Papers by Stamatis-Nick Liossis
Seminars in Arthritis and Rheumatism, 2018
OBJECTIVE Regulatory B cells (Bregs) are a new subset of B cells with immunoregulatory functions,... more OBJECTIVE Regulatory B cells (Bregs) are a new subset of B cells with immunoregulatory functions, mainly through IL-10 production. Bregs suppress inflammatory Th1 and Th17 differentiation and induce Tregs suppressing autoimmune diseases. The aim of the study was to review the literature related to Bregs in autoimmune rheumatic diseases (ARDs). METHODS A literature review of publications in PUBMED published in English was performed using the relevant combinations of terms. RESULTS All relevant publications are discussed. Overall, recent studies in rheumatic diseases found Bregs to be decreased in ANCA-associated vasculitides (AAV) and in systemic sclerosis (SSc), particularly in SSc-associated lung fibrosis. In AAV Bregs levels are negatively correlated with autoantibody levels whereas in SSc this association is less clear but there is an inverse association with Th1 and Th17 cells. In rheumatoid arthritis (RA), Bregs were decreased, particularly in RA-associated lung fibrosis. In psoriatic arthritis IL-10 + Bregs are decreased and inversely associated with Th1 and Th17 cells. In systemic lupus erythematosus (SLE), the role of Bregs is unclear. In experimental diseases, when Bregs were expanded ex-vivo, they ameliorated established disease. CONCLUSION Bregs appear to be a new player in the pathogenesis of ARDs, and may offer a new strategy for therapeutic intervention.
Rheumatology, 2006
Objectives. CD40L is a costimulatory molecule and an early activation marker of T-lymphocytes. Ba... more Objectives. CD40L is a costimulatory molecule and an early activation marker of T-lymphocytes. Based on the hypothesis that activated T-cells may play a role in the pathogenesis of psoriatic arthritis (PsA), we evaluated the level of CD40L expression on T-cells from patients with PsA. Methods. We analysed 12 patients with PsA, six patients with rheumatoid arthritis (RA) and four healthy volunteers. T-cell surface expression of CD40L was evaluated using two-colour flow cytometry in (i) the resting state and (ii) following stimulation with phorbol myristate acetate/ionomycin, with or without ciclosporin (CsA)-mediated inhibition. Results. Expression of CD40L was significantly increased on activated T-cells from patients with PsA, particularly those with active disease, when compared with normal individuals and patients with RA (mean percentages of CD3 þ CD40L þ cells: 23.74, 11.59 and 9.57% for patients with active PsA, patients with RA and healthy volunteers, respectively). CsA-mediated inhibition of CD40L induction was equally effective in all study groups. Conclusion. CD40L is overexpressed on T-cells from patients with active PsA. This may indicate a role for CD40L in PsA pathogenesis. Larger-scale studies are warranted to address these issues.
OBJECTIVES The activity of the Wnt pathway, a critical mediator of fibrosis, is regulated by Dick... more OBJECTIVES The activity of the Wnt pathway, a critical mediator of fibrosis, is regulated by Dickkopf-1 (Dkk-1). Dkk-1 is absent from scleroderma skin in contrast to skin from healthy subjects where it is clearly expressed. There are no data on circulating levels and function of Dkk-1 in patients with systemic sclerosis (SSc). Our objectives are to assess: i) circulating and functional levels of Dkk-1 in patients with SSc and ii) whether the striking lack of Dkk-1 skin expression is also evident in a) clinically uninvolved skin from patients with SSc and b) very early disease prior to skin thickening. METHODS Circulating Dkk-1 levels were measured in 50 patients with SSc and 50 controls. Skin biopsies were obtained from SSc patients from a) clinically involved skin b) clinically uninvolved skin, c) oedematous skin prior to skin thickening. RESULTS Circulating and functional Dkk-1 levels were similar in patients with SSc and controls. Healthy skin displayed a high Dkk-1 immuno-expres...
Frontiers in Medicine
Systemic lupus erythematosus (SLE) is a chronic autoimmune multisystem disease with a variable pr... more Systemic lupus erythematosus (SLE) is a chronic autoimmune multisystem disease with a variable presentation and manifestations ranging from mild to severe or even life-threatening. There is an ongoing and unmet need for novel, disease-specific, effective and safe treatment modalities. The aim of this review is to summarize data on SLE treatment that have emerged over the last 3 years. We will put emphasis on studies evaluating potential treatments on severe lupus manifestations such as lupus nephritis. Despite the existence of several therapeutic agents in SLE, the disease keeps causing significant morbidity. It is encouraging that a variety of therapeutic options are currently under investigation, although there are occasional trial failures.
Abstracts accepted for Publication
Background: Our group, among others, has shown that B cell depletion therapy may improve skin thi... more Background: Our group, among others, has shown that B cell depletion therapy may improve skin thickening and interstitial lung disease (ILD) related to systemic sclerosis (SSc). All studies assessing the clinical efficacy of B cell depletion therapy in SSc have recruited patients with established disease fulfilling the old classification criteria. In our previous studies we have found that patients with shorter disease duration had a better clinical response to RTX. Objectives: It is unknown whether treatment in very early SSc can affect long term outcomes. We aimed at assessing the effect of rituximab (RTX) in patients with very early SSc. Methods: We report 2 cases where RTX was administered within 24 months from the appearance of Raynaud's. Results: A 56 year-year-old female with an 18-month history of Raynaud's developed interstitial lung disease (ILD) with extensive ground glass lesions, a normal FVC (82%) but decreased DLco (44%). A diagnosis of SSc was made based on the presence of positive anti-centromere antibodies, puffy fingers, telangiectasias, positive capillaroscopy, ILD and Raynaud's. Six months following RTX treatment, her PFT's had increased (FVC 94% and DLco 55%) and chest HRCT showed an obvious improvement. One year later the patient no longer reported dyspnea. She remained on RTX for 5 years with no respiratory symptoms, stable PFTs and no evidence of disease progression. The second case is a 27-year old female with a 1-year history of Raynaud's, puffy fingers, positive anti-Scl70 and capillaroscopy. Within a few months her skin thickened rapidly reaching an MRSS of 12 and developed tendon friction rubs. Six months following RTX treatment skin thickening had almost resolved; she only had mild sclerodactyly. Tendon friction rubs disappeared. The patient received 8 consecutive RTX courses throughout a period of 4 years. During this period the patient remained in a steady clinical condition with no signs of disease progression. Conclusion: It is generally accepted that autoimmunity/immune dysregulation and vasculopathy are the primary events in SSc that eventually trigger the fibrotic process. Based on this pathogenetic model, one can hypothesize that a therapeutic intervention very early in the disease course, prior to the appearance of fibrotic manifestations could potentially prevent permanent organ damage. Our data suggest that there may be a window of opportunity in SSc. This is why we propose that large scale, controlled studies assessing the efficacy of RTX (or other immune based therapies such as mycophenolate) in patients with very early disease are highly needed.
Saturday, 15 June 2019
CCL2, CXCL10, TNF-a, and IFN-a were detected in PM/DM-ILD cases, suggesting the pathological invo... more CCL2, CXCL10, TNF-a, and IFN-a were detected in PM/DM-ILD cases, suggesting the pathological involvement of activated macrophages, type 1 T helper (Th1) cells, and neutrophils (ref 1, 2). However, investigation of the pathomechanism using serum cytokines remains insufficient in PM/ DM-ILD. We hypothesised that multiple inflammatory cytokine pathways related to the above inflammatory cells would be involved in the pathomechanism of PM/DM-ILD. Objectives: We measured serum cytokine levels before and during treatment of patients with PM/DM-ILD and examined the associated pathomechanism. Methods: Serum cytokines were collected from 40 PM/DM-ILD patients. Principal components analysis (PCA) and cluster analysis were used to classify patients into subgroups. We compared cytokine profile of the survivors and dead patients as well as anti-MDA5 antibody-associated ILD and anti-ARS antibody-associated ILD. We also examined the association of various cytokines with disease activity indicators and prognosis of ILD. Results: PCA revealed that the diversity of cytokines was driven by three groups: (1) neutrophilic and M1-macrophage-driven cytokines, (2) Th1 celldriven and M2-macrophage-induced cytokines, and (3) M2-macrophagedriven cytokine. Based on cluster analysis, patients were classified into two subgroups according to the cytokine levels of all groups (Figure A). Ninety percent of patients who died of ILD were included in clusters with high cytokine levels (Figure B). Serum cytokine levels of all groups were significantly higher in the anti-MDA5 antibody-positive patients than in the anti-ARS antibody-positive patients. Factors of poor prognosis in PM/DM-ILD correlated significantly with serum cytokine levels of groups 1 and 2. Among the 3 groups, serum cytokine levels of group 1 were significantly higher initially and at 2 and 4 weeks in the death group. Conclusion: These findings suggest that the activation of monocytes, macrophages, and Th1 cells, and neutrophils plays a role in the pathomechanism. Group 1 cytokines could be efficient biomarkers for predicting prognosis of PM/DM-ILD.
Arthritis research & therapy, Jan 21, 2016
Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (... more Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway. Fourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration. In baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.03...
JCR: Journal of Clinical Rheumatology
Blood
Increased Age-Related B-cells in Patients with Aplastic Anemia Introduction: Aplastic anemia is a... more Increased Age-Related B-cells in Patients with Aplastic Anemia Introduction: Aplastic anemia is a rare disease characterized by immune dysregulation. T cells in aplastic anemia are characterized by various intrinsic defects leading to increased IFN-g levels and Fas-mediated apoptosis of hematopoietic stem cells. We and others, have previously shown that the transcription factor T-bet is over-expressed in T cells from patients with aplastic anemia. Recently it was shown that a subpopulation of B cells also express T-bet; these cells are characterized as age-related B cells (ABCs) and express high levels of CD11c and CD19, they are CD21 negative and express T-bet. These T-bet+ ABCs are found increased in patients with autoimmune diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis). Stimulation of B cells with antigens, Toll-like receptors and IFN-g leads to the formation of ABCs, which in turn "talk" to the T cells and stimulate them. St...
Clinics in Chest Medicine
Rheumatology International
Arthritis Research & Therapy
Background: Comorbidities are common in chronic systemic connective tissue diseases and are assoc... more Background: Comorbidities are common in chronic systemic connective tissue diseases and are associated with adverse outcomes, increased morbidity and mortality. Although the prevalence of comorbidities has been wellstudied in isolated diseases, comparative studies between different autoimmune diseases are limited.
Seminars in Arthritis and Rheumatism
Seminars in arthritis and rheumatism, Jan 23, 2018
Low disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy.... more Low disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy. The aim of this study was to assess the ability of belimumab to achieve low disease activity states in real-life settings. Multicentre prospective observational study of consecutive SLE patients receiving belimumab for at least 3 months, due to active disease refractory to at least one conventional immunosuppressant. Disease activity, including the recently defined lupus low disease activity state (LLDAS) and remission (clinical SLEDAI-2K = 0), accrual of organ damage, flares and side effects were documented. Ninety-one patients were included [94.5% women, mean (SD) age 45.9 (12.5) years]. Most frequent manifestations were arthritis (76.7%), rash (72.5%), serologic activity (low C3/C4 and/or high anti-dsDNA; 54.9%), hair loss (47.2%) and mucosal ulcers (27.5%). Median (range) duration of treatment was 10.5 (3.0-42.1) months. Belimumab significantly decreased average SLEDAI-2K, physician...
Frontiers in microbiology, 2017
Rheumatoid arthritis (RA) is associated with HLA-DRB1 shared epitope (HLA-DRB1SE) and anti-citrul... more Rheumatoid arthritis (RA) is associated with HLA-DRB1 shared epitope (HLA-DRB1SE) and anti-citrullinated protein autoantibodies (ACPAs). ACPAs precedes the onset of clinical and subclinical RA. There are strong data for three infectious agents as autoimmunity triggers in RA, namely Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans causes of periodontal disease (PD), and Epstein-Barr virus (EBV). P. gingivalis expresses arginine gingipains, that cleave proteins at the arginine residues, and peptidyl arginine deiminase (PPAD), which citrullinates arginine residues of proteins, thus forming neoantigens that lead to ACPA production. Peripheral blood plasmablasts from ACPA+RA patients produce ACPAs the majority of which react against P. gingivalis. A. actinocycetemcomitans produces leukotoxin A, a toxin that forms pores in the neutrophil membranes and leads to citrullination and release of citrullinated autoantigens in the gums. EBV can infect B cells and epithelial cell...
Seminars in Arthritis and Rheumatism
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, autoimmunity, an... more Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, autoimmunity, and widespread dermal and visceral fibrosis. This article summarizes the current knowledge about the potential contribution of platelets in the disease process and the rationale of targeting platelets as an adjunct treatment for SSc. We performed an electronic search (Medline) using the keywords platelets, systemic sclerosis, autoimmunity, fibrosis, Raynaud, and pulmonary arterial hypertension. The link that connects vasculopathy, autoimmunity, and fibrosis in SSc remains obscure. Experimental data suggest that platelets are not solely cell fragments regulating hemostasis but they have a pleiotropic role in several biologic processes including immune regulation, vasculopathy, fibrosis, and all key features of SSc. Platelets interplay with the impaired endothelium, can interact with immune cells, and they are storages of bioactive molecules involved in tissue injury and remodeling. The potential role of platelets in the pathogenesis of SSc is further supported by experimental data in animal models of SSc. Platelet-derived serotonin represents a novel target in SSc and serotonin blockade is currently being tested in clinical trials. Platelets may be actively involved in the pathogenesis of SSc by activating immune responses and facilitating the fibrotic process. However, definite conclusions cannot be drawn until more data from both basic and clinical research are available.
Seminars in Arthritis and Rheumatism, 2016
Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical role... more Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical roles in embryonic development. Evidence suggests that this molecule regulates several aspects of both bone biology and fibrosis. To provide an overview of our current knowledge of the role of Dkk-1 in joint remodeling and fibrosis. We performed an electronic search (Medline) using the following key words: Dickkopf-1 (or Dkk-1), new bone formation, joint remodeling, ankylosing spondylitis, systemic sclerosis (or scleroderma), and fibrosis, supplemented by a manual search of references from retrieved articles. Dkk-1 is a master regulator of joint remodeling in animal models of arthritis shifting the balance toward new bone formation when its expression is decreased and toward erosion/joint destruction when its expression is increased. In humans, evidence suggests that Dkk-1 may be dysfunctional in patients with ankylosing spondylitis, a prototype bone forming disease. Moreover, data from animal models indicate that Dkk-1 has a protective role against fibrosis in several organs. Recent data suggest that inhibiting the canonical Wnt pathway by overexpression of Dkk-1 could be a way to target TGF-β signaling in fibrotic diseases. Finally, B-cell depletion therapy in systemic sclerosis may exert its effects through TGF-β dependent upregulation of Dkk-1. Dkk-1 appears to play a crucial role in both joint remodeling/ectopic ossification and fibrosis, and may be a prospective therapeutic modality for fibrotic diseases or diseases characterized by pathologic joint remodeling.
The Journal of Immunology
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Papers by Stamatis-Nick Liossis