: mdl-32296421

ABSTRACT

Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.


Subject(s)
Autoimmune Diseases/therapy , Immunotherapy/methods , Immunotherapy/trends , Humans
3.
Sci Signal ; 10(496)2017 Sep 12.
Article in English | MEDLINE | ID: mdl-28900043

ABSTRACT

GPR15 is an orphan G protein-coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines. GPR15L was found in some human and mouse epithelia exposed to the environment, such as the colon and skin. In humans, GPR15L was also abundant in the cervix. In skin, GPR15L was readily detected after immunologic challenge and in human disease, for example, in psoriatic lesions. Allotransplantation of skin from Gpr15l-deficient mice onto wild-type mice resulted in substantial graft protection, suggesting nonredundant roles for GPR15 and GPR15L in the generation of effector T cell responses. Together, these data identify a receptor-ligand pair that is required for immune homeostasis at epithelia and whose modulation may represent an alternative approach to treating conditions affecting the skin such as psoriasis.


Subject(s)
Colon/immunology , Intestinal Mucosa/immunology , Receptors, G-Protein-Coupled/immunology , Skin/immunology , T-Lymphocytes/immunology , Allografts , Animals , Colon/cytology , Female , Humans , Intestinal Mucosa/cytology , Mice , Receptors, G-Protein-Coupled/genetics , Skin/cytology , Skin Transplantation , Swine , T-Lymphocytes/cytology , Transplantation Immunology
4.
J Med Chem ; 57(24): 10343-54, 2014 Dec 26.
Article in English | MEDLINE | ID: mdl-25411721

ABSTRACT

GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Indoles/pharmacology , Inflammation/metabolism , Interleukin-10/metabolism , Interleukin-12/metabolism , Macrophages/metabolism , Monocytes/metabolism , Niacinamide/analogs & derivatives , Receptors, G-Protein-Coupled/agonists , Tumor Necrosis Factor-alpha/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Calcium/metabolism , Cyclic AMP/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Indoles/chemistry , Inflammation/drug therapy , Inflammation/immunology , Jurkat Cells , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/drug effects , Monocytes/immunology , Niacinamide/chemistry , Niacinamide/pharmacology , Receptors, G-Protein-Coupled/physiology
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