ABSTRACT
A low-grade inflammatory phenomenon is a feature of overweight and metabolic syndrome. The involvement of a pro-inflammatory Th17 lymphocyte subset and the CD69+ T regulatory (Treg) cell subtype in patients with metabolic dysfunction associated with or without overweight has not been fully elucidated. The aim of this study was to perform a quantitative and functional analysis of pathogenic Th17 lymphocytes and CD69+ Treg cells in patients with metabolic dysfunction (insulin resistance and dyslipidemia). The number of pathogenic Th17 cells and the levels and function of CD69+ Treg cells were analyzed in blood samples from individuals with metabolic dysfunction, associated with or without overweight. Pathogenic and non-pathogenic Th17 lymphocytes as well as Th22 cells were determined by eight-color flow cytometry analysis, whereas the levels and suppressive function of CD69+ Treg cells were also analyzed by multiparametric flow cytometry. We detected increased levels of pro-inflammatory Th17 pathogenic cells and Th22 lymphocytes in overweight unhealthy individuals (P < 0.001, compared to normal weight healthy). Conversely, diminished numbers of CD69+ Treg lymphocytes were observed in metabolically unhealthy individuals, with or without overweight. Likewise, the immunosuppressive function of CD69+ Treg cells was also defective in these patients. The increased levels of pathogenic Th17 cells along with a diminished number and function of CD69+ Treg lymphocytes may significantly contribute to the low-grade inflammatory phenomenon of metabolically unhealthy patients.
Subject(s)
T-Lymphocytes, Regulatory , Th17 Cells , Flow Cytometry , Humans , Lymphocyte Subsets , Overweight/metabolism , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/metabolismABSTRACT
Dendritic cells (DCs) have a key role in the regulation of immune response. We herein explored, in patients with inflammatory diseases, the role of monocyte derived DC's (mo-DCs) on the generation of Th17 and T regulatory (Treg) lymphocytes. Peripheral blood was obtained from thirty-five patients with rheumatoid arthritis (RA), twelve with systemic lupus erythematosus (SLE), and twenty healthy subjects. Mo-DCs were generated under standard (IL-4/GM-CSF) or tolerogenic (IL-4/GM-CSF plus recombinant P-selectin or PD-1 or IL-10) conditions, and their ability to induce Th17 and Treg lymphocytes was tested. We detected that mo-DCs from patients with RA showed an enhanced release of IL-6 and IL-23 as well as an increased capability to induce Th17 cells. Although mo-DCs from SLE patients also released high levels of IL-6/IL-23, it did not show an increased ability to induce Th17 lymphocytes. In addition, mo-DCs, from patients with RA and SLE generated under the engagement of PSGL-1, showed a defective capability to induce Foxp3+ Treg cells. A similar phenomenon was observed in SLE, when DC's cells were generated under PDL-1 engagement. Our data indicate that DCs from patients with rheumatic inflammatory disease show an aberrant function that may have an important role in the pathogenesis of these conditions.
Subject(s)
Arthritis, Rheumatoid/immunology , Dendritic Cells/immunology , Lupus Erythematosus, Systemic/immunology , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Adolescent , Adult , Arthritis, Rheumatoid/metabolism , Cell Differentiation , Coculture Techniques , Cytokines/metabolism , Dendritic Cells/metabolism , Female , Humans , Immunophenotyping , Lupus Erythematosus, Systemic/metabolism , Middle Aged , Phenotype , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/cytology , Th17 Cells/metabolism , Young AdultABSTRACT
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease. Natural T regulatory (nTreg) cells, which constitutively express the CTLA-4 molecule, have an important role in the pathogenesis of autoimmune conditions. Although it has been reported that biological agents are able to modulate the levels or function of Treg lymphocytes, the possible effect of Abatacept (CTLA-4-Ig) therapy on these cells has not been studied in autoimmune conditions. We explored the effect of Abatacept therapy on Treg cells in patients with RA. The number of different subsets of Treg cells was analyzed by flow cytometry in the peripheral blood from 45 patients with RA that were (n = 30) or not (n = 15) under Abatacept therapy as well as in 20 healthy controls. The function of Treg cells was assessed by an assay of inhibition of lymphocyte proliferation. We found that Abatacept therapy was associated with a significant diminution in the levels of CD4+CD25(bright)Foxp3+, and CD4+CTLA-4+ nTreg cells. In contrast, the regulatory function of CD4+CD25+ lymphocytes was significantly enhanced after the administration of Abatacept. Our data suggest that CTLA-4-Ig exerts a complex and interesting effect on Treg cells in patients with RA.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Immunoconjugates/therapeutic use , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Abatacept , Adolescent , Adult , Arthritis, Rheumatoid/pathology , CD4 Antigens/immunology , Cell Proliferation , Female , Flow Cytometry , Forkhead Transcription Factors/immunology , Humans , Immunoconjugates/administration & dosage , Immunoconjugates/metabolism , Interleukin-2 Receptor alpha Subunit/immunology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Lymphocyte Activation/immunology , Male , Middle Aged , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/pathologyABSTRACT
Human leukocyte antigen (HLA)-G is a class I non-classical HLA molecule with an important regulatory role on the immune response. The possible role of this molecule in the pathogenesis of SLE has not been explored. In this work, we evaluated the expression and function of HLA-G in SLE patients. We studied 37 SLE patients as well as 25 healthy donors. Peripheral blood monocytes and in vitro-generated dendritic cells (DCs) were analyzed for HLA-G expression by flow cytometry. We found that monocytes from SLE patients as well as mature CD83+ DCs showed a diminished expression of HLA-G compared with healthy controls. In addition, monocytes from SLE patients showed a diminished induction of HLA-G expression in response to stimulation with IL-10. Furthermore, functional assays showed that these monocytes pre-treated with IFN-γ exhibited a diminished capability to inhibit the proliferation of autologous lymphocytes. Finally, lymphocytes from SLE patients tended to display a lower acquisition of HLA-G (by trogocytosis) from autologous monocytes compared to controls. Our results might have implications for the immune abnormalities observed in patients with SLE.
