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Muro-Perez M, González-Martínez G, Martínez-García P, Legaz I, Zafrilla P, Muro M. Analysis of null deletion polymorphism of glutathione S-transferase theta (GSTT-1), associated with anti-GSTT-1 antibodies development in transplantation. Int J Immunogenet 2023; 50:264-271. [PMID: 37612787 DOI: 10.1111/iji.12635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/03/2023] [Accepted: 08/15/2023] [Indexed: 08/25/2023]
Abstract
Glutathione S-transferase theta 1 (GSTT1) is an enzyme involved in phase II biotransformation processes and a member of a multigene family of detoxifying and clearing reactive oxygen species. GSTT1 is polymorphic like other biotransforming enzymes, allowing variability in hepatic conjugation processes. Immunological recognition of the GSTT1 alloantigen, as evidenced by donor-specific antibodies formation, has previously been observed in recipients lacking GSTT1 protein (called GSTT1-, GSTT*0, null phenotype or homozygous for the GSTT1 deletion) who receive liver or kidney transplants from GSTT1+ donors and is a risk factor for the development of de novo hepatitis following liver transplants from a GSTT1 expressing donor. Antibodies against GSTT1 are demonstrated in patients who are GSTT1 null and received a transplant from a GSTT1+ donor. Understanding the local population frequency of the GSTT1 deletion is of value in understanding the potential clinical risk of developing post-transplant complications, which can be attributed to the nonexpression of GSTT1. A population of 173 healthy donors of the Murcia Region in Southeast Spain was evaluated for a null allele of GSTT1 (n = 173). DNA was extracted, and GSTT-1 null allele detection was performed by real-time polymerase chain reaction. The frequency of the null GSTT1 genotype (nonexpression or deletion of the homozygous polymorphism of the GSTT1 protein) was 17.9% (n = 31 null allele GSTT1/173 total individuals). Our data suggest that the frequency of null GSTT1 mutations in our population in Southeast Spain is 17.9%, lower than in other Caucasoid populations. This would convert our recipient population into more susceptible to nonlocal potential organ donors and less susceptible to local donors. All recipients bearing this GSTT1 deletion homozygous would be without the protein and triggering an alloantigen in the case of transplantation with a donor without deletion.
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Affiliation(s)
- Manuel Muro-Perez
- Immunology Service, University Clinical Hospital "Virgen de la Arrixaca" - IMIB, Murcia, Spain
| | - Gema González-Martínez
- Immunology Service, University Clinical Hospital "Virgen de la Arrixaca" - IMIB, Murcia, Spain
| | - Pedro Martínez-García
- Immunology Service, University Clinical Hospital "Virgen de la Arrixaca" - IMIB, Murcia, Spain
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute of Murcia (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia (UMU), Murcia, Spain
| | - Pilar Zafrilla
- Faculty of Pharmacy, San Antonio Catholic University of Murcia (UCAM), Murcia, Spain
| | - Manuel Muro
- Immunology Service, University Clinical Hospital "Virgen de la Arrixaca" - IMIB, Murcia, Spain
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Aguilera I, Sousa JM. Comments on: Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis. Transpl Int 2022; 35:10590. [PMID: 35992745 PMCID: PMC9389647 DOI: 10.3389/ti.2022.10590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/21/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Isabel Aguilera
- Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Seville, Spain
- *Correspondence: Isabel Aguilera,
| | - Jose Manuel Sousa
- Digestive Diseases Service, Hospital Universitario Virgen del Rocío, Seville, Spain
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Miura K, Shirai Y, Kaneko N, Yabuuchi T, Ishizuka K, Horita S, Furusawa M, Unagami K, Okumi M, Ishida H, Tanabe K, Koike J, Honda K, Yamaguchi Y, Hattori M. Chronic Active Antibody-Mediated Rejection with Linear IgG Deposition on Glomerular Capillaries in a Kidney Transplant Recipient. Nephron Clin Pract 2020; 144 Suppl 1:97-101. [PMID: 33238286 DOI: 10.1159/000511322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/02/2020] [Indexed: 11/19/2022] Open
Abstract
Glomerular IgG deposition is rarely observed in antibody-mediated rejection. Here, we report chronic active antibody-mediated rejection with linear IgG deposition on glomerular capillary walls in a pediatric kidney transplant recipient. A 6-year-old boy with bilateral renal hypoplasia underwent preemptive deceased-donor kidney transplantation. Five years after the transplantation, an allograft biopsy revealed chronic active antibody-mediated rejection with diffuse linear IgG deposition on glomerular capillaries. Anti-glomerular basement membrane antibody, donor-specific anti-human leukocyte antigen (HLA) antibodies, and anti-angiotensin II type 1 receptor antibody were negative. A multiplex antibody assay identified anti-major histocompatibility complex class I chain-related molecule A antibody. Additionally, a single-antigen bead assay identified autoantibodies to 12 non-HLA antigens, including vimentin and glutathione S-transferase theta-1. To investigate whether IgG autoantibodies in the patient's serum bind to antigens on glomerular capillaries, we incubated the patient's serum with 0-h biopsy specimens of tissue donated to the patient and a control subject, both obtained immediately after nephrectomy from respective donors. IgG signals were observed in neither patient nor control samples. Nevertheless, linear IgG deposition may be explained by the binding of autoantibodies to non-HLA antigens that are usually hidden and only exposed via severe endothelial cell injury. Further studies are needed to confirm the significance of non-HLA antibodies in glomerular IgG deposition.
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Affiliation(s)
- Kenichiro Miura
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoko Shirai
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Naoto Kaneko
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Tomoo Yabuuchi
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kiyonobu Ishizuka
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Shigeru Horita
- Department of Pathology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Miyuki Furusawa
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kohei Unagami
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Junki Koike
- Department of Diagnostic Pathology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, Tokyo, Japan
| | | | - Motoshi Hattori
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan,
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McAlister VC. Anti-donor immunoglobulin G subclass in liver transplantation. Hepatobiliary Surg Nutr 2019; 8:125-128. [PMID: 31098359 PMCID: PMC6503250 DOI: 10.21037/hbsn.2018.12.09] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/18/2018] [Indexed: 11/06/2022]
Abstract
Immunoglobulin G (IgG) subclasses in human health and immunity have only be sporadically studied in the half century since their discovery. Different patterns of IgG subclass production are seen if the immune response is deviated towards type 1 versus type 2. The current state of our knowledge of IgG subclasses in liver transplantation is reviewed here. While several studies have been conducted in liver disease, only four relatively small studies have been undertaken in liver transplant recipients. Total IgG4 elevation in serum is related to sclerosing pancreatico-cholangiopathy that is sensitive to treatment with steroids. Conventional immunosuppressive regimes, especially with a combination of tacrolimus and sirolimus, reduce the production of all IgG subclasses after transplantation but it is not known if they deviate the immune response. Presence of anti-donor IgG3 before transplantation, or its expansion after transplantation, has been associated with rejection and liver graft loss. Anti-GSTT1 IgG4 production after transplantation is associated with de-novo immune hepatitis. Greater knowledge of anti-donor IgG subclass responses after transplantation will allow us tailor novel treatments for greater effect.
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Affiliation(s)
- Vivian C McAlister
- Department of Surgery, University of Western Ontario, London, ON, Canada
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Aguilera I, Aguado-Dominguez E, Sousa JM, Nuñez-Roldan A. Rethinking de novo immune hepatitis, an old concept for liver allograft rejection: Relevance of glutathione S-transferase T1 mismatch. World J Gastroenterol 2018; 24:3239-3249. [PMID: 30090004 PMCID: PMC6079293 DOI: 10.3748/wjg.v24.i29.3239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/28/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
Antibody-mediated rejection (AMR) in liver transplantation has long been underestimated. The concept of the liver as an organ susceptible to AMR has emerged in recent years, not only in the context of the major histocompatibility complex with the presence of HLA donor-specific antibodies, but also with antigens regarded as “minor”, whose role in AMR has been demonstrated. Among them, antibodies against glutathione S-transferase T1 have been found in 100% of patients with de novo autoimmune hepatitis (dnAIH) when studied. In its latest update, the Banff Working Group for liver allograft pathology proposed replacing the term dnAIH with plasma cell (PC)-rich rejection. Antibodies to glutathione S-transferase T1 (GSTT1) in null recipients of GSTT1 positive donors have been included as a contributory but nonessential feature of the diagnosis of PC-rich rejection. Also in this update, non-organ-specific anti-nuclear or smooth muscle autoantibodies are no longer included as diagnostic criteria. Although initially found in a proportion of patients with PC-rich rejection, the presence of autoantibodies is misleading since they are not disease-specific and appear in many different contexts as bystanders. The cellular types and proportions of the inflammatory infiltrates in diagnostic biopsies have been studied in detail very recently. PC-rich rejection biopsies present a characteristic cellular profile with a predominance of T lymphocytes and a high proportion of PCs, close to 30%, of which 16.48% are IgG4+. New data on the relevance of GSTT1-specific T lymphocytes to PC-rich rejection will be discussed in this review.
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Affiliation(s)
- Isabel Aguilera
- Department of Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
| | - Elena Aguado-Dominguez
- Department of Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
| | - Jose Manuel Sousa
- Digestive and Liver Diseases Service, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
| | - Antonio Nuñez-Roldan
- Department of Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
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Aguado-Domínguez E, Gómez L, Sousa JM, Gómez-Bravo MÁ, Núñez-Roldán A, Aguilera I. Identification of the cellular components involved in de novo immune hepatitis: a quantitative immunohistochemical analysis. J Transl Med 2018. [PMID: 29534755 PMCID: PMC5851325 DOI: 10.1186/s12967-018-1440-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Diagnosis of de novo immune hepatitis (dnIH) after liver transplantation relies on biopsy findings, with an abundance of plasma cells (PCs) in the inflammatory infiltrates a hallmark of the disease. Very little is known about what other types of immune cells exist in the infiltrates mainly located in the portal areas of the liver tissue. Methods We analyzed the composition of T cells, B cells, PCs, and macrophages in the liver biopsies of 12 patients with dnIH, 9 of them obtained at the time of diagnosis. For comparison, biopsies from 9 patients with chronic rejection (CR) were included in the study. The results were analyzed by a computer-assisted stereology quantification method. Results The major components of the infiltrates in the portal areas were CD3+ T lymphocytes in both groups, with 36.6% in the dnIH group versus 49.4% in the CR group. CD20+ B lymphocytes represented 14.9% in the dnIH group and 29.1% in the CR group. Macrophage levels were very similar in the dnIH and CR group (19.7% versus 16.8%, respectively). PCs were much less represented in CR biopsies than those from the dnIH group (mean value of 4.7% versus 28.8%). Conclusion In conclusion, the determination of a characteristic cellular profile could be an important tool for a more reliable diagnosis of dnIH, in support of the histological evaluation made by the pathologist, which in most cases is challenging. Recognition of this condition is crucial because it leads to graft failure if left untreated. Electronic supplementary material The online version of this article (10.1186/s12967-018-1440-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Elena Aguado-Domínguez
- Department of Immunology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Avda. Manuel Siurot s/n, 41013, Seville, Spain
| | - Lourdes Gómez
- Department of Pathology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - José Manuel Sousa
- Department of Digestive Diseases, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Miguel Ángel Gómez-Bravo
- Liver Transplant Unit, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Antonio Núñez-Roldán
- Department of Immunology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Avda. Manuel Siurot s/n, 41013, Seville, Spain
| | - Isabel Aguilera
- Department of Immunology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Avda. Manuel Siurot s/n, 41013, Seville, Spain.
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Abstract
Recurrent autoimmune hepatitis (AIH) and de novo AIH are 2 important causes of late graft failure after liver transplantation (LT). Recurrent AIH occurs in patients who undergo LT for AIH. De novo AIH occurs in patients who are transplanted for etiologies other than AIH. Although typically treated with standard treatment for AIH, including corticosteroids and azathioprine, both recurrent and de novo AIH may progress to end-stage liver disease requiring retransplantation.
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Affiliation(s)
- Eliza W Beal
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Sylvester M Black
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Anthony Michaels
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 200, Columbus, OH 43210, USA.
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