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Zheng H, Savitz J. Effect of Cytomegalovirus Infection on the Central Nervous System: Implications for Psychiatric Disorders. Curr Top Behav Neurosci 2022; 61:215-241. [PMID: 35505056 DOI: 10.1007/7854_2022_361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latent infections and interacts extensively with the host immune system, potentially contributing to immune activation and inflammation. Given its proclivity for infecting the brain and its reactivation by inflammatory stimuli, CMV is well known for causing central nervous system complications in the immune-naïve (e.g., in utero) and in the immunocompromised (e.g., in neonates, individuals receiving transplants or cancer chemotherapy, or people living with HIV). However, its potentially pathogenic role in diseases that are characterized by more subtle immune dysregulation and inflammation such as psychiatric disorders is still a matter of debate. In this chapter, we briefly summarize the pathogenic role of CMV in immune-naïve and immunocompromised populations and then review the evidence (i.e., epidemiological studies, serological studies, postmortem studies, and recent neuroimaging studies) for a link between CMV infection and psychiatric disorders with a focus on mood disorders and schizophrenia. Finally, we discuss the potential mechanisms through which CMV may cause CNS dysfunction in the context of mental disorders and conclude with a summary of the current state of play as well as potential future research directions in this area.
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Affiliation(s)
- Haixia Zheng
- Laureate Institute for Brain Research, Tulsa, OK, USA.
| | - Jonathan Savitz
- Laureate Institute for Brain Research, Tulsa, OK, USA.,Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA
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Lum SH, Selvarajah S, Deya-Martinez A, McNaughton P, Sobh A, Waugh S, Burton-Fanning S, Newton L, Gandy J, Nademi Z, Owens S, Williams E, Emonts M, Flood T, Cant A, Abinun M, Hambleton S, Gennery AR, Slatter M. Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency. J Allergy Clin Immunol 2020; 146:406-416. [PMID: 32442647 DOI: 10.1016/j.jaci.2020.04.053] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 04/02/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking. OBJECTIVES This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab. METHODS We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018. RESULTS Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died. CONCLUSIONS The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.
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Affiliation(s)
- Su Han Lum
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands.
| | - Sabeena Selvarajah
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Angela Deya-Martinez
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Peter McNaughton
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Ali Sobh
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Sheila Waugh
- Microbiology and Virology, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | | | - Lisa Newton
- Microbiology and Virology, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Julie Gandy
- Microbiology and Virology, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Zohreh Nademi
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Stephen Owens
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Eleri Williams
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Marieke Emonts
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Terry Flood
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Andrew Cant
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Mario Abinun
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Microbiology and Virology, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Sophie Hambleton
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Andrew R Gennery
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Mary Slatter
- Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom
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Neo JYJ, Wee SYK, Bonne I, Tay SH, Raida M, Jovanovic V, Fairhurst AM, Lu J, Hanson BJ, MacAry PA. Characterisation of a human antibody that potentially links cytomegalovirus infection with systemic lupus erythematosus. Sci Rep 2019; 9:9998. [PMID: 31292492 PMCID: PMC6620320 DOI: 10.1038/s41598-019-46329-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 06/26/2019] [Indexed: 11/08/2022] Open
Abstract
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been linked with the development of systemic lupus erythematosus (SLE). Thus far, molecular mimicry has been implicated as the principal mechanism that explains this association. In this study, we characterise a potential alternative process whereby HCMV contributes to SLE. In a cohort of SLE patients, we show a significant association between HCMV infection and SLE through a human antibody response that targets UL44. UL44 is an obligate nuclear-resident, non-structural viral protein vital for HCMV DNA replication. The intracellular nature of this viral protein complicates its targeting by the humoral response - the mechanism remains unresolved. To characterise this response, we present a thorough molecular analysis of the first human monoclonal antibody specific for UL44 derived from a HCMV seropositive donor. This human antibody immunoprecipitates UL44 from HCMV-infected cells together with known nuclear-resident SLE autoantigens - namely, nucleolin, dsDNA and ku70. We also show that UL44 is redistributed to the cell surface during virus-induced apoptosis as part of a complex with these autoantigens. This phenomenon represents a potential mechanism for the bystander presentation of SLE autoantigens to the humoral arm of our immune system under circumstances that favour a break in peripheral tolerance.
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Affiliation(s)
- Jie Ying Jacklyn Neo
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Seng Yin Kelly Wee
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Isabelle Bonne
- Electron Microscopy Laboratory, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Sen Hee Tay
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, National University Health System, Singapore, Singapore
- Division of Rheumatology, Department of Medicine, National University Hospital, National University Health System, Singapore, Singapore
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Manfred Raida
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Vojislav Jovanovic
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Anna-Marie Fairhurst
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Jinhua Lu
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Paul A MacAry
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Kruizinga MD, van Tol MJ, Bekker V, Netelenbos T, Smiers FJ, Bresters D, Jansen-Hoogendijk AM, van Ostaijen-ten Dam MM, Kollen WJ, Zwaginga JJ, Lankester AC, Bredius RG. Risk Factors, Treatment, and Immune Dysregulation in Autoimmune Cytopenia after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients. Biol Blood Marrow Transplant 2018; 24:772-778. [DOI: 10.1016/j.bbmt.2017.12.782] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/09/2017] [Indexed: 10/18/2022]
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Vukotic R, Vitale G, D’Errico-Grigioni A, Muratori L, Andreone P. De novo autoimmune hepatitis in liver transplant: State-of-the-art review. World J Gastroenterol 2016; 22:2906-2914. [PMID: 26973387 PMCID: PMC4779914 DOI: 10.3748/wjg.v22.i10.2906] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necro-inflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of non-organ specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.
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Baştürk B, Kantaroğlu B, Noyan ZA, Yıldırım S, Sarıtürk Ç. Association between panel reactive antibody and antiendothelial cell antibody positivity in kidney transplant patients. EXP CLIN TRANSPLANT 2015; 13 Suppl 1:269-72. [PMID: 25894170 DOI: 10.6002/ect.mesot2014.p77] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Endothelium is the major tissue for hyperacute and acute rejection. Binding of antibody to endothelium activates several immunologic mechanisms. Antiendothelial cell antibodies are a group of nonhuman leukocyte antigen antibodies that may play a role in the induction of an immunologic reaction that triggers inflammation. The aim of this study was to investigate whether there was an association between antiendothelial cell antibody positivity and panel reactive antibody positivity in renal transplant patients. MATERIALS AND METHODS In this study, we investigated the association between antiendothelial cell antibodies and panel reactive antibody Class I class II crossmatch positivity in patients, and compared these results with results from 100 healthy volunteers. All serum samples were analyzed by bead-based technology for calculated panel reactive antibody positivity; in addition, slides were used, each containing human umbilical vein endothelial cells and capillary-rich tissue for antiendothelial cell antibody positivity. RESULTS Antiendothelial cell antibodies was positive in 48 of 89 patients (panel reactive antibody Class I class II negative), 22 of 35 patients (class I-positive), 25 of 39 patients (class II-positive), 26 of 40 (class I class II positive), and 37 of 57 serologic and flow cytometry crossmatch-positive patients (P ≤ .016), and ultimately, in 122 of 205 patients and 25 of 100 volunteers (P ≤ .001). Antiendothelial cell antibody positivity was more frequent in panel reactive antibody-positive than negative patients and the control group. CONCLUSIONS Binding of antiendothelial cell antibodies to endothelial cells may activate complement by the classical pathway and cause upregulation of adhesion molecules. This study questioned the antigenic specificity of antiendothelial cell antibodies. Our study results showed that antiendothelial cell antibodies may play an important role for graft destruction, independent of panel reactive antibody and crossmatch positivity.
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Affiliation(s)
- Bilkay Baştürk
- From the Department of Immunology, and Immunology-Tissue Typing Laboratory, Adana Research and Medical Center, Başkent University, Adana, Turkey
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Chen CY, Ho MC, Wu JF, Jeng YM, Chen HL, Chang MH, Lee PH, Hu RH, Ni YH. Development of autoantibodies after pediatric liver transplantation. Pediatr Transplant 2013; 17:144-8. [PMID: 23217026 DOI: 10.1111/petr.12032] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/22/2012] [Indexed: 12/25/2022]
Abstract
Dn-AIH is a long-term complication after LT. The aim of this study was to analyze the occurrence of autoantibodies in pediatric recipients and the clinical significance. From 1992 to 2008, 96 pediatric LT for non-autoimmune liver diseases were performed in 94 children in our institution. Serum autoantibodies were checked in 68 subjects (73.9%). A positive autoantibody was defined as titers ≥1:40 for ANA, or ≥1:20 for ASMA, anti-LKM, and AMA. Autoantibodies were detectable in 51 of 68 patients (75.0%). There was positivity for ANA in 30 patients, ASMA in 32, and AMA in three, while anti-LKM was all negative. Immunosuppressive treatment with CsA, more than one episode of rejection, and abnormal ALT were risk factors for the development of autoantibodies. The incidence of the development of autoantibodies was 75.0% in pediatric LT cases in this study. ASMA was the most commonly found autoantibody. Autoantibodies may not play a sentinel role for dn-AIH after LT.
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Affiliation(s)
- Ching-Yi Chen
- Department of Pediatrics, College of Medicine and Children's Hospital, Taipei, Taiwan
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8
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Tsai WP, Chen MH, Lee MH, Yu KH, Wu MW, Liou LB. Cytomegalovirus infection causes morbidity and mortality in patients with autoimmune diseases, particularly systemic lupus: in a Chinese population in Taiwan. Rheumatol Int 2011; 32:2901-8. [PMID: 21898057 DOI: 10.1007/s00296-011-2131-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 08/22/2011] [Indexed: 11/26/2022]
Abstract
To investigate the clinical outcome of cytomegalovirus (CMV) infection in febrile hospitalized patients with autoimmune diseases, mostly systemic lupus erythematosus (SLE). Fifty-four febrile patients were analyzed retrospectively. Half were diagnosed as CMV infection, by positive CMV pp65 antigenemia assay. Clinical and laboratory data between two groups were compared. Correlation between laboratory data and SELENA-SLEDAI scores/mortality were analyzed in the CMV infection group. Receiver operating characteristic analysis was performed to determine the cutoff points of different parameters for predicting mortality or morbidity. The CMV infection group received a higher corticosteroid dosage (mean 26.3 mg/day) and a higher percentage of azathioprine use before admission than the non-CMV infection group. In the former, the deceased subgroup had a significantly higher number of infected leukocytes for CMV (shortened as CMV counts, P = 0.013), more cases of bacterial infection (P = 0.090), and a higher SLE disease activity index score (P = 0.072) than the alive subgroup. The CMV infection group had lower lymphocyte count and more positive bacterial infection than the non-CMV infection group did (P = 0.013 and P = 0.027, respectively). A level of 25 CMV particles/5 × 10(5) polymorphonuclear neutrophils (PMN) was the best cutoff point for predicting CMV-associated mortality, with a sensitivity of 75.0% and specificity of 72.2%. Moderate dose (30 mg/day) of prednisolone or azathioprine use predisposes patients with autoimmune diseases to CMV infection with concurrent bacterial infection. In particular, peak CMV counts at 25/5 × 10(5) PMN or low lymphocyte counts predict mortality or morbidity, respectively.
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Affiliation(s)
- W P Tsai
- Chang Gung Memorial Hospital, Lin-kou, Tao-yuan, Taiwan
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Varani S, Landini MP. Cytomegalovirus-induced immunopathology and its clinical consequences. HERPESVIRIDAE 2011; 2:6. [PMID: 21473750 PMCID: PMC3082217 DOI: 10.1186/2042-4280-2-6] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Accepted: 04/07/2011] [Indexed: 12/23/2022]
Abstract
Human cytomegalovirus (CMV) is a ubiquitous DNA virus that causes severe disease in patients with immature or impaired immune systems. During active infection, CMV modulates host immunity, and CMV-infected patients often develop signs of immune dysfunction, such as immunosuppression and autoimmune phenomena. Furthermore, active viral infection has been observed in several autoimmune diseases, and case reports have linked primary CMV infection and the onset of autoimmune disorders. In addition, CMV infection promotes allograft rejection and graft-versus-host disease in solid organ and bone marrow transplant recipients, respectively, further implicating CMV in the genesis and maintenance of immunopathological phenomena. The mechanisms by which CMV could induce inhibition of host defense, inflammation, and autoimmunity are discussed, as is the treatment of virus-induced immunopathology with antivirals.
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Affiliation(s)
- Stefania Varani
- Section of Microbiology, Department of Hematology and Oncology, University of Bologna, Bologna, Italy.
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Costa C, Touscoz GA, Bergallo M, Terlizzi ME, Astegiano S, Sidoti F, Sinesi F, Segoloni GP, Cavallo R. Non-organ-specific and anti-endothelial antibodies in relation to CMV infection and acute rejection in renal transplant recipients. Clin Transplant 2010; 24:488-92. [DOI: 10.1111/j.1399-0012.2009.01092.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Varani S, Frascaroli G, Landini MP, Söderberg-Nauclér C. Human cytomegalovirus targets different subsets of antigen-presenting cells with pathological consequences for host immunity: implications for immunosuppression, chronic inflammation and autoimmunity. Rev Med Virol 2009; 19:131-45. [DOI: 10.1002/rmv.609] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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12
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Varani S, Cederarv M, Feld S, Tammik C, Frascaroli G, Landini MP, Söderberg-Nauclér C. Human cytomegalovirus differentially controls B cell and T cell responses through effects on plasmacytoid dendritic cells. THE JOURNAL OF IMMUNOLOGY 2008; 179:7767-76. [PMID: 18025223 DOI: 10.4049/jimmunol.179.11.7767] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Plasmacytoid dendritic cells (PDCs), the main producers of type I IFN in response to viral infection, are essential in antiviral immunity. In this study, we assessed the effect of human CMV (HCMV) infection on PDC function and on downstream B and T cell responses in vitro. HCMV infection of human PDCs was nonpermissive, as immediate-early but not late viral Ags were detected. HCMV led to partial maturation of PDCs and up-regulated MHC class II and CD83 molecules but not the costimulatory molecules CD80 and CD86. Regardless of viral replication, PDCs secreted cytokines after contact with HCMV, including IFN-alpha secretion that was blocked by inhibitory CpG, suggesting an engagement of the TLR7 and/or TLR9 pathways. In the presence of B cell receptor stimulation, soluble factors produced by HCMV-matured PDCs triggered B cell activation and proliferation. Through PDC stimulation, HCMV prompted B cell activation, but only induced Ab production in the presence of T cells or T cell secreted IL-2. Conversely, HCMV hampered the allostimulatory ability of PDCs, leading to decreased proliferation of CD4(+) and CD8(+) T cells. These findings reveal a novel mechanism by which HCMV differentially controls humoral and cell-mediate immune responses through effects on PDCs.
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Affiliation(s)
- Stefania Varani
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Avitzur Y, Ngan BY, Lao M, Fecteau A, Ng VL. Prospective evaluation of the prevalence and clinical significance of positive autoantibodies after pediatric liver transplantation. J Pediatr Gastroenterol Nutr 2007; 45:222-7. [PMID: 17667719 DOI: 10.1097/mpg.0b013e31805ce219] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND AND OBJECTIVES De novo autoimmune hepatitis (AIH) recently was recognized as an important cause of late graft dysfunction after pediatric liver transplantation (LT). However, the significance of isolated elevation of autoantibodies in children after LT without history of prior autoimmune liver disease scarcely has been studied. The aim of the present study was to determine the prevalence and risk factors for autoantibodies production in pediatric LT recipients and to assess the impact of isolated elevation of autoantibodies over time on graft function. METHODS Sixty-eight children without history of autoimmune disease were recruited over the course of 1 year into this cross-sectional study. A single blood specimen was drawn at study entry to determine titers of autoantibodies. Clinical and laboratory assessment and medical history were obtained at study entry as well. Patients were then divided into positive and negative autoantibodies groups, and prospectively followed for 18 months for evidence of abnormal liver function tests. RESULTS One or more autoantibodies were detected in 18 (26%) patients. Anti-smooth muscle was the most common (n = 13) antibody. Time since transplant (>4 years) was the only risk factor identified for the presence of autoantibodies (univariate risk ratio, 3.3; 95% confidence interval, 1.2-9). During the follow-up period, 5 patients with positive autoantibody screen developed de novo AIH (n = 3) or chronic rejection (n = 2), compared with 0 in the negative autoantibody group. Children with positive autoantibody screen were at higher risk for development of de novo AIH or chronic rejection (univariate risk ratio 13.9; 95% confidence interval, 1.7-111; P = 0.004). CONCLUSIONS Positive autoantibodies are common in children after LT and their presence may denote a higher risk for the development of de novo AIH or chronic rejection over time.
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Affiliation(s)
- Yaron Avitzur
- Paediatric Academic Multi-organ Transplantation (PAMOT) Program, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
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Sanz J, Arriaga F, Montesinos P, Ortí G, Lorenzo I, Cantero S, Puig N, Moscardó F, de la Rubia J, Sanz G, Sanz MA. Autoimmune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients. Bone Marrow Transplant 2007; 39:555-61. [PMID: 17351645 DOI: 10.1038/sj.bmt.1705641] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Autoimmune hemolytic anemia (AIHA) after allogeneic hematopoietic stem cell transplantation (HSCT) is still not well characterized. The aim of this study was to analyze the incidence and risk factors for the development of AIHA, as well as its prognosis and response to treatment in a series of patients undergoing allogeneic HSCT at a single institution. Between 1996 and 2004, 272 adult patients with a variety of malignant hematopoietic disorders underwent allogeneic HSCT. Direct antiglobulin testing was performed in routine pretransfusion compatibility testing or after clinical suspicion of AIHA. Twelve patients developed AIHA after HSCT at a median time of 147 days (range, 41-170). The 3-year cumulative incidence of AIHA was 4.44%. Eight cold antibodies and four warm antibodies were detected. Multivariate analysis shows that HSCT from unrelated donors (P=0.02) and the development of chronic extensive graft-versus-host disease (GVHD) (P=0.0004) were the only independent factors associated with AIHA. Two patients are still alive. AIHA was never the primary cause of death but added morbidity in patients with other concomitant complications. Patients undergoing HSCT from unrelated donors and those who develop chronic extensive GVHD are especially predisposed for this complication.
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Affiliation(s)
- J Sanz
- Hematology Department, Hospital Universitario La Fe, Valencia, Spain
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Alessandri C, Bombardieri M, Valesini G. Pathogenic mechanisms of anti-endothelial cell antibodies (AECA): their prevalence and clinical relevance. Adv Clin Chem 2006; 42:297-326. [PMID: 17131630 PMCID: PMC7119199 DOI: 10.1016/s0065-2423(06)42008-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Anti‐endothelial cell antibodies (AECA) represent a heterogeneous family of autoantibodies directed against structural endothelial proteins, as well as antigens adhering to endothelial cells. Although AECA immunoassays still show a high‐interlaboratory variability, several findings suggest a pathogenic role of these autoantibodies in diseases characterized by endothelial damage. In this chapter, we analyze the knowledge about AECA prevalence, clinical relevance, and their pathogenic role in autoimmune diseases focusing in particular on systemic lupus erythematosus, antiphospholipid syndrome, systemic sclerosis (SSc), and systemic vasculitis.
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Díaz F, Urkijo JC, Mendoza F, De la Viuda JM, Blanco M, Flores M, Berdonces P. Systemic Lupus Erythematosus Associated With Acute Cytomegalovirus Infection. J Clin Rheumatol 2006; 12:263-4. [PMID: 17023817 DOI: 10.1097/01.rhu.0000239832.74804.17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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17
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Demetris AJ, Adeyi O, Bellamy COC, Clouston A, Charlotte F, Czaja A, Daskal I, El-Monayeri MS, Fontes P, Fung J, Gridelli B, Guido M, Haga H, Hart J, Honsova E, Hubscher S, Itoh T, Jhala N, Jungmann P, Khettry U, Lassman C, Ligato S, Lunz JG, Marcos A, Minervini MI, Mölne J, Nalesnik M, Nasser I, Neil D, Ochoa E, Pappo O, Randhawa P, Reinholt FP, Ruiz P, Sebagh M, Spada M, Sonzogni A, Tsamandas AC, Wernerson A, Wu T, Yilmaz F. Liver biopsy interpretation for causes of late liver allograft dysfunction. Hepatology 2006; 44:489-501. [PMID: 16871565 DOI: 10.1002/hep.21280] [Citation(s) in RCA: 226] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.
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Hermann J, Demel U, Stünzner D, Daghofer E, Tilz G, Graninger W. Clinical interpretation of antineutrophil cytoplasmic antibodies: parvovirus B19 infection as a pitfall. Ann Rheum Dis 2005; 64:641-3. [PMID: 15485998 PMCID: PMC1755429 DOI: 10.1136/ard.2004.024877] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND While antibodies directed against proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) have a high specificity for the diagnosis of systemic vasculitis, they may also be found as an epiphenomenon of acute viral infection. OBJECTIVE To investigate whether positive ANCA test results may be a common feature of acute parvovirus B19 infection. METHODS Sera were analysed from 1242 patients from a rheumatology outpatient clinic for reactivity with parvovirus B19 and EBV antibodies. They were tested for the presence of PR3-ANCA and MPO-ANCA, along with sera known to contain IgM antibodies to these viruses obtained from among 41,366 samples submitted for virological screening. RESULTS ANCA were found in 10% (5/50) of the sera positive for IgM antibodies to parvovirus and in 3/51 sera containing IgM antibodies to EBV. Three of six patients with arthritis and concomitant parvovirus infection were found positive for PR3-ANCA and two were found positive for MPO-ANCA. All six patients tested negative for ANCA after six months of follow up. CONCLUSIONS PR3-ANCA and MPO-ANCA may occur transiently in patients with acute B19 infection or infectious mononucleosis, highlighting the importance of repeated antibody tests in oligosymptomatic clinical conditions in which systemic autoimmune disease is suspected.
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Affiliation(s)
- J Hermann
- Medical University, Graz, Department of Internal Medicine, Division of Rheumatology, Auenbruggerplatz 15, A-8036 Graz, Austria.
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Varani S, Frascaroli G, Homman-Loudiyi M, Feld S, Landini MP, Söderberg-Nauclér C. Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5. J Leukoc Biol 2004; 77:219-28. [PMID: 15522919 DOI: 10.1189/jlb.0504301] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Dendritic cells (DC) play a key role in the host immune response to infections. Human cytomegalovirus (HCMV) infection can inhibit the maturation of DC and impair their ability to stimulate T cell proliferation and cytotoxicity. In this study, we assessed the effects of HCMV infection on the migratory behavior of human DC. The HCMV strain TB40/E inhibited the migration of immature monocyte-derived DC in response to inflammatory chemokines by 95% 1 day after infection. This inhibition was mediated by early viral replicative events, which significantly reduced the cell-surface expression of CC chemokine receptor 1 (CCR1) and CCR5 by receptor internalization. HCMV infection also induced secretion of the inflammatory chemokines CC chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1alpha (MIP-1alpha), CCL4/MIP-1beta, and CCL5/regulated on activation, normal T expressed and secreted (RANTES). Neutralizing antibodies for these chemokines reduced the effects of HCMV on chemokine receptor expression and on DC migration by approximately 60%. Interestingly, the surface expression of the lymphoid chemokine receptor CCR7 was not up-regulated after HCMV infection on immature DC, and immature-infected DC did not migrate in response to CCL19/MIP-3beta. These findings suggest that blocking the migratory ability of DC may be a potent mechanism used by HCMV to paralyze the early immune response of the host.
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Affiliation(s)
- Stefania Varani
- Department of Medicine, Karolinska Systems Biomedicine Center, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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20
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Rahbar AR, Sundqvist VAS, Wirgart BZ, Grillner L, Söderberg-Naucler C. Recognition of cytomegalovirus clinical isolate antigens by sera from cytomegalovirus-negative blood donors. Transfusion 2004; 44:1059-66. [PMID: 15225248 DOI: 10.1111/j.1537-2995.2004.03292.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The most common way to prevent transmission of CMV by blood transfusion is to use blood products from seronegative donors. Screening of blood donors for CMV infection is usually based on detection of antigens obtained from the CMV laboratory strain AD 169. Recent evidence suggests that approximately up to 20 percent of CMV-negative blood donors may in fact be CMV-DNA positive by PCR analyses. STUDY DESIGN AND METHODS In this study, sera from CMV-seronegative, CMV-seropositive, and CMV-DNA-positive/seronegative individuals, and from patients with acute and convalescent CMV infection for detection of CMV antibodies were analyzed. CMV antigens prepared from cells infected with CMV clinical isolates or the CMV laboratory strain AD 169 in ELISA and Western blot assays were used. RESULTS All CMV-positive sera from blood donors were seropositive for the CMV antigens prepared from AD 169 (A2) or from a CMV clinical isolate (C6). Interestingly, whereas all CMV-negative blood donors were negative in tests for the CMV antigen A2, 36 percent were CMV seropositive using the CMV antigen C6 in ELISA. CONCLUSION The data suggest that a substantial number of CMV-seronegative/CMV-DNA-positive serum samples contain antibodies that recognize CMV clinical isolate antigens.
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Affiliation(s)
- A R Rahbar
- Department of Medicine, Center for Molecular Medicine, and the Department of Laboratory Medicine, H5, Karolinska Institute, Stockholm, Sweden.
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21
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Abstract
Cytomegalovirus (CMV) remains one of the most frequent viral infections and the most common cause of death after liver transplantation (LT). Chronic allograft liver rejection remains the major obstacle to long-term allograft survival and CMV infection is one of the suggested risk factors for chronic allograft rejection. The precise relationship between cytomegalovirus and chronic rejection remains uncertain. This review addresses the morbidity of cytomegalovirus infection and the risk factors associated with it, the relationship between cytomegalovirus and chronic allograft liver rejection and the potential mechanisms of it.
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Affiliation(s)
- Liang-Hui Gao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, PO Box 4193, Hubin Campus, 353 Yan'an Road, Hangzhou 310031, Zhejiang Province, China.
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22
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Michelson S. Consequences of human cytomegalovirus mimicry. Hum Immunol 2004; 65:465-75. [PMID: 15172446 DOI: 10.1016/j.humimm.2004.02.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2003] [Revised: 01/15/2004] [Accepted: 02/03/2004] [Indexed: 12/19/2022]
Abstract
The HCMV genome has evolved with its host by incorporating a series of genes that are homologous to, or functionally mimic, cellular genes. Some are designed to counteract the stress of infection on the host cell, notably the viral antiapoptotic proteins (vICA, vMIA). Others potentially help the infected cell maintain a low immunologic profile. These include virus-encoded chemokine receptors (UL33, UL78, US27, US28), FcRs (gp TRL11/IRL11, gp UL119-118), and proteins that directly or indirectly thwart natural killer cell activity (UL16, gpUL40). In addition, some viral proteins may play a role in immunopathology because of fortuitous cross-reactivity with host cell proteins. This overview discusses how these proteins affect the life of the host cell and its immediate neighbors.
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Affiliation(s)
- Susan Michelson
- Unité d'Immunologie Virale, Institut Pasteur, Paris, France.
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Mattey DL, Dawes PT, Nixon NB, Goh L, Banks MJ, Kitas GD. Increased levels of antibodies to cytokeratin 18 in patients with rheumatoid arthritis and ischaemic heart disease. Ann Rheum Dis 2004; 63:420-5. [PMID: 15020337 PMCID: PMC1754968 DOI: 10.1136/ard.2003.008011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To determine whether raised levels of antibodies to CK18 in patients with RA are associated with ischaemic heart disease (IHD). METHODS IgA, IgG, and IgM antibodies to CK18 were measured by enzyme linked immunosorbent assay (ELISA) in patients with RA with (n = 34) or without (n = 28) IHD. The relationship between CK18 antibody levels and markers of inflammatory and/or cardiovascular disease was examined. RESULTS Initial analysis showed that IgG antibody levels to CK18 were higher in patients with RA with IHD than in those without (50.1 v 34.5 AU, p = 0.047), although significance was lost after correction for multiple comparisons. Further analysis showed a significant difference (p = 0.015) between patients with IHD and a positive family history, and patients without IHD and a negative family history (53.7 v 29.0 AU, Kruskal-Wallis multiple comparison Z value test). There was also a significant trend of increasing 10 year cardiovascular risk with increasing CK18 IgG antibody levels (p = 0.01). No association was found between CK18 antibody levels and conventional markers of inflammation or cardiovascular disease, but an association was found between levels of CK18 IgG and IgG antibodies to cytomegalovirus (CMV) (Spearman's r(s) = 0.379, p(corr) = 0.04). No evidence for cross reactivity of CK18 antibodies with CMV antigens was found. CONCLUSION Levels of IgG antibodies to CK18 are raised in patients with RA with IHD, particularly if they also have a positive family history. This may reflect damage to CK18 containing cells in the cardiac vasculature and/or in atherosclerotic plaques, and may be a useful additional marker for the identification of patients with, or likely to develop, IHD.
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Affiliation(s)
- D L Mattey
- Staffordshire Rheumatology Centre, The Haywood, High Lane, Burslem, Stoke-on-Trent, Staffordshire ST6 7AG, UK.
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Aiello FB, Calabrese F, Rigotti P, Furian L, Marino S, Cusinato R, Valente M. Acute rejection and graft survival in renal transplanted patients with viral diseases. Mod Pathol 2004; 17:189-96. [PMID: 14657951 DOI: 10.1038/modpathol.3800033] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Transplanted patients are susceptible to viral infections; thus, the aim of this study was to evaluate the features of acute rejections and the outcome of the renal graft in transplanted patients with herpes virus diseases. Renal biopsies from 30 renal transplanted patients undergoing early acute rejection (type IA and IB according to the Banff 97 classification) were evaluated. In total, 15 of these patients experienced cytomegalovirus (CMV) or Epstein-Barr virus disease within the first year following transplantation (group I) and 15 patients showed no evidence of viral infection (group II). No significant differences between the groups in terms of age, male/female ratio, living/cadaveric donor ratio, cold ischemia time, HLA A-B matching, pretransplant panel reactive antibody test, occurrence of post-transplant tubular necrosis, plasma levels of cyclosporin A and mean percent increase of serum creatinine at the time of the biopsy were observed. In group I biopsies, the mean number of interstitial plasma cells, as well as the mean number of CD79a-positive cells (B lymphocytes and plasma cells) was significantly higher than in group II (P<0.01 and <0.01, respectively). There was a positive correlation between the number of infections and the number of plasma cells (P<0.05). In transplanted patients, CMV can trigger the formation of anti-endothelial cell antibodies, which have been proposed to play a role in antibody-mediated rejections. We investigated whether a deposition of C4d, a marker of antibody-mediated reactions, was present in renal peritubular capillaries. In group I C4d deposition was found in five cases, while in group II it was not observed (P<0.05). In group I, 7/15 patients developed chronic allograft nephropathy vs 1/15 patients in group II (P<0.05). The estimated 1-, 5- and 8-year cumulative graft survival rates were 80, 66 and 57%, respectively, in group I, while in group II the estimated 8-year cumulative survival rate was 100% (P<0.05). In conclusion, acute rejection biopsies of patients with viral infections displayed plasma cell infiltrates and, in several cases, C4d deposition. Our study suggests a role of B lymphocytes in the pathology of these rejections and confirms the association between viral infections and poor graft survival.
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Affiliation(s)
- Francesca B Aiello
- Department of Oncology and Neuroscience, University of Chieti, Chieti, Italy
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