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  • ESTROGEN, ESTROGEN-LIKE MOLECULES AND AUTOIMMUNE DISEASES
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-10
    Judith Merrheim; José Villegas; Jérôme Van Wassenhove; Rémi Khansa; Sonia Berrih-Aknin; Rozen le Panse; Nadine Dragin

    In western countries, the slope of autoimmune disease (AD) incidence is increasing and affects 5-8% of the population. Mainly prevalent in women, these pathologies are due to thymic tolerance processes breakdown. The female sex hormone, estrogen, is involved in this AD female susceptibility. However, predisposition factors have to act in concert with unknown triggering environmental factors (virus, microbiota, pollution) to initiate AD. Individuals are exposed to various environmental compounds that display endocrine disruption abilities. The cellular effects of some of these molecules may be mediated through the aryl hydrocarbon receptor (AhR). Here, we review the effects of these molecules on the homeostasis of the thymic cells, the immune tolerance intrinsic factors (transcription factors, epigenetic marks) and on the immune tolerance extrinsic factors (microbiota, virus sensibility). This review highlights the contribution of estrogen and endocrine disruptors on the dysregulation of mechanisms sustaining AD development.

    更新日期:2020-01-10
  • Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud's phenomenon and systemic sclerosis
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-10
    Vanessa Smith; Ariane L. Herrick; Francesca Ingegnoli; Nemanja Damjanov; Angelis; Christopher P. Denton; Oliver Distler; Karinna Espejo; Ivan Foeldvari; Tracy Frech; Boris Garro; Marwin Gutierrez; Genevieve Gyger; Eric Hachulla; Roger Hesselstrand; Annamaria Iagnocco; Cristiane Kayser; Karin Melsens; Maurizio Cutolo

    Capillaroscopy is a non-invasive and safe tool which allows the evaluation of the morphology of the microcirculation. Since its recent incorporation in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis together with its assessed role to monitor disease progression, capillaroscopy became a ‘mainstream’ investigation for rheumatologists. Given its increasing use by a variety of physicians internationally both in daily practice to differentiate primary from secondary Raynaud's phenomenon, as well as in research context to predict disease progression and monitor treatment effects, standardisation in capillaroscopic image acquisition and analysis seems paramount. To step forward to this need, experts in the field of capillaroscopy/microcirculation provide in this very consensus paper their view on image acquisition and analysis, different capillaroscopic techniques, normal and abnormal capillaroscopic characteristics and their meaning, scoring systems and reliability of image acquisition and interpretation.

    更新日期:2020-01-10
  • A review and meta-analysis of anti-ribosomal P autoantibodies in systemic lupus erythematosus
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-09
    May Y. Choi; Rachael D. Fitzpatrick; Katherine Buhler; Michael Mahler; Marvin J. Fritzler

    The discovery of autoantibodies to ribosomal proteins (anti-RibP) dates back more than fifty years when antibodies to ribosomes were identified in systemic lupus erythematosus (SLE) sera. Over the years, anti-RibP autoantibodies have been the subject of extensive study and became known as a highly specific biomarker for the diagnosis of SLE and were associated with neuropsychiatric SLE (NPSLE), lupus nephritis (LN) and hepatitis (LH). As demonstrated by experiments on cultured human cells and of murine models, there is evidence to suggest that anti-RibP may have a pathogenic role in LN and NPSLE. Despite a wealth of evidence, in comparison to other SLE autoantibodies such as anti-Sm and anti-dsDNA, anti-RibP has not been included in classification criteria for SLE. A significant challenge is the variability of assays used to detect anti-RibP, including the antigens and diagnostic platforms employed. This may account for the marked variation in frequencies (10–47%) in SLE and its association with clinical and demographic features reported in SLE cohorts. We performed a systematic literature review and meta-analysis to help clarify its prevalence, various clinical and serological associations in SLE based on the different RIBP antigens and assay platforms used.

    更新日期:2020-01-10
  • Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene therapy: A comprehensive review
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Keum Hwa Lee; Byung Soo Ahn; Dohyeon Cha; Won Woo Jang; Eugene Choi; Soohyun Park; Jun Hyeong Park; Junseok Oh; Da Eun Jung; Heeryun Park; Ju Ha Park; Youngsong Suh; Dongwan Jin; Siyeon Lee; Yong-Hwan Jang; Tehwook Yoon; Min-Kyu Park; Yoonje Seong; Andreas Kronbichler

    Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation such as T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene therapy has become a potential approach for the tailored treatment of autoimmune disorders. Gene therapy can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using siRNA or by inhibiting cytokine signaling using small molecules. In addition, gene therapy delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for immunomodulation and gene therapy in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene therapy may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.

    更新日期:2020-01-07
  • Post-rituximab immunoglobulin M (IgM) hypogammaglobulinemia
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Khalaf Kridin; A. Razzaque Ahmed

    Rituximab is a B cell depleting monoclonal antibody that targets the B cell-specific cell surface antigen CD20 and is currently used to treat several autoimmune diseases. The elimination of mature CD20-positive B lymphocytes committed to differentiate into autoantibody-producing plasma cells is considered to be the major effect of rituximab, that makes it a beneficial biological agent in treating autoimmune diseases. Hypogammaglobulinemia has been reported after rituximab therapy in patients with lymphoma and rheumatoid arthritis. Similar data are scarce for other autoimmune diseases. Low immunoglobulin G (IgG) or hypogammaglobulinemia has attracted the most attention because of its significant role in protective immunity. However, the incidence and clinical implications of low immunoglobulin M (IgM) or hypogammaglobulinemia have not been studied in detail. This review will focus on the frequency and the clinical concerns of low IgM levels that result as a consequence of the administration of rituximab. The etiopathogenic mechanisms underlying post-rituximab IgM hypogammaglobulinemia and its implications are presented. The long-term consequences, if any, are not known or documented. Multiple factors may be involved in whether IgG or IgM decreases secondary to rituximab therapy. It is possible that the autoimmune disease itself may be one of the important factors. The dose, frequency and number of infusions appear to be important variables. Post-rituximab therapy immunoglobulin levels return to normal. During this process. IgM levels take a longer time to return to normal levels when compared to IgG or other immunoglobulins. IgM deficiency persists after B cell repopulation to normal levels has occurred. Laboratory animals and humans deficient in IgM can have multiple infections. Specific pharmacologic agents or biologic therapy that address and resolve IgM deficiency are currently unavailable. If the clinical situation so warrants, then prophylactic antibiotics may be indicated and perhaps helpful. Research in this iatrogenic phenomenon will provide a better understanding of not only the biology of IgM, but also the factor(s) that control its production and regulation, besides its influence if any, on rituximab therapy.

    更新日期:2020-01-07
  • IRAK family in inflammatory autoimmune diseases
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Lin-Chong Su; Wang-Dong Xu; An-Fang Huang

    Innate immune signaling plays an important role in inflammation, and dysregulation of signaling components within this pathway has been focused as a critical mediator in initiation, progression of inflammatory autoimmune diseases. Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the immune cells, detecting pathogen associated molecular patterns, initiating signal transduction, by which interleukin-1 receptor-associated kinase (IRAK) family mediates activating signal from TLRs and interleukin-1 receptor. The family comprises of four members, IRAK1, IRAK2, IRAK-M, IRAK4. The family members have a role in either positive or negative regulation of innate immunity, adaptive immunity and inflammation. Accumulated evidence proves that IRAK performs significantly in the pathogenesis of inflammatory autoimmune disorders. On the one hand, both patients and animal modes reported abnormal expression of the family members. On the other hand, functional study in vivo and in vitro demonstrated that the members are implicated in the development of the diseases. Interestingly, IRAK inhibition has potential therapeutic benefits. In this review, we focus on the family, review the physiological roles in different immune cells, and summarize emerging data for highlighting the importance of them in inflammatory autoimmunity.

    更新日期:2020-01-07
  • Immune response biomarkers as indicators of sarcoidosis presence, prognosis, and possible treatment: An immunopathogenic perspective
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Anna Tarasidis; Sergio Arce

    Sarcoidosis has been a disease of puzzling occurrence and clinical course. Multiple immunological markers have been noted to be altered within sarcoidosis, however there is variable consistency among these reports. Previous studies have shown sarcoidosis to be a primary T cell-mediated disease, yet new data concerning B cell and mycobacterial involvement have been brought to light. The possibility of a uniform biomarker to characterize sarcoidosis presence, severity and prognosis greatly increases the movement towards directed and specialized treatment for this rare disease.

    更新日期:2020-01-07
  • Interaction between food antigens and the immune system: Association with autoimmune disorders
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Aristo Vojdani; Lydia R. Gushgari; Elroy Vojdani

    It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.

    更新日期:2020-01-07
  • Characterization of auto-immune hepatitis associated with the use of anti-TNFα agents: An analysis of 389 cases in VigiBase
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Olivier Vollmer; Renaud Felten; Philippe Mertz; Bénédicte Lebrun-Vignes; Joe-Elie Salem; Laurent Arnaud

    Auto-immune diseases, including auto-immune hepatitis may be associated with the use of drugs, such as anti-TNF-α inhibitors. The aim of the study was to analyze the characteristics of anti-TNF-α inhibitor-associated auto-immune hepatitis (ATIAIH) in a large international pharmacovigilance database. We analyzed all ICSRs classified as “Autoimmune hepatitis” according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase, the World Health Organization global pharmacovigilance database of adverse drug reactions collected by national drug authorities in >130 countries (>90% of the world population). Bayesian disproportionality analysis was used to compute IC025, which is the lower end of the 95% credibility interval for the association between a suspected treatment and an adverse event. IC025 > 0 are considered statistically significant. A total of 389 ATIAIH ICSRs were identified. The median age at ATIAIH onset was 44 years and the female to male sex ratio was 3.72. Infliximab (IC025 = 2.98), adalimumab (IC025 = 0.32) and etanercept (IC025 = 0.19) yielded a statistically significant signal in disproportionality analysis. Infliximab was the most frequently involved drug (50.1%). The median treatment duration before ATIAH occurrence was 4.9 months. ATIAIH was reported as serious adverse event in 91%. Death (directly linked to AIH or not) occurred in 10 cases (2.9% of ICSRs). The most frequent reported indication for anti-TNF-α agent was rheumatoid arthritis (31.9%). This study enables the identification and a detailed study of 389 new cases of ATIAIH and confirms a significant association of ATIAIH with infliximab, adalimumab and etanercept.

    更新日期:2020-01-07
  • Systemic lupus erythematosus associated with thymoma: A fifteen-year observational study in France
    Autoimmun. Rev. (IF 7.716) Pub Date : 2020-01-07
    Nicolas Noël; Audrey Le Roy; Arnaud Hot; David Saadoun; Estebaliz Lazaro; Hervé Lévesque; Noémie Le Gouellec; Nadine Meaux-Ruault; Thierry Nguyen; Nathalie Costedoat-Chalumeau; Béatrice Amieux; Aurélie Fontana; Christian De Gennes; Jean Fulpin; Pascal-Alexandre Thomas; Maria-Virginia Bluthgen; Benjamin Besse; Olivier Lambotte

    Objective To describe the clinical, biological and pathological characteristics of patients with the association of SLE and thymic epithelial tumors (TET) in a retrospective multicenter series. Methods Cases diagnosed in France between 2000 and 2015 were collected after a call for observations from the French network for thymic epithelial tumors (RYTHMIC database) and the French National Society of Internal Medicine (SNFMI). Results Fourteen patients were identified, the majority were women (93%). The median age at diagnosis of lupus was 43.5 [range: 30–66] years and 43.5 [range: 26–73] years at diagnosis of thymoma. TET required chemotherapy and/or radiotherapy complementary to surgery in >90% cases. Lupus was diagnosed before, simultaneously, or after diagnosis of thymoma in 6, 3 and 5 cases, respectively. Among the lupus manifestations, joint involvement was predominant (78.6%), followed by autoimmune cytopenia (35.7%), cutaneous affections (28.6%), serositis (28.6%) and renal involvement (21.4%). SLE was associated with one or more AID in 5/14 patients. These characteristics were compared with those from 17 patients identified in the literature. Among them, joint and skin involvement as well as pleural/pericardial effusions occurred in >50%. SLE was controlled by prednisone and hydroxychloroquine in the majority of cases, but 7 out of 31 patients had an immunosuppressant. Conclusion The association of SLE and TET is rare, and its clinical profile seems to be distinguished by the frequency of cytopenias. The management of these patients is complicated by the need to treat cancer, lupus and/or associated autoimmune diseases.

    更新日期:2020-01-07
  • Giant-cell arteritis associated with myelodysplastic syndrome: French multicenter case control study and literature review
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-13
    Anne Laure Roupie; Hubert de Boysson; Sara Thietart; Fabrice Carrat; Julie Seguier; Louis Terriou; Mathilde Versini; Viviane Queyrel; Matthieu Groh; Ygal Benhamou; Francois Maurier; Olivier Decaux; Maud d'Aveni; Julien Rossignol; Joris Galland; Eric Solary; Lise Willems; Nicolas Schleinitz; Arsène Mekinian

    Introduction Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MDS/MPN) can be associated with giant cell arteritis (GCA). In this nationwide study by the “French Network of dysimmune disorders associated with hemopathies” (MINHEMON) the objective was to evaluate characteristics, treatment and outcome of GCA MDS-MDS/MPN. Patients and methods Retrospective analysis of patients that presented a MDS or MDS/MPN associated with GCA. Treatment efficiency, relapse-free and overall survival of GCA MDS-MDS/MPN were compared to GCA alone. Results Twenty-one patients with GCA MDS-MDS/MPN were included with median age 76 [42–92], M/F ratio 2.5, 8 MDS with multilineage dysplasia (38%), 4 chronic myelomonocytic leukemia (19%), at low or intermediate risk according to IPPS and IPSS-R. The prevalence of headaches, jaw claudication and anterior ischemic optic neuropathy was significantly lower in patients with GCA MDS-MDS/MPN compared to idiopathic GCA (14.3%, 0% and 0% versus 30%, 25%, and 25%, respectively; p < .05). Other clinical and histology findings were similar. All GCA patients received steroid therapy as first-line treatment. Complete or partial response was observed in 14 GCA MDS-MDS/MPN patients (66.7%), of whom 6 (28.6%) received combined immunosuppressive therapies (versus 10% of idiopathic GCA; p = .07). Relapse incidence was similar in the two groups. Steroid dependence was more frequent among GCA MDS-MDS/MPN patients (12 (57%) versus 18 (22.5%); p < .05). Relapse-free and steroid-free survivals were significantly decreased in GCA MDS-MDS/MPN patients (log rank 0.002 and 0.049 respectively), but not overall survival. Conclusion Characteristics of GCA MDS-MDS/MPN seem different than idiopathic GCA, with a distinct clinical phenotype and poorer outcome with a higher risk of steroid dependence and relapse.

    更新日期:2019-12-13
  • Interstitial pneumonia with autoimmune features: A single center prospective follow-up study
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Marco Sebastiani; Giulia Cassone; Lisa De Pasquale; Stefania Cerri; Giovanni Della Casa; Caterina Vacchi; Fabrizio Luppi; Carlo Salvarani; Andreina Manfredi

    Background and objective Recently the term “interstitial pneumonia with autoimmune features” (IPAF) has been proposed to identify patients with interstitial lung disease and autoimmune characteristics, not fulfilling the criteria for specific connective tissue diseases (CTD). Only few data are available about the clinical and serological features of IPAF patients, their survival and the possible evolution in a CTD. The aims of the study were to investigate the demographic and clinico-serologic features of patients with IPAF, their relationship to survival, and the possible evolution in a definite CTD. Patients and methods Fifty-two patients were consecutively enrolled and prospectively followed for 45 ± 31.6 months. Data about disease onset, serological, clinical and therapeutic features, pulmonary function tests and high-resolution computed tomography were periodically repeated. The survival of patients with IPAF was compared with that of 104 patients with idiopathic pulmonary fibrosis (IPF). Results The clinical domain for IPAF was satisfied in 44 patients, serological domain in 49 and the morphological domain in 29 patients. During the follow-up, a definite CTD was diagnosed in 7 patients, in particular Sjogren's syndrome in 4 patients, rheumatoid arthritis in 2, and polymyositis in the last. The estimated 5-year survival of IPAF patients 69.5 ± 7.8%, significantly higher than survival observed in IPF patients, and the baseline value of FVC and DLCO were the only factors associated to death. Conclusions IPAF seems to a distinct entity, with a low tendency to evolve in a definite CTD. Nevertheless, further studies are needed to better define the clinical evolution and the outcome of IPAF.

    更新日期:2019-12-13
  • Outcomes of limited cutaneous systemic sclerosis patients: Results on more than 12,000 patients from the EUSTAR database
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Camelia Frantz; Dorte Huscher; Jérôme Avouac; Eric Hachulla; Alexandra Balbir-Gurman; Gabriela Riemekasten; Elise Siegert; Maria-Grazia Lazzaroni; Patricia E. Carreira; Serena Vettori; Elisabetta Zanatta; Susanne Ullman; Laszlo Czirjàk; Otylia Kowal-Bielecka; Oliver Distler; Marco Matucci-Cerinic; Yannick Allanore

    Objectives Limited cutaneous systemic sclerosis (LcSSc) is the most common subset of SSc but it has been overlooked in the past years. At a time at which clinical trials focus on diffuse cutaneous SSc (DcSSc) we aimed at clarifying the outcomes of LcSSc and at evaluating whether potential drug positioned in DcSSc may also be used in LcSSc. Methods The EUSTAR database was used to investigate skin, lung and peripheral vasculopathy outcomes in LcSSc. Worsening of skin fibrosis, ILD and peripheral vasculopathy were defined by an increase in modified Rodnan skin score (mRSS) > 3.5 points, a decrease of FVC > 10% in patients with ILD at baseline, and by the development of new digital ulcers (DU) in patients without DU at baseline. Results 8013 LcSSc and 4786 DcSSc patients were included. In contrast to DcSSc, skin disease was remarkably stable in the majority of LcSSc patients with >80% having a change lower than ±4 units of mRSS at 12, 24 and 36 months follow-up. Conversely, FVC changes over time were very similar between LcSSc and DcSSc. Regarding DU, numbers of patients with new DU over time seemed to be almost similar between the two subsets. Conclusions LcSSc patients have a low mRSS at baseline with marginal changes with time. Conversely, SSc-ILD can be as progressive as in DcSSc supporting the inclusion of LcSSc patients in SSc-ILD trials and suggesting potential benefit of any anti-ILD drugs. Similarly, although slightly less common, DU should receive the same attention in the two subsets.

    更新日期:2019-12-13
  • Mechanistic classification of immune checkpoint inhibitor toxicity as a pointer to minimal treatment strategies of selected emergent autoimmune disease to further improve survival
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Dennis McGonagle; Nicola Luigi Bragazzi; Howard Amital; Abdulla Watad

    Improved anti-tumour responses under immune checkpoint inhibition (ICI) are associated with concomitant autoimmune disease development termed immune related adverse events (irAEs), of which approximately 5% are rheumatic in nature. Generally, oncologists and other specialists vigorously treat irAEs in spite of the generally accepted beneficial effect of irAEs on tumour survival. Herein, we highlight mechanistic insights on how tumour responses and certain types of autoimmunity appear to be inextricably linked around CD8+ T-cell mediated responses and that strategies that interfere with such shared immunopathgenesis could impact of survival. We discuss the possible circumstances in which intensive immunosuppressive therapy for irAEs that occur with ICIs might blunt anti-tumour immunity. We also discuss potential therapeutic strategies for emergent ICI related autoimmunity and propose some treatment considerations and research questions to minimize the impact of overzealous immunosuppression strategies on tumour responses. Refraining from using powerful therapeutic armamentarium to treat irAEs, especially when these are not considered as life-threating might improve the prognosis of ICI therapy.

    更新日期:2019-12-13
  • Targeting CD20 in the treatment of interstitial lung diseases related to connective tissue diseases: A systematic review
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Mattia Bellan; Filippo Patrucco; Francesco Barone-Adesi; Francesco Gavelli; Luigi Mario Castello; Alessandra Nerviani; Laura Andreoli; Lorenzo Cavagna; Mario Pirisi; Pier Paolo Sainaghi

    Introduction The effectiveness of CD20 targeting in connective tissue diseases (CTD) with lung involvement is controversial. This paper aims to review the current evidence about rituximab (RTX) use in CTD-related interstitial lung disease (ILD). Methods We performed a systematic review of papers published between January 2009 and May 2019. We included clinical trials, case/control studies and cohort studies. We excluded letters, case reports, case series, reviews, and full articles when not in English. The selected studies listed as primary or secondary outcome a variation in pulmonary function tests or in the scores used to radiologically stage lung involvement, in CTD-related ILD patients after RTX. Results Out of 1206 potentially eligible articles, 24 papers were selected: 3 retrospectively described cohorts of patients with different CTD, 14 dealt with systemic sclerosis (SSc)-related ILD, 5 with idiopathic inflammatory myopathies (IIMs)-related ILD, and 2 with Sjögren's Syndrome-related ILD. A direct comparison of the selected studies was hampered by their heterogeneity for outcomes, follow-up duration, the severity of lung involvement, and clinical features of study populations. However, an overall agreement existed concerning the effectiveness of RTX in the stabilization of lung disease, with some studies reporting an improvement of functional parameters from baseline. IIM-related ILD appeared more responsive than other CTD-related ILD to CD20 targeting. Conclusion RTX is a promising therapeutic tool in CTD-related ILD. This systematic review remarks the unmet need of multicenter prospective studies aiming to evaluate the effectiveness of RTX with adequate sample size and study design.

    更新日期:2019-12-13
  • Isolated autoimmune adrenocorticotropic hormone deficiency: From a rare disease to the dominant cause of adrenal insufficiency related to check point inhibitors
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Ruth Percik; Gadi Shlomai; Amir Tirosh; Amit Tirosh; Raya Leibowitz-Amit; Yael Eshet; Gahl Greenberg; Alex Merlinsky; Ehud Barhod; Yael Steinberg-Silman; Tal Sella

    Objective Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies. Design A retrospective cohort study of a tertiary cancer center. Methods Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis. Results Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38–20.47, p < .001] and 3.67 [95% CI 1.13–11.84, p = .03]), respectively. Conclusions IAD, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.

    更新日期:2019-12-13
  • Autoantigenomics: Holistic characterization of autoantigen repertoires for a better understanding of autoimmune diseases
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Christian P. Moritz; Stéphane Paul; Oda Stoevesandt; Yannick Tholance; Jean-Philippe Camdessanché; Jean-Christophe Antoine
    更新日期:2019-12-13
  • Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Ana Matas-García; José C. Milisenda; Albert Selva-O'Callaghan; Sergio Prieto-González; Joan Padrosa; Carlos Cabrera; Noemi Reguart; Natalia Castrejón; Manel Solé; Javier Ros; Ernesto Trallero-Araguas; Maria Noelia Antoniol; Gemma Vila-Pijoan; Josep María Grau

    Background and objective Drug-induced myopathy is among the most common causes of muscle disease. An association has recently been described between programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and immune-related adverse events (irAE) affecting the muscle. Here, we report the clinical and pathological findings of nine unrelated patients with PD-1 and PD-L1 inhibitors-associated myopathy. Methods We retrospectively analyzed 317 muscle biopsies performed for diagnostic purposes from January 2017 to June 2019. Patients were attended in two tertiary centers and muscle biopsies were performed and analyzed by two myology experts. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned and stained. Immunohistochemistry studies were also performed as a routine procedure in our lab. Results We identified 9 patients receiving anti-PD-1 or PD-L1 inhibitors consulting for either muscle weakness, asthenia, myasthenic-like syndrome or other muscle related-symptoms, along with biopsy-proven inflammatory myopathy. One had concomitant myocarditis. In most of the cases muscle biopsy showed a marked phenomenon of necrosis, macrophagy and muscle regeneration with perivascular inflammatory infiltrates with a large component of macrophagic cells. A tendency to perifascicular atrophy was also noticed. The expression of MHC class I antigens predominated in the perifascicular zones. Raised muscle enzymes were detected in 7 patients. Conclusion A characteristic clinic-pathological pattern, including a myasthenia gravis-like syndrome plus myositis was found in patients receiving PD-1 and PD-1 L inhibitors. A large component of macrophages resembling granulomas seems to be the pathological hallmark of the syndrome. Further information is required to understand the wide spectrum of immune-related adverse events involving the muscle during or after treatment with anti-PD-1 inhibitors, but the pathological picture seems to be characteristic.

    更新日期:2019-12-13
  • Enteropathic spondyloarthritis: Results from a large nationwide database analysis
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-12-12
    Andrea Picchianti Diamanti; Roberto Lorenzetti; Maria Sole Chimenti; Michele Maria Luchetti; Paola Conigliaro; Claudia Canofari; Devis Benfaremo; Vincenzo; Bruno Laganà; Roberto Perricone

    Introduction Spondyloarthrits (SpA) share clinical, genetic and immunological features with Inflammatory Bowel Diseases (IBD), and enteropathic SpA (eSpA) represent the clinical evidence of the association between gut and joint diseases. This cross-sectional study aimed to report data of eSpA patients collected from the first Italian database. Patients and methods A specific web-based interface has been created to insert and collect the main clinical, serologic and imaging data from patients with eSpA, as well as disease activity, comorbidities and treatment, in a real-life scenario. Results Data were collected in 14 Italian centers (7 rheumatology and 7 gastroenterology units). A total of 347 eSpA patients were enrolled in the study. Type 1 peripheral eSpA was the most frequent form. Crohn’ Disease (CD) was the most represented IBD. CD activity was similar among eSpA, whereas UC activity was slightly higher in the axial and mixed form than in the peripheral eSpA. The disease was active in less than half of axial eSpA patients and in only 18% of patients with peripheral eSpA. Furthermore, most of the patients had an inactive IBD. Nineteen percent of the total eSpA patients were free of therapy at the time of the enrollment and 61% of the patients were receiving biotechnological agents. Conclusions The multidisciplinary management of eSpA patients, favored by this ad hoc created web-based platform, allowed to obtain data from the largest eSpA cohort. The information coming of this database might advance knowledge of eSpA and improve their standard of care.

    更新日期:2019-12-13
  • A measles-derived peptide treats and vaccinates against adjuvant arthritis
    Autoimmun. Rev. (IF 7.716) Pub Date : 2006-04-19
    Robert Root-Bernstein

    Measles vaccine and porcine myelin basic protein were both found to ameliorate or abolish the symptoms of adjuvant arthritis (AA) in Lewis rats whether inoculated at the time of adjuvant administration or after the onset of arthritis. These results are consistent with clinical observations that measles infection can sometimes cause remission of juvenile rheumatoid arthritis. The fact that measles virus proteins and myelin basic protein have significant regions of homology allowed peptides based on these regions to be synthesized. A twenty-amino acid sequence exhibits significant anti-arthritic activity when inoculated into rats with pre-existing AA and it also prevented onset of AA when a single dose was preinoculated three weeks prior to AA induction. These data suggest the possibility of developing novel therapeutic vaccines against some forms of arthritis.

    更新日期:2019-11-18
  • Multiple sclerosis, the microbiome, TLR2, and the hygiene hypothesis
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-15
    Nicholas Wasko, Frank Nichols, Robert B. Clark

    The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the “Hygiene Hypothesis,” have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too “clean” lack the requisite exposure to “immune-tolerizing” microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS. Our central hypothesis is that the microbiome in MS represents a “defective environment” that fails to provide normal levels of “TLR2-tolerizing” bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.

    更新日期:2019-11-15
  • Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-15
    Benoit Brilland, Anne-Sophie Garnier, Alain Chevailler, Pascale Jeannin, Jean-François Subra, Jean-François Augusto

    Anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAVs) are small vessel vasculitides involving predominantly ear-nose-throat, kidneys, lungs and nerves. AAVs are life-threatening diseases, especially in their most severe forms such as necrotizing crescentic glomerulonephritis (GN) and/or intra-alveolar hemorrhage. Unlike immune complex GN or anti-glomerular basement membrane GN, AAVs are classified as pauci-immune GN. However, based on recent insights from animal models, the view of AAVs as a complement-unrelated disease has been challenged. Indeed, complement activation, and especially complement alternative pathway (cAP) activation, has been shown to be determinant in AAV pathogenesis through C5a generation, a potent chemoattractant for neutrophils with priming capacities. Here, we review in vitro and in vivo data supporting the role of cAP in murine models and in human AAVs. These findings, together with the need to eradicate glucocorticoid toxicity, led to the development of an anti-C5aR molecule, CCX168, also known as avacopan. Its development and future opportunities are also discussed.

    更新日期:2019-11-15
  • Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-15
    José María G. Ruiz de Morales, Lluís Puig, Esteban Daudén, Juan D. Cañete, José Luis Pablos, Antonio Olveira Martín, Carlos González Juanatey, Alfredo Adán, Xavier Montalbán, Natalia Borruel, Guillermo Ortí, Esther Holgado Martín, Carolina García-Vidal, Cynthia Vizcaya Morales, Víctor Martín Vázquez, Miguel Ángel González-Gay

    Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.

    更新日期:2019-11-15
  • Corticosteroid-sparing benefit of intravenous immunoglobulin in systemic sclerosis-associated myopathy: A comparative study in 52 patients
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-14
    Benjamin Chaigne, Simao Rodeia, Nouria Benmostefa, Alice Bérézné, Jérôme Authier, Pascal Cohen, Alexis Régent, Benjamin Terrier, Nathalie Costedoat-Chalumeau, Loïc Guillevin, Claire Le Jeunne, Luc Mouthon

    Introduction Little is known about systemic sclerosis (SSc)-associated myopathy (SScAM) treatment. Herein we evaluated the use of intravenous immunoglobulin (IVIg) in SScAM. Methods We conducted a retrospective study of patients with SScAM in the Internal medicine department of Cochin University Hospital between 1993 and 2017. Results Fifty-two patients were included comprising 18 (34.6%) with limited SSc and 34 (65.4%) with diffuse SSc. SScAM occurred at a median [interquartile range (IQR)] time of 1 month [0–15] after SSc diagnosis. Thirty-four patients (65.4%) had muscle weakness, 28 (53.8%) had myalgia and 24 (46.2%) had dysphagia. Fifty patients (96.2%) had increased creatine kinase, 22/26 (84.6%) had myopathic electromyography, 10/12 (83.3%) had a high intensity signal of girdle muscles on MRI and 49/50 (98%) had abnormal muscle biopsy. Eighteen (34.6%) patients received IVIg. Severe adverse events occurred in 3/18 (16.7%) patients. When compared to patients who did not receive IVIg, patients who received IVIg had a significantly higher maximal corticosteroid (CS) dose ever, a greater decrease of CS at 3 months, and a lower CS dose at one year and at the end of follow up. Conclusions This study suggests the benefit of IVIg as adjunctive therapy, with an acceptable tolerance profile, and supports its use as a CS-sparing agent, in SScAM.

    更新日期:2019-11-14
  • The Giants (biologicals) against the Pigmies (small molecules), pros and cons of two different approaches to the disease modifying treatment in rheumatoid arthritis
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-14
    Ennio Giulio Favalli, Marco Matucci-Cerinic, Zoltan Szekanecz

    Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that, if untreated, can lead to disability and reduce the life expectancy of affected patients. Over the last two decades the improvement of knowledge of the pathogenetic mechanisms leading to the development of the disease has profoundly changed the treatment strategies of RA through the development of biotechnological drugs (bDMARDs) directed towards specific pro-inflammatory targets involved in the RA network. To date, the therapeutic armamentarium for RA includes ten bDMARDs able to produce the depletion B-cells, the blockade of three different pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-6 and interleukin-1), or the inhibition of T-cell co-stimulation. The introduction of these new compounds has dramatically improved outcomes in the short and long term, although still a significant proportion of patients are unable to reach or maintain the treatment target over time. The identification of the fundamental role of Janus kinases in the process of transduction of the inflammatory signal within the immune cells has recently provided the opportunity to use the new pharmacological class of small molecules for the therapy of RA, further increasing the number of treatment options. In this review the PROS and CONS of these two drug classes will be discussed, trying to provide the evidence currently available to make the right choice based on the analysis of the efficacy and safety profile of the different drugs on the market and close to marketing.

    更新日期:2019-11-14
  • Systemic sclerosis induced by CNS stimulants for ADHD: A case series and review of the literature
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-14
    Katya Meridor, Yair Levy

    Introduction Methylphenidate (Ritalin) is a CNS stimulant, and is a common treatment for children and adults with ADHD. It has been associated with Raynaud's phenomenon (RP) but not with Systemic Sclerosis (SSc). We report a case series of patients pointing out the connection between Methylphenidate and SSc. Cases We identified three patients in a single Rheumatology clinic in Israel, who developed SSc following treatment with CNS stimulants for ADHD. All three cases had Raynaud's phenomenon, skin changes, pathological capillaroscopy and positive ANA. Symptoms appeared and worsened over months following the use of methylphenidate and subsided after its cessation. Conclusion This is the first report in the literature of a causative relation between methylphenidate and the development of SSc, a serious, life-threatening condition. Patients treated with CNS stimulants should be followed closely for side-effects such as RP and skin changes.

    更新日期:2019-11-14
  • Comparative United States autoimmune disease rates for 2010–2016 by sex, geographic region, and race
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-14
    Melissa H. Roberts, Esther Erdei

    Purpose: AIDs may disproportionately impact specific racial groups, but autoimmune (AID) prevalence information by minority racial group is sparse for many AIDs. The objective of this analysis was to supplement previously published AID prevalence rates by providing information on race rate ratios (minority race populations compared to Caucasian populations) in the United States. Preliminary to estimating race rate ratios, contemporary US-specific, health care utilization-based AID prevalence rates and female-to-male ratios were estimated and compared to previously published AID prevalence rates. Methods: We used a large national electronic medical record database of 52 million individuals to estimate age-adjusted direct standardized rates for 22 AIDs for 2010 through 2016 by gender, race, and US census division. These were compared to previously published estimates. Results: Female-to-male ratios were comparable with published studies. Almost all observed Multiracial AID rates were significantly higher than Caucasian rates, as well as 9 of 22 AID rates observed among Native Americans and 8 of 22 AID rates estimated among African-American patients. Regional variation was noted: highest African-American systemic lupus erythematosus rates were observed in the West North Central and South Atlantic divisions, highest African-American multiple sclerosis rates in the South Atlantic and Pacific divisions, and highest Native American rheumatoid arthritis rates in the West North Central, Mountain, and Pacific divisions. Conclusions: Substantial AID heterogeneity exists by race and by geographic area. An important research area is further exploring factors related to heterogeneity such as potential interactions between genetic susceptibility and environmental factors.

    更新日期:2019-11-14
  • Subcutaneous immunoglobulin in inflammatory myopathies: efficacy in different organ systems
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-14
    Maria Giovanna Danieli, Chiara Gelardi, Veronica Pedini, Denise Menghini, Devis Benfaremo, Armando Gabrielli

    MGD and CG were responsible for the study's conception and design. VP and DM contributed to data acquisition. VP and DB planned and performed the statistical analyses. All Authors contributed to data interpretation. MGD, CG, VP and DM drafted the manuscript. AG and DB revised the manuscript critically for intellectual content. All authors gave their final approval of the version of the manuscript to be published.

    更新日期:2019-11-14
  • Aetiology and pathogenesis of paraneoplastic autoimmune disorders
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-13
    Guojun Geng, Xiuyi Yu, Jie Jiang, Xinhua Yu

    Paraneoplastic autoimmune disorders (PAD) represent a group of autoimmune diseases associated with neoplasms. As a consequence of a remote autoimmunity-mediated effect, PAD are found in multiple organs or tissues, including the skin, blood and nervous system. Compared with non-paraneoplastic autoimmune diseases, PAD have different aetiologies, pathologies, disease symptoms and treatment responses. There are two main origins of autoimmunity in PAD: neoplasm-mediated dysregulated homeostasis in immune cells/organs and in autoantigens. Pathologically, PAD are mediated predominantly by either autoantibodies or autoreactive T-cells. In the past decade, significant progress has been achieved in increasing our understanding of the aetiology and pathology of PAD. In this review article, we aim to provide a comprehensive overview of the recent advances in this field.

    更新日期:2019-11-13
  • Coronary artery disease in systemic lupus: A case-controlled angiographic study.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-18
    Thibaud Chazal,Mathieu Kerneis,Paul Guedeney,Julien Haroche,Alexis Mathian,Pierre Rufat,Fleur Cohen Aubart,Gilles Montalescot,Zahir Amoura

    更新日期:2019-11-01
  • Serum amyloid A as a marker of disease activity in Giant cell arteritis.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-18
    Anais Dartevel,Bertrand Toussaint,Candice Trocme,Mélanie Arnaud,Nicolas Simon,Patrice Faure,Laurence Bouillet

    更新日期:2019-11-01
  • Validation of anti-Mi2 autoantibody testing by line blot.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-18
    Iago Pinal-Fernandez,Katherine Pak,Maria Casal-Dominguez,Yuji Hosono,Christopher Mecoli,Lisa Christopher-Stine,Andrew L Mammen

    更新日期:2019-11-01
  • Letter to the Editor: Protein phosphatase 1 subunit Ppp1r15a/GADD34 is overexpressed in systemic lupus erythematosus and related to the expression of type I interferon response genes.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2018-12-24
    Caroline Plazy,Chantal Dumestre-Pérard,Françoise Sarrot-Reynauld,Pierre Audoin,Jean-Louis Quesada,Philippe Pierre,Laurence Bouillet,Jean-Yves Cesbron,Giovanna Clavarino

    更新日期:2019-11-01
  • Autoimmune pancreatitis in children: The impact of immune system in a challenging disease.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2018-12-21
    Danilo Pagliari,Rossella Cianci,Donato Rigante

    更新日期:2019-11-01
  • X chromosome and female bias in systemic lupus erythematosus: Focus on population-based evidence.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2018-11-09
    Dongsheng Di,Hui Yuan,Linlin Zhang,Xiaoxiao Wu,Haifeng Pan,Dongqing Ye,Ruixue Leng

    更新日期:2019-11-01
  • Dampness and mold hypersensitivity syndrome and vaccination as risk factors for chronic fatigue syndrome.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2018-11-09
    Tamara Tuuminen,Tiina Jääskeläinen,Kirsi Vaali,Olli Polo

    更新日期:2019-11-01
  • Should we combine biologics with methotrexate in axial spondyloarthritis?
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-11-02
    Denis Poddubnyy,Howard Amital,Andrea Rubbert-Roth

    更新日期:2019-11-01
  • Do DMARDs and biologic agents protect from cardiovascular disease in patients with inflammatory arthropathies?
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-10-28
    Fabiola Atzeni,Elisabet Svenungsson,Michael T Nurmohamed

    更新日期:2019-11-01
  • Treatment for refractory lupus nephritis: Rituximab vs triple target therapy.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2019-10-28
    Ricard Cervera,Marta Mosca,Roberto Ríos-Garcés,Gerard Espinosa,Hernando Trujillo,Teresa Bada,Manuel Praga

    更新日期:2019-11-01
  • Donato Alarcón-Segovia: a life dedicated to the study of autoimmunity.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2005-10-22
    Antonio R Cabral,Javier Cabiedes,Jorge Alcocer-Varela,Yehuda Shoenfeld

    更新日期:2019-11-01
  • Autoimmune diseases: role of coxsackieviruses in their pathogenesis.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2004-08-18
    D A Liakos,A Triantafyllopoulou,E K Kapsogeorgou,H M Moutsopoulos

    更新日期:2019-11-01
  • HLA class II alleles and genetic predisposition to the antiphospholipid syndrome.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Gian Domenico Sebastiani,Giovanni Minisola,Mauro Galeazzi

    The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL). Its etiology is linked to genetic predisposition, which is accounted for, at least in part, by genes of major histocompatibility complex (HLA system). The association of APS with human leukocyte antigen (HLA) alleles is a consequence of the association of aPL with HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent of the clinical context. In fact, we find the same associations between HLA and aPL in primary APS and in APS secondary to systemic lupus erythematosus (SLE). The association of HLA-DR4, -DR7, -DRw53 and -DQB1*0302 with aCL that has been demonstrated in primary APS can also be found in SLE, a disease with a completely different pattern of HLA allele association (DR2, DR3, DRw52). In addition, the various aPL (anticardiolipin antibodies, lupus anticoagulant, anti-beta2GPI antibodies, antiphosphatidylserine/prothrombin antibodies) show similar HLA association, again independent of the clinical context (primary APS or SLE), and across various ethnic groups.

    更新日期:2019-11-01
  • The etiology of autoimmune diabetes and thyroiditis: evidence for common genetic susceptibility.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Lara Levin,Yaron Tomer

    Type 1 diabetes (T1D) and the autoimmune thyroid diseases (AITD) are the most common autoimmune endocrine diseases. Both are organ-specific T-cell mediated diseases. Abundant epidemiological data support a strong genetic basis for both T1D and AITD. Furthermore, both diseases commonly occur in the same individuals and in the same families. Indeed, studies suggest that the etiology of T1D and AITD may involve common genetic factors. Two immune regulatory genes, HLA and CTLA-4 contribute to the susceptibility to both diseases. Additionally, two tissue-specific genes, the insulin VNTR in T1D and Thyroglobulin in AITD play a major role in their pathogenesis. Therefore, it is likely that both immune regulatory and target tissue genes contribute to these and other autoimmune diseases.

    更新日期:2019-11-01
  • The assessment of the patient with systemic sclerosis.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Gabriele Valentini

    Systemic sclerosis presents a great deal of variability among different patients in the extent of skin and internal organ involvement, the pace of the disease and consequently, the prognosis. In addition, the single patient, during his/her disease course, can present with distinct manifestations. Each patient must, therefore, be carefully investigated. The assessment should be adapted to the setting, i.e. clinical practice, clinical investigation, therapeutic trials. The clinician cannot confine the diagnostic process to labelling the disease. He must define the subset, the extent of internal organ involvement, and the type of lesions underlying the clinical manifestations, i.e. fibrotic lesions, reflecting irreversible damage should be separated from active lesions (such as alveolitis) which can be reversed by drug treatment. The clinical investigator must assure that his/her patients are comparable to other series. ACR criteria have been shown to not assure such comparability. To this purpose, a core set of variables to be assessed in any clinical investigation study has been proposed. Finally, the clinical researcher should enrol patients with active disease and must rely for his/her conclusions on feasible and sensitive to change measures. An OMERACT committee has recently reviewed the literature selecting those ready for use in clinical trials.

    更新日期:2019-11-01
  • Immune deficiency and autoimmunity.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Amos Etzioni

    Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. Hematological manifestations, such as thrombocytopenia and hemolytic anemia, are the most common presentation, but many other autoimmune mediated conditions have also been described. Persistent antigen stimulation, due to an inherently defective immune system ability to eradicate pathogenesis is the primary cause leading to autoimmunity in patients with primary immunodeficiency states. Other factors leading to the increase incidence of autoimmune manifestion will be discussed in the present review. Treatment with intravenous gammagluobuilin may ameliorate the autoimmune disorder and bone marrow transplantation can cure both conditions.

    更新日期:2019-11-01
  • Association of celiac disease with connective tissue diseases and autoimmune diseases of the digestive tract.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Nicola Bizzaro,Danilo Villalta,Elio Tonutti,Marilina Tampoia,Danila Bassetti,Renato Tozzoli

    Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten in susceptible individuals, and is one of the most frequent genetically based diseases, with a prevalence of 1:200 in the general population. The association between CD and connective tissue diseases (CTD) and autoimmune diseases of the digestive tract (DT) has been described in several case reports but in few extensive studies, with varying prevalence. A high rate of false positive results were observed when low specific tests, such as the anti-gliadin and the guinea pig tissue transglutaminase (tTG) antibody assays were used. In a study of 400 patients with CTD and 218 with autoimmune DT disease, tested for IgA and IgG anti-tTG using the more specific human recombinant antigen, 12 cases (1.9%) of anti-tTG antibody positivity were found, but only 2 (0.3%) were confirmed as affected by CD following small bowel biopsy. Most of the patients testing false positive had primary biliary cirrhosis. In this short review we describe the association between CD and CTD, inflammatory bowel disease and primary biliary cirrhosis, with special emphasis on the diagnostic accuracy of CD antibody assays.

    更新日期:2019-11-01
  • The biology of TNF blockade.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Arun G Suryaprasad,T Prindiville

    Rheumatoid arthritis and Crohn's disease are costly diseases that result in significant long-term patient disability. They are chronic inflammatory diseases that are associated with increased production of Tumor Necrosis Factor (TNF). Blockage of this cytokine with bio-engineered compounds has significantly changed therapy of these diseases and has ushered in the era of biological therapy. The pro-inflammatory role of TNF is mediated by its essential respiratory burst function that is effectively inhibited by anti-TNF therapy. Anti-TNF therapy is effective in approximately two-thirds of patients to whom it is administered, but the effect is temporary. Lack of response to anti-TNF therapy stems from interplay of host-factors including: host cytokine response, disease phenotype, and antibody response to the anti-TNF agents. NOD 2, a defect present in approximately 50% of Crohn's disease patients, bears no relationship to non-response. Additionally, TNF promoter gene polymorphisms and TNF receptor gene heterogeneity play a significant role in non-response and disease course/severity. Adverse effects of anti-TNF therapy include early and delayed hypersensitivity reactions, cell-mediated infections, lupus-like syndrome, demyelinating diseases, and exacerbation of CHF.

    更新日期:2019-11-01
  • Autoimmunity seen through the SEREX-scope.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Philippe Krebs,Michael Kurrer,Ugur Sahin,Ozlem Türeci,Burkhard Ludewig

    Autoantibodies can be detected in autoimmune diseases with a long prodromal phase and may serve as early indicators of disease activity. Autoantibody-based screening methods are therefore potent tools for the identification of target antigens. The SEREX method (serological identification of antigens by recombinant expression cloning) has been developed for the serological definition of immunogenic tumor antigens. Recent studies indicate that the SEREX approach may also be utilized for the analysis of complex immune responses involved in autoimmune diseases.

    更新日期:2019-11-01
  • Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Brenda R Kwak,Flore Mulhaupt,François Mach

    Large clinical trials have demonstrated that HMG-CoA reductase inhibitors or 'statins' greatly reduce cardiovascular-related morbidity and mortality. The beneficial effects of statins were first assumed to result from their ability to reduce cholesterol synthesis and improve serum lipid profiles. In recent years, however, numerous pleiotropic effects of statins on atherosclerotic lesions have been described. In this review, we summarize the actions of statins on different aspects of atherosclerotic plaque development. These include endothelial dysfunction, leukocyte recruitment and inflammation, smooth muscle cell activation/proliferation, and finally plaque rupture and thrombosis.

    更新日期:2019-11-01
  • Autoimmunity and hepatitis C.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Christian P Strassburg,Arndt Vogel,Michael P Manns

    Hepatitis C is a widespread chronic liver disease leading to cirrhosis and to the complications of portal hypertension. Based on biochemical and clinical features, it is almost indistinguishable from autoimmune hepatitis, which is characterized by the absence of viral infection, and other causes of chronic liver diseases, and represents a classical autoimmune disease with loss of immunological tolerance of liver tissue. Although the differentiation between both diseases is not difficult due the availability of diagnostic viral markers, it is well recognized that not only are autoantibodies present in autoimmune hepatitis frequently detected in hepatitis C, but also that an array of immune-mediated symptoms and diseases occur in patients with chronic hepatitis C. This has prompted research aimed at identifying a link between hepatitis C and autoimmunity, and autoimmune hepatitis in particular. This review focuses on the general immunological mechanisms linking viral infections with autoimmunity and includes the specific features of hepatitis C- and D-associated autoimmunity. Virus infection remains at the center of molecular and cellular research aimed at identifying the forces driving human autoimmunity and autoimmune diseases.

    更新日期:2019-11-01
  • Autoantigenicity of nucleolar complexes.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Tim J M Welting,Reinout Raijmakers,Ger J M Pruijn

    Autoantibodies targeting nucleolar autoantigens (ANoA) are most frequently found in sera from patients with systemic sclerosis (SSc, also designated scleroderma) or with SSc overlap syndromes. During the last decade an extensive number of nucleolar components have been identified and this allowed a more detailed analysis of the identity of nucleolar autoantigens. This review intends to give an overview of the molecular composition of the major (families of) autoantigenic nucleolar complexes, to provide some insight into their functions and to summarise the data concerning their autoantigenicity.

    更新日期:2019-11-01
  • Primary sclerosing cholangitis.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-10-11
    Sue Cullen,Roger Chapman

    Primary sclerosing cholangitis (PSC) is a fibrosing disease of the intra- and extra-hepatic bile ducts, and is closely associated with inflammatory bowel disease. It is immune mediated, rather than being a classical autoimmune disease. A range of immune abnormalities have been demonstrated in PSC, in particular the findings of a range of autoantibodies, a portal tract infiltrate of functional T cells, a restricted T-cell receptor repertoire, and aberrant expression of HLA molecules on biliary epithelial cells. The immunogenetics of PSC is currently under study and to date 4 key HLA haplotypes associated with PSC have been developed. The trigger factor for the initiation of the immune response may be the ingress of bacteria or other toxic metabolites into the portal circulation through a diseased and permeable bowel wall.

    更新日期:2019-11-01
  • Computer-assisted classification of HEp-2 immunofluorescence patterns in autoimmune diagnostics.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Ulrich Sack,Stephan Knoechner,Holger Warschkau,Ullrich Pigla,Frank Emmrich,Manja Kamprad

    Indirect immunofluorescence with HEp-2 cells presents the major screening method for detection of autoantibodies in systemic autoimmune diseases. Hereby, a large variety of autoantibody entities can be detected and recognized by at least partially typic fluorescence patterns. Currently, this method requires highly specialized technicians and resists automatization. Nevertheless, requirements of good laboratory practice, especially standardization and documentation are hampered by the common microscopic technique. Here, we present a computer-assisted system for classification of interphase HEp-2 immunofluorescence patterns in autoimmune diagnostics. Designed as an assisting system, representative patterns are acquired by an operator with a digital microscope camera and transferred to a personal computer. By use of a novel software package based on image analysis, feature extraction and machine learning algorithms, relevant characteristics describing patterns could be found out. Our results show that identification of positive fluorescence and pre-differentiation between most important HEp-2 staining patterns can be performed by this system. Results and documentation of fluorescence patterns can be integrated into the laboratory system. To enable the usage of such a system in routine diagnostics, accuracy of this system and correct recognition of interferring patterns must be further improved.

    更新日期:2019-11-01
  • LEDGF/p75: a novel nuclear autoantigen at the crossroads of cell survival and apoptosis.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Vidya Ganapathy,Tracy Daniels,Carlos A Casiano

    Intracellular autoantigens recognized by autoantibodies in systemic autoimmune and other chronic inflammatory disorders often undergo proteolytic cleavage during apoptosis. Cleaved autoantigens may display altered functions and higher immunogenicity, and could potentially elicit autoantibody responses under a pro-inflammatory environment. LEDGF/p75 (lens epithelium derived growth factor p75) is a ubiquitous nuclear autoantigen targeted by autoantibodies in subsets of patients with atopic disorders, mainly atopic dermatitis, and other inflammatory conditions involving dysregulated apoptosis. Anti-LEDGF/p75 autoantibodies have been shown to have cytotoxic activity, suggesting their involvement in pathogenesis. LEDGF/p75 confers cellular protection against stress-induced apoptosis via transcriptional activation of stress-related genes. Recent studies in our laboratory established that LEDGF/p75 belongs to a selected group of autoantigens that are targeted for cleavage during cell death. In apoptotic cells, caspases cleave this protein at three sites located within functionally important domains, generating two fragments of 65 and 58 kD. Caspase cleavage not only abolishes the survival function of LEDGF/p75 but may generate variants of the protein that enhance apoptosis. A model is proposed in which caspase-induced LEDGF/p75 cleavage and the generation of autoantibodies to the protein might contribute to the pathogenesis of various human atopic and inflammatory disorders associated with dysregulated apoptosis.

    更新日期:2019-11-01
  • Environmental factors in autoimmune diseases, February 4-5, 2003, Durham, NC, USA.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Vered Molina,Michael Ehrenfeld

    更新日期:2019-11-01
  • T-cellular autoimmunity against desmogleins in pemphigus, an autoantibody-mediated bullous disorder of the skin.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Michael Hertl,Christian Veldman

    Pemphigus encompasses a group of life-threatening blistering diseases of the skin in which loss of adhesion between keratinocytes is caused by autoantibodies (Ab) against desmogleins (Dsg) 1 and 3. There is major interest in characterizing autoreactive T cells that are presumably critical for the induction and regulation of Ab production. In a recent study, peripheral Dsg3-reactive T helper (Th) cells from patients with acute onset, chronic active and remittent pemphigus vulgaris (PV) were quantitated by MACS secretion assay. Dsg3-reactive Th2 cells were detected at similar frequencies in all the studied PV patients while the number of autoreactive Th1 cells exceeded those of the Th2 cells in chronic active PV. Noteworthy, healthy carriers of the PV-associated HLA class II alleles, DRbeta1*0402 and DQbeta1*0503, exhibited exclusively Th1 reactivity against Dsg3. The titers of Dsg3-reactive IgG were directly related to the ratio of autoreactive Th1/Th2 cells. Moreover, T cell recognition of Dsg3 was restricted by these HLA class II alleles. These findings strongly suggest that (1) Dsg3-reactive Th2 cells are restricted to PV, (2) distinct HLA class II alleles are critical for T cell recognition of Dsg3, and (3) Ab production is associated with both, Th1 and Th2 cells.

    更新日期:2019-11-01
  • Anti-cholesterol antibodies in human sera.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Anna Horváth,Adrienn Bíró

    In the last 30 years many research showed that high serum cholesterol level is a great risk for the atherosclerosis. In recent years, it has become clear that the immune system has a major role in atherosclerosis development and progression, and has binding capacity to cholesterol as well. It has been demonstrated in animal experiments, that anti-cholesterol antibodies (ACHA) can prevent cholesterol diet induced atherosclerosis. Our group is looking for the answer, whether ACHA have the same function in animals and in humans, or not. In this review we summarize our studies in human sera. We measured serum ACHA levels in different groups of patients with atherosclerotic diseases in patients with viral infections and in healthy population. In the summary we write about the possible functions of ACHA in the human immune system.

    更新日期:2019-11-01
  • General network of natural autoantibodies as immunological homunculus (Immunculus).
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Alexander Poletaev,Leeza Osipenko

    The term 'Immunculus' has been proposed for designation of the global system (network) of constitutively expressed natural autoantibodies (na-Ab) interacting specifically with different extracellular, membrane, cytoplasmic, and nuclear self-antigens. In healthy persons the repertoires of such na-Ab are surprisingly constant and characterized by minimal individual quantitative variations. On the other hand, abnormal metabolic deviations, which precede or accompany different diseases show easily detectable prominent changes, rather quantitative than qualitative, in the network of na-Ab in the patient's sera (Immunculus distortions). This phenomenon can be used for 'mapping' the state of physiological norm in terms of the millennia of na-Ab repertoires, and for the elaboration of methods for an early (pre-clinical) detection of potentially pathogenic metabolic changes. Can the individual features of the general network of constitutively expressed na-Ab reflect the functional state of the body and be used for 'mapping' of normal and pathological functional state? Can the changes in production of some biologically active na-Ab not only reflect the state of the body, but also be used for partial compensation of functional deficiency of certain molecular systems? These and related questions are discussed in this article. The research project 'Immunculus' is proposed for international cooperative investigations.

    更新日期:2019-11-01
  • An update on Kawasaki disease.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    Rolando Cimaz,Fernanda Falcini

    Kawasaki disease (KD) is a febrile systemic vasculitis complicated by coronary and peripheral arterial aneurysms in 20-35% of untreated patients. It is reported as the commonest cause of acquired heart disease in children in developed countries, and may be a risk for adult ischaemic heart disease. Although KD has been reported all over the world, it is overexpressed among Asian populations, especially Japanese. The disease pathogenesis is still unknown and several theories have been proposed, including the possibility of an infection by a toxin-secreting microorganism and of a superantigen-driven process. Despite numerous efforts there is still no diagnostic test available for KD, and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high persistent fever. Prompt diagnosis is critical, since the early administration of intravenous immunoglobulins and aspirin reduces the rate of coronary abnormalities to less than 5% of patients.

    更新日期:2019-11-01
  • Immunogenetics of the response to HBsAg vaccination.
    Autoimmun. Rev. (IF 7.716) Pub Date : 2003-09-11
    David R Milich,Geert G Leroux-Roels

    The major envelope protein of the hepatitis B virus (HBV), the HBsAg, constitutes the current preventative vaccine, which represents the first subunit viral vaccine developed. The genetics of the immune response to HBsAg has been extensively studied both in humans and mice. Murine studies begun over 20 years ago indicated that at least two MHC class II and one MHC class III genes regulate anti-HBs immune responses. Additional MHC-linked genes influence the immune responses to the higher molecular weight (pre-S) components of the HBV envelope. The murine studies predicted even more complex MHC gene regulation of human immune responses to the HBsAg and that complexity certainly has been demonstrated during the ensuing years. This brief review is an attempt to summarize our current understanding of the MHC genes that influence the immune response to the HBsAg and possible mechanisms of action.

    更新日期:2019-11-01
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