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Liu Q, Zhou X, Liu K, Wang Y, Liu C, Gao C, Cai Q, Sun C. Exploring risk factors for autoimmune diseases complicated by non-hodgkin lymphoma through regulatory T cell immune-related traits: a Mendelian randomization study. Front Immunol 2024; 15:1374938. [PMID: 38863695 PMCID: PMC11165099 DOI: 10.3389/fimmu.2024.1374938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/08/2024] [Indexed: 06/13/2024] Open
Abstract
Background The effect of immune cells on autoimmune diseases (ADs) complicated by non-Hodgkin lymphoma (NHL) has been widely recognized, but a causal relationship between regulatory T cell (Treg) immune traits and ADs complicated by NHL remains debated. Methods Aggregate data for 84 Treg-related immune traits were downloaded from the Genome-Wide Association Study (GWAS) catalog, and GWAS data for diffuse large B-cell lymphoma (DLBCL; n=315243), follicular lymphoma (FL; n=325831), sjögren's syndrome (SS; n=402090), rheumatoid arthritis (RA; n=276465), dermatopolymyositis (DM; n=311640), psoriasis (n=407876), atopic dermatitis (AD; n=382254), ulcerative colitis (UC; n=411317), crohn's disease(CD; n=411973) and systemic lupus erythematosus (SLE; n=307587) were downloaded from the FinnGen database. The inverse variance weighting (IVW) method was mainly used to infer any causal association between Treg-related immune traits and DLBCL, FL, SS, DM, RA, Psoriasis, AD, UC, CD and SLE, supplemented by MR-Egger, weighted median, simple mode, and weighted mode. Moreover, we performed sensitivity analyses to assess the validity of the causal relationships. Results There was a potential genetic predisposition association identified between CD39+ CD8br AC, CD39+ CD8br % T cell, and the risk of DLBCL (OR=1.51, p<0.001; OR=1.25, p=0.001) (adjusted FDR<0.1). Genetic prediction revealed potential associations between CD25++ CD8br AC, CD28- CD25++ CD8br % T cell, CD39+ CD8br % CD8br, and the risk of FL (OR=1.13, p=0.022; OR=1.28, p=0.042; OR=0.90, p=0.016) (adjusted FDR>0.1). Furthermore, SLE and CD exhibited a genetically predicted potential association with the CD39+ CD8+ Tregs subset. SS and DM were possibly associated with an increase in the quantity of the CD4+ Tregs subset; RA may have reduced the quantity of the CD39+ CD8+ Tregs subset, although no causal relationship was identified. Sensitivity analyses supported the robustness of our findings. Conclusions There existed a genetically predicted potential association between the CD39+ CD8+ Tregs subset and the risk of DLBCL, while SLE and CD were genetically predicted to be potentially associated with the CD39+ CD8+ Tregs subset. The CD39+ CD8+ Tregs subset potentially aided in the clinical diagnosis and treatment of SLE or CD complicated by DLBCL.
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Affiliation(s)
- Qi Liu
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xintong Zhou
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Kunjing Liu
- School of Traditional Chinese Medicine Department, Beijing University of Chinese Medicine, Beijing, China
| | - Yimin Wang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Cun Liu
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
| | - Chundi Gao
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
| | - Qingqing Cai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Changgang Sun
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
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Tsai YG, Liao PF, Hsiao KH, Wu HM, Lin CY, Yang KD. Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus. Front Immunol 2023; 14:1230264. [PMID: 37771588 PMCID: PMC10522836 DOI: 10.3389/fimmu.2023.1230264] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/15/2023] [Indexed: 09/30/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous multisystem inflammatory disease with wide variability in clinical manifestations. Natural arising CD4+ regulatory T cells (Tregs) play a critical role in maintaining peripheral tolerance by suppressing inflammation and preventing autoimmune responses in SLE. Additionally, CD8+ regulatory T cells, type 1 regulatory T cells (Tr1), and B regulatory cells also have a less well-defined role in the pathogenesis of SLE. Elucidation of the roles of various Treg subsets dedicated to immune homeostasis will provide a novel therapeutic approach that governs immune tolerance for the remission of active lupus. Diminished interleukin (IL)-2 production is associated with a depleted Treg cell population, and its reversibility by IL-2 therapy provides important reasons for the treatment of lupus. This review focuses on the pathogenesis and new therapeutics of human Treg subsets and low-dose IL-2 therapy in clinical benefits with SLE.
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Affiliation(s)
- Yi-Giien Tsai
- Department of Pediatrics, Changhua Christian Children’s Hospital, Changhua, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Pei-Fen Liao
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Kai-Hung Hsiao
- Department of Allergy, Immunology and Rheumatology, Changhua Christian Hospital, Changhua, Taiwan
| | - Hung-Ming Wu
- Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
| | - Ching-Yuang Lin
- Division of Pediatric Nephrology, Children’s Hospital, China Medical University Hospital, Taichung, Taiwan
| | - Kuender D. Yang
- Department of Pediatrics, Mackay Memorial Hospital, New Taipei City, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells. Pediatr Res 2022; 92:1099-1107. [PMID: 34952938 DOI: 10.1038/s41390-021-01882-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 11/05/2021] [Accepted: 11/11/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy. METHODS We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients. RESULTS We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells. CONCLUSIONS Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN. IMPACT In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.
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Singh RP, Hahn BH, Bischoff DS. Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8 + and CD4 + Regulatory T Cells in Lupus. Front Immunol 2021; 12:718359. [PMID: 34867947 PMCID: PMC8640085 DOI: 10.3389/fimmu.2021.718359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45β and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 μg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.
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Affiliation(s)
- Ram P Singh
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States.,Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Bevra H Hahn
- Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - David S Bischoff
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States.,Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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Singh RP, Bischoff DS, Hahn BH. CD8 + T regulatory cells in lupus. RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2021; 2:147-156. [PMID: 35880241 PMCID: PMC9242525 DOI: 10.2478/rir-2021-0021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/23/2021] [Indexed: 04/11/2023]
Abstract
T regulatory cells (Tregs) have a key role in the maintenance of immune homeostasis and the regulation of immune tolerance by preventing the inflammation and suppressing the autoimmune responses. Numerical and functional deficits of these cells have been reported in systemic lupus erythematosus (SLE) patients and mouse models of SLE, where their imbalance and dysregulated activities have been reported to significantly influence the disease pathogenesis, progression and outcomes. Most studies in SLE have focused on CD4+ Tregs and it has become clear that a critical role in the control of immune tolerance after the breakdown of self-tolerance is provided by CD8+ Tregs. Here we review the role, cellular and molecular phenotypes, and mechanisms of action of CD8+ Tregs in SLE, including ways to induce these cells for immunotherapeutic modulation in SLE.
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Affiliation(s)
- Ram P. Singh
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA
- Department of Medicine, Division of Rheumatology, University of California, Los Angeles, USA
| | - David S. Bischoff
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Bevra H. Hahn
- Department of Medicine, Division of Rheumatology, University of California, Los Angeles, USA
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
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Datta SK. Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future). Front Immunol 2021; 12:629807. [PMID: 33936042 PMCID: PMC8080879 DOI: 10.3389/fimmu.2021.629807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/23/2021] [Indexed: 12/11/2022] Open
Abstract
Autoantigen-directed tolerance can be induced by certain nucleosomal histone peptide epitope/s in nanomolar dosage leading to sustained remission of disease in mice with spontaneous SLE. By contrast, lupus is accelerated by administration of intact (whole) histones, or whole nucleosomes in microparticles from apoptotic cells, or by post-translationally acetylated histone-peptides. Low-dose therapy with the histone-peptide epitopes simultaneously induces TGFβ and inhibits IL-6 production by DC in vivo, especially pDC, which then induce CD4+CD25+ Treg and CD8+ Treg cells that suppress pathogenic autoimmune response. Both types of induced Treg cells are FoxP3+ and act by producing TGFβ at close cell-to-cell range. No anaphylactic adverse reactions, or generalized immunosuppression have been detected in mice injected with the peptides, because the epitopes are derived from evolutionarily conserved histones in the chromatin; and the peptides are expressed in the thymus during ontogeny, and their native sequences have not been altered. The peptide-induced Treg cells can block severe lupus on adoptive transfer reducing inflammatory cell reaction and infiltration in the kidney. In Humans, similar potent Treg cells are generated by the histone peptide epitopes in vitro in lupus patients’ PBMC, inhibiting anti-dsDNA autoantibody and interferon production. Furthermore, the same types of Treg cells are generated in lupus patients who are in very long-term remission (2-8 years) after undergoing autologous hematopoietic stem cell transplantation. These Treg cells are not found in lupus patients treated conventionally into clinical remission (SLEDAI of 0); and consequently they still harbor pathogenic autoimmune cells, causing subclinical damage. Although antigen-specific therapy with pinpoint accuracy is suitable for straight-forward organ-specific autoimmune diseases, Systemic Lupus is much more complex. The histone peptide epitopes have unique tolerogenic properties for inhibiting Innate immune cells (DC), T cells and B cell populations that are both antigen-specifically and cross-reactively involved in the pathogenic autoimmune response in lupus. The histone peptide tolerance is a natural and non-toxic therapy suitable for treating early lupus, and also maintaining lupus patients after toxic drug therapy. The experimental steps, challenges and possible solutions for successful therapy with these peptide epitopes are discussed in this highly focused review on Systemic Lupus.
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Affiliation(s)
- Syamal K Datta
- Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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7
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Kuo HL, Huang CC, Lin TY, Lin CY. IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy. Nephrol Dial Transplant 2019; 33:248-256. [PMID: 28339909 DOI: 10.1093/ndt/gfw397] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 09/28/2016] [Indexed: 12/17/2022] Open
Abstract
Background Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN. Methods The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis. Results CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes. Conclusions IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.
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Affiliation(s)
- Huey-Liang Kuo
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, China.,Department of Medicine, Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan, China
| | - Chiu-Ching Huang
- Department of Medicine, Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan, China
| | - Tze-Yi Lin
- Department of Pathology, China Medical University Hospital, Taichung, Taiwan, China
| | - Ching-Yuang Lin
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, China.,Clinical Immunological Center, Children's Hospital, China Medical University, Taichung, Taiwan, China
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8
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Tsai YG, Yang KD, Wen YS, Hung CH, Chien JW, Lin CY. Allergen-specific immunotherapy enhances CD8 + CD25 + CD137 + regulatory T cells and decreases nasal nitric oxide. Pediatr Allergy Immunol 2019; 30:531-539. [PMID: 30968455 DOI: 10.1111/pai.13061] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/31/2018] [Accepted: 01/18/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND 4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8+ Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8+ CD25+ CD137+ Treg suppressive function to decrease nasal nitric oxide (nNO) levels. METHODS Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8+ CD25+ T cells and suppressive function of CD8+ CD25+ CD137+ Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8+ CD25+ CD137+ T cells was analyzed by Western blotting. RESULTS Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8+ T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8+ CD25+ CD137+ population in PBMCs. Pam3CSK4-stimulated CD8+ CD25+ CD137+ Tregs induced IL-10 and TGF-β and suppressed CD4+ CD25- T-cell proliferation mainly by cell contact inhibition. CD8+ CD25+ CD137+ Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8+ CD25+ T cells decreased Pam3CSK4-activated Foxp3 expression. CONCLUSION Der p IT expanded CD8+ CD25+ CD137+ Tregs and decreased nNO levels. Induced CD137 expression on CD8+ CD25+ Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.
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Affiliation(s)
- Yi-Giien Tsai
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan
| | - Kuender D Yang
- Mackay Children's Hospital, and Institute of Biomedical Sciences, Mackay Medical College, Taipei, Taiwan
| | - Yung-Sung Wen
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Hsing Hung
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jien-Wen Chien
- Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan
| | - Ching-Yuang Lin
- Clinical Immunological Center, China Medical University Hospital, College of Medicine, Division of Pediatric Nephrology, China Medical University, Taichung, Taiwan
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9
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Mesquita D, Kirsztajn GM, Franco MF, Reis LA, Perazzio SF, Mesquita FV, Ferreira VDS, Andrade LEC, de Souza AWS. CD4 + T helper cells and regulatory T cells in active lupus nephritis: an imbalance towards a predominant Th1 response? Clin Exp Immunol 2017; 191:50-59. [PMID: 28945272 DOI: 10.1111/cei.13050] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2017] [Indexed: 01/22/2023] Open
Abstract
The objective of this study was to evaluate the frequency of CD4+ T cell subsets in peripheral blood mononuclear cells (PBMC), urine and renal tissue from patients with lupus nephritis (LN). PBMC and urinary cells were collected from 17 patients with active LN, 20 disease controls (DC) with primary glomerulonephritis and 10 healthy controls (HC) and were analysed by flow cytometry with markers for T helper type 1 (Th1), Th2, Th17 and regulatory T cells (Treg ) cells. T cell subsets were assessed by immunohistochemistry from LN biopsy specimens from 12 LN patients. T cell subtypes in PBMC were re-evaluated at 6 months of therapy. CD4+ T cells were decreased in PBMC in LN compared with DC and HC (P = 0·0001). No differences were observed in urinary CD4+ T cell subsets between LN and DC. The frequency of urinary Th17 cells was higher in patients with non-proliferative than in proliferative LN (P = 0·041). CD3+ and T-box 21 ( Tbet+) cells were found in glomeruli and interstitium of LN patients, while forkhead box protein 3 (FoxP3), retinoid-related orphan receptor gamma (ROR-γ) and GATA binding protein 3 (GATA-3) were present only in glomeruli. Th1 cells in PBMC were correlated negatively with urinary Th1 cells (Rho = -0·531; P = 0·028) and with Tbet in renal interstitium (Rho = -0·782; P = 0·004). At 6 months, LN patients showed an increase in Th17 cells in PBMC. In conclusion, the inverse association between Th1 cells from PBMC and urinary/renal tissue indicate a role for Th1 in LN pathophysiology. Urinary Th17 cells were associated with less severe LN, and Th17 increased in PBMC during therapy. Urinary CD4+ T cells were not different between LN and DC.
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Affiliation(s)
- D Mesquita
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - G Mastroianni Kirsztajn
- Nephrology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - M F Franco
- Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - L A Reis
- Nephrology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - S F Perazzio
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - F V Mesquita
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - V da Silva Ferreira
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - L E Coelho Andrade
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
| | - A W Silva de Souza
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo-SP, Brazil
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Abstract
T regulatory cells (Tregs) represent a phenotypically and functionally heterogeneous group of lymphocytes that exert immunosuppressive activities on effector immune responses. Tregs play a key role in maintaining immune tolerance and homeostasis through diverse mechanisms which involve interactions with components of both the innate and adaptive immune systems. As in many autoimmune diseases, Tregs have been proposed to play a relevant role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease characterized by a progressive breakdown of tolerance to self-antigens and the presence of concomitant hyperactive immune responses. Here, we review how Tregs dysfunction in SLE has been manipulated experimentally and preclinically in the attempt to restore, at last in part, the immune disturbances in the disease.
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Abstract
Regulatory T cells (Tregs) represent a cell type that promotes immune tolerance to autologous components and maintains immune system homeostasis. The abnormal function of Tregs is relevant to the pathogenesis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other autoimmune diseases. Therefore, therapeutic modulation of Tregs could be a potent means of treating autoimmune diseases. Human Tregs are diverse, however, and not all of them have immunosuppressive effects. Forkhead box P3 (Foxp3), a pivotal transcription factor of Tregs that is crucial in maintaining Treg immunosuppressive function, can be expressed heterogeneously or unstably across Treg subpopulations. Insights into modulating Treg differentiation on the level of DNA transcription or protein modification may improve the success of Treg modifying immunotherapies. In this review, we will summarize three main prospects: the regulatory mechanism of Foxp3, the influence on Foxp3 and Tregs in autoimmune diseases, then finally, how Tregs can be used to treat autoimmune diseases.
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Affiliation(s)
- G. Moroni
- Nephrological Unit, Divisione di Nefrologia e Dialisi, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - C. Ponticelli
- Nephrological Unit, Humanitas Clinical and Research Center, Rozzano (Milano), Italy
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13
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Ilan Y, Ben Ya'acov A, Shabbat Y, Gingis-Velitski S, Almon E, Shaaltiel Y. Oral administration of a non-absorbable plant cell-expressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis. World J Gastroenterol 2016; 22:8760-8769. [PMID: 27818591 PMCID: PMC5075550 DOI: 10.3748/wjg.v22.i39.8760] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/21/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the immunomodulatory effect of oral administration of PRX-106 in the high-fat diet model. METHODS For 22 wk, C57BL/6 HFD-fed mice received daily oral treatments with BY-2 cells expressing recombinant anti-tumor necrosis factor alpha fusion protein (PRX-106). Mice were followed for serum liver enzyme and triglyceride levels, liver histology and intrahepatic and systemic FACS. RESULTS The orally administered non-absorbable PRX-106 was biologically active. Altered distribution of CD4+CD25+FoxP3+ between the liver and spleen and an increase in the intrasplenic-to-intrahepatic CD4+CD25+FoxP3+ ratio and a decrease in the intrasplenic-to-intrahepatic CD8+CD25+FoxP3+ ratio were observed. An increase in intrahepatic NKT cells and a decrease in the intrasplenic-to-intrahepatic NKT ratio were noted. Assessment of the CD4-to-CD8 ratios showed sequestration of CD8+ lymphocytes in the liver. These effects were associated with a decrease in serum triglyceride levels, decrease in the aspartate aminotransferase levels, serum glucose levels, and HOMA-IR score. A decrease in hepatic triglycerides content was observed in the high dose-treated mice. CONCLUSION Orally administered PRX-106 shows biological activity and exerts an immunomodulatory effect, alleviating liver damage. The data suggest that PRX-106 may provide an oral immunotherapy for nonalcoholic steatohepatitis.
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Zahran AM, Elsayh KI, Saad K, Eloseily EMA, Osman NS, Alblihed MA, Badr G, Mahmoud MH. Effects of royal jelly supplementation on regulatory T cells in children with SLE. Food Nutr Res 2016; 60:32963. [PMID: 27887663 PMCID: PMC5124115 DOI: 10.3402/fnr.v60.32963] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 10/16/2016] [Accepted: 10/27/2016] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND OBJECTIVE To our knowledge, no previous studies have focused on the immunomodulatory effects of fresh royal jelly (RJ) administration on systemic lupus erythematosus (SLE) in humans. Our aim was to study the effect of fresh RJ administration on the disease course in children with SLE with some immunological markers (CD4+ and CD8+ regulatory T cells and T lymphocytes apoptosis). METHODS This was an open-label study in which 20 SLE children received 2 g of freshly prepared RJ daily, for 12 weeks. RESULTS The percentages of CD4+ CD25+high FOXP3+cells (CD4+ regulatory T cells) and CD8+CD25+high FOXP3+cells (CD8+ regulatory T cells) were significantly increased after RJ treatment when compared with baseline values. Apoptotic CD4 T lymphocytes were significantly decreased after RJ therapy when compared with baseline values and the control group. CONCLUSION This is the first human study on the effect of RJ supplementation in children with SLE. Our results showed improvements with 3-month RJ treatment with regard to the clinical severity score and laboratory markers for the disease. At this stage, it is a single study with a small number of patients, and a great deal of additional wide-scale randomized controlled studies are needed to critically validate the efficacy of RJ in SLE.
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Affiliation(s)
- Asmaa M Zahran
- Clinical Pathology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Khalid I Elsayh
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Khaled Saad
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt; ;
| | - Esraa M A Eloseily
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Naglaa S Osman
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamd A Alblihed
- Medical Biochemistry Department, College of Medicine, Taif University, Taif, Kingdom of Saudi Arabia
| | - Gamal Badr
- Zoology Department, Laboratory of Immunology & Molecular Physiology, Faculty of Science, Assiut University, Assiut, Egypt
| | - Mohamed H Mahmoud
- Deanship of Scientific Research, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Food Science and Nutrition Department, National Research Center, Dokki, Cairo, Egypt
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Geng S, Zhang H, Zhou X, He Y, Zhang X, Xie X, Li C, He Z, Yu Q, Zhong Y, Lowrie DB, Zheng G, Wang B. Diabetes tolerogenic vaccines targeting antigen-specific inflammation. Hum Vaccin Immunother 2015; 11:522-30. [PMID: 25622092 DOI: 10.1080/21645515.2014.1004024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Tolerance controls the magnitude of inflammation, and balance between beneficial and harmful effects of inflammation is crucial for organ function and survival. Inadequate tolerance leads to various inflammatory diseases. Antigen specific tolerance is ideal for inflammation control as alternative anti-inflammatory interventions are non-specific and consequently increase the risk of infection and tumorigenesis. With inherent antigen specificity, tolerogenic vaccines are potentially ideal for control of inflammation. Although the concept of tolerogenic vaccines is still in its infancy, tolerogenic mucosal vaccines and specific immuno-therapies have long been proven effective in pioneering examples. Now a body of evidence supporting the concept of tolerogenic vaccines has also accumulated. Here we comment on recent successes of the tolerogenic vaccine concept, present new evidence with a type 1 diabetes vaccine as an example and draw conclusions on the advantages and potential for inflammatory disease control at the bedside.
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Affiliation(s)
- Shuang Geng
- a Key Laboratory of Medical Molecular Virology of MOH and MOE ; Fudan University Shanghai Medical College ; Shanghai , China
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Lin HH, Huang CC, Lin TY, Lin CY. p-Cresol mediates autophagic cell death in renal proximal tubular cells. Toxicol Lett 2015; 234:20-9. [DOI: 10.1016/j.toxlet.2015.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 01/27/2015] [Accepted: 02/06/2015] [Indexed: 10/24/2022]
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Abstract
Lupus nephritis is a serious potential feature of systemic lupus erythematous (SLE). Though SLE typically cycles through periods of flares and remission, patients often eventually succumb to end-stage kidney or cardiovascular damage. This review of the pathogenesis of lupus nephritis examines the role of the complement cascade; the significance of autoantibodies, the breaking of tolerance, and the implications of altered apoptosis in breaking tolerance; and the contributions of adaptive immunity and cross-talk with the innate immune system in driving renal damage. Delineation of basic mechanisms underlying the development of acute and chronic renal damage in lupus nephritis can result in the continued development of more specific and effective treatments.
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Affiliation(s)
- Rosalie M Sterner
- Department of Laboratory Medicine & Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA ; Medical Scientist Training Program, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Stella P Hartono
- Department of Laboratory Medicine & Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA ; Medical Scientist Training Program, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
| | - Joseph P Grande
- Department of Laboratory Medicine & Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA
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