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Boleto G, Vieira M, Saadoun D, Cacoub P. Hepatitis C virus-related vasculitis. Clin Res Hepatol Gastroenterol 2021; 45:101575. [PMID: 33268038 DOI: 10.1016/j.clinre.2020.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/06/2020] [Indexed: 02/04/2023]
Abstract
Cryoglobulinemic vasculitis (CryoVas) is a small-to-medium vessel systemic vasculitis caused by the deposition of mixed cryoglobulins and immune complexes. Clinical spectrum of CryoVas ranges from mild symptoms to vasculitis involving multiple organs that may progress to more life-threatening ilness. Hepatitis C virus (HCV) chronic infection is the most frequent condition to be assessed in patients with CryoVas. The mortality rate among patients with HCV-associated CryoVas is 3× that of the general population, with a 63% 10-year survival rate. The recent advent of interferon-free direct-acting antivirals (DAAs), which have the potential to induce sustained virological response rates greater than 95%, has dramatically changed the management of chronic HCV infection and HCV-related CryoVas. B-cell depleting strategies, mainly with rituximab, are the main therapeutic option in severe and refractory cases of HCV-associated CryoVas. Despite the progress in the last years on the management of chronic HCV infection, there are still unmet needs regarding therapeutic management of severe and refractory HCV-associated CryoVas.
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Affiliation(s)
- Gonçalo Boleto
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France; Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose, France
| | - Matheus Vieira
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France; Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose, France
| | - David Saadoun
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France; Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose, France; Sorbonne Université, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France; INSERM, UMR S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France
| | - Patrice Cacoub
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France; Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose, France; Sorbonne Université, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France; INSERM, UMR S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France.
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Comarmond C, Lorin V, Marques C, Maciejewski-Duval A, Joher N, Planchais C, Touzot M, Biard L, Hieu T, Quiniou V, Desbois AC, Rosenzwajg M, Klatzmann D, Cacoub P, Mouquet H, Saadoun D. TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses. J Hepatol 2019; 71:908-919. [PMID: 31279905 DOI: 10.1016/j.jhep.2019.06.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 06/24/2019] [Accepted: 06/27/2019] [Indexed: 01/22/2023]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/- atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity. METHODS The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronicallyHCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies. RESULTS The Tbet+CD11c+CD27+CD21- AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127-/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region. CONCLUSION Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses. LAY SUMMARY B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells.
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Affiliation(s)
- Cloé Comarmond
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France; Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France
| | - Valérie Lorin
- Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France
| | - Cindy Marques
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France; Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France
| | - Anna Maciejewski-Duval
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France
| | - Nizar Joher
- Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France
| | - Cyril Planchais
- Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France
| | - Maxime Touzot
- INSERM U932, 26 rue d'Ulm, 75005 Paris, France; Institut Curie, Section Recherche, 26 rue d'Ulm, 75005 Paris, France; Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
| | - Lucie Biard
- AP-HP, SBIM, Hôpital Saint-Louis, Université Paris Diderot, Paris 7, Paris, France; INSERM, ECSTRA Team, CRESS UMR-S 1153, 75010 Paris, France
| | - Thierry Hieu
- Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France
| | - Valentin Quiniou
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France
| | - Anne-Claire Desbois
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France
| | - Michelle Rosenzwajg
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France
| | - David Klatzmann
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France
| | - Patrice Cacoub
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France
| | - Hugo Mouquet
- Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France; INSERM U1222, Paris, France.
| | - David Saadoun
- Sorbonne Université, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunotherapie, i3 and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, i2B, F-75651 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Biothérapie, F-75013 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, F-75013 Paris, France.
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Xie Z, Chen E, Ouyang X, Xu X, Ma S, Ji F, Wu D, Zhang S, Zhao Y, Li L. Metabolomics and Cytokine Analysis for Identification of Severe Drug-Induced Liver Injury. J Proteome Res 2019; 18:2514-2524. [PMID: 31002254 DOI: 10.1021/acs.jproteome.9b00047] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM To evaluate the levels of metabolites and cytokines in the serum of patients with severe and non-severe idiosyncratic drug-induced liver injury (DILI) and to identify biomarkers of DILI severity. METHODS Gas chromatography-mass spectrometry (GC-MS) and ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) based metabolomic approaches were used to evaluate the metabolome of serum samples from 29 DILI patients of severity grade 3 (non-severe), 27 of severity grade 4 (severe), and 36 healthy control (HC). The levels of total keratin-18 (K18), fragment K18, and 27 cytokines were determined by enzyme-linked immunosorbent assay. RESULTS The alkaline phosphatase activity ( p = 0.021) and international normalized ratio (INR) ( p < 0.001) differed significantly between the severe and non-severe groups. The severe group had a higher serum fragment K18 level than the non-severe group. A multivariate analysis showed good separation between all pairs of the HC, non-severe, and severe groups. According to the orthogonal partial least-squares-discriminant analysis (OPLS-DA) model, 14 metabolites were selected by GC-MS and 17 by UPLC-MS. Among these metabolites, the levels of 16 were increased and of 15 were decreased in the severe group. A pathway analysis revealed major changes in the primary bile acid biosynthesis and alpha-linolenic acid metabolic pathways. The levels of PDGF-bb, IP-10, IL-1Rα, MIP-1β, and TNF-α differed significantly between the severe and non-severe groups, and the levels of most of the metabolites were negatively correlated with those of these cytokines. An OPLS-DA model that included the detected metabolites and cytokines revealed clear separation of the severe and non-severe groups. CONCLUSION We identified 31 metabolites and 5 cytokines related to the severity of idiosyncratic DILI. The primary bile acid biosynthesis and alpha-linolenic acid metabolism pathways were also related to the severity of DILI. A model that incorporated the metabolites and cytokines showed clear separation between patients with severe and non-severe DILI, suggesting that these biomarkers have potential as indicators of DILI severity.
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Affiliation(s)
- Zhongyang Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Ermei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Xiaoxi Ouyang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Xiaowei Xu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
- Department of Infectious Disease, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
| | - Shanshan Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Feiyang Ji
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Daxian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou 310003 , China
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Heterogeneity and coexistence of oncogenic mechanisms involved in HCV-associated B-cell lymphomas. Crit Rev Oncol Hematol 2019; 138:156-171. [PMID: 31092372 DOI: 10.1016/j.critrevonc.2019.04.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.
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Cacoub P, Comarmond C. Considering hepatitis C virus infection as a systemic disease. Semin Dial 2018; 32:99-107. [PMID: 30549107 DOI: 10.1111/sdi.12758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection has been demonstrated to result in several adverse hepatic outcomes and has been associated with a number of important extrahepatic manifestations. The scope of extrahepatic clinical possibilities includes systemic diseases such as vasculitis and lymphoproliferative disorders, cardiovascular disease, myalgia, arthritis, and sicca syndrome. These end-organ effects of HCV may dominate the clinical course beyond the hepatic complications and significantly worsen the long-term prognosis of infected patients. Until several years ago, the standard of care for the treatment of HCV infection had been interferon-alpha-based regimens, which not only had limited effectiveness in achieving a cure but were often poorly tolerated, especially in patients with kidney disease. In those HCV-infected patients with significant systemic manifestations, the interferon-based regimens were problematic given their association with a wide variety of toxicities. The development of highly effective direct-acting antiviral agents to treat HCV infection presented an opportunity to improve the HCV care cascade with the eradication of HCV in most infected patients and by reducing the burden of both hepatic and extrahepatic complications.
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Affiliation(s)
- Patrice Cacoub
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Cloé Comarmond
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Konstantinides P, Alexopoulou A, Hadziyannis E, Kanellopoulou T, Dourakis SP. Interleukin-17A and B-cell activating factor in chronic hepatitis C patients with or without asymptomatic mixed cryoglobulinemia: effects of antiviral treatment and correlations with vitamin D. Ann Gastroenterol 2018; 31:705-711. [PMID: 30386121 PMCID: PMC6191865 DOI: 10.20524/aog.2018.0310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 08/23/2018] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Several studies have provided conflicting results regarding the immune responses in chronic hepatitis C (CHC) patients with mixed cryoglobulinemia (MC). The importance of B-cell activating factor (BAFF) in MC has been described, but the role of interleukin (IL)-17A is less clear. METHODS Serum concentrations of IL-17A, BAFF and 25-OH vitamin D were measured in CHC patients at baseline, end of treatment, and 6 months post-treatment with pegylated interferon-α and ribavirin, versus 12 healthy controls. RESULTS Thirty-four patients (20 male, mean age 40.7±9.2 years, 12 of genotype 1 or 4, 22 of genotype 2 or 3) were included, of whom 64.7% achieved a sustained virological response (SVR). MC was detected in 52.9% of the patients. Higher levels of both cytokines were found in patients with MC compared to those without. Patients who achieved SVR had higher pretreatment IL-17A and lower BAFF levels compared to those without SVR. IL-17A was downregulated during and following treatment in responders, whereas upregulation was observed in non-responders. CHC patients demonstrated low vitamin D levels compared to HC. Moreover, the changes in IL-17A over the treatment period were significantly associated with vitamin D changes (β=-0.04, SE=0.02, P=0.046). No difference in IL-17A, BAFF and vitamin D values was seen between patients with cirrhosis (n=14) and those without. CONCLUSIONS CHC patients with asymptomatic MC have increased levels of IL-17A and BAFF. IL-17A levels decline significantly while BAFF increases during treatment in responders. An interplay between IL-17A and vitamin D concentrations was revealed during the antiviral treatment.
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Affiliation(s)
- Polydoros Konstantinides
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Alexandra Alexopoulou
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Emilia Hadziyannis
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Theoni Kanellopoulou
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Spyridon P. Dourakis
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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Immune-Mediated Systemic Vasculitis as the Proposed Cause of Sudden-Onset Sensorineural Hearing Loss following Lassa Virus Exposure in Cynomolgus Macaques. mBio 2018; 9:mBio.01896-18. [PMID: 30377282 PMCID: PMC6212830 DOI: 10.1128/mbio.01896-18] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Lassa virus (LASV) causes a severe, often fatal hemorrhagic disease in regions in Africa where the disease is endemic, and approximately 30% of patients develop sudden-onset sensorineural hearing loss after recovering from acute disease. The causal mechanism of hearing loss in LASV-infected patients remains elusive. Here, we report findings after closely examining the chronic disease experienced by surviving macaques assigned to LASV exposure control groups in two different studies. All nonhuman primates (NHPs) developed typical signs and symptoms of Lassa fever, and seven succumbed during the acute phase of disease. Three NHPs survived beyond the acute phase and became chronically ill but survived to the study endpoint, 45 days postexposure. All three of these survivors displayed continuous disease symptoms, and apparent hearing loss was observed using daily subjective measurements, including response to auditory stimulation and tuning fork tests. Objective measurements of profound unilateral or bilateral sensorineural hearing loss were confirmed for two of the survivors by brainstem auditory evoked response (BAER) analysis. Histologic examination of inner ear structures and other tissues revealed the presence of severe vascular lesions consistent with systemic vasculitides. These systemic immune-mediated vascular disorders have been associated with sudden hearing loss. Other vascular-specific damage was also observed to be present in many of the sampled tissues, and we were able to identify persistent virus in the perivascular tissues in the brain tissue of survivors. Serological analyses of two of the three survivors revealed the presence of autoimmune disease markers. Our findings point toward an immune-mediated etiology for Lassa fever-associated sudden-onset hearing loss and lay the foundation for developing potential therapies to prevent and/or cure Lassa fever-associated sudden-onset hearing loss.IMPORTANCE Lassa virus is one of the most common causes of viral hemorrhagic fever. A frequent, but as yet unexplained, consequence of infection with Lassa virus is acute, sudden-onset sensorineural hearing loss in one or both ears. Deafness is observed in approximately 30% of surviving Lassa fever patients, an attack rate that is approximately 300% higher than mumps virus infection, which was previously thought to be the most common cause of virus-induced deafness. Here, we provide evidence from Lassa virus-infected cynomolgus macaques implicating an immune-mediated vasculitis syndrome underlying the pathology of Lassa fever-associated deafness. These findings could change the way human Lassa fever patients are medically managed in order to prevent deafness by including diagnostic monitoring of human survivors for onset of vasculitides via available imaging methods and/or other diagnostic markers of immune-mediated vascular disease.
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Abstract
Cryoglobulins are immunoglobulins that undergo reversible precipitation at low temperatures. They can induce systemic vasculitis, characterized by purpuric cutaneous lesions, arthritis, peripheral neuropathy, hypocomplementemia and glomerular disease. Renal pathology reveals membranoproliferative glomerulonephritis, with particularly intense mesangial cell proliferation and infiltration by macrophages, associated with intracapillary thrombi. This renal disease presents as a nephritic syndrome, with heavy proteinuria, haematuria severe hypertension and rapidly progressive kidney failure that can lead to end-stage renal disease. Hepatitis C is the main cause of mixed (type 2 or 3) cryoglobulinemia and requires the initiation of a specific antiviral therapy, together with immunosuppressive drugs. Rituximab is now considered as the best immunosuppressive therapy in this situation, inducing B-cell depletion, clearance of circulating cryoglobulin and resolution of renal symptoms. Monoclonal (type 1) cryoglobulinemia, is a rare condition, but it usually reveals an B-cell or a plasma cell proliferation, that require a specific hematological treatment to obtain remission of the renal disease.
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Comstock E, Kim CW, Murphy A, Emmanuel B, Zhang X, Sneller M, Poonia B, Kottilil S. Transcriptional profiling of PBMCs unravels B cell mediated immunopathogenic imprints of HCV vasculitis. PLoS One 2017; 12:e0188314. [PMID: 29228031 PMCID: PMC5724854 DOI: 10.1371/journal.pone.0188314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 11/03/2017] [Indexed: 01/22/2023] Open
Abstract
B cell depletion therapy using rituximab has been shown to be effective in achieving remission in patients with HCV-mixed cryoglobulinemic (MC) vasculitis. Previously, we have demonstrated abnormalities in peripheral immune cells involving neutrophils, chemotaxis, and innate immune activation among patients with HCV-MC vasculitis when compared to HCV patients without vasculitis. In this study, we evaluated the effect of B cell depletion therapy on transcriptional profiles of peripheral blood mononuclear cells before and after riruximab therapy, in order to unravel the pathogenic mechanism involved in HCV-MC vasculitis induced by abnormal B cell proliferation. DNA microarray analysis was performed using RNA from PBMCs from seven patients with HCV-MC vasculitis and seven normal volunteers. DNA was hybridized to Affymetrix U133A chips. After normalization, differentially expressed gene list with treatment was generated using partitional clustering. RT-PCR, flow cytometry, and enzyme immunoassay (EIA) was used to validate DNA microarray findings. Differentially expressed genes included B cells and non-B cell genes. Validation of genes using purified cell subsets demonstrated distinct effect of B cell depletion therapy on non-B cells, such as monocytes, T cells, and NK cells. Notably, B lymphocyte stimulator (BLyS) levels were persistently elevated in patients who subsequently relapsed. In conclusion, pathogenesis of HCV-MC vasculitis is mediated by abnormal proliferation of B cells, driven by BLyS, leading to significant effects on non-B cells in mediating symptomatology. Future therapeutics using a combination approach of B cell depletion and proliferation may be desired to achieve long-term remission.
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Affiliation(s)
- Emily Comstock
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Cheol-Woo Kim
- Department of Internal Medicine, Inha University, Incheon, South Korea
| | - Alison Murphy
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
| | - Benjamin Emmanuel
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Xi Zhang
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
| | - Michael Sneller
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
| | - Bhawna Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Shyamasundaran Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
- * E-mail:
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10
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Ilyas SZ, Tabassum R, Hamed H, Rehman SU, Qadri I. Hepatitis C Virus-Associated Extrahepatic Manifestations in Lung and Heart and Antiviral Therapy-Related Cardiopulmonary Toxicity. Viral Immunol 2017; 30:633-641. [PMID: 28953449 DOI: 10.1089/vim.2017.0009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Besides liver cirrhosis and hepatocellular carcinoma, chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations (EHMs). HCV exhibits lymphotropism that is responsible for various EHM. An important characteristic of HCV is escape from the immune system, which enables it to produce chronic infections and autoimmune disorders along with accumulation of circulating immune complexes. These EHMs have large spectrum, because they affect many organs such as heart, lungs, kidney, brain, thyroid, and skin. HCV-related cardiac and pulmonary manifestations include myocarditis, cardiomyopathies, cardiovascular diseases (i.e., Stroke, ischemic heart disease), chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, and interstitial lung diseases. This review discusses etiology and pathogenesis of HCV-associated cardiac and pulmonary manifestations and how different genes, immune system, indirectly linked factors (mixed cryoglobulinemia), liver cirrhosis, and antiviral treatment are involved in HCV-related heart and lung diseases, however, their exact mechanism is not clear.
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Affiliation(s)
- Syeda Zainab Ilyas
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Rabia Tabassum
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Haroon Hamed
- 2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia
| | - Shafiq Ur Rehman
- 1 Department of Microbiology and Molecular Genetics, University of the Punjab , Lahore, Pakistan
| | - Ishtiaq Qadri
- 2 Department of Biological Sciences, King Abdul Aziz University , Jeddah, Kingdom of Saudi Arabia
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11
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Cusato J, Boglione L, De Nicolò A, Cardellino CS, Carcieri C, Cariti G, Di Perri G, D'Avolio A. Pharmacogenetic analysis of hepatitis C virus related mixed cryoglobulinemia. Pharmacogenomics 2017; 18:607-611. [PMID: 28453396 DOI: 10.2217/pgs-2016-0040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM Mixed cryoglobulinemia (MC) is an extra hepatic hepatitis C virus related problem and different studies suggested genetics' role in predicting this complication. We evaluated the influence of SNPs in IL-28B, SLC29A1, SLC28A2, NT5C2, HNF4 and ABCB1 genes in MC prediction. PATIENTS & METHODS SNPs were evaluated through real-time PCR. RESULTS ABCB1 (gene encoding P-glycoprotein) 3435C>T SNP was associated with MC presence (p = 0.034): related to T allele carriers (CC vs CT/TT), we reached a p-value of 0.013. In the logistic regression analysis baseline viral load >600.000 IU/ml (p < 001), IL28B rs8099917/rs12979860 TT/CC (p < 0.001), NT5 (gene encoding for 5' nucleotidase) 153 TC (p = 0.012) and ABCB1 3435 CT/TT (p = 0.034) genotypes predicted MC presence. CONCLUSION These data could help clinicians to identify patients with higher probability to show MC extra hepatic complication.
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Affiliation(s)
- Jessica Cusato
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Lucio Boglione
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Amedeo De Nicolò
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Chiara Simona Cardellino
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Chiara Carcieri
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Giuseppe Cariti
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Antonio D'Avolio
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
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12
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Vitamin D pathway gene polymorphisms as predictors of hepatitis C virus-related mixed cryoglobulinemia. Pharmacogenet Genomics 2017; 26:307-10. [PMID: 27139837 DOI: 10.1097/fpc.0000000000000223] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mixed cryoglobulinemia (MC) is the most frequent extrahepatic hepatitis C virus (HCV) complication. Vitamin D is a modulator of several biological processes, including immune and skeletal systems and MC presence and systemic vasculitis were associated independently with low levels of vitamin D. Considering the impact of vitamin D, we aimed to evaluate the role of some single nucleotide polymorphisms (SNPs) of vitamin D pathway genes in the prediction of MC in HCV patients treated with pegylated interferon and ribavirin. We investigated SNPs in IL-28B, CYP27B1, CYP27A1, CYP24A1, VDBP, and VDR genes through real-time PCR. VDR gene SNPs were related to baseline viral load: VDR BsmI AA (P=0.018), TaqI CC (P=0.009), and ApaI AA (P=0.004) showed a lower baseline HCV count. Among vitamin D pathway gene polymorphisms, VDR FokI T>C was a factor associated with the presence of MC in the study population (P=0.011): related to C allele carriers (TT vs. TC/CC), we obtained a P-value of 0.003. In the logistic regression analysis to assess which demographic, clinical, or genetic factors could predict the presence of cryoglobulin, the TT/CC IL-28B rs8099917/rs12979860 haplotype [P<0.001; odds ratio (OR) 3.516 (1.951-6.336)], baseline viral load [P<0.001; OR 1.000 (0.999-1.001)], and VDR FokI TC/CC genotypes [0.044; OR 0.463 (0.218-0.981)] remained in the final regression model. These data could help physicians identify patients with a higher probability of developing MC extrahepatic complications.
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13
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Ragab G, Hussein MA. Vasculitic syndromes in hepatitis C virus: A review. J Adv Res 2017; 8:99-111. [PMID: 28149646 PMCID: PMC5272950 DOI: 10.1016/j.jare.2016.11.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/07/2016] [Accepted: 11/07/2016] [Indexed: 12/20/2022] Open
Abstract
Vasculitis is a remarkable presentation of the extrahepatic manifestations of HCV. According to the presence or absence of cryoglobulins it is subdivided into two main types: cryoglobulinemic vasculitis and non cryoglobulinemic vasculitis based on the attribution of vasculitis to serum cryoglobulins as a pathogenic factor. The attribution of cryoglobulinemia to HCV represents a success story in the history of immunology, microbiology, and clinical medicine. HCV can bind to and invade lymphocytes, consequently triggering an immune response through different mechanisms. The epidemiology of the disease is well described and the clinical picture describes cutaneous, pulmonary, musculoskeletal, neurological, renal, endocrine, gastrointestinal, hepatic and cardiovascular manifestations. It may also be associated with sicca symptoms, an increased risk of lymphoma and serious catastrophic events. The pathology is well characterized. A classification criteria of the syndrome that was validated in 2014 is discussed. Management of CV is decided according to the presence and severity of its clinical presentation. It is divided into asymptomatic, mild, moderate, severe and life threatening disease. Recently introduced direct antiviral agents are proving safe and effective in the management of cryoglobulinemic vasculitis, and it is advocated that the two types of vasculitis be given prioritization in the Egyptian mass campaign to eradicate HCV.
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Key Words
- ANCA, antineutrophil cytoplasmic antibody
- APS, antiphospholipid syndrome
- BAL, bronchoalveolar lavage
- CAPS, catastrophic antiphospholipid syndrome
- CRP, C reactive protein
- CTD, connective tissue disease
- Cryoglobulins
- DAA, direct acting antiviral drugs
- Direct acting anti-HCV drugs
- ESR, erythrocyte sedimentation rate
- Extrahepatic manifestations vasculitis
- GIT, gastrointestinal tract
- HSP, Henoch-Schonlein Purpura
- HUS, hemolytic uremic syndrome
- Hepatitis C virus
- IFN α, interferon alpha
- IHD, ischemic heart disease
- MOH, minister of health
- MRI, magnetic resonance imaging
- NHL, non Hodgkin lymphoma
- PAN, polyarteritis nodosa
- PCR, polymerase chain reaction
- PFT, pulmonary function test
- PN, peripheral neuropathy
- RNA, ribonucleic acid
- TIAs, transient ischemic attacks
- TTP, thrombotic thrombocytopenic purpura
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Affiliation(s)
- Gaafar Ragab
- Rheumatology and Clinical Immunology Unit, Department of Internal Medicine, Cairo University, Egypt
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14
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Cacoub P, Comarmond C. New insights into HCV-related rheumatologic disorders: A review. J Adv Res 2016; 8:89-97. [PMID: 28149645 PMCID: PMC5272935 DOI: 10.1016/j.jare.2016.07.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infected patients are known to be exposed to major liver complications i.e. cirrhosis and hepatocellular carcinoma. In addition, many extrahepatic manifestations including rheumatologic disorders have been reported in up to two-third of HCV infected patients. These manifestations include frank auto-immune and rheumatic diseases (such as arthralgia, myalgia, arthritis, sicca syndrome and vasculitis) which may dominate the course of infection. Until recently, the standard of care of HCV has been the use of interferon-alpha based regimens, which not only had limited effectiveness in HCV cure but were poorly tolerated. In patients with rheumatic diseases interferon-based regimens may be problematic given their association with a wide variety of autoimmune toxicities. Recent therapeutic advances with new direct anti-HCV therapies (interferon-free) which are more effective and better tolerated, make screening for this comorbidity in patients with rheumatic disorders more important than ever. This review aimed to outline main HCV extrahepatic with a special focus on rheumatologic manifestations.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 Paris, France; INSERM, UMR_S 959, F-75013 Paris, France; CNRS, FRE3632, F-75005 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013 Paris, France
| | - Cloé Comarmond
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 Paris, France; INSERM, UMR_S 959, F-75013 Paris, France; CNRS, FRE3632, F-75005 Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013 Paris, France
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15
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Isnard Bagnis C, Cacoub P. Hepatitis C Therapy in Renal Patients: Who, How, When? Infect Dis Ther 2016; 5:313-27. [PMID: 27388502 PMCID: PMC5019972 DOI: 10.1007/s40121-016-0116-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Indexed: 02/07/2023] Open
Abstract
Renal patients are overexposed to hepatitis C virus (HCV) infection. Hepatitis C virus infection may induce renal disease, i.e., cryoglobulinemic membrano-proliferative glomerulopathy and non-cryoglobulinemic nephropathy. Hepatitis C virus impacts general outcomes in chronic kidney disease, dialysis or transplanted patients. Hepatitis C virus infection is now about to be only part of their medical history thanks to new direct acting antiviral drugs exhibiting as much as over 95% of sustained virological response. All HCV-infected patients potentially can receive the treatment. Control of the virus is associated with better outcomes in all cases, whatever the severity of the hepatic or renal disease. This article focuses on HCV-induced renal diseases, the reciprocal impact of HCV infection on the renal outcome and renal status in liver disease, use of new direct-acting antiviral drugs with dosage adaptations and the most recent safety data.
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Affiliation(s)
- Corinne Isnard Bagnis
- Department of Nephrology AP-HP, Groupe Hospitalier Pitié Salpêtrière, 75013, Paris, France. .,UPMC Univ Paris 06, Paris, France.
| | - Patrice Cacoub
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 75005, Paris, France.,INSERM, UMR_S 959, 75013, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.,Sorbonne University, UPMC Univ Paris 06, UMR 7211, Paris, France
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16
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Roffê E, Marino APMP, Weaver J, Wan W, de Araújo FF, Hoffman V, Santiago HC, Murphy PM. Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice. Infect Immun 2016; 84:1123-1136. [PMID: 26857570 PMCID: PMC4807493 DOI: 10.1128/iai.01497-15] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 01/26/2016] [Indexed: 11/20/2022] Open
Abstract
Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80(+)macrophages, and T. cruzi tetramer-specific CD8(+) T lymphocytes capable of producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus,T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses.
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Affiliation(s)
- Ester Roffê
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Ana Paula M P Marino
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Joseph Weaver
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Wuzhou Wan
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Fernanda F de Araújo
- Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Victoria Hoffman
- Division of Veterinary Resources, Office of Research Services, Office of the Director, NIH, Bethesda, Maryland, USA
| | - Helton C Santiago
- Helminth Immunology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA
| | - Philip M Murphy
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
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17
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Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC, Saadoun D. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis 2016; 3:3-14. [PMID: 26862398 DOI: 10.1177/2049936115585942] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
During hepatitis C virus (HCV) chronic infection, extrahepatic manifestations are frequent and polymorphous. This article reports on a large cohort of patients with HCV-related autoimmune or lymphoproliferative disorders, from mixed cryoglobulinemia vasculitis to frank lymphomas. The relationship between HCV infection and such immune-related diseases has been formally demonstrated by epidemiological, clinical, immunological and pathological data, and results of therapeutic trials. More recently, other nonliver-related HCV disorders have been reported, including cardiovascular (i.e. stroke, ischemic heart disease), renal, metabolic and central nervous system diseases. For these manifestations, most evidence comes from large epidemiological studies; there is a need for mechanistic studies and therapeutic trials for confirmation. Beyond the risk of developing liver complications, that is, cirrhosis and liver cancer, patients with HCV infection have an increased risk of morbidity and mortality related to nonliver diseases. HCV chronic infection should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. The need for effective viral eradication measures is underlined.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, and Inflammation Immunopathology Biotherapy Department (DHU i2B), Paris, France
| | | | | | - Léa Savey
- Sorbonne Universités, UPMC Univ Paris 06, and Inflammation Immunopathology Biotherapy Department (DHU i2B), Paris, France
| | | | - David Saadoun
- Sorbonne Universités, UPMC Univ Paris 06, and Inflammation Immunopathology Biotherapy Department (DHU i2B), Paris, France
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18
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Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D, Fallahi P, Antonelli A, Ferri C. Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. Expert Rev Clin Immunol 2015; 11:15-31. [PMID: 25534977 DOI: 10.1586/1744666x.2015.997214] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.
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Affiliation(s)
- Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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19
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Kong F, Zhang W, Feng B, Zhang H, Rao H, Wang J, Cong X, Wei L. Abnormal CD4 + T helper (Th) 1 cells and activated memory B cells are associated with type III asymptomatic mixed cryoglobulinemia in HCV infection. Virol J 2015; 12:100. [PMID: 26129991 PMCID: PMC4501109 DOI: 10.1186/s12985-015-0324-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 06/12/2015] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Mixed cryoglobulinemia (MC) in hepatitis C virus (HCV) infection is associated with abnormal immune responses mediated by T cells and B cells, while the relationships of different subsets of CD4 + T helper (Th) cells, B cells and associated cytokines with type III asymptomatic MC in HCV infection are poorly understood. METHODS Fifty-four chronic hepatitis C (CHC) patients and 23 healthy controls (HCs) were enrolled in the study. Serum cryoglobulins were detected by cryoprecipitation. The types of cryoglobulin were determined by western blot. The phenotypes and frequencies of Th cell and B cell subsets were detected by flow cytometric analysis. The cytokines IFN-γ, IL-4, IL-17, IL-21, IL-22, and TGF-β were measured by enzyme-linked immunosorbent assay. RESULTS Twenty-six CHC patients were detected with type III asymptomatic MC. The frequencies of Th2, Th17, follicular helper T (Tfh cells), Th22, and tissue-like B cells were significantly higher in CHC patients compared to HCs, while these cell subsets were not significantly different between CHC patients and HCV-related MC patients. The frequencies of Th1 and activated memory B cells increased in HCV-related MC patients compared to HCs, although the difference between the two cell subsets in CHC patients and HCs was not significant. The frequency of regulatory T cells (Treg cells) was higher in CHC patients than in HCV-related MC patients and HCs. Higher expressions of serum IFN-γ, IL-17, IL-21, and IL-22 were observed in CHC patients than in HCs, but the differences were not significantly different in CHC patients and HCV-related MC patients. The frequency of Th1 cells was associated with activated memory B cells in HCV-related MC patients, and the frequency of Th1 cells and activated memory B cells was closely related to HCV RNA in HCV-related MC patients. CONCLUSIONS The increased frequencies of Th17 cells, Tfh cells, Th22 cells, Treg cells, cytokines IL-17, IL-21, IL-22, and tissue-like B cells, were related to HCV infection but not type III asymptomatic MC. Higher frequencies of Th1 cells and activated memory B cells were associated with type III asymptomatic MC in HCV infection.
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Affiliation(s)
- Fanyun Kong
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
- Department of Pathogenic biology and Laboratory of Infection and Immunology, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu Province, China.
| | - Wei Zhang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Bo Feng
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Henghui Zhang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Jianghua Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Xu Cong
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, No.11 Xizhimen South Street, Beijing, 100044, China.
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20
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Cacoub P, Gragnani L, Comarmond C, Zignego AL. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis 2014; 46 Suppl 5:S165-73. [PMID: 25458776 DOI: 10.1016/j.dld.2014.10.005] [Citation(s) in RCA: 190] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 10/03/2014] [Indexed: 02/09/2023]
Abstract
Hepatitis C virus (HCV) infected patients are known to be at risk of developing liver complications i.e. cirrhosis and liver cancer. However, the risks of morbidity and mortality are underestimated because they do not take into account non-liver consequences of chronic hepatitis C virus infection. Numerous extrahepatic manifestations have been reported in up to 74% of patients, from perceived to disabling conditions. The majority of data concern hepatitis C virus-related autoimmune and/or lymphoproliferative disorders, from mixed cryoglobulinaemia vasculitis to frank lymphomas. More recently, other hepatitis C virus-associated disorders have been reported including cardiovascular, renal, metabolic, and central nervous system diseases. This review aims to outline most of the extrahepatic manifestations that are currently being investigated, including some of autoimmune and/or lymphoproliferative nature, and others in which the role of immune mechanisms appears less clear. Beyond the liver, hepatitis C virus chronic infection should be analyzed as a multifaceted systemic disease leading to heavy direct and indirect costs. The accurate consideration of extrahepatic consequences of such a systemic infection significantly increases the weight of its pathological burden. The need for effective viral eradication measures is underlined.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France.
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Cloe Comarmond
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Tampaki M, Koskinas J. Extrahepatic immune related manifestations in chronic hepatitis C virus infection. World J Gastroenterol 2014; 20:12372-12380. [PMID: 25253938 PMCID: PMC4168071 DOI: 10.3748/wjg.v20.i35.12372] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 03/23/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
The association of chronic hepatitis C with immune related syndromes has been frequently reported. There is a great range of clinical manifestations affecting various systems and organs such as the skin, the kidneys, the central and peripheral nervous system, the musculoskeletal system and the endocrine glands. Despite the high prevalence of immune related syndromes in patients with chronic hepatitis C, the exact pathogenesis is not always clear. They have been often associated with mixed cryoglobulinemia, a common finding in chronic hepatitis C, cross reaction with viral antigens, or the direct effect of virus on the affected tissues. The aim of this review is to analyze the reported hepatitis C virus immune mediated syndromes, their prevalence and clinical manifestations and to discuss the most supported theories regarding their pathogenesis.
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Abstract
The vasculitides are a large group of heterogeneous diseases for which it has been assumed that pathogenesis is largely autoimmune. As clinicians, we distinguish one form of vasculitis from another on the basis of observed patterns of organ injury, the size of the vessels affected and histopathological findings. The terms 'small-vessel', 'medium-vessel' and 'large-vessel' vasculitis are useful clinical descriptors, but fail to inform us about why vessels of a certain calibre are favoured by one disease and not another. Classification based on vessel size also fails to consider that vessels of a specific calibre are not equally prone to injury. Distinct vulnerabilities undoubtedly relate to the fact that same-size vessels in different tissues may not be identical conduits. In fact, vessels become specialized, from the earliest stages of embryonic development, to suit the needs of different anatomical locations. Vessels of the same calibre in different locations and organs are as different as the organ parenchymal cells through which they travel. The dialogue between developing vessels and the tissues they perfuse is designed to meet special local needs. Added to the story of vascular diversity and vulnerability are changes that occur during growth, development and ageing. An improved understanding of the unique territorial vulnerabilities of vessels could form the basis of new hypotheses for the aetiopathogenesis of the vasculitides. This Review considers how certain antigens, including infectious agents, might become disease-relevant and how vascular diversity could influence disease phenotypes and the spectrum of vascular inflammatory diseases.
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Affiliation(s)
- Gary S Hoffman
- Department of Rheumatic and Immunologic Diseases, A50, 9500 Euclid Avenue, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Leonard H Calabrese
- Department of Rheumatic and Immunologic Diseases, A50, 9500 Euclid Avenue, Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
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Sidharthan S, Kim CW, Murphy AA, Zhang X, Yang J, Lempicki RA, Sneller MC, Kottilil S. Hepatitis C-associated mixed cryoglobulinemic vasculitis induces differential gene expression in peripheral mononuclear cells. Front Immunol 2014; 5:248. [PMID: 24904592 PMCID: PMC4034044 DOI: 10.3389/fimmu.2014.00248] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 05/12/2014] [Indexed: 11/13/2022] Open
Abstract
This study examines the distinct gene expression profile of peripheral blood mononuclear cells from patients with chronic hepatitis C infection and mixed cryoglobulinemic (MC) vasculitis. Our DNA microarray analysis indicates that hepatitis C virus (HCV)-associated MC vasculitis is characterized by compromised neutrophil function, impaired chemotaxis, and increased interferon-stimulated gene (ISG) expression, contributing to overall MC pathogenesis and end-organ damage. Increased ISG expression is suggestive of an enhanced endogenous interferon gene signature. PBMC depletion assays demonstrate that this increased expression is likely due to an activation of monocytes and not a direct result of B cell expansion. Notably, this monocyte activation of ISG expression in HCV-associated MC vasculitis suggests a poor predictor status of interferon-based treatment. Further analysis of PBMC gene expression profiles before and after in vivo B cell depletion therapy is critical to completely understanding the mechanisms of MC vasculitis pathogenesis.
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Affiliation(s)
- Sreetha Sidharthan
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Department of Health and Human Services , Bethesda, MD , USA
| | - Cheol-Woo Kim
- Department of Internal Medicine, Inha University , Incheon , South Korea
| | - Alison A Murphy
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services , Bethesda, MD , USA
| | - Xiaozhen Zhang
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services , Bethesda, MD , USA
| | - Jun Yang
- Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, MD , USA
| | - Richard A Lempicki
- Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, MD , USA
| | - Michael C Sneller
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services , Bethesda, MD , USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services , Bethesda, MD , USA
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Suzuki K, Nagao T, Itabashi M, Hamano Y, Sugamata R, Yamazaki Y, Yumura W, Tsukita S, Wang PC, Nakayama T, Suzuki K. A novel autoantibody against moesin in the serum of patients with MPO-ANCA-associated vasculitis. Nephrol Dial Transplant 2013; 29:1168-77. [PMID: 24319012 DOI: 10.1093/ndt/gft469] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Antineutrophil cytoplasmic autoantibody (ANCA) directed against myeloperoxidase (MPO), a diagnostic criterion in MPO-ANCA-associated vasculitis (MPO-AAV), does not always correlate with disease activity. Here, we detected autoantibodies against moesin, which was located on the surface of stimulated endothelial cells, in the serum of patients. METHODS The anti-moesin autoantibody titer was evaluated by ELISA. Seventeen kinds of cytokines/chemokines were measured by a Bio-Plex system. RESULTS Serum creatinine in the anti-moesin autoantibody-positive group was higher than that in the negative group. Additionally, interferon (IFN)-γ, macrophage chemotactic peptide-1 (MCP-1), interleukin (IL)-2, IL-7, IL-12p70, IL-13, granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor were significantly higher in the positive group. Furthermore, IL-7 and IL-12p70 levels correlated with the anti-moesin autoantibody titer. Based on these findings and the binding of anti-moesin IgG to neutrophils and monocytes, we detected the secretion of cytokines/chemokines such as IFN-γ, MCP-1 and GM-CSF from these cells. CONCLUSIONS The anti-moesin autoantibody existed in the serum of patients with MPO-AAV and was associated with the production of inflammatory cytokines/chemokines targeting neutrophils with a cytoplasmic profile, which suggests that the anti-moesin autoantibody has the possibility to be a novel autoantibody developing vasculitis via neutrophil and endothelial cell activation.
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Affiliation(s)
- Koya Suzuki
- Inflammation Program, Chiba University, Graduate School of Medicine, Chiba City, Japan Graduate School of Life and Environmental Science, Tsukuba University, Tsukuba, Ibaragi, Japan Laboratory of Biological Science, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Tomokazu Nagao
- Inflammation Program, Chiba University, Graduate School of Medicine, Chiba City, Japan
| | - Mitsuyo Itabashi
- Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoshitomo Hamano
- Department of Internal Medicine, Jichi University, School of Medicine, Shimotsuke, Tochigi, Japan
| | - Ryuichi Sugamata
- Inflammation Program, Chiba University, Graduate School of Medicine, Chiba City, Japan
| | - Yuji Yamazaki
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Wako Yumura
- Department of Internal Medicine, Jichi University, School of Medicine, Shimotsuke, Tochigi, Japan
| | - Sachiko Tsukita
- Laboratory of Biological Science, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Pi-Chao Wang
- Graduate School of Life and Environmental Science, Tsukuba University, Tsukuba, Ibaragi, Japan
| | - Toshinori Nakayama
- Department of Immunology, Chiba University, Graduate School of Medicine, Chiba City, Japan
| | - Kazuo Suzuki
- Inflammation Program, Chiba University, Graduate School of Medicine, Chiba City, Japan Asia International Institute of Infectious Disease Control, Department of Health Protection, Graduate School of Medicine, Teikyo University, Tokyo, Japan
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25
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Marginal zone lymphomas and infectious agents. Semin Cancer Biol 2013; 23:431-40. [PMID: 24090976 DOI: 10.1016/j.semcancer.2013.09.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 09/18/2013] [Accepted: 09/19/2013] [Indexed: 12/18/2022]
Abstract
A link with infectious agents, bacteria and viruses in particular, has been reported for many lymphoma entities. Marginal zone lymphomas (extranodal, nodal and splenic forms) are frequently associated with chronic infections, with important clinical, molecular, biological, and therapeutic implications. The well-known correlation between Helicobacter pylori and gastric MALT-lymphoma, the recently reported links between Chlamydophila psittaci and ocular adnexal MALT-lymphoma and Borrelia burgdorferi and cutaneous MALT lymphoma constitute the best studied examples of lymphomagenic activity of bacteria, while the hepatitis C virus represents the most extensively investigated virus associated with marginal zone lymphomas. Biological and clinical features, therapeutic implications and future perspectives of these lymphoma-microbial associations are discussed in this review.
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Renal involvement in HCV-related vasculitis. Clin Res Hepatol Gastroenterol 2013; 37:334-9. [PMID: 23562337 DOI: 10.1016/j.clinre.2013.02.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 02/07/2013] [Indexed: 02/07/2023]
Abstract
Renal involvement has been frequently reported in the setting of hepatitis C virus (HCV) infection. The most common renal pathology associated with chronic HCV infection is type I membranoproliferative glomerulonephritis associated with type II mixed cryoglobulinemia, while membranoproliferative glomerulonephritis without cryoglobulinemia and membranous nephropathy were less frequently reported. Rarely, focal segmental glomerulosclerosis, fibrillary and immunotactoid glomerulopathies, and thrombotic microangiopathies were described during the course of HCV infection. In the present review, we have focused on renal involvement in HCV-related vasculitis.
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Ojaimi S, Lin MW, Singh KP, Woolley I. The two-edged sword: vasculitis associated with HIV and hepatitis C coinfection. Int J STD AIDS 2013; 25:77-88. [PMID: 23970639 DOI: 10.1177/0956462413495671] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vasculitis has long been associated with chronic viral infections, thus the twin perils of the infection and the immune response against it that bedevils the specialties of infection and immunity. After HIV was identified, it too became associated with vasculitic syndromes. Later, hepatitis C virus was also isolated, identified and described with its own spectrum of vasculitic diseases, including hepatitis C virus-associated cryoglobulinaemia. With the increasing prevalence of HIV and hepatitis C virus coinfection, there has come an increasing recognition of the range of vasculitides that can occur in this population leading to significant morbidity, diagnostic and treatment challenges. In this review, we examine the epidemiology, pathogenesis and general principles of treatment of these systemic diseases in HIV/hepatitis C virus coinfected individuals.
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Affiliation(s)
- Samar Ojaimi
- Department of Infectious Diseases, Southern Health, Clayton, Australia
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Abstract
Vasculitis is a primary phenomenon in autoimmune diseases such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and essential mixed cryoglobulinemia. As a secondary feature vasculitis may complicate, for example, connective tissue diseases, infections, malignancies, and diabetes. Vasculitic neuropathy is a consequence of destruction of the vessel wall and occlusion of the vessel lumen of small epineurial arteries. Sometimes patients present with nonsystemic vasculitic neuropathy, i.e., vasculitis limited to peripheral nerves and muscles with no evidence of further systemic involvement. Treatment with corticosteroids, sometimes in combination with other immunosuppressants, is required to control the inflammatory process and prevent further ischemic nerve damage.
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Affiliation(s)
- Alexander F J E Vrancken
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre, Utrecht, The Netherlands
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30
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Fabrizi F, Plaisier E, Saadoun D, Martin P, Messa P, Cacoub P. Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. Am J Kidney Dis 2012; 61:623-37. [PMID: 23102733 DOI: 10.1053/j.ajkd.2012.08.040] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Accepted: 08/28/2012] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis.
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Affiliation(s)
- Fabrizio Fabrizi
- Division of Nephrology, Maggiore Policlinico Hospital, IRCCS Foundation, Milano, Italy.
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31
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Abstract
Hepatitis C Virus (HCV) is a major health problem, infecting about 3 % of people worldwide and leading to liver as well as extrahepatic diseases. This justifies the definition of HCV infection as a systemic disease. Based on available data, the link between the virus and some of these extrahepatic disorders is certain, whereas for some others needs further confirmation. HCV-related lymphoproliferative disorders, ranging from benign, but pre-lymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas, represent the extrahepatic manifestations most closely related to HCV. The primary involvement of the liver and lymphatic system corresponds to the double viral tropism, being HCV able to infect both hepatic and lymphatic cells. Other HCV-associated disorders include renal, endocrine, dermatological, cardiovascular, rheumatologic and central nervous system diseases. On the whole, the HCV disease appears a very important, mainly hidden, public health problem leading to heavy direct and indirect costs. The possibility that HCV may be eradicated following antiviral therapy is important for both the therapeutic and preventive points of view, making the HCV disease an ideal model for pathogenetic studies.
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Affiliation(s)
- Anna Linda Zignego
- Department of Internal Medicine, Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), University of Florence, Largo Brambilla 3, 50134, Florence, Italy.
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Terrier B, Jehan F, Munteanu M, Geri G, Saadoun D, Sène D, Poynard T, Souberbielle JC, Cacoub P. Low 25-hydroxyvitamin D serum levels correlate with the presence of extra-hepatic manifestations in chronic hepatitis C virus infection. Rheumatology (Oxford) 2012; 51:2083-90. [PMID: 22908327 DOI: 10.1093/rheumatology/kes209] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Chronic HCV infection is associated with extra-hepatic manifestations. Recent studies have suggested an immunomodulatory role for vitamin D during HCV infection. We investigated the association between serum vitamin D status and the presence of HCV extra-hepatic manifestations. METHODS 25(OH)D serum levels were assessed in 94 HCV(+)RNA(+) patients [including 48 patients with mixed cryoglobulinaemia (MC) vasculitis]. Correlations between serum 25(OH)D levels and the presence of extra-hepatic manifestations of HCV infection were analysed. RESULTS Overall, 84 of 94 patients (89%) had hypovitaminosis D (≤30 ng/ml). Patients with vitamin D deficiency vs insufficiency vs sufficiency more frequently had systemic vasculitis (P = 0.02), in particular purpura (P = 0.006), detectable MC (P = 0.008) and low C4 serum levels (P = 0.006). Serum levels of 25(OH)D were also correlated with cryoglobulin and C4 levels and with marginal zone B cells and regulatory T cells. In multivariate analysis, the presence of MC and systemic vasculitis remained independently associated with low 25(OH)D levels. CONCLUSION In chronic HCV infection, low 25(OH)D levels correlate with the presence of mixed cryoglobulinaemia and systemic vasculitis in chronic HCV infection. These findings suggest the potential multifaceted benefits of vitamin D supplementation in HCV-infected patients with extra-hepatic manifestations, but interventional studies are needed to confirm these data.
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Affiliation(s)
- Benjamin Terrier
- Department of Internal Medicine, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France
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Abstract
Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury--potentially evolving to cirrhosis and hepatocellular carcinoma--but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.
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Hepatitis C virus infection and mixed cryoglobulinemia. Clin Dev Immunol 2012; 2012:502156. [PMID: 22844322 PMCID: PMC3403343 DOI: 10.1155/2012/502156] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 06/11/2012] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) chronic infection is recognized as the major cause of mixed cryoglobulinemia (MC). Its persistence represents a continuous stimulus for host immune system with production of circulating immune complexes (ICs), one-third of them with cryoprecipitate property. Several factors contribute to the biological activities of ICs, many of which are not completely known. Among them, complement factors play a crucial role in the cold-insoluble ICs-mediated vasculitis, involving primarily small blood vessels in different tissues including skin, kidney, peripheral, and central nervous system. Liver represents the major target of HCV infection with inflammatory infiltrates, resembling secondary lymphoid follicles. Cytokine like CXCL13 contribute to B-cell homing in intraportal lymphoid aggregates, in which B-cell clonal selection may arise. B-cell clonal expansion starts as an antigen-driven event and expands towards indolent and malignant B-cell proliferation. Occurrence of intrahepatic B-cell clonalities correlates with extrahepatic clinical manifestations of HCV infection. In this context, cryoglobulinemic patients should be considered a peculiar HCV-infected population that needs a clinical multidisciplinary approach and more articulated therapeutic measures.
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Üçeyler N, Topuzoğlu T, Schiesser P, Hahnenkamp S, Sommer C. IL-4 deficiency is associated with mechanical hypersensitivity in mice. PLoS One 2011; 6:e28205. [PMID: 22164245 PMCID: PMC3229527 DOI: 10.1371/journal.pone.0028205] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 11/03/2011] [Indexed: 12/27/2022] Open
Abstract
Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion.
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Affiliation(s)
- Nurcan Üçeyler
- Department of Neurology, University of Würzburg, Würzburg, Germany.
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Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010; 8:1017-29. [PMID: 20870037 DOI: 10.1016/j.cgh.2010.08.026] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 08/20/2010] [Accepted: 08/24/2010] [Indexed: 02/06/2023]
Abstract
In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to anti-HCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients.
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Affiliation(s)
- Ira M Jacobson
- Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
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The potential of cytokines as safety biomarkers for drug-induced liver injury. Eur J Clin Pharmacol 2010; 66:961-76. [PMID: 20694460 DOI: 10.1007/s00228-010-0862-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2010] [Accepted: 06/23/2010] [Indexed: 12/12/2022]
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Antonelli A, Ferri C, Ferrari SM, Ghiri E, Marchi S, Sebastiani M, Fallahi P. Serum concentrations of interleukin 1beta, CXCL10, and interferon-gamma in mixed cryoglobulinemia associated with hepatitis C infection. J Rheumatol 2009; 37:91-7. [PMID: 19918044 DOI: 10.3899/jrheum.090246] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Mixed cryoglobulinemia (MC) is a systemic vasculitis of small and medium-size vessels, often associated with the hepatitis C virus. Research has shown an emerging role for chemokines and type 1 cytokines in the pathophysiology of this vasculitis. Interleukin 1 (IL-1) plays a role in initiating the cascade of immunoinflammatory responses, and levels of the interferon-gamma (IFN-gamma) inducible chemokine CXCL10 have been shown to be significantly associated with the presence of active vasculitis in patients with MC. We evaluated serum levels of IL-1beta, IFN-gamma, and CXCL10 in a series of patients with hepatitis C-related MC (MC+HCV), and correlated these measurements with clinical disease features. METHODS Serum IL-1beta, IFN-gamma, and CXCL10 were assayed in 54 patients with MC+HCV, in 54 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 54 controls. RESULTS MC+HCV patients showed significantly higher mean IL-1beta and CXCL10 serum levels than controls (p < 0.01) or HCV+ patients (p < 0.01). CXCL10 was significantly increased in 14 cryoglobulinemic patients with active vasculitis (necrotizing vasculitis or vasculitic skin ulcers) compared to those without (p < 0.001); IL-1beta was increased in cryoglobulinemic patients with active vasculitis (p = 0.06). No differences were observed for serum IFN-gamma levels. CONCLUSION Serum levels of IL-1beta and CXCL10 were high in patients with MC+HCV. Increased CXCL10 and IL-1beta levels were associated with the presence of active vasculitis in MC+HCV patients.
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Affiliation(s)
- Alessandro Antonelli
- Department of Internal Medicine, University of Pisa School of Medicine, Via Roma 67, I-56100, Pisa, Italy.
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Cacoub P. Vascularites cryoglobulinémiques et hépatite C : avancées physiopathologiques, implications thérapeutiques. Rev Med Interne 2009. [DOI: 10.1016/j.revmed.2009.02.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Landau DA, Rosenzwajg M, Saadoun D, Klatzmann D, Cacoub P. The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis 2009; 68:337-44. [PMID: 18434450 DOI: 10.1136/ard.2007.085910] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The study aim was to examine the B lymphocyte stimulator (BLyS) receptor-ligand system in hepatitis C virus (HCV)-induced B lymphocyte clonal disorders. METHODS 94 patients with chronic HCV (including 35 with HCV+ mixed cryoglobulinaemia (MC)-vasculitis and nine with HCV+ B cell non-Hodgkin's lymphoma (B-NHL)) and 15 healthy volunteers were included. RESULTS A twofold serum BLyS increase was associated with HCV-induced MC-vasculitis, and a threefold increase with HCV-induced B-NHL, compared with patients that were HCV+, but without vasculitis, or healthy controls (p<0.05). Lower membrane BLyS expression in HCV-induced MC-vasculitis was observed. CD19+ BLyS binding and BLyS receptor 3 (BR3) staining showed a stepwise decrease with highest values in healthy controls and who were HCV+ without MC, and lowest in B-NHL (p<0.05, p<0.0001, respectively) with a further decrease in VH1-69+ clonal B cells. BLyS anti-apoptotic effects were maintained despite this decrease in BR3 staining. Complete clinical remission after antiviral treatment was associated with a decrease in serum BLyS, and an increase in BR3 staining. Rituximab treatment was associated with a fivefold increase in serum BLyS (p<0.001), mirroring the depletion of CD19+ cells. BR3 staining in repopulating B cells was significantly decreased (p<0.005). CONCLUSIONS The BLyS ligand-receptor activity is increased in HCV-induced B cell clonal disorders, indicating a possible role for treatment targeting the BLyS receptor-ligand system.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Murine-Derived
- Antineoplastic Agents/therapeutic use
- Antiviral Agents/therapeutic use
- Apoptosis/immunology
- B-Cell Activating Factor/blood
- B-Cell Activation Factor Receptor/blood
- B-Lymphocytes/immunology
- Cryoglobulinemia/drug therapy
- Cryoglobulinemia/immunology
- Cryoglobulinemia/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Humans
- Ligands
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/virology
- Middle Aged
- Rituximab
- Vasculitis/drug therapy
- Vasculitis/immunology
- Vasculitis/virology
- Young Adult
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Affiliation(s)
- D-A Landau
- Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Sientifique, Universite Pierre et Marrie Curie UMR 7087, Paris, France
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Abstract
Chronic infection with the hepatitis C virus, a noncytopathic hepatotropic RNA virus, affects over 170 million people worldwide. In the majority of cases, neither the early innate immune response nor the later adaptive immune response succeeds in clearing the virus, and the infection becomes chronic. Furthermore, in many patients, the ineffective inflammatory response drives fibrogenesis and the development of cirrhosis. It is critical to understand this immune pathology if preventative and curative therapies are to be developed. Chemokines are a superfamily of small proteins that promote leukocyte migration and orchestrate the immune response to viruses, including hepatitis C virus. Chemokines are crucial for viral elimination, but inappropriate persistence of expression in chronic hepatitis C infection can drive tissue damage and inflammation. Here we review the role of chemokines and their receptors in hepatitis C virus infection.
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Affiliation(s)
- Mathis Heydtmann
- NIHR Biomedical Research Unit for Liver Disease, MRC Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
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Moreau AS, Sebti Y, Duhamel A, Roccaro AM, Coiteux V, Gastinne T, Le Friec G, Burwick N, Amiot L, Ho AW, Poulain S, Hennache B, Hunter ZR, Dessaint JP, Ghobrial IM, Treon SP, Facon T, Zorn E, Leleu X. Clinical relevance of soluble HLA class I molecules in Waldenstrom Macroglobulinemia. Eur J Haematol 2008; 80:503-9. [PMID: 18331603 DOI: 10.1111/j.1600-0609.2008.01060.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVES Waldenstrom Macroglobulinemia (WM) is a B-cell neoplasm characterised by secretion of IgM by lymphoplasmacytic bone marrow cells and by cytopenias and hypogammaglobulinemia in a subset of patients. Beta-2 microglobulin (b2m) is a major prognostic factor in WM and the heavy chain of HLA class I molecules, which are known to have immunosuppressive properties and have been implicated in the pathogeny of several malignancies. METHODS We assessed the serum levels of the total soluble HLA-I molecules and the HLA-Gs molecules in 105 patients with IgM-related disorders [WM (n = 42) and IgM MGUS (n = 63)], and compared the results to 41 healthy subjects. RESULTS We found higher levels of HLA-Is in WM, compared to IgM MGUS and healthy donors. HLA-Gs levels were similar in WM and in IgM MGUS, but higher than in healthy donors. The association between HLA-Is at the cut-off of 1.8 microg/mL and known markers of poor prognosis was then evaluated among WM patients using univariate and multivariate methods. Based on this, high HLA-Is level was strongly associated with high serum beta2M level >3 mg/L [OR = 2, (CI 95% 1.1-5.7); P = 0.04], age > 65 yrs [OR = 1.5, (CI 95% 0.5-4.1), P = 0.06] and haemoglobin < or =11.5 g/dL [OR = 3.3, (CI 95% 1.2-9.7); P = 0.03]. High levels of serum HLA-Is were also found in patients with cryoglobulinemia, however irrespectively of WM or IgM-MGUS status. CONCLUSION Together our results suggest a possible role for soluble MHC class I molecules in WM disease. Further investigations are necessary to further demonstrate the prognostic impact of soluble MHC class I molecules in Waldenstrom Macroglobulinemia.
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Cacoub P, Delluc A, Saadoun D, Landau DA, Sene D. Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis 2008; 67:283-7. [PMID: 17644544 DOI: 10.1136/ard.2006.065565] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Mixed cryoglobulinemia (MC) vasculitis represents a complication of the B cell response to a variety of chronic inflammatory diseases. Recent reports describe the use of monoclonal antibodies directed to CD20 antigen (rituximab), a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytes. The goal of this article is therefore to review published data in order to better analyse the efficacy and tolerance of rituximab treatment in patients with MC vasculitis. After systematic review of the literature and exclusion of review papers, 13 manuscripts were identified that reported on a total number of 57 cases of MC secondary to hepatitis C virus (HCV) infection (75.4%) or essential mixed cryoglobulinemia (24.6%). Previous treatments failed to control the main signs of vasculitis; these were either HCV (n = 37) or immunomodulating treatments. Most patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m(2) of rituximab. The duration of follow-up after rituximab therapy was 9.7 months. Rituximab infusions had great efficacy on the main vasculitis signs, with a clinical response in 80-93% patients. A relapse of MC was noted in 14 out of 36 (39%) patients. A relatively small number of side effects were reported. We conclude that rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients. A relapse of cryoglobulinemia vasculitis was frequently noted. Randomised controlled trials with long-term study are needed to form definitive conclusions on the benefit/risk ratio of rituximab therapy in such patients.
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Affiliation(s)
- P Cacoub
- Université Pierre et Marie Curie Paris 6, CNRS, UMR 7087, Paris, France.
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Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 2008; 111:5334-41. [PMID: 18292291 DOI: 10.1182/blood-2007-11-122713] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as mixed cryoglobulinemia (MC). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of peripheral blood B- and T-cell subsets, the clonal VH1-69 cells, as well as the cytokine profile following rituximab therapy. The study involved 21 patients with hepatitis C-related MC who received rituximab, of whom 14 achieved a complete response. Compared with healthy and hepatitis C virus (HCV) controls, pretreatment abnormalities in MC patients included a decreased percentage of naive B cells (P < .05) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (P = .02) with an increase in memory B cells (P = .03) and plasmablasts (P < .05). These abnormalities were reverted at 12 months after rituximab. Clonal VH1-69(+) B cells dramatically decreased following treatment (32% +/- 6% versus 8% +/- 2%, P = .01). Complete responders of rituximab exhibited an expansion of regulatory T cells (P < .01) accompanied with a decrease in CD8(+) T-cell activation (P < .01) and decreased production of interleukin 12 (IL-12; P = .02) and interferon-gamma (IFN-gamma; P = .01). Our findings indicate that in patients with MC, response to B-cell depletion induced by rituximab effectively normalizes many of the disturbances in peripheral B- and T-lymphocyte homeostasis.
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Landau DA, Saadoun D, Calabrese LH, Cacoub P. The pathophysiology of HCV induced B-cell clonal disorders. Autoimmun Rev 2007; 6:581-7. [PMID: 17854753 DOI: 10.1016/j.autrev.2007.03.010] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2007] [Accepted: 03/22/2007] [Indexed: 11/20/2022]
Abstract
Hepatitis C virus (HCV) has been shown in epidemiologic studies to be associated with immune system disorders. Primarily disorders that stem from B-cell regulatory control disturbance, such as mixed cryoglobulinemia (MC) and non-Hodgkin's lymphoma (NHL). The causative role of HCV in these disorders is supported by the response to anti-viral treatment. The understanding of the pathophysiological process leading from HCV infection to B-cell clonal expansion has improved significantly. Data supports an antigen-driven indirect stimulation of clonal expansion model, leading from oligoclonal to monoclonal expansion and in some instances to frank malignancy. HCV-E2 antigen has been suggested as a candidate antigen as well as NS3. Binding of the B-cell receptor by viral antigens coupled with direct binding of CD-81 by HCV-E2 has been shown to provide a strong proliferative signal. Additional regulatory elements are also affected in HCV-related B-cell clonal expansion, including the Fas and BLyS signaling mechanisms. Finally, genetic events such as bcl-2 rearrangement may also be involved in clonal expansion. In this review, evidence linking HCV with MC and NHL, as well as known events in the pathophysiological process are described.
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Affiliation(s)
- Dan-Avi Landau
- Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7087, Paris, F-75013 France
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Saadoun D, Bieche I, Authier FJ, Laurendeau I, Jambou F, Piette JC, Vidaud M, Maisonobe T, Cacoub P. Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress-derived molecules in hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. ACTA ACUST UNITED AC 2007; 56:1315-24. [PMID: 17393409 DOI: 10.1002/art.22456] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Mixed cryoglobulinemia (MC) is a systemic vasculitis, usually associated with hepatitis C virus (HCV) infection. The molecular mechanisms responsible for HCV-associated MC (HCV-MC) vasculitis are largely unknown. This study was undertaken to assess the expression profile of selected genes involved in inflammatory vascular damage in patients with HCV-MC vasculitis, patients with polyarteritis nodosa (PAN), and patients with noninflammatory idiopathic neuropathy. METHODS The quantitative expression levels of 42 selected genes involved in inflammatory vascular damage were assessed in nerve lesions of patients with HCV-MC vasculitis, PAN (rheumatic disease controls), and noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls), using real-time reverse transcriptase-polymerase chain reaction. Genes were considered to be differentially expressed when there was a >2-fold difference in mean expression levels between groups and the P value was less than 0.05. RESULTS Expression levels of 8 genes were significantly increased in HCV-MC patients versus control patients with noninflammatory idiopathic neuropathy, with the highest increase for metallothionein 1 H (MT1H), a hypoxic and oxidative stress protein. Compared with PAN patients, HCV-MC patients had higher expression levels of genes encoding oxidative stress-derived molecules (MT1H, endothelial cell nitric oxide synthase 3, Hsp70, and Hsp90) and tissue plasminogen activator and lower expression levels of matrix metalloproteinase 7 (MMP-7). HCV-MC neuropathies were classified according to their morphologic pattern and the presence or absence of necrotizing arteritis. MMP-1, MMP-7, MMP-9, and interleukin-1beta were up-regulated in patients with necrotizing arteritis. CONCLUSION This comprehensive molecular study of HCV-MC vasculitis provides strong evidence that MMPs, proinflammatory cytokines, and oxidative stress-derived molecules have a role in the pathogenesis of HCV-MC vasculitis neuropathy.
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Affiliation(s)
- David Saadoun
- Université Pierre et Marie Curie-Paris VI, CNRS UMR 7087, and Hôpital Pitié-Salpétrière, Paris, France
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Bibliography. Current world literature. Vasculitis syndromes. Curr Opin Rheumatol 2006; 19:81-5. [PMID: 17143101 DOI: 10.1097/bor.0b013e32801437a8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Abstract
Paraproteinemic neuropathies comprise a diverse group of disorders that includes monoclonal gammopathy of undetermined significance, primary amyloidosis, multiple myeloma, cryoglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome, and Waldenstrom macroglobulinemia. Various factors including hepatitis C virus, vascular endothelial growth factor, and an array of cytokines are implicated in the pathogenesis of these conditions. More recently, a variety of novel antibody specificities, and vasculitis, have also been described as contributory factors in the development of these neuropathies. Therapeutic approaches for paraproteinemic neuropathies have included administration of cytotoxic agents, steroids, interferon-alpha, intravenous immunoglobulin, radiation, bone marrow transplantation, and more recently, drugs such as rituximab and bevacizumab. In this article, we review some of the well-known features of these diseases, and highlight some of the more recent findings from the vast literature for these diseases.
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