ABSTRACT
The prevalence of autoimmune disorders in affluent countries has reached epidemic proportions. Over the past 50 years, a reverse trend between the frequency of infectious diseases and the incidence of autoimmune and allergic diseases led to the so-called 'hygiene hypothesis'. Given the epidemiological evidence and recent experimental data, we propose that this concept should also include metabolic pressure secondary to exposure to excessive daily caloric intake and overnutrition. We discuss how metabolic workload can modulate immunological tolerance and review the molecular mechanisms and the state of the art of the field. We also critically evaluate possibilities for restoring immunological homeostasis under conditions of metabolic pressure.
Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Homeostasis/immunology , Hygiene Hypothesis , Self Tolerance/immunology , Animals , Humans , Metabolic Networks and Pathways/immunology , Models, Immunological , Nutritional Physiological Phenomena/immunologyABSTRACT
Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.
Subject(s)
Forkhead Transcription Factors/genetics , Glycolysis/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Adult , Alternative Splicing , Autoimmunity , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , CD4-Positive T-Lymphocytes/classification , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Case-Control Studies , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Exons , Fatty Acids/metabolism , Female , Forkhead Transcription Factors/antagonists & inhibitors , Forkhead Transcription Factors/metabolism , Gene Knockdown Techniques , Genetic Variation , Humans , In Vitro Techniques , Male , Metabolome , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/immunology , Multiple Sclerosis, Relapsing-Remitting/metabolism , Oxidation-Reduction , Phosphopyruvate Hydratase/antagonists & inhibitors , Phosphopyruvate Hydratase/genetics , Phosphopyruvate Hydratase/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/immunology , T-Lymphocytes, Regulatory/classification , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Young AdultABSTRACT
Brain ischemia inhibits immune function systemically, with resulting infectious complications. Whether in stroke different immune alterations occur in brain and periphery and whether analogous mechanisms operate in these compartments remains unclear. Here we show that in patients with ischemic stroke and in mice subjected to middle cerebral artery occlusion, natural killer (NK) cells display remarkably distinct temporal and transcriptome profiles in the brain as compared to the periphery. The activation of catecholaminergic and hypothalamic-pituitary-adrenal axis leads to splenic atrophy and contraction of NK cell numbers in the periphery through a modulated expression of SOCS3, whereas cholinergic innervation-mediated suppression of NK cell responses in the brain involves RUNX3. Importantly, pharmacological or genetic ablation of innervation preserved NK cell function and restrained post-stroke infection. Thus, brain ischemia compromises NK cell-mediated immune defenses through mechanisms that differ in the brain versus the periphery, and targeted inhibition of neurogenic innervation limits post-stroke infection.
Subject(s)
Brain Ischemia/immunology , Brain/immunology , Killer Cells, Natural/immunology , Spleen/immunology , Aged , Animals , Brain Ischemia/complications , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Gene Expression Profiling , Humans , Infections/etiology , Infections/immunology , Male , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , TranscriptomeABSTRACT
Human CD4(+)CD25(hi)Foxp3(+)CD127(-) Treg and CD4(+)CD25(-)Foxp3(-) Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells.
Subject(s)
Fatty Acids/metabolism , Glucose/metabolism , Glycolysis , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , CD4 Antigens/metabolism , Cell Proliferation , Cells, Cultured , Forkhead Transcription Factors/metabolism , Humans , Interleukin-2 Receptor alpha Subunit/metabolism , Oxidation-Reduction , Proteomics , TranscriptomeABSTRACT
OBJECTIVE: To examine whether a weight loss intervention programme improves RA disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients. METHODS: We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with 28-joint DAS (DAS28) ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention (n = 20) or control group (n = 20). Diet intervention consisted of a hypocaloric diet of 1000-1500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and power Doppler ultrasound (PDUS)-34. Clinical disease activity, imaging, biomarkers, adipokines and patient-reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05. RESULTS: The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (P < 0.001). Routine Assessment of Patient Index Data 3 (RAPID3) improved, serum leptin decreased and serum adiponectin increased significantly within the diet group and between the groups (all P < 0.03). DAS28 decreased, 5.2 to 4.2, within the diet group (P < 0.001; -0.51 [95% CI -1.01, 0.00], P = 0.056, between groups). HAQ-Disability Index (HAQ-DI) improved significantly within the diet group (P < 0.04; P = 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS-34 -2.0 [95% CI -7.00, 3.1], P = 0.46 between groups). CONCLUSION: Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Synovitis , Humans , Leptin , Antirheumatic Agents/therapeutic use , Adiponectin , Diet, Reducing , Single-Blind Method , Obesity/complications , Obesity/therapy , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/therapy , Synovitis/drug therapy , Biomarkers , Severity of Illness IndexABSTRACT
During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.
Subject(s)
Autoimmune Diseases/immunology , Homeostasis/immunology , Animals , Autoimmunity/immunology , Dendritic Cells/immunology , Humans , Inflammation/immunology , T-Lymphocytes/immunologyABSTRACT
Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post-ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus-pituitary-adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.-Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang, Z., Yu, C., Zhang, F., Song, L., Dong, J.-F., La Cava, A., Sheth, K. N., Shi, F.-D. Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.
Subject(s)
Cerebral Hemorrhage/immunology , Aged , Animals , Brain Edema/diagnostic imaging , Cerebral Hemorrhage/diagnostic imaging , Disease Models, Animal , Disease Progression , Female , Hematoma/diagnostic imaging , Humans , Hypothalamo-Hypophyseal System/immunology , Immunity, Cellular , Killer Cells, Natural/immunology , Lymphopenia/immunology , Magnetic Resonance Imaging , Male , Mice , Mice, Inbred C57BL , Middle Aged , Neuroimmunomodulation , Pituitary-Adrenal System/immunology , Spleen/diagnostic imaging , Spleen/immunology , T-Lymphocytes/immunologyABSTRACT
There is a discrepancy between the in vitro anergic state of CD4(+)CD25(hi)FoxP3(+) regulatory T (Treg) cells and their in vivo proliferative capability. The underlying mechanism of this paradox is unknown. Here we show that the anergic state of Treg cells depends on the elevated activity of the mammalian target of rapamycin (mTOR) pathway induced by leptin: a transient inhibition of mTOR with rapamycin, before T cell receptor (TCR) stimulation, made Treg cells highly proliferative in the absence of exogenous interleukin-2 (IL-2). This was a dynamic and oscillatory phenomenon characterized by an early downregulation of the leptin-mTOR pathway followed by an increase in mTOR activation necessary for Treg cell expansion to occur. These data suggest that energy metabolism, through the leptin-mTOR-axis, sets responsiveness of Treg cells that use this information to control immune tolerance and autoimmunity.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/metabolism , Leptin/metabolism , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , CD4 Antigens/biosynthesis , Cell Proliferation/drug effects , Cells, Cultured , Clonal Anergy/drug effects , Clonal Anergy/genetics , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Forkhead Transcription Factors/biosynthesis , Humans , Interleukin-2/immunology , Interleukin-2/metabolism , Interleukin-2 Receptor alpha Subunit/biosynthesis , Leptin/immunology , Mice , Mice, Inbred C57BL , Signal Transduction , Sirolimus/pharmacology , Sirolimus/therapeutic use , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/immunologyABSTRACT
Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.
Subject(s)
Immunity, Innate/genetics , Inflammation/genetics , Leptin/genetics , Lupus Erythematosus, Systemic/genetics , Animals , Autoantibodies/biosynthesis , Autoantibodies/immunology , Autoimmunity/immunology , Disease Models, Animal , Humans , Immunity, Innate/drug effects , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/pathology , Leptin/antagonists & inhibitors , Leptin/therapeutic use , Lupus Erythematosus, Systemic/chemically induced , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/immunology , Mice , Mice, Inbred NZB , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Terpenes/toxicityABSTRACT
BACKGROUND AND PURPOSE: Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. METHODS: Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. RESULTS: By coupling transfer of labeled MOG35-55-specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG91-108 and MOG103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. CONCLUSIONS: Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.
Subject(s)
Brain Injuries/immunology , Brain Ischemia/immunology , Stroke/immunology , T-Lymphocytes/immunology , Adoptive Transfer/methods , Animals , Brain/immunology , Central Nervous System/immunology , Humans , Infarction, Middle Cerebral Artery/immunology , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein/immunologyABSTRACT
PURPOSE OF REVIEW: There has been great interest in understanding why T regulatory cells (Tregs) are reduced in number and/or in function in several autoimmune diseases including systemic lupus erythematosus (SLE). Although research has provided some answers, there is still much to learn. RECENT FINDINGS: Recent investigations on the mechanisms responsible for the impairment of the Tregs in SLE have identified relevant abnormalities in cellular and molecular pathways that have been instrumental in the design of studies in animal models and in the development of pilot immunotherapeutic studies in lupus patients. We review the progress made in the field in the last 5 years, discussing the mechanistic studies, together with the preclinical and clinical works that are moving forward the understanding of the physiopathology of Tregs in SLE.
Subject(s)
Lupus Erythematosus, Systemic/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Epigenesis, Genetic , Humans , Immune Tolerance/immunology , Interleukin-2/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/genetics , T-Lymphocyte Subsets/immunologyABSTRACT
Intracellular metabolism is central to cell activity and function. CD4(+)CD25(+) regulatory T cells (Tregs) that express the transcription factor FOXP3 play a pivotal role in the maintenance of immune tolerance to self. Recent studies showed that the metabolism and function of Tregs are influenced significantly by local environmental conditions and the availability of certain metabolites. It also was reported that defined metabolic programs associate with Treg differentiation, expression of FOXP3, and phenotype stabilization. This article reviews how metabolism modulates FOXP3 expression and Treg function, what environmental factors are involved, and how metabolic manipulation could alter Treg frequency and function in physiopathologic conditions.
Subject(s)
T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Animals , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , HumansABSTRACT
After its discovery as a key controller of metabolic function, leptin has been later extensively implicated in additional functions including important modulatory activities on the innate and adaptive immune response. This review analyzes the known implications of leptin in multiple inflammatory conditions, including autoimmune diseases, and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses.
Subject(s)
Autoimmunity , Inflammation/immunology , Leptin/physiology , Adaptive Immunity , Animals , Humans , Immunity, Innate , Inflammation/physiopathology , Leptin/deficiency , Leptin/genetics , Mice , Obesity/metabolism , Obesity/physiopathologyABSTRACT
Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain.
Subject(s)
Brain Infarction/immunology , Brain Infarction/physiopathology , Brain Ischemia/immunology , Brain/immunology , Immunity, Innate/immunology , Killer Cells, Natural/immunology , Stroke/immunology , Animals , Brain/cytology , Brain Infarction/etiology , Brain Ischemia/complications , Chemokine CX3CL1/metabolism , DNA-Binding Proteins/genetics , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/metabolism , Stroke/complicationsABSTRACT
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.
Subject(s)
Autoimmunity/immunology , Immune Tolerance/immunology , Immunotherapy/methods , Lupus Erythematosus, Systemic/immunology , T-Lymphocytes, Regulatory/immunology , Humans , Lupus Erythematosus, Systemic/therapyABSTRACT
The proinflammatory activity of IL-17-producing Th17 cells has been associated with the pathogenesis of several autoimmune diseases. In this article, we provide direct evidence for a role of IL-17 in the pathogenesis of systemic lupus erythematosus (SLE). The induction of SLE by pristane in IL-17-sufficient wild-type mice did not occur in IL-17-deficient mice, which were protected from development of lupus autoantibodies and glomerulonephritis. The protection from SLE in IL-17-deficient mice was associated with a reduced frequency of CD3(+)CD4(-)CD8(-) double-negative T cells and an expansion of CD4(+) regulatory T cells, and did not depend on Stat-1 signaling. These data affirm the key role of IL-17 in the pathogenesis of SLE and strengthen the support for IL-17 blockade in the therapy of SLE.
Subject(s)
Autoantibodies/immunology , Interleukin-17/immunology , Lupus Erythematosus, Systemic/immunology , Lupus Nephritis/immunology , Animals , Autoantibodies/blood , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fluorescent Antibody Technique , Interleukin-17/deficiency , Interleukin-17/genetics , Lupus Erythematosus, Systemic/chemically induced , Lupus Erythematosus, Systemic/genetics , Lupus Nephritis/blood , Lupus Nephritis/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred NZB , Mice, Inbred Strains , Mice, Knockout , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Terpenes , Th17 Cells/immunology , Th17 Cells/metabolismABSTRACT
To prevent autoimmunity, anergy of autoreactive B cells needs to be maintained, together with the suppression of hyperactive B cells. We previously reported that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) can directly suppress autoantibody-producing autoreactive B cells in systemic lupus erythematosus. In this article, we show that Tregs can also reduce the production of autoantibodies in (NZB × NZW)F1 mouse lupus B cells by promoting B cell anergy, both in vitro and in vivo. This phenomenon associated with a reduction in Ca(2+) flux in B cells, and CTLA-4 blockade inhibited the effects of Tregs on anergic lupus B cells. These findings identify a new mechanism by which Tregs can control production of autoantibodies in lupus B cells and, more generally, B cell activity in physiopathological conditions.
Subject(s)
Autoimmunity/immunology , B-Lymphocytes/immunology , Clonal Anergy/immunology , Lupus Erythematosus, Systemic/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Antibody Formation/immunology , Autoantibodies/immunology , Cell Separation , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Mice , Mice, Inbred BALB CABSTRACT
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
Subject(s)
Genetic Predisposition to Disease/genetics , Leptin/genetics , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide/genetics , Case-Control Studies , Genotype , HumansABSTRACT
Programmed death-1 (PD-1) usually acts as a negative signal for T cell activation, and its expression on CD8(+)Foxp3(+) T cells is required for their suppressive capacity. In this study, we show that PD-1 signaling is required for the maintenance of functional regulatory CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD4(+) T(reg)) that can control autoimmunity in (New Zealand Black × New Zealand White)F1 lupus mice. PD-1 signaling induced resistance to apoptosis and prolonged the survival of CD4(+) T(reg). In vivo, the blockade of PD-1 with a neutralizing Ab reduced PD-1 expression on CD4(+) T(reg) (PD1(lo)CD4(+) T(reg)). PD1(lo)CD4(+) T(reg) had an increased ability to promote B cell apoptosis and to suppress CD4(+) Th as compared with CD4(+) T(reg) with elevated PD-1 expression (PD1(hi)CD4(+) T(reg)). When PD-1 expression on CD4(+) T(reg) was blocked in vitro, PD1(lo)CD4(+) T(reg) suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4(+) T(reg) depended on PD-1 expression and that a fine-tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses.