Reactivation of Rheumatoid Arthritis After Pregnancy Increased Phagocyte and Recurring Lymphocyte Gene Activity

Department of Rheumatology and Clinical Immunology, Charité-University Medicine, Berlin, Germany.
Arthritis & Rheumatology (Impact Factor: 7.76). 10/2008; 58(10):2981-92. DOI: 10.1002/art.23907
Source: PubMed


Pregnancy is associated with reduced disease activity in rheumatoid arthritis (RA) and frequently with disease exacerbation after delivery. This study was undertaken to generate a systematic overview of the molecular mechanisms related to disease remission and postpartum reactivation.
Transcriptomes of peripheral blood mononuclear cells (PBMCs) were generated from RA patients and healthy women by transcription profiling during the third trimester and 24 weeks after delivery. For functional interpretation, signatures of highly purified immune cells as well as Kyoto Encyclopedia of Genes and Genomes pathway annotations were used as a reference.
Only minor differences in gene expression in PBMCs during pregnancy were found between RA patients and controls. In contrast, RA postpartum profiles presented the most dominant changes. Systematic comparison with expression signatures of monocytes, T cells, and B cells in healthy donors revealed reduced lymphocyte and elevated monocyte gene activity during pregnancy in patients with RA and in controls. Monocyte activity decreased after delivery in controls but persisted in RA patients. Furthermore, analysis of 32 immunologically relevant cellular pathways demonstrated a significant additional activation of genes related to adhesion, migration, defense of pathogens, and cell activation, including Notch, phosphatidylinositol, mTOR, Wnt, and MAPK signaling, in RA patients postpartum.
Our findings indicate that innate immune functions play an important role in postpartum reactivation of arthritis. However, this may depend not only on the monocyte itself, but also on the recurrence of lymphocyte functions postpartum and thus on a critical interaction between both arms of the immune system.

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Available from: Thomas Häupl, Sep 02, 2014
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    • "The overexpression of inflammationrelated genes in the monocytes of patients was in agreement with accumulating evidence pointing to an abnormal activation of the immune system as a central phenomenon in the pathogenesis of mood disorders (Drexhage et al., 2010a,b; Weigelt et al., 2011). It is also noteworthy that the postpartum period is considered as a period of immune activation and many inflammatory diseases like rheumatoid arthritis (Haupl et al., 2008; Wallenius et al., 2010) and multiple sclerosis (Hellwig et al., 2009) flare up or have their first episode in this period, e.g. autoimmune thyroiditis often starts in the postpartum period (Bergink et al., 2011a; Nicholson et al., 2006). "
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    ABSTRACT: Background: Postpartum psychosis (PP) is thought to belong to the bipolar spectrum. Recently we described an immune activation signature in monocytes of patients with PP using gene expression profiling. Immune activation genes are regulated by microRNAs (miRNAs). We therefore profiled miRNA expression in monocytes of PP patients to identify differentially expressed miRNAs between PP and the healthy state. Methods: In a profiling study we carried out miRNA profiling using TaqMan array human microRNA A cards v2.0 and monocytes of 8 PP patients. Data were analyzed against monocytes of healthy postpartum women (CP). Nine miRNAs were selected and tested using individual Q-PCR in a larger validation study on monocytes of 20 PP patients, 20 CP and 20 healthy non-postpartum women (HC). Results: In the validation study miR-146a expression was significantly down-regulated in the monocytes of first onset PP patients as compared to CP and HC; miR-212 expression was significantly down-regulated in PP patients with prior bipolar disorder. In silico miR-146a targeted 4 genes of the previously described monocyte activation signature in bipolar disorder; miR-212 targeted 2 of such genes. In a correlation study decreased expression of miR-146a in monocytes was related to decreased natural T regulator cells in PP patients; decreased miR-212 was correlated to increased Adrenomedulin and decreased IL-6 expression in monocytes and to higher Th2 cell levels. Conclusions: This study identified changes in miR-146a and -212 expression in PP. Since these miRNAs are linked to inflammation, the study strengthens the view that PP is an inflammation-like condition.
    Brain Behavior and Immunity 01/2013; 29. DOI:10.1016/j.bbi.2012.12.018 · 5.89 Impact Factor
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    • "It is well known that many autoimmune diseases are more prevalent in women than in men [1]. More specifically, rheumatoid arthritis (RA) is often diagnosed in the childbearing years when both onset and exacerbations are associated with the post-partum period, and pregnancy is associated with milder disease symptoms [2,3]. In addition, RA incidence peaks in the postmenopausal state associated with a drop in endogenous estrogen levels [4,5]. "
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    ABSTRACT: Introduction The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)α and β. The contribution of ERα and ERβ to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis Methods ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERβ agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERα selective agonist (ERA-63) and a selective ERβ agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERα - or ERβ-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction. Results EE was found to suppress clinical signs and symptoms in rat AA. The selective ERβ agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERα agonist ERA-63 suppressed the TT-specific swelling response in WT and ERβKO mice but not in ERαKO mice. As seen in the AA model, the selective ERβ agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints. Conclusions ERα, but not ERβ, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.
    Arthritis research & therapy 05/2010; 12(3):R101. DOI:10.1186/ar3032 · 3.75 Impact Factor
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    • "There is hope that appropriate tools to elucidate the function behind these data will improve constantly and give much better insight within the next few years. Based on own experience, functional interpretation improves with the number of comparisons performed with different if possible defined reference signatures and therefore is a cornerstone for future array analysis [35]. Such signatures depend on high quality experiments and will be the least ones to be shared publicly. "
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    BMC Genomics 02/2009; 10(1):98. DOI:10.1186/1471-2164-10-98 · 3.99 Impact Factor
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