|
1
|
Su X, Yu H, Lei Q, Chen X, Tong Y, Zhang Z, Yang W, Guo Y, Lin L. Systemic lupus erythematosus: pathogenesis and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:54. [PMID: 39472388 PMCID: PMC11522254 DOI: 10.1186/s43556-024-00217-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/16/2024] [Indexed: 11/02/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease severity. The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can act as triggers. This review provides a comprehensive discussion of the pathogenesis and treatment strategies of SLE and focuses on the progress and status of traditional and emerging treatment strategies for SLE. Traditional treatment strategies for SLE have mainly employed non-specific approaches, including cytotoxic and immunosuppressive drugs, antimalarials, glucocorticoids, and NSAIDs. These strategies are effective in mitigating the effects of the disease, but they are not a complete cure and are often accompanied by adverse reactions. Emerging targeted therapeutic drugs, on the other hand, aim to control and treat SLE by targeting B and T cells, inhibiting their activation and function, as well as the abnormal activation of the immune system. A deeper understanding of the pathogenesis of SLE and the exploration of new targeted treatment strategies are essential to advance the treatment of this complex autoimmune disease.
Collapse
Affiliation(s)
- Xu Su
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China
| | - Hui Yu
- Department of Urology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610014, China
| | - Qingqiang Lei
- Center of Bone Metabolism and Repair, Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400000, China
| | - Xuerui Chen
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China
| | - Yanli Tong
- Université Paris Cité, INSERM U1151, CNRS UMR8253, Institut Necker Enfants Malades, Paris, F-75015, France
| | - Zhongyang Zhang
- Department of Health Technology, The Danish National Research Foundation and Villum Foundation's Center IDUN, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Wenyong Yang
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
- Department of Neurosurgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610014, China.
| | - Yuanbiao Guo
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
| | - Liangbin Lin
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
- Obesity and Metabolism Medicine-Engineering Integration Laboratory, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
- The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
| |
Collapse
|
|
2
|
Accapezzato D, Caccavale R, Paroli MP, Gioia C, Nguyen BL, Spadea L, Paroli M. Advances in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. Int J Mol Sci 2023; 24:6578. [PMID: 37047548 PMCID: PMC10095030 DOI: 10.3390/ijms24076578] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. Although progress in understanding the pathogenesis of SLE has been slower than in other rheumatic diseases, new knowledge has recently led to the development of effective targeted therapies, that hold out hope for personalized therapy. However, the new drugs available to date are still an adjunct to conventional therapy, which is known to be toxic in the short and long term. The purpose of this review is to summarize recent advances in understanding the pathogenesis of the disease and discuss the results obtained from the use of new targeted drugs, with a look at future therapies that may be used in the absence of the current standard of care or may even cure this serious systemic autoimmune disease.
Collapse
Affiliation(s)
- Daniele Accapezzato
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Rosalba Caccavale
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Pia Paroli
- Eye Clinic, Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy
| | - Chiara Gioia
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Bich Lien Nguyen
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Luca Spadea
- Post Graduate School of Public Health, University of Siena, 53100 Siena, Italy
| | - Marino Paroli
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| |
Collapse
|
|
3
|
Bruera S, Chavula T, Madan R, Agarwal SK. Targeting type I interferons in systemic lupus erythematous. Front Pharmacol 2023; 13:1046687. [PMID: 36726783 PMCID: PMC9885195 DOI: 10.3389/fphar.2022.1046687] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/05/2022] [Indexed: 01/18/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the type I interferon (IFN) pathway has been identified in SLE patients and mouse models of lupus. These studies have led to the development of therapeutics targeting type I IFN and related pathways for the treatment of certain manifestations of SLE. In the current narrative review, we will discuss the role of type I IFN in SLE pathogenesis and the potential translation of these data into strategies using type I IFN as a biomarker and therapeutic target for patients with SLE.
Collapse
Affiliation(s)
- Sebastian Bruera
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Thandiwe Chavula
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Riya Madan
- Section of General Internal Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Sandeep K. Agarwal
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
4
|
Hsiao SW, Fan CS, Yen HH, Huang SP, Chen YY, Su PY. A retrospective study of prevalence and pattern of international consensus on ANA patterns among patients with hepatitis C virus infection. PeerJ 2022; 10:e14200. [PMID: 36275455 PMCID: PMC9586114 DOI: 10.7717/peerj.14200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/16/2022] [Indexed: 01/24/2023] Open
Abstract
Background A previous study reported a 30% prevalence of various autoantibodies among patients with hepatitis C virus (HCV) infection. The International Consensus on Anti-Nuclear Antibody (ANA) Patterns was recently introduced to classify ANA patterns based on immunoassay on HEp-2 cells. There is no previous report with this newly developed classification to evaluate patients with HCV infection. The study aims to study the prevalence and pattern of ANA patterns among HCV-infected patients. Methods We retrospectively analyzed the medical records of patients with HCV infection from September 2020 to June 2021 at our institution. A positive ANA is defined as a titer of more than 1:320. We compared patient features among the positive and negative groups. Results Overall, 258 patients were enrolled-184 patients with negative ANA and 74 patients (28.7%) with positive ANA. The mean age was 67.3 in ANA positive group and 61.2 ANA negative group. Female was prominent with ANA positive and accounted for 63.5%. The most detected ANA pattern was AC-1(homogeneous) (25.9%), followed by AC-4(fine speckled) (25.2%) and AC-21(anti-mitochondrial antibody) (9.6%). In ANA positive group, we found a trend of lower HCV viral load (5.72 log10 IU/ML vs. 6.02 log10 IU/ML), lower alanine aminotransferase level (39.5 U/L vs. 44 U/L), and higher advanced fibrosis (F3 and F4) (38.5% vs. 26.1%). In addition, higher positive ANA (more than 1:640) is significantly associated with lower estimated glomerular filtration rate (eGFR) (77.76 vs. 87.94 mL/min/1.73 m2, P = 0.044). Conclusions A high prevalence (28.7%) of ANA was found in patients with chronic hepatitis C. The presence of positive ANA is not related to the severity of their hepatic manifestation. However, higher positive ANA was significantly associated with lower eGFR.
Collapse
Affiliation(s)
- Shun-Wen Hsiao
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chuan-San Fan
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan,General Education Center, Chienkuo Technology University, Changhua, Taiwan,Department of Electrical Engineering, Chung Yuan Christian University, Taoyuan, Taiwan,College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Siou-Ping Huang
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan
| | - Yang-Yuan Chen
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan,Division of Gastroenterology, Yuanlin Christian Hospital, Changhua, Taiwan,Department of Hospitality Management, MingDao University, Changhua, Taiwan
| | - Pei-Yuan Su
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan
| |
Collapse
|
|
5
|
Li J, Ma Y, Paquette JK, Richards AC, Mulvey MA, Zachary JF, Teuscher C, Weis JJ. The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical regulator of IFNβ-mediated Lyme arthritis. PLoS Pathog 2022; 18:e1010365. [PMID: 35324997 PMCID: PMC8946740 DOI: 10.1371/journal.ppat.1010365] [Citation(s) in RCA: 1] [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: 09/14/2021] [Accepted: 02/11/2022] [Indexed: 11/18/2022] Open
Abstract
Type I interferon (IFN) has been identified in patients with Lyme disease, and its abundant expression in joint tissues of C3H mice precedes development of Lyme arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. burgdorferi-induced IFNβ expression and Lyme arthritis severity. B6 mice introgressed with the C3H allele for Bbaa1 (B6.C3-Bbaa1 mice) displayed increased severity of arthritis, which is initiated by myeloid lineage cells in joints. Using advanced congenic lines, the physical size of the Bbaa1 interval has been reduced to 2 Mbp, allowing for identification of potential genetic regulators. Small interfering RNA (siRNA)-mediated silencing identified Cdkn2a as the gene responsible for Bbaa1 allele-regulated induction of IFNβ and IFN-stimulated genes (ISGs) in bone marrow-derived macrophages (BMDMs). The Cdkn2a-encoded p19 alternative reading frame (p19ARF) protein regulates IFNβ induction in BMDMs as shown by siRNA silencing and overexpression of ARF. In vivo studies demonstrated that p19ARF contributes to joint-specific induction of IFNβ and arthritis severity in B. burgdorferi-infected mice. p19ARF regulates B. burgdorferi-induced IFNβ in BMDMs by stabilizing the tumor suppressor p53 and sequestering the transcriptional repressor BCL6. Our findings link p19ARF regulation of p53 and BCL6 to the severity of IFNβ-induced Lyme arthritis in vivo and indicate potential novel roles for p19ARF, p53, and BCL6 in Lyme disease and other IFN hyperproduction syndromes. Lyme disease is caused by infection with the tick-transmitted bacterium Borrelia burgdorferi. Although different isolates of B. burgdorferi have distinct potential for dissemination and tissue invasion, factors intrinsic to the infected host also play an important role in directing the severity of Lyme disease. In the animal model, infected C3H mice develop severe Lyme arthritis following elevation of type I IFN in joint tissue, while in C57BL/6 (B6) mice arthritis is mild and not associated with type I IFN. We demonstrated that the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) intrinsically controls the magnitude of IFNβ production and the severity of Lyme arthritis in C3H vs B6 mice. The Cdkn2a gene was positionally identified as the regulator of IFNβ within Bbaa1, and determined to function through its protein product p19 alternative reading frame (p19ARF). ARF regulates IFNβ expression and Lyme arthritis severity by modulating the activities of the tumor suppressor p53 and transcriptional repressor BCL6. Our study provides new insight and potential therapeutic targets for the investigation of type I IFN-dependent Lyme arthritis and other IFN-driven diseases.
Collapse
Affiliation(s)
- Jinze Li
- Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - Ying Ma
- Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - Jackie K. Paquette
- Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - Amanda C. Richards
- Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - Matthew A. Mulvey
- Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
| | - James F. Zachary
- Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Cory Teuscher
- Department of Medicine, Vermont Center for Immunology and Infectious Diseases, Larner College of Medicine, The University of Vermont, Burlington, Vermont, United States of America
| | - Janis J. Weis
- Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America
- * E-mail:
| |
Collapse
|
|
6
|
Sternhagen E, Bettendorf B, Lenert A, Lenert PS. The Role of Clinical Features and Serum Biomarkers in Identifying Patients with Incomplete Lupus Erythematosus at Higher Risk of Transitioning to Systemic Lupus Erythematosus: Current Perspectives. J Inflamm Res 2022; 15:1133-1145. [PMID: 35210816 PMCID: PMC8863324 DOI: 10.2147/jir.s275043] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/02/2022] [Indexed: 12/16/2022] Open
Abstract
Discovery of antinuclear antibodies (ANA) enabled earlier diagnosis of systemic lupus erythematosus (SLE) and other ANA+ connective tissue diseases (CTD). Rheumatologists increasingly encounter high referral volume of ANA+ patients. It has been estimated that only a small percentage of these patients will eventually transition to either SLE or other specified CTD. Incomplete lupus erythematosus (ILE) has been defined as a subset of patients who have some SLE-specific clinical manifestations but do not meet currently accepted classification criteria for SLE. Several studies have been performed with the goal of identifying clinical features, serum and tissue biomarkers that can distinguish those patients with ILE at risk of transitioning to SLE from those who will not. Increased autoantibody diversity, presence of anti-double-stranded DNA (dsDNA) antibodies, high expression of type I and type II interferon (IFN)-gene products, increased serum levels of B-cell-activating factor of the TNF family (BAFF), and certain serum cytokines and complement products have been identified as markers with positive predictive value, particularly when combined together. Once this patient population is better characterized biochemically, clinical trials should be considered with the primary objective to completely halt or slow down the transition from ILE to SLE. Hydroxychloroquine (HCQ) appears to be a promising agent due to its good tolerability and low toxicity profile and open-label studies in ILE patients have already shown its ability to delay the onset of SLE. Other therapeutics, like those targeting abnormal type I and type II IFN-signatures, B-cell specific signaling pathways, complement activation pathways and high BAFF levels should also be evaluated, but the risk to benefit ratio must be carefully determined before they can be considered.
Collapse
Affiliation(s)
- Erin Sternhagen
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Brittany Bettendorf
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Aleksander Lenert
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Petar S Lenert
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
- Correspondence: Petar S Lenert, Clinical Professor of Medicine, C428-2GH, 200 Hawkins Drive, Iowa City, Iowa City, 52242, USA, Email
| |
Collapse
|
|
7
|
Abstract
Skewing of type I interferon (IFN) production and responses is a hallmark of systemic lupus erythematosus (SLE). Genetic and environmental contributions to IFN production lead to aberrant innate and adaptive immune activation even before clinical development of disease. Basic and translational research in this arena continues to identify contributions of IFNs to disease pathogenesis, and several promising therapeutic options for targeting of type I IFNs and their signaling pathways are in development for treatment of SLE patients.
Collapse
Affiliation(s)
- Sirisha Sirobhushanam
- Department of Internal Medicine, Division of Rheumatology, University of Michigan, 5568 MSRB 2, 1150 West Medical Center Drive, Ann Arbor, MI 49109, USA
| | - Stephanie Lazar
- Department of Internal Medicine, Division of Rheumatology, University of Michigan, 5568 MSRB 2, 1150 West Medical Center Drive, Ann Arbor, MI 49109, USA
| | - J Michelle Kahlenberg
- Department of Internal Medicine, Division of Rheumatology, University of Michigan, 5570A MSRB 2, 1150 West Medical Center Drive, Ann Arbor, MI 49109, USA; Department of Dermatology, University of Michigan, 5570A MSRB 2, 1150 West Medical Center Drive, Ann Arbor, MI 49109, USA.
| |
Collapse
|
|
8
|
Deshayes S, Dolladille C, Dumont A, Martin Silva N, Chretien B, De Boysson H, Alexandre J, Aouba A. A worldwide pharmacoepidemiological update of drug-associated ANCA-associated vasculitis at the time of targeted therapies. Arthritis Rheumatol 2021; 74:134-139. [PMID: 34164938 DOI: 10.1002/art.41902] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/10/2021] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The literature data supporting the role of a drug in the onset of drug-associated anti-neutrophil cytoplasmic antibody-associated vasculitis (DA-AAV) mainly rely on case reports or short series and implicate old treatments. The advent of new treatments may have modified the epidemiology of these adverse drug reactions (ADRs). We therefore aimed to update this list by using a pharmacovigilance-based data mining approach. METHODS We collected data on ADRs reported with the MedDRA preferred term "Anti-neutrophil cytoplasmic antibody positive vasculitis" up to November 2020 from the World Health Organization pharmacovigilance database (VigiBase® ). For each retrieved drug, a case/noncase analysis was performed, and disproportionate reporting was calculated by using the information component (IC). A positive IC025 value, which is the lower end of the 95% credibility interval, was considered significant. RESULTS A total of 483 deduplicated individual case safety reports of DA-AAV involving 15 drugs with an IC025 >0 were retrieved. DA-AAV occurred in 264 (71.2%, n=371) women, the median age at onset was 62 years [45-72], and the median time to onset between the introduction of the suspected drug and DA-AAV was 9 months [1-36]. DA-AAV occurrence was considered serious in 472 (97.7%, n=481) cases and fatal in 43 (8.9%) cases. The drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron, and nintedanib. CONCLUSION This study strengthens the previously suspected association but also identifies 3 new drugs that may cause DA-AAV. Particular attention should be given to these drugs by prescribers and in experimental studies.
Collapse
Affiliation(s)
- Samuel Deshayes
- Department of Internal Medicine, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000, Caen, France.,Normandie Univ, UNICAEN, EA4650 SEILIRM, CHU de Caen Normandie, 14000, Caen, France
| | - Charles Dolladille
- Normandie Univ, UNICAEN, EA4650 SEILIRM, CHU de Caen Normandie, 14000, Caen, France.,Department of Pharmacology, CHU de Caen Normandie, 14000, Caen, France
| | - Anaël Dumont
- Department of Internal Medicine, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000, Caen, France
| | - Nicolas Martin Silva
- Department of Internal Medicine, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000, Caen, France
| | - Basile Chretien
- Department of Pharmacology, CHU de Caen Normandie, 14000, Caen, France
| | - Hubert De Boysson
- Department of Internal Medicine, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000, Caen, France.,Normandie Univ, UNICAEN, EA4650 SEILIRM, CHU de Caen Normandie, 14000, Caen, France
| | - Joachim Alexandre
- Normandie Univ, UNICAEN, EA4650 SEILIRM, CHU de Caen Normandie, 14000, Caen, France.,Department of Pharmacology, CHU de Caen Normandie, 14000, Caen, France
| | - Achille Aouba
- Department of Internal Medicine, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000, Caen, France.,Normandie Univ, UNICAEN, EA4650 SEILIRM, CHU de Caen Normandie, 14000, Caen, France
| |
Collapse
|
|
9
|
McWhirter SM, Jefferies CA. Nucleic Acid Sensors as Therapeutic Targets for Human Disease. Immunity 2021; 53:78-97. [PMID: 32668230 DOI: 10.1016/j.immuni.2020.04.004] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/26/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022]
Abstract
Innate immune sensors that detect nucleic acids are attractive targets for therapeutic intervention because of their diverse roles in many disease processes. In detecting RNA and DNA from either self or non-self, nucleic acid sensors mediate the pathogenesis of many autoimmune and inflammatory conditions. Despite promising pre-clinical data and investigational use in the clinic, relatively few drugs targeting nucleic acid sensors are approved for therapeutic use. Nevertheless, there is growing appreciation for the untapped potential of nucleic acid sensors as therapeutic targets, driven by the need for better therapies for cancer, infectious diseases, and autoimmune disorders. This review highlights the diverse mechanisms by which nucleic acid sensors are activated and exert their biological effects in the context of various disease settings. We discuss current therapeutic strategies utilizing agonists and antagonists targeting nucleic acid sensors to treat infectious disease, cancer, and autoimmune and inflammatory disorders.
Collapse
Affiliation(s)
| | - Caroline A Jefferies
- Department of Biomedical Sciences and Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| |
Collapse
|
|
10
|
Impact of Interferon-Based Therapy on Hepatitis C-Associated Rheumatic Diseases: A Nationwide Population-Based Cohort Study. J Clin Med 2021; 10:jcm10040817. [PMID: 33671397 PMCID: PMC7922671 DOI: 10.3390/jcm10040817] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/06/2021] [Accepted: 02/12/2021] [Indexed: 12/29/2022] Open
Abstract
Whether hepatitis C virus (HCV) infection-associated risk of rheumatic diseases is reversed by anti-HCV therapy remain elusive. A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database was conducted. Of 19,298,735 subjects, 3 cohorts (1:4:4, propensity score-matched), including HCV-treated (6919 HCV-infected subjects with interferon and ribavirin therapy ≥ 6 months), HCV-untreated (n = 27,676) and HCV-uninfected (n = 27,676) cohorts, were enrolled and followed (2003–2015). The HCV-uninfected cohort had the lowest cumulative incidence of rheumatic diseases (95% confidence interval (CI): 8.416–10.734%), while HCV-treated (12.417–17.704%) and HCV-untreated (13.585–16.479%) cohorts showed no difference in the cumulative incidences. Multivariate analyses showed that HCV infection (95% CI hazard ratio (HR): 1.54–1.765), female sex (1.57–1.789), age ≥ 49 years (1.091–1.257), Charlson comorbidity index ≥ 1 (1.075–1.245), liver cirrhosis (0.655–0.916), chronic obstruction pulmonary disease (1.130–1.360), end-stage renal disease (0.553–0.98), diabetes mellitus (0.834–0.991) and dyslipidemia (1.102–1.304) were associated with incident rheumatic diseases. Among the 3 cohorts, the untreated cohort had the highest cumulative incidence of overall mortality, while the treated and un-infected cohorts had indifferent mortalities. Conclusions: HCV infection, baseline demographics and comorbidities were associated with rheumatic diseases. Although HCV-associated risk of rheumatic diseases might not be reversed by interferon-based therapy, which reduced the overall mortality in HCV-infected patients.
Collapse
|
|
11
|
Pacella I, Spinelli FR, Severa M, Timperi E, Tucci G, Zagaglioni M, Ceccarelli F, Rizzo F, Coccia EM, Patel RS, Martin-Fernandez M, Bogunovic D, Conti F, Barnaba V, Piconese S. ISG15 protects human Tregs from interferon alpha-induced contraction in a cell-intrinsic fashion. Clin Transl Immunology 2020; 9:e1221. [PMID: 33376595 PMCID: PMC7758615 DOI: 10.1002/cti2.1221] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/10/2020] [Accepted: 11/09/2020] [Indexed: 01/02/2023] Open
Abstract
Objectives Type I interferons (IFNs) inhibit regulatory T-cell (Treg) expansion and activation, making them beneficial in antiviral responses, but detrimental in autoimmune diseases. Herein, we investigate the role of ISG15 in human Tregs in the context of refractoriness to type I IFN stimulation. Methods ISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency. Results ISG15 is expressed at high levels in human Tregs, renders them refractory to the IFN-STAT1 signal, and protects them from IFN-driven contraction. In vitro, Tregs from healthy controls upregulate ISG15 upon activation to higher levels than conventional CD4 T cells, and ISG15-silenced Tregs are more susceptible to IFNα-induced contraction. In human ISG15 deficiency, patient Tregs display an elevated IFN signature relative to Tregs from healthy control. In vivo, in patients with chronic hepatitis C, 2 days after starting pegIFN/ribavirin therapy, a stronger ISG15 inducibility correlates with a milder Treg depletion. Ex vivo, in systemic lupus erythematosus patients, higher levels of ISG15 are associated to reduced STAT1 phosphorylation in response to IFNα, and also to increased frequencies of Tregs, characterising active disease. Conclusion Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions.
Collapse
Affiliation(s)
- Ilenia Pacella
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy
| | - Francesca Romana Spinelli
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy
| | - Martina Severa
- Department of Infectious Diseases Istituto Superiore di Sanità Rome Italy
| | - Eleonora Timperi
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy.,Present address: Eleonora Timperi Institut Curie Paris France
| | - Gloria Tucci
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy
| | - Marta Zagaglioni
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti Rome Italy
| | - Fulvia Ceccarelli
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy
| | - Fabiana Rizzo
- Department of Infectious Diseases Istituto Superiore di Sanità Rome Italy
| | - Eliana M Coccia
- Department of Infectious Diseases Istituto Superiore di Sanità Rome Italy
| | - Roosheel S Patel
- Center for Inborn Errors of Immunity Icahn School of Medicine at Mount Sinai New York NY USA.,Precision Immunology Institute Icahn School of Medicine at Mount Sinai New York NY USA.,Mindich Child Health and Development Institute Icahn School of Medicine at Mount Sinai New York NY USA.,Department of Pediatrics Icahn School of Medicine at Mount Sinai New York NY USA.,Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY USA
| | - Marta Martin-Fernandez
- Center for Inborn Errors of Immunity Icahn School of Medicine at Mount Sinai New York NY USA.,Precision Immunology Institute Icahn School of Medicine at Mount Sinai New York NY USA.,Mindich Child Health and Development Institute Icahn School of Medicine at Mount Sinai New York NY USA.,Department of Pediatrics Icahn School of Medicine at Mount Sinai New York NY USA.,Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY USA
| | - Dusan Bogunovic
- Center for Inborn Errors of Immunity Icahn School of Medicine at Mount Sinai New York NY USA.,Precision Immunology Institute Icahn School of Medicine at Mount Sinai New York NY USA.,Mindich Child Health and Development Institute Icahn School of Medicine at Mount Sinai New York NY USA.,Department of Pediatrics Icahn School of Medicine at Mount Sinai New York NY USA.,Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY USA
| | - Fabrizio Conti
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy
| | - Vincenzo Barnaba
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti Rome Italy
| | - Silvia Piconese
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti Rome Italy
| |
Collapse
|
|
12
|
Fu B, Wang D, Shen X, Guo C, Liu Y, Ye Y, Sun R, Li J, Tian Z, Wei H. Immunomodulation Induced During Interferon-α Therapy Impairs the Anti-HBV Immune Response Through CD24 +CD38 hi B Cells. Front Immunol 2020; 11:591269. [PMID: 33424840 PMCID: PMC7786281 DOI: 10.3389/fimmu.2020.591269] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022] Open
Abstract
Type I interferon is widely used for antiviral therapy, yet has yielded disappointing results toward chronic HBV infection. Here we identify that PEG-IFNα-2b therapy toward persistent infection in humans is a double-edged sword of both immunostimulation and immunomodulation. Our studies of this randomised trial showed persistent PEG-IFNα-2b therapy induced large number of CD24+CD38hi B cells and launched a CD24+CD38hi B cells centered immunosuppressive response, including downregulating functions of T cells and NK cells. Patients with low induced CD24+CD38hi B cells have achieved an improved therapeutic effect. Specifically, using the anti-CD24 antibody to deplete CD24+CD38hi B cells without harming other B cell subsets suggest a promising strategy to improve the therapeutic effects. Our findings show that PEG-IFNα-2b therapy toward persistent infection constitutes an immunomodulation effect, and strategies to identifying the molecular basis for the antiviral versus immunomodulatory effects of PEG-IFNα-2b to selectively manipulate these opposing activities provide an opportunity to ameliorate anti-virus immunity and control viral infection.
Collapse
Affiliation(s)
- Binqing Fu
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Dongyao Wang
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Xiaokun Shen
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Chuang Guo
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Yanyan Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ying Ye
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Sun
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhigang Tian
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
13
|
Nikolopoulou A, Teixeira C, Cook HT, Roufosse C, Cairns THD, Levy JB, Pusey CD, Griffith ME. Membranous nephropathy associated with viral infection. Clin Kidney J 2020; 14:876-883. [PMID: 33777370 PMCID: PMC7986439 DOI: 10.1093/ckj/sfaa026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 01/28/2020] [Indexed: 12/27/2022] Open
Abstract
Background Membranous nephropathy (MN) can be associated with hepatitis infection and less commonly with human immunodeficiency virus (HIV) infection. The significance of anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibodies in this setting is unclear. Methods We describe the clinical, histopathological and outcome data of 19 patients with MN and hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection identified through our renal biopsy database and the association with anti-PLA2R antibodies and anti-THSD7A antibodies. Results The cohort consisted of 19 patients, 8 male and 11 female, with a median age of 42 years (range 23–74). HBV infection was found in six cases, HCV in four and HIV in nine (two HIV patients had HBV co-infection and one HCV co-infection). PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN and 3 with HIV-MN and circulating anti-PLA2R antibodies were detected in 7/10 cases. THSD7A staining on biopsy was positive in three PLA2R-negative cases, one with HBV-MN and two with HIV-MN. Mean proteinuria was higher in the PLA2R-positive group and the median urinary protein:creatinine ratio (uPCR) was 963 mg/mmol (range 22–2406) compared with the PLA2R-negative group [median uPCR 548 mg/mmol (range 65–1898); P = 0.18 Mann–Whitney]. Spontaneous remission occurred in 6/19 patients and after-treatment remission occurred in 7/11 patients. Renal function was preserved in all but two patients who required haemodialysis 2 and 11 years from diagnosis. Conclusions We describe a cohort of patients with MN associated with viral infection, including rare cases of HIV-MN with PLA2R and THSD7A positivity. The mechanism of coincidental or viral-related MN needs to be investigated further.
Collapse
Affiliation(s)
- Aikaterini Nikolopoulou
- Renal Department, Imperial College Healthcare NHS Trust, London, UK.,Department of Immunology and Inflammation, Centre for Inflammatory Diseases, Imperial College, London, UK
| | - Catarina Teixeira
- Nephrology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal
| | - H Terry Cook
- Department of Immunology and Inflammation, Centre for Inflammatory Diseases, Imperial College, London, UK
| | - Candice Roufosse
- Department of Immunology and Inflammation, Centre for Inflammatory Diseases, Imperial College, London, UK
| | | | - Jeremy B Levy
- Renal Department, Imperial College Healthcare NHS Trust, London, UK
| | - Charles D Pusey
- Department of Immunology and Inflammation, Centre for Inflammatory Diseases, Imperial College, London, UK
| | - Megan E Griffith
- Renal Department, Imperial College Healthcare NHS Trust, London, UK
| |
Collapse
|
|
14
|
Klarquist J, Cantrell R, Lehn MA, Lampe K, Hennies CM, Hoebe K, Janssen EM. Type I IFN Drives Experimental Systemic Lupus Erythematosus by Distinct Mechanisms in CD4 T Cells and B Cells. Immunohorizons 2020; 4:140-152. [PMID: 32161059 PMCID: PMC7294741 DOI: 10.4049/immunohorizons.2000005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/20/2020] [Indexed: 12/20/2022] Open
Abstract
Myriad studies have linked type I IFN to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). Although increased levels of type I IFN are found in patients with SLE, and IFN blockade ameliorates disease in many mouse models of lupus, its precise roles in driving SLE pathogenesis remain largely unknown. In this study, we dissected the effect of type I IFN sensing by CD4 T cells and B cells on the development of T follicular helper cells (TFH), germinal center (GC) B cells, plasmablasts, and antinuclear dsDNA IgG levels using the bm12 chronic graft-versus-host disease model of SLE-like disease. Type I IFN sensing by B cells decreased their threshold for BCR signaling and increased their expression of MHC class II, CD40, and Bcl-6, requirements for optimal GC B cell functions. In line with these data, ablation of type I IFN sensing in B cells significantly reduced the accumulation of GC B cells, plasmablasts, and autoantibodies. Ablation of type I IFN sensing in T cells significantly inhibited TFH expansion and subsequent B cell responses. In contrast to the effect in B cells, type I IFN did not promote proliferation in the T cells but protected them from NK cell-mediated killing. Consequently, ablation of either perforin or NK cells completely restored TFH expansion of IFNAR-/- TFH and, subsequently, restored the B cell responses. Together, our data provide evidence for novel roles of type I IFN and immunoregulatory NK cells in the context of sterile inflammation and SLE-like disease.
Collapse
Affiliation(s)
- Jared Klarquist
- Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045;
| | - Rachel Cantrell
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and
| | - Maria A Lehn
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and
| | - Kristin Lampe
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and
| | - Cassandra M Hennies
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and
| | - Kasper Hoebe
- Janssen Research and Development, Johnson & Johnson, Spring House, PA 19477
| | - Edith M Janssen
- Janssen Research and Development, Johnson & Johnson, Spring House, PA 19477
| |
Collapse
|
|
15
|
Chodisetti SB, Fike AJ, Domeier PP, Singh H, Choi NM, Corradetti C, Kawasawa YI, Cooper TK, Caricchio R, Rahman ZSM. Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2020; 204:796-809. [PMID: 31900342 DOI: 10.4049/jimmunol.1901175] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/18/2019] [Indexed: 01/12/2023]
Abstract
TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-γ signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-γ signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-γ reporter mice show that CD4+ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-γ. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-γR indicates that TLR7-induced IFN-γ activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-γ signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-γ and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.
Collapse
Affiliation(s)
- Sathi Babu Chodisetti
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Adam J Fike
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | - Phillip P Domeier
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | | | - Nicholas M Choi
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | | | - Yuka Imamura Kawasawa
- Department of Pharmacology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033.,Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033; and
| | - Timothy K Cooper
- Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033
| | | | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
| |
Collapse
|
|
16
|
Han S, Zhuang H, Lee PY, Li M, Yang L, Nigrovic PA, Reeves WH. Differential Responsiveness of Monocyte and Macrophage Subsets to Interferon. Arthritis Rheumatol 2020; 72:100-113. [PMID: 31390156 PMCID: PMC6935410 DOI: 10.1002/art.41072] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/01/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients exhibit a gene expression program (interferon [IFN] signature) that is attributed to overproduction of type I IFNs by plasmacytoid dendritic cells. Type I IFNs have been thought to play a role in the pathogenesis of SLE. This study was undertaken to examine an unexpected influence of monocyte/macrophages on the IFN signature. METHODS Proinflammatory (classic) and antiinflammatory (nonclassic) monocyte/macrophages were sorted from mice and analyzed by RNA sequencing and quantitative polymerase chain reaction (qPCR). Type I IFN-α/β/ω receptor (IFNAR-1) expression was determined by qPCR and flow cytometry. Macrophages were stimulated in vitro with IFNα, and pSTAT1was measured. RESULTS Transcriptional profiling of peritoneal macrophages from mice with pristane-induced SLE unexpectedly indicated a strong IFN signature in classic, but not nonclassic, monocyte/macrophages exposed to the same type I IFN concentrations. Ifnar1 messenger RNA and IFNAR surface staining were higher in classic monocyte/macrophages versus nonclassic monocyte/macrophages (P < 0.0001 and P < 0.05, respectively, by Student's t-test). Nonclassic monocyte/macrophages were also relatively insensitive to IFNα-driven STAT1 phosphorylation. Humans exhibited a similar pattern: higher IFNAR expression (P < 0.0001 by Student's t-test) and IFNα-stimulated gene expression (P < 0.01 by paired Wilcoxon's rank sum test) in classic monocyte/macrophages and lower levels in nonclassic monocyte/macrophages. CONCLUSION This study revealed that the relative abundance of different monocyte/macrophage subsets helps determine the magnitude of the IFN signature. Responsiveness to IFNα signaling reflects differences in IFNAR expression in classic (high IFNAR) compared to nonclassic (low IFNAR) monocyte/macrophages. Thus, the IFN signature depends on both type I IFN production and the responsiveness of monocyte/macrophages to IFNAR signaling.
Collapse
Affiliation(s)
| | | | - Pui Y Lee
- Boston Children's Hospital, Boston, Massachusetts
| | | | | | - Peter A Nigrovic
- Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts
| | | |
Collapse
|
|
17
|
Mejia-Vilet JM, Parikh SV, Song H, Fadda P, Shapiro JP, Ayoub I, Yu L, Zhang J, Uribe-Uribe N, Rovin BH. Immune gene expression in kidney biopsies of lupus nephritis patients at diagnosis and at renal flare. Nephrol Dial Transplant 2019; 34:1197-1206. [PMID: 29800348 PMCID: PMC7967887 DOI: 10.1093/ndt/gfy125] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Up to 50% of lupus nephritis (LN) patients experience renal flares after their initial episode of LN. These flares contribute to poor renal outcomes. We postulated that intrarenal immune gene expression is different in flares compared with de novo LN, and conducted these studies to test this hypothesis. METHODS Glomerular and tubulointerstitial immune gene expression was evaluated in 14 patients who had a kidney biopsy to diagnose LN and another biopsy at their first LN flare. Ten healthy living kidney donors were included as controls. RNA was extracted from laser microdissected formalin-fixed paraffin-embedded kidney biopsies. Gene expression was analyzed using the Nanostring nCounter® platform and validated by quantitative real-time polymerase chain reaction. Differentially expressed genes were analyzed by the Ingenuity Pathway Analysis and Panther Gene Ontology tools. RESULTS Over 110 genes were differentially expressed between LN and healthy control kidney biopsies. Although there was considerable molecular heterogeneity between LN biopsies at diagnosis and flare, for about half the LN patients gene expression from the first LN biopsy clustered with the repeated LN biopsy. However, in all patients, a set of eight interferon alpha-controlled genes had a significantly higher expression in the diagnostic biopsy compared with the flare biopsy. In contrast, nine tumor necrosis factor alpha-controlled genes had higher expression in flare biopsies. CONCLUSIONS There is significant heterogeneity in immune-gene expression of kidney tissue from LN patients. There are limited but important differences in gene expression between LN flares, which may influence treatment decisions.
Collapse
Affiliation(s)
- Juan M Mejia-Vilet
- Division of Nephrology, Department of Internal Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Samir V Parikh
- Division of Nephrology, Department of Internal Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA
| | - Huijuan Song
- Division of Nephrology, Department of Internal Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA
| | - Paolo Fadda
- Genomics Shared Resource (GSR)-Comprehensive Cancer Center (CCC)
| | - John P Shapiro
- Division of Nephrology, Department of Internal Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA
| | - Isabelle Ayoub
- Division of Nephrology, Department of Internal Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA
| | - Lianbo Yu
- Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jianying Zhang
- Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Norma Uribe-Uribe
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Brad H Rovin
- Division of Nephrology, Department of Internal Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA
| |
Collapse
|
|
18
|
Johansson A, Nyberg WA, Sjöstrand M, Moruzzi N, Bergman P, Khademi M, Andersson M, Piehl F, Berggren PO, Covacu R, Jagodic M, Espinosa A. miR-31 regulates energy metabolism and is suppressed in T cells from patients with Sjögren's syndrome. Eur J Immunol 2018; 49:313-322. [PMID: 30307034 DOI: 10.1002/eji.201747416] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 09/24/2018] [Accepted: 10/09/2018] [Indexed: 01/14/2023]
Abstract
Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a T cell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFNβ and in patients with Sjögren's syndrome (SjS). To interrogate the role of miR-31-51p in T cells we transfected human CD4+ T cells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN-α also increased the basal levels of human CD4+ T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in T cells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure.
Collapse
Affiliation(s)
- Alina Johansson
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| | - William A Nyberg
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| | - Maria Sjöstrand
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| | - Noah Moruzzi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Petra Bergman
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Mohsen Khademi
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Magnus Andersson
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Division of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Piehl
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Division of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ruxandra Covacu
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Maja Jagodic
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Alexander Espinosa
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
19
|
Murakami N, Ding Y, Cohen DJ, Chandraker AK, Rennke HG. Recurrent membranous nephropathy and acute cellular rejection in a patient treated with direct anti-HCV therapy (ledipasvir/sofosbuvir). Transpl Infect Dis 2018; 20:e12959. [PMID: 29968947 DOI: 10.1111/tid.12959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 05/13/2018] [Accepted: 06/19/2018] [Indexed: 01/04/2023]
Abstract
Direct-acting antiviral agents (DAAs) are very effective therapy for chronic hepatitis C infection, and have revolutionized the treatment of hepatitis C in kidney allograft recipients. Although well tolerated in general, rare renal complications have been reported. We describe a case of recurrent membranous nephropathy and acute cellular rejection in a kidney allograft recipient after DAA (ledipasvir/sofosbuvir) therapy, whose allograft function had been stable for more than 30 years. The patient was presented with nephrotic range proteinuria with stable creatinine. The kidney allograft biopsy revealed recurrent membranous nephropathy with fine granular deposits of IgG1/IgG4 codominance and positive phospholipase A2 receptor (PLA2R) staining. The patient was treated with pulse steroid and rituximab, leading to a decrease in proteinuria. As DAAs are more frequently used, physicians should be aware of immune-related renal complications.
Collapse
Affiliation(s)
- Naoka Murakami
- Schuster Transplant Research Center, Brigham and Women's Hospital, Boston, Massachusetts
| | - Yanli Ding
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - David J Cohen
- West Palm Beach VA Medical Canter, West Palm Beach, Florida
| | - Anil K Chandraker
- Schuster Transplant Research Center, Brigham and Women's Hospital, Boston, Massachusetts
| | - Helmut G Rennke
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| |
Collapse
|
|
20
|
Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis 2018; 77:175-187. [PMID: 28765121 DOI: 10.1136/annrheumdis-2017-211555] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 05/31/2017] [Accepted: 07/01/2017] [Indexed: 01/11/2023]
Abstract
The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.
Collapse
Affiliation(s)
- Kenneth F Baker
- Musculoskeletal Research Group and Arthritis Research UK Centre of Excellence in Rheumatoid Arthritis Pathogenesis, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK
| | - John D Isaacs
- Musculoskeletal Research Group and Arthritis Research UK Centre of Excellence in Rheumatoid Arthritis Pathogenesis, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK
| |
Collapse
|
|
21
|
Abstract
Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.
Collapse
Affiliation(s)
- Phillip P Domeier
- a Department of Microbiology and Immunology, Penn State College of Medicine , USA
| | - Stephanie L Schell
- a Department of Microbiology and Immunology, Penn State College of Medicine , USA
| | - Ziaur S M Rahman
- a Department of Microbiology and Immunology, Penn State College of Medicine , USA
| |
Collapse
|
|
22
|
Affiliation(s)
- Wing Bun Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT HKSAR.
| | | | | |
Collapse
|
|
23
|
Duan J, Wang Y, Liu D, Ma J. Induction of Vogt-Koyanagi-Harada Disease by Interferon-Alpha and Ribavirin Treatment in Patients with Hepatitis C: A Case Report and Review of the Literature. Ocul Immunol Inflamm 2017; 27:229-234. [PMID: 29023176 DOI: 10.1080/09273948.2017.1373827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE To describe a case of Vogt-Koyanagi-Harada disease (VKH) presenting in a hepatitis C patient after interferon-alpha (IFN-α) and ribavirin treatment. METHODS A retrospective review of our patient and a review of the published literature. RESULTS A 59 year-old man developed VKH after the four months of IFN-α and ribavirin therapy for hepatitis C. The patient's VKH was controlled by systemic corticosteroids. The relationship between VKH and IFN-α is discussed based on the published literature. CONCLUSIONS VKH is a rare autoimmune complication triggered by interferon-alpha therapy; the T-cell modulatory properties of IFN-α possibly contribute to this association. Early diagnosis of VKH and aggressive systemic corticosteroid intervention are essential for this type of IFN-α -related autoimmune complication.
Collapse
Affiliation(s)
- Jialiang Duan
- a Department of Ophthalmology , The Second Hospital of Hebei Medical University , Shijiazhuang , China
| | - Yang Wang
- b Department of Hepatobiliary Surgery , The Third Hospital of Hebei Medical University , Shijiazhuang , China
| | - Danyan Liu
- a Department of Ophthalmology , The Second Hospital of Hebei Medical University , Shijiazhuang , China
| | - Jingxue Ma
- a Department of Ophthalmology , The Second Hospital of Hebei Medical University , Shijiazhuang , China
| |
Collapse
|
|
24
|
Paquette JK, Ma Y, Fisher C, Li J, Lee SB, Zachary JF, Kim YS, Teuscher C, Weis JJ. Genetic Control of Lyme Arthritis by Borrelia burgdorferi Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin. THE JOURNAL OF IMMUNOLOGY 2017; 199:3525-3534. [PMID: 28986440 DOI: 10.4049/jimmunol.1701011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/14/2017] [Indexed: 01/29/2023]
Abstract
Previously, using a forward genetic approach, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus underlying Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1). In this study, we show that mAb blockade revealed a unique role for IFN-β in Lyme arthritis development in B6.C3-Bbaa1 mice. Genetic control of IFN-β expression was also identified in bone marrow-derived macrophages stimulated with B. burgdorferi, and it was responsible for feed-forward amplification of IFN-stimulated genes. Reciprocal radiation chimeras between B6.C3-Bbaa1 and C57BL/6 mice revealed that arthritis is initiated by radiation-sensitive cells, but orchestrated by radiation-resistant components of joint tissue. Advanced congenic lines were developed to reduce the physical size of the Bbaa1 interval, and confirmed the contribution of type I IFN genes to Lyme arthritis. RNA sequencing of resident CD45- joint cells from advanced interval-specific recombinant congenic lines identified myostatin as uniquely upregulated in association with Bbaa1 arthritis development, and myostatin expression was linked to IFN-β production. Inhibition of myostatin in vivo suppressed Lyme arthritis in the reduced interval Bbaa1 congenic mice, formally implicating myostatin as a novel downstream mediator of the joint-specific inflammatory response to B. burgdorferi.
Collapse
Affiliation(s)
- Jackie K Paquette
- Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Ying Ma
- Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Colleen Fisher
- Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Jinze Li
- Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Sang Beum Lee
- Department of Human Nutrition, Food, and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI 96822
| | - James F Zachary
- Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61820; and
| | - Yong Soo Kim
- Department of Human Nutrition, Food, and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI 96822
| | - Cory Teuscher
- Department of Medicine, University of Vermont, Burlington, VT 05405
| | - Janis J Weis
- Department of Pathology, University of Utah, Salt Lake City, UT 84112;
| |
Collapse
|
|
25
|
Dalvi P, Sun B, Tang N, Pulliam L. Immune activated monocyte exosomes alter microRNAs in brain endothelial cells and initiate an inflammatory response through the TLR4/MyD88 pathway. Sci Rep 2017; 7:9954. [PMID: 28855621 PMCID: PMC5577170 DOI: 10.1038/s41598-017-10449-0] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 08/08/2017] [Indexed: 12/22/2022] Open
Abstract
The host immune response is critical for homeostasis; however, when chronic low level activation of the immune response with or without the driver continues, a cascade of events can trigger immunological dysfunction. Monocytes are key peripheral sensors of the immune response and their activation is instrumental in the development of cognitive impairment. Here, we show that monocytes activated by interferon alpha, lipopolysaccharide or a combination of both generate exosomes carrying significantly altered microRNA profiles compared to non-activated monocytes. These exosomes alone can activate human brain microvascular endothelial cells to stimulate adhesion molecules, CCL2, ICAM1, VCAM1 and cytokines, IL1β and IL6. This activation is through the toll like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) pathway that activates nuclear factor-κB and increases monocyte chemotaxis. Inhibition of monocyte exosome release reverses endothelial cell activation and monocyte chemotaxis. Our study suggests that activated monocytes have an impact on brain vascular function through intercellular exosome signaling.
Collapse
Affiliation(s)
- Pranjali Dalvi
- Department of Laboratory Medicine, Veterans Administration Medical Center, San Francisco, CA, USA
| | - Bing Sun
- Department of Laboratory Medicine, Veterans Administration Medical Center, San Francisco, CA, USA
| | - Norina Tang
- Department of Laboratory Medicine, Veterans Administration Medical Center, San Francisco, CA, USA
| | - Lynn Pulliam
- Department of Laboratory Medicine, Veterans Administration Medical Center, San Francisco, CA, USA. .,Departments of Laboratory Medicine and Medicine, University of California, San Francisco, CA, USA.
| |
Collapse
|
|
26
|
You M, Dong G, Li F, Ma F, Ren J, Xu Y, Yue H, Tang R, Ren D, Hou Y. Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells. Cell Mol Immunol 2017; 14:192-202. [PMID: 26277892 PMCID: PMC5301152 DOI: 10.1038/cmi.2015.61] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 06/02/2015] [Accepted: 06/03/2015] [Indexed: 12/21/2022] Open
Abstract
A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-α (IFN-α) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-α signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-α signaling in B cells. We found that the number of CD180-negative B cells was increased in MRL/Mp-Fas(lpr/lpr) lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138+ plasmablast/plasma cells and GL-7+ germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-α-induced phosphorylation of signal transducer and activator of transcription 2 (STAT-2) and expression of IFN-stimulated genes (ISGs) in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-α-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of IFN-α signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-α signaling in SLE. Our data provide molecular insight into the mechanism of IFN-α signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment.
Collapse
Affiliation(s)
- Ming You
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Guanjun Dong
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Fanlin Li
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Feiya Ma
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Jing Ren
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Yujun Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Huimin Yue
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Ruijing Tang
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Deshan Ren
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University Nanjing 210093, People's Republic of China
| |
Collapse
|
|
27
|
Sise ME, Wisocky J, Rosales IA, Chute D, Holmes JA, Corapi KM, Babitt JL, Tangren JS, Hashemi N, Lundquist AL, Williams WW, Mount DB, Andersson KL, Rennke HG, Smith RN, Colvin R, Thadhani RI, Chung RT. Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy. Kidney Int Rep 2016; 1:135-143. [PMID: 27990496 PMCID: PMC5155703 DOI: 10.1016/j.ekir.2016.06.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- Meghan E Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jessica Wisocky
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Donald Chute
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jacinta A Holmes
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Kristin M Corapi
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jodie L Babitt
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jessica S Tangren
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Nikroo Hashemi
- Department of Gastroenterology and Hepatology, Brigham and Women's Hospital, Boston, MA
| | - Andrew L Lundquist
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Winfred W Williams
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - David B Mount
- Renal Unit, Brigham and Women's Hospital, Boston, MA
| | - Karin L Andersson
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Helmut G Rennke
- Department of Pathology, Brigham and Women's Hospital, Boston, MA
| | - R Neal Smith
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Robert Colvin
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Ravi I Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Raymond T Chung
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
| |
Collapse
|
|
28
|
Menon M, Blair PA, Isenberg DA, Mauri C. A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus. Immunity 2016; 44:683-697. [PMID: 26968426 PMCID: PMC4803914 DOI: 10.1016/j.immuni.2016.02.012] [Citation(s) in RCA: 267] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 10/26/2015] [Accepted: 12/14/2015] [Indexed: 01/05/2023]
Abstract
Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.
pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism pDCs are hyperactivated in SLE and fail to induce Breg cells Patients responding to rituximab display a normalized pDC-Breg cell interaction
Collapse
Affiliation(s)
- Madhvi Menon
- Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK
| | - Paul A Blair
- Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK
| | - David A Isenberg
- Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK
| | - Claudia Mauri
- Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK.
| |
Collapse
|
|
29
|
Singh N, Kumar B, Aluri V, Lenert P. Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations. J Allergy Clin Immunol 2016; 137:1325-33. [PMID: 26953155 DOI: 10.1016/j.jaci.2015.12.1326] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 10/30/2015] [Accepted: 12/21/2015] [Indexed: 11/25/2022]
Abstract
B cells play an important role in systemic lupus erythematosus by acting not only as precursors of autoantibody-producing cells but also as antigen-presenting, cytokine-secreting, and regulatory cells. Unopposed activation of B cells through their B-cell receptor for antigen, as seen in B cells lacking Lyn kinase, results in systemic autoimmunity. The B-cell activating factor of the TNF family (BAFF), nucleic acid-sensing Toll-like receptors (TLRs), and type I interferon can affect B-cell survival and decrease their threshold for activation. Herein we discuss both direct and indirect strategies aimed at targeting B cells in patients with lupus by blocking BAFF, type I interferon, or TLR7 to TLR9. Although BAFF-depleting therapy with belimumab achieved approval for lupus, other BAFF inhibitors were much less beneficial in clinical trials. Inhibitors of the B-cell receptor for antigen signaling and antibodies against type I interferon are in the pipeline. The TLR7 to TLR9 blocker hydroxychloroquine has been in use in patients with lupus for more than 50 years, but oligonucleotide-based inhibitors of TLR7 to TLR9, despite showing promise in animal models of lupus, have not reached the primary end point in a recent phase 1 trial. These data point toward possible redundancies in B-cell signaling/survival pathways, which must be better understood before future clinical trials are executed.
Collapse
Affiliation(s)
- Namrata Singh
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Bharat Kumar
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Vijay Aluri
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Petar Lenert
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
| |
Collapse
|
|
30
|
Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells. J Immunol Res 2016; 2016:6269157. [PMID: 27034965 PMCID: PMC4789470 DOI: 10.1155/2016/6269157] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/15/2016] [Accepted: 02/07/2016] [Indexed: 02/06/2023] Open
Abstract
Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensive in vitro and in vivo studies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.
Collapse
|
|
31
|
Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases. Autoimmun Rev 2015; 14:127-39. [DOI: 10.1016/j.autrev.2014.10.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 09/30/2014] [Indexed: 12/11/2022]
|
|
32
|
Iferkhass S, Elasri F, Chatioui S, Khoyaali A, Bargach T, Reda K, Oubaaz A. [Bilateral non-arteritic ischemic optic neuropathy during treatment of viral hepatitis C with pegylated interferon and Ribavirin]. J Fr Ophtalmol 2014; 38:34-40. [PMID: 25533994 DOI: 10.1016/j.jfo.2014.06.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Revised: 05/22/2014] [Accepted: 06/16/2014] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Hepatitis C is a serious viral infection, for which the current treatment is based on the combination of pegylated interferon (IFN) and Ribavirin(®). Ophthalmic complications observed with PEG-IFN are infrequent and of variable prognosis. They often include an ischemic retinopathy with typical cotton-wool spots, hemorrhage and retinal edema, and rarely acute non-arteritic anterior ischemic optic neuropathy as illustrated by our report. OBSERVATION We report the case of a 51-year-old man followed for chronic active hepatitis C, who presented in the fourth month of treatment with pegylated interferon and vidarabine with a sharp decline in visual acuity secondary to acute bilateral non-arteritic anterior ischemic optic neuropathy. The hepatitis C treatment was discontinued. His course was notable by the third week for a significant regression of papilledema with improvement in visual acuity in the right eye and no change in the left eye, remaining at counting fingers. After regressing for four years, the disease progressed to bilateral temporal optic atrophy without change in visual acuity. CONCLUSION Pegylated interferon and Ribavirin(®) are commonly used in the treatment of chronic hepatitis C. They are the source of various ophthalmologic complications of varied severity. The pathophysiology of this ocular toxicity currently remains hypothetical. Non-arteritic ischemic optic neuropathy is still a relatively rare complication with a poor functional prognosis, often requiring discontinuation of treatment. Thus, careful ophthalmologic monitoring before and during antiviral treatment of patients with hepatitis C appears necessary.
Collapse
Affiliation(s)
- S Iferkhass
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc.
| | - F Elasri
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc
| | - S Chatioui
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc
| | - A Khoyaali
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc
| | - T Bargach
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc
| | - K Reda
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc
| | - A Oubaaz
- Service d'ophtalmologie, hôpital militaire d'instruction Mohamed V, Madinat Al Irfane, Rabat, Maroc
| |
Collapse
|
|
33
|
Ma Y, Bramwell KKC, Lochhead RB, Paquette JK, Zachary JF, Weis JH, Teuscher C, Weis JJ. Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production. THE JOURNAL OF IMMUNOLOGY 2014; 193:6050-60. [PMID: 25378596 DOI: 10.4049/jimmunol.1401746] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Localized upregulation of type I IFN was previously implicated in development of Borrelia burgdorferi-induced arthritis in C3H mice, and was remarkable due to its absence in the mildly arthritic C57BL/6 (B6) mice. Independently, forward genetics analysis identified a quantitative trait locus on Chr4, termed B. burgdorferi-associated locus 1 (Bbaa1), that regulates Lyme arthritis severity and includes the 15 type I IFN genes. Involvement of Bbaa1 in arthritis development was confirmed in B6 mice congenic for the C3H allele of Bbaa1 (B6.C3-Bbaa1), which developed more severe Lyme arthritis and K/B×N model of rheumatoid arthritis (RA) than did parental B6 mice. Administration of a type I IFN receptor blocking mAb reduced the severity of both Lyme arthritis and RA in B6.C3-Bbaa1 mice, formally linking genetic elements within Bbaa1 to pathological production of type I IFN. Bone marrow-derived macrophages from Bbaa1 congenic mice implicated this locus as a regulator of type I IFN induction and downstream target gene expression. Bbaa1-mediated regulation of IFN-inducible genes was upstream of IFN receptor-dependent amplification; however, the overall magnitude of the response was dependent on autocrine/paracrine responses to IFN-β. In addition, the Bbaa1 locus modulated the functional phenotype ascribed to bone marrow-derived macrophages: the B6 allele promoted expression of M2 markers, whereas the C3H allele promoted induction of M1 responses. This report identifies a genetic locus physically and functionally linked to type I IFN that contributes to the pathogenesis of both Lyme and RA.
Collapse
Affiliation(s)
- Ying Ma
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Kenneth K C Bramwell
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Robert B Lochhead
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Jackie K Paquette
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - James F Zachary
- Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802; and
| | - John H Weis
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Cory Teuscher
- Department of Medicine, University of Vermont, Burlington, VT 05405
| | - Janis J Weis
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112;
| |
Collapse
|
|
34
|
Abstract
Cholesterol and components of the cholesterol biosynthetic pathway have fundamental roles in all mammalian cells. Hydroxylated forms of cholesterol are now emerging as important regulators of immune function. This involves effects on the cholesterol biosynthetic pathway and cell membrane properties, which can have antiviral and anti-inflammatory influences. In addition, a dihydroxylated form of cholesterol functions as an immune cell guidance cue by engaging the G protein-coupled receptor EBI2, and it is required for mounting adaptive immune responses. In this Review, we summarize the current understanding of the closely related oxysterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, and the growing evidence that they have wide-ranging influences on innate and adaptive immunity.
Collapse
|
|
35
|
Mackern-Oberti JP, Vega F, Llanos C, Bueno SM, Kalergis AM. Targeting dendritic cell function during systemic autoimmunity to restore tolerance. Int J Mol Sci 2014; 15:16381-417. [PMID: 25229821 PMCID: PMC4200801 DOI: 10.3390/ijms150916381] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/29/2014] [Accepted: 09/05/2014] [Indexed: 12/11/2022] Open
Abstract
Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders.
Collapse
Affiliation(s)
- Juan P Mackern-Oberti
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Portugal 49, Santiago 8330025, Chile.
| | - Fabián Vega
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 350, Santiago 8330033, Chile.
| | - Carolina Llanos
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 350, Santiago 8330033, Chile.
| | - Susan M Bueno
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Portugal 49, Santiago 8330025, Chile.
| | - Alexis M Kalergis
- Millennium Institute of Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Portugal 49, Santiago 8330025, Chile.
| |
Collapse
|
|
36
|
Pathogenesis and potential therapeutic targets in systemic lupus erythematosus: from bench to bedside. AUTOIMMUNITY HIGHLIGHTS 2014; 5:33-45. [PMID: 26000154 PMCID: PMC4389042 DOI: 10.1007/s13317-014-0058-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 06/12/2014] [Indexed: 12/18/2022]
Abstract
Systemic lupus erythematosus (SLE) is considered an autoimmune disease with multiorgan involvement. Many advances have been made during the last decade regarding inflammatory pathways, genetic and epigenetic alterations, adaptive and innate immune system mechanisms specifically involved in SLE pathogenesis. Apoptosis has been proposed as an important player in SLE pathogenesis more than a decade ago. However, only recently new key apoptotic pathways have been investigated and the link between apoptotic debris containing autoantigens, innate immunity and ongoing inflammation has been further elucidated. Better understanding of cellular mechanisms and involved cytokines contributed to the development of new biological drugs specifically addressed for SLE therapy.
Collapse
|
|
37
|
Sanayama Y, Ikeda K, Saito Y, Kagami SI, Yamagata M, Furuta S, Kashiwakuma D, Iwamoto I, Umibe T, Nawata Y, Matsumura R, Sugiyama T, Sueishi M, Hiraguri M, Nonaka K, Ohara O, Nakajima H. Prediction of Therapeutic Responses to Tocilizumab in Patients With Rheumatoid Arthritis: Biomarkers Identified by Analysis of Gene Expression in Peripheral Blood Mononuclear Cells Using Genome-Wide DNA Microarray. Arthritis Rheumatol 2014; 66:1421-31. [DOI: 10.1002/art.38400] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 02/04/2014] [Indexed: 01/13/2023]
Affiliation(s)
| | - Kei Ikeda
- Chiba University Hospital; Chiba Japan
| | | | - Shin-ichiro Kagami
- Chiba University Hospital, Chiba, Japan, and Asahi General Hospital; Asahi Japan
| | - Mieko Yamagata
- Chiba University Hospital, Chiba, Japan, and Asahi General Hospital; Asahi Japan
| | - Shunsuke Furuta
- Chiba University Hospital, Chiba, Japan, and Asahi General Hospital; Asahi Japan
| | | | | | | | | | | | - Takao Sugiyama
- National Hospital Organization Shimoshizu Hospital; Yotsukaido Japan
| | - Makoto Sueishi
- National Hospital Organization Shimoshizu Hospital; Yotsukaido Japan
| | | | - Ken Nonaka
- Kazusa DNA Research Institute; Kisarazu Japan
| | - Osamu Ohara
- Kazusa DNA Research Institute; Kisarazu Japan
| | | |
Collapse
|
|
38
|
Llanos C, Mackern-Oberti JP, Vega F, Jacobelli SH, Kalergis AM. Tolerogenic dendritic cells as a therapy for treating lupus. Clin Immunol 2013; 148:237-45. [PMID: 23773922 DOI: 10.1016/j.clim.2013.04.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/03/2013] [Accepted: 04/29/2013] [Indexed: 11/28/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by the over production of auto-antibodies against nuclear components. Thus, SLE patients have increased morbidity and, mortality compared to healthy individuals. Available therapies are not curative and are associated with unwanted adverse effects. During the last few years, important advances in immunology research have provided rheumatologists with new tools for designing novel therapies for treating autoimmunity. However, the complex nature of SLE has played a conflicting role, hindering breakthroughs in therapeutic development. Nonetheless, new advances about SLE pathogenesis could open a fruitful line of research. Dendritic cells (DCs) have been established as essential players in the mechanisms underlying SLE, making them attractive therapeutic targets for fine-tuning the immune system. In this review, we discuss the recent advances made in revealing the mechanisms of SLE pathogenesis, with a focus on the use of DCs as a target for therapy development.
Collapse
Affiliation(s)
- Carolina Llanos
- Millennium Institute on Immunology and Immunotherapy, Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile.
| | | | | | | | | |
Collapse
|
|
39
|
Moritoki M, Kadowaki T, Niki T, Nakano D, Soma G, Mori H, Kobara H, Masaki T, Kohno M, Hirashima M. Galectin-9 ameliorates clinical severity of MRL/lpr lupus-prone mice by inducing plasma cell apoptosis independently of Tim-3. PLoS One 2013; 8:e60807. [PMID: 23585851 PMCID: PMC3621869 DOI: 10.1371/journal.pone.0060807] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 03/03/2013] [Indexed: 11/19/2022] Open
Abstract
Galectin-9 ameliorates various murine autoimmune disease models by regulating T cells and macrophages, although it is not known what role it may have in B cells. The present experiment shows that galectin-9 ameliorates a variety of clinical symptoms, such as proteinuria, arthritis, and hematocrit in MRL/lpr lupus-prone mice. As previously reported, galectin-9 reduces the frequency of Th1, Th17, and activated CD8(+) T cells. Although anti-dsDNA antibody was increased in MRL/lpr lupus-prone mice, galectin-9 suppressed anti-dsDNA antibody production, at least partly, by decreasing the number of plasma cells. Galectin-9 seemed to decrease the number of plasma cells by inducing plasma cell apoptosis, and not by suppressing BAFF production. Although about 20% of CD19(-/low) CD138(+) plasma cells expressed Tim-3 in MRL/lpr lupus-prone mice, Tim-3 may not be directly involved in the galectin-9-induced apoptosis, because anti-Tim-3 blocking antibody did not block galectin-9-induced apoptosis. This is the first report of plasma cell apoptosis being induced by galectin-9. Collectively, it is likely that galectin-9 attenuates the clinical severity of MRL lupus-prone mice by regulating T cell function and inducing plasma cell apoptosis.
Collapse
Affiliation(s)
- Masahiro Moritoki
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Takeshi Kadowaki
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Holistic Immunology, Kagawa University, Kagawa, Japan
| | - Toshiro Niki
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Genichiro Soma
- Department of Holistic Immunology, Kagawa University, Kagawa, Japan
| | - Hirohito Mori
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masakazu Kohno
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Mitsuomi Hirashima
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- * E-mail:
| |
Collapse
|
|
40
|
Tran HA, Jones TL, Ianna EA, Foy A, Reeves GEM. Thyroid disease in chronic hepatitis C infection treated with combination interferon-α and ribavirin: management strategies and future perspective. Endocr Pract 2013; 19:292-300. [PMID: 23186968 PMCID: PMC4134094 DOI: 10.4158/ep12195.ra] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Hepatitis C virus (HCV) infection is one of the major epidemics afflicting young people in both developed and developing countries. The most common endocrine disorder associated with this infection, especially in conjunction with interferon-α (IFN-α)-based therapy, is thyroid disease (TD). This review examines the development of TD before, during, and after the completion of treatment with combination IFN-α and ribavirin (RBV) for chronic HCV infection. We also summarize the current understanding of the natural history of the condition and propose management and follow-up guidelines. METHODS PubMed was searched up to June 30, 2011 for English-language publications that contained the search terms "hepatitis C virus," "chronic hepatitis C," "HCV," "thyroid disease," "thyroiditis," "autoimmunity," "interferon-alpha," and "ribavirin." Additional publications were identified from the reference lists of identified papers. The included studies were original research publications and included combination IFN-α and RBV use in patients that developed TD. RESULTS The prevalence of TD before combination IFN-α and RBV therapy ranges from 4.6 to 21.3%; during therapy, 1.1 to 21.3%; and after therapy, 6.7 to 21.3%. The most common TD is thyroiditis. Thyroid function testing (TFT) frequency and diagnostic criteria for various thyroid conditions are not standardized, and many of the existing studies are retrospective. CONCLUSION Patients undergoing this therapy should be assessed with a standardized protocol to appropriately detect and manage developed TD. Based on the currently available literature, we recommend that patients receiving combination interferon-α and RBV therapy undergo monthly thyrotropin (TSH) level testing.
Collapse
Affiliation(s)
- Huy A Tran
- Department of Clinical Chemistry, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.
| | | | | | | | | |
Collapse
|
|
41
|
Kirou KA, Gkrouzman E. Anti-interferon alpha treatment in SLE. Clin Immunol 2013; 148:303-12. [PMID: 23566912 DOI: 10.1016/j.clim.2013.02.013] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Revised: 02/20/2013] [Accepted: 02/21/2013] [Indexed: 01/08/2023]
Abstract
Several studies in the last decade have highlighted the role of the type I interferon (IFN-I) pathway, and particularly interferon alpha (IFNα) in SLE pathogenesis. As a result, a multitude of potential treatments targeting IFNα have emerged in the last few years, a few of which have already completed phase II clinical trials. Some of the treatment strategies have focused on blocking IFNα or its receptor and others the plasmacytoid dendritic cell (pDC), which is the principal IFNα producing cell. In this review, we will discuss the evidence supporting a pathogenic role of IFNα and pDC in SLE, provide an update on the current status of these therapeutic strategies, and discuss the potential advantages and disadvantages of each therapeutic approach.
Collapse
Affiliation(s)
- Kyriakos A Kirou
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY 10021, USA.
| | | |
Collapse
|
|
42
|
Poddar N, Wang JC. Thrombotic thrombocytopenic purpura in a patient with interferon treated hepatitis C successfully treated with rituximab. Hematol Rep 2013; 5:5-7. [PMID: 23888238 PMCID: PMC3719105 DOI: 10.4081/hr.2013.e2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 12/18/2012] [Accepted: 01/07/2013] [Indexed: 01/16/2023] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a life threatening condition associated with formation of platelet thrombi. Deficiency of ADAM TS 13 with presence of inhibitory anti-ADAM TS 13 Immunoglobulin G antibody is seen in patients with acquired TTP. TTP in patients on interferon therapy for chronic hepatitis C has rarely been reported. Furthermore, successful treatment of an initial episode of acute refractory acquired TTP, in a patient of chronic hepatitis C during interferon therapy with Rituximab, has not been previously reported. Here we describe a case of acute refractory acquired TTP associated with pegylated interferon therapy for her chronic hepatitis C infection. Initially refractory to plasmapheresis and steroids, she was successfully treated with Rituximab and plasmaphersis without any evidence of reactivation of hepatitis.
Collapse
Affiliation(s)
- Nishant Poddar
- Division of Hematology/Oncology, Brookdale University Hospital Medical Center , Brooklyn, NY, USA
| | | |
Collapse
|
|
43
|
Ohshima M, Kanda H, Kubo K, Yonezumi-Hayashi A, Tateishi S, Yamamoto K. Characterization of 5C11-positive activated interferon-producing cells in patients with systemic lupus erythematosus. Lupus 2012; 22:44-51. [PMID: 23087259 DOI: 10.1177/0961203312463620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE 5C11 antibody is a novel monoclonal antibody against human BST2 and can be used to detect activation of interferon-producing cells (IPCs). Activated IPCs, which produce large amounts of interferon-α (IFNα), are considered to play an important role in the pathogenesis of systemic lupus erythematosus (SLE). We investigated the characterization of 5C11-positive cells in patients with SLE. METHODS The proportions of 5C11-positive cells among blood dendritic cell antigen 2 (BDCA-2)-, CD3-, CD19- and CD14-positive cells in peripheral blood from SLE patients (SLE-PBMCs) and healthy controls (control-PBMCs) were analyzed by flow cytometry. The effect of 5C11 antibody on IFNα production from SLE-PBMCs under stimulation with cytosine-phosphate-guanosine (CpG2216, bacterial oligonucleotide motif) was also examined by enzyme-linked immunosorbent assay (ELISA). RESULTS The proportions of 5C11-positive cells among BDCA-2-, CD3- and CD19-, but not CD14-positive cells in SLE-PBMCs were significantly increased compared to those in control-PBMCs (p < 0.0001, all). Especially, the number of 5C11-positive cells among BDCA-2-positive cells was significantly increased in SLE-PBMCs by about six-fold compared to that in control-PBMCs (p < 0.0001). 5C11 antibody inhibited IFNα production by SLE-PBMCs induced by CpG and the inhibition rates was 27% (p < 0.001). CONCLUSION SLE patients had a significantly higher proportion of 5C11-positive cells among CD3 and CD19 cells, and especially BDCA-2 positive cells. The ability of 5C11 antibody to inhibit IFNα production from SLE-PBMCs warrants further investigation for its possible clinical application for the treatment of SLE.
Collapse
Affiliation(s)
- M Ohshima
- Department of Allergy and Rheumatology, University of Tokyo, Japan
| | | | | | | | | | | |
Collapse
|
|
44
|
Lochhead RB, Sonderegger FL, Ma Y, Brewster JE, Cornwall D, Maylor-Hagen H, Miller JC, Zachary JF, Weis JH, Weis JJ. Endothelial cells and fibroblasts amplify the arthritogenic type I IFN response in murine Lyme disease and are major sources of chemokines in Borrelia burgdorferi-infected joint tissue. THE JOURNAL OF IMMUNOLOGY 2012; 189:2488-501. [PMID: 22851707 DOI: 10.4049/jimmunol.1201095] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Localized elevation in type I IFN has been uniquely linked to the severe Lyme arthritis that develops in C3H mice infected with the spirochete Borrelia burgdorferi. In this study, the dynamic interactions that result in generation of these responses were further examined in C3H mice carrying the type I IFN receptor gene ablation, which effectively blocks all autocrine/paracrine signaling crucial to induction of downstream effectors. Reciprocal radiation chimeras between C3H and IFNAR1⁻/⁻ mice implicated both radiation-sensitive and radiation-resistant cells of the joint tissue in the proarthritic induction of type I IFN. Ex vivo analysis of cells from the naive joint revealed CD45⁺ cells residing in the tissue to be uniquely capable of initiating the type I IFN response to B. burgdorferi. Type I IFN responses were analyzed in real time by lineage sorting of cells from infected joint tissue. This demonstrated that myeloid cells, endothelial cells, and fibroblasts were responsible for propagating the robust IFN response, which peaked at day 7 postinfection and rapidly resolved. Endothelial cells and fibroblasts were the dominant sources of IFN signature transcripts in the joint tissue. Fibroblasts were also the major early source of chemokines associated with polymorphonuclear leukocyte and monocyte/macrophage infiltration, thus providing a focal point for arthritis development. These findings suggest joint-localized interactions among related and unrelated stromal, endothelial, and myeloid cell lineages that may be broadly applicable to understanding the pathogeneses of diseases associated with type I IFN signature, including systemic lupus erythematosus and some rheumatoid arthritides.
Collapse
Affiliation(s)
- Robert B Lochhead
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Lood C, Allhorn M, Lood R, Gullstrand B, Olin AI, Rönnblom L, Truedsson L, Collin M, Bengtsson AA. IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: A possible new treatment? ACTA ACUST UNITED AC 2012; 64:2698-706. [DOI: 10.1002/art.34454] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
|
|
46
|
Autoantigen TRIM21/Ro52 as a Possible Target for Treatment of Systemic Lupus Erythematosus. Int J Rheumatol 2012; 2012:718237. [PMID: 22701487 PMCID: PMC3373075 DOI: 10.1155/2012/718237] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 04/01/2012] [Accepted: 04/02/2012] [Indexed: 11/18/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic, systemic, and autoimmune disease, whose etiology is still unknown. Although there has been progress in the treatment of SLE through the use of glucocorticoid and immunosuppressive drugs, these drugs have limited efficacy and pose significant risks of toxicity. Moreover, prognosis of patients with SLE has remained difficult to assess. TRIM21/Ro52/SS-A1, a 52-kDa protein, is an autoantigen recognized by antibodies in sera of patients with SLE and Sjögren's syndrome (SS), another systemic autoimmune disease, and anti-TRIM21 antibodies have been used as a diagnostic marker for decades. TRIM21 belongs to the tripartite motif-containing (TRIM) super family, which has been found to play important roles in innate and acquired immunity. Recently, TRIM21 has been shown to be involved in both physiological immune responses and pathological autoimmune processes. For example, TRIM21 ubiquitylates proteins of the interferon-regulatory factor (IRF) family and regulates type I interferon and proinflammatory cytokines. In this paper, we summarize molecular features of TRIM21 revealed so far and discuss its potential as an attractive therapeutic target for SLE.
Collapse
|
|
47
|
Macaluso FS, Alessi N, Cabibi D. Antimitochondrial antibody -M2 positive autoimmune hepatitis during standard of care for chronic hepatitis C. Hepatol Res 2012; 42:428-32. [PMID: 22443693 DOI: 10.1111/j.1872-034x.2011.00931.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The current standard of care (SoC) for chronic hepatitis C, i.e. the combination of a pegylated-interferon (PEG-IFN) with ribavirin (RBV), may activate underlying autoimmune conditions. Particularly, interferon (IFN) has been known to induce or exacerbate autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) in hepatitis C virus patients. We describe a severe, acute-onset antimitochondrial antibody (AMA)-M2 positive AIH appearing during the last weeks of SoC in a woman with chronic hepatitis C and no previous history of autoimmunity, and resolving on protracted steroids. In this context, the relevance of the characterization of the immunoglobulin isotype of portal plasma cells for a more appropriate diagnosis of autoimmune liver diseases can be emphasized.
Collapse
Affiliation(s)
- Fabio Salvatore Macaluso
- Biomedical Department of Internal and Specialist Medicine, Section of Gastroenterology, University of Palermo, Palermo, Italy Department of Human Pathology, University of Palermo, Palermo, Italy
| | | | | |
Collapse
|
|
48
|
Kiefer K, Oropallo MA, Cancro MP, Marshak-Rothstein A. Role of type I interferons in the activation of autoreactive B cells. Immunol Cell Biol 2012; 90:498-504. [PMID: 22430248 DOI: 10.1038/icb.2012.10] [Citation(s) in RCA: 173] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Type I interferons (IFNs) are a family of cytokines involved in the defense against viral infections that play a key role in the activation of both the innate and adaptive immune system. IFNs both directly and indirectly enhance the capacity of B lymphocytes to respond to viral challenge and produce cytotoxic and neutralizing antibodies. However, prolonged type I IFN exposure is not always beneficial to the host. If not regulated properly IFN can drive autoantibody production as well as other parameters of systemic autoimmune disease. Type I IFNs impact B-cell function through a variety of mechanisms, including effects on receptor engagement, Toll-like receptor expression, cell migration, antigen presentation, cytokine responsiveness, cytokine production, survival, differentiation and class-switch recombination. Type I IFNs are also cytotoxic for a variety of cell types and thereby contribute to the accumulation of cell debris that serves as a potential source for autoantigens. Type I IFN engagement of a variety of accessory cells further promotes B-cell survival and activation, as exemplified by the capacity of type I IFNs to increase the level of B-cell survival factors, such as B lymphocyte stimulator, produced by dendritic cells. Therefore, it is not surprising that the loss of expression of the type I IFN receptor can have dramatic effects on the production of autoantibodies and on the clinical features of systemic autoimmune diseases such as systemic lupus erythematosus.
Collapse
Affiliation(s)
- Kerstin Kiefer
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605, USA
| | | | | | | |
Collapse
|
|
49
|
Potts JR, Atkinson S, Aram JA, Tibble J, Davies KA, Verma S. De novo Cryoglobulinaemic Mononeuritis Multiplex during Treatment of Chronic Hepatitis C Infection: A Viral Effect or Induced by Pegylated Interferon Alpha? Case Rep Gastroenterol 2012; 6:155-61. [PMID: 22679403 PMCID: PMC3364041 DOI: 10.1159/000337871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Cryoglobulinaemic mononeuritis multiplex (MNM) is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection for which interferon-based antiviral therapy is currently the treatment of choice. Rarely MNM can be associated with HCV treatment though generally in the setting of pre-existing cryoglobulinaemia and detectable HCV viraemia. We report an unusual case of de novo MNM occurring late during the course of pegylated interferon and ribavirin therapy for chronic HCV infection, following a prolonged period of viral suppression. The patient had no evidence of cryoglobulinaemia prior to HCV treatment and undetectable HCV RNA levels at the time of presentation with MNM. The case raises the possibility that MNM could develop as an adverse immunomodulatory effect of pegylated interferon therapy.
Collapse
Affiliation(s)
- J R Potts
- Department of Medicine, Brighton and Sussex Medical School, Brighton, UK
| | | | | | | | | | | |
Collapse
|
|
50
|
Hunyady B, Kovács B, Battyáni Z. Side-effects of pegylated interferon plus ribavirin therapy with or without protease inhibitor direct acting antiviral agents during treatment of chronic hepatitis C virus infection. Orv Hetil 2011; 152:1997-2009. [DOI: 10.1556/oh.2011.29266] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Hepatitis C virus (HCV) infection affects 2–3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15–20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10–15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts – with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients. Orv. Hetil., 2011, 152, 1997–2009.
Collapse
Affiliation(s)
- Béla Hunyady
- Kaposi Mór Oktató Kórház Belgyógyászati Osztály Kaposvár
- Pécsi Tudományegyetem, Klinikai Központ I. Belgyógyászati Klinika Pécs Ifjúság u. 13. 7624
| | - Balázs Kovács
- Kaposi Mór Oktató Kórház Szemészeti Osztály Kaposvár
| | - Zita Battyáni
- Kaposi Mór Oktató Kórház Bőrgyógyászati Osztály Kaposvár
| |
Collapse
|