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      Tolerogenic versus Inflammatory Activity of Peripheral Blood Monocytes and Dendritic Cells Subpopulations in Systemic Lupus Erythematosus

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          Abstract

          Abnormalities in monocytes and in peripheral blood dendritic cells (DC) subsets have been reported in systemic lupus erythematosus (SLE). We aim to clarify the tolerogenic or inflammatory role of these cells based on ICOSL or IFN- α and chemokine mRNA expression, respectively, after cell purification. The study included 18 SLE patients with active disease (ASLE), 25 with inactive disease (ISLE), and 30 healthy controls (HG). In purified plasmacytoid DC (pDC) was observed a lower ICOSL mRNA expression in ASLE and an increase in ISLE; similarly, a lower ICOSL mRNA expression in monocytes of ALSE patients was found. However, a higher ICOSL mRNA expression was observed in ASLE compared to HG in myeloid DCs. Interestingly, clinical parameters seem to be related with ICOSL mRNA expression. Regarding the inflammatory activity it was observed in purified monocytes and CD14 −/low CD16 + DCs an increase of CCL2, CXCL9, and CXCL10 mRNA expression in ASLE compared to HG. In myeloid DC no differences were observed regarding chemokines, and IFN- α mRNA expression. In pDC, a higher IFN- α mRNA expression was observed in ASLE. Deviations in ICOSL, chemokine, and IFN- α mRNA expression in peripheral blood monocytes and dendritic cells subpopulations in SLE appear to be related to disease activity.

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          Most cited references63

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          Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

          Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
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            Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease.

            Gene-expression studies have demonstrated increased expression of interferon (IFN)-inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway. Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFNalpha, and the data were used to derive IFNalpha scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFNalpha scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses. SLE patients with a high IFNalpha score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFNalpha scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFNalpha score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti-RNA binding protein (RBP) autoantibodies were associated with a high IFNalpha score. Activation of the IFNalpha pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.
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              Pathogenesis of systemic lupus erythematosus.

              The exact patho-aetiology of systemic lupus erythematosus (SLE) remains elusive. An extremely complicated and multifactorial interaction among various genetic and environmental factors is probably involved. Multiple genes contribute to disease susceptibility. The interaction of sex, hormonal milieu, and the hypothalamo-pituitary-adrenal axis modifies this susceptibility and the clinical expression of the disease. Defective immune regulatory mechanisms, such as the clearance of apoptotic cells and immune complexes, are important contributors to the development of SLE. The loss of immune tolerance, increased antigenic load, excess T cell help, defective B cell suppression, and the shifting of T helper 1 (Th1) to Th2 immune responses leads to B cell hyperactivity and the production of pathogenic autoantibodies. Finally, certain environmental factors are probably required to trigger the disease.
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                Author and article information

                Journal
                Clin Dev Immunol
                Clin. Dev. Immunol
                CDI
                Clinical and Developmental Immunology
                Hindawi Publishing Corporation
                1740-2522
                1740-2530
                2012
                30 August 2012
                : 2012
                : 934161
                Affiliations
                1Histocompatibility Centre of Coimbra, Edifício São Jerónimo, 4 Piso, Praceta Mota Pinto, 3001-301 Coimbra, Portugal
                2College of Health Technology of Coimbra, S. Martinho do Bispo, 3046-854 Coimbra, Portugal
                3Rheumatology Department, University Hospital of Coimbra, 3000-075 Coimbra, Portugal
                4Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal
                5Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
                Author notes

                Academic Editor: Timothy B. Niewold

                Article
                10.1155/2012/934161
                3437291
                22969819
                4d44d330-4bf2-41d0-86e8-7c643f26ed3f
                Copyright © 2012 Tiago Carvalheiro et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 May 2012
                : 10 July 2012
                : 17 July 2012
                Categories
                Research Article

                Immunology
                Immunology

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