Isabel Aguilera1*
Jose Manuel Sousa2- 1Immunology, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Seville, Spain
- 2Digestive Diseases Service, Hospital Universitario Virgen del Rocío, Seville, Spain
A Forum discussing:
Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis
by Horwich BH, Liang TZ, Dodge JL, Chopra S, Kahn JA and Saito T (2022). Transpl Int 35:10182. doi: 10.3389/ti.2022.10182
We read with interest the article by Horwich et al. about IgG4-producing plasma cells. The aim of the study was to use IgG4-positivity as a differential biomarker for distinct clinical presentations of plasma cell hepatitis before and after liver transplantation. They found a high degree of IgG4-PC infiltration more frequently associated with plasma cell rejection (PCR) than other types of AIH and concluded that IgG4-positivity might serve as a valuable diagnostic tool in the post-LT setting.
It is very gratifying to see a confirmation of our previous report regarding the presence of IgG4 PCs in plasma cell-rich rejection (PC-rich R) biopsies. Our group identified the cellular profile associated with PC-rich R, and quantified the number of cells per mm2 of tissue by using a Computer-Assisted System Technology (newCAST™). The relative proportion of the main cell types was assessed. The results showed an important representation of IgG4+ PCs with a mean value of 5.9% (0.5%–19.8%) of the total number of immune cells in the inflammatory infiltrates found in portal areas (1).
A search in the scientific literature is complicated since de novo autoimmune hepatitis, first described in 1998 (2), has received many different names throughout these years until, in a recent update, the Banff Working group recommended to replace all these terms by “plasma cell-rich rejection” (PC-rich R) (3). We agree with the authors that AIH and PC-rich R are histologically very difficult to distinguish but fortunately, we have now a very specific serology pattern.
PC-rich R is a true rejection process that starts with the recognition of a donor antigen expressed in the graft by the recipient immune system. This is due to a genetic mismatch when the recipient lacks any copy of the Glutathione S-transferase T1 (GSTT1) gene and the donor carries at least one copy of this gene (4–6). Some of these mismatched patients develop a specific immune response by producing GSTT1 donor-specific antibodies, which is a required but not sufficient condition to develop PC-rich R. We have characterized anti-GSTT1 antibodies and the predominant IgG subclasses were IgG1 and IgG4 (7). Interestingly, IgG4 appear again involved in PC-rich R, this time as donor-specific antibodies.
It is clear that rAIH and PC-rich R represent distinctive clinical entities. The results presented in the article by Horwich et al. and the knowledge of the GSTT1 genetic mismatch with subsequent production of anti-GSTT1 antibodies (especially IgG4) should facilitate differential diagnoses between PC-rich R and other inflammatory post-transplant pathologies that have been particularly difficult when pre-LT disease was uncertain as mentioned by the authors.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This study was supported by FEDER funds and by the Spanish Ministry of Economy, Instituto de Salud Carlos III, Grant 17/01403.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Aguado-Domínguez, E, Gómez, L, Sousa, JM, Gómez-Bravo, MÁ, Núñez-Roldán, A, and Aguilera, I. Identification of the Cellular Components Involved in De Novo Immune Hepatitis: a Quantitative Immunohistochemical Analysis. J Transl Med (2018) 16:62–73. doi:10.1186/s12967-018-1440-8
2. Kerkar, N, Hadzic, N, Davies, ET, Portmann, B, Donaldson, PT, Rela, M, et al. De-novo Autoimmune Hepatitis after Liver Transplantation. The Lancet (1998) 351:409–13. doi:10.1016/S0140-6736(97)06478-7
3. Demetris, AJ, Bellamy, C, Hübscher, SG, O'Leary, J, Randhawa, PS, Feng, S, et al. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transpl (2016) 16(10):2816–35. doi:10.1111/ajt.13909
4. Aguilera, I, Wichmann, I, Sousa, JM, Bernardos, A, Franco, E, García-Lozano, JR, et al. Antibodies against Glutathione S-Transferase T1 (GSTT1) in Patients with De Novo Immune Hepatitis Following Liver Transplantation. Clin Exp Immunol (2002) 126:535–9. doi:10.1046/j.1365-2249.2001.01682.x
5. Aguilera, I, Sousa, JM, Gavilán, F, Bernardos, A, Wichmann, I, and Nuñez-Roldán, A. Glutathione S-Transferase T1 Mismatch Constitutes a Risk Factor Forde Novoimmune Hepatitis after Liver Transplantation. Liver Transpl (2004) 10:1166–72. doi:10.1002/lt.20209
6. Rodriguez-Mahou, M, Salcedo, M, Fernandez-Cruz, E, Tiscar, JLR, Bañares, R, Clemente, G, et al. Antibodies against Glutathione S-Transferase T1 (GSTT1) in Patients with GSTT1 Null Genotype as Prognostic Marker: Long-Term Follow-Up after Liver Transplantation. Transplantation (2007) 83(8):1126–9. doi:10.1097/01.tp.0000259963.47350.da
Keywords: IgG4, PC-rich R, GSTT1, liver transplant, plasma cells
Citation: Aguilera I and Sousa JM (2022) Comments on: Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis. Transpl Int 35:10590. doi: 10.3389/ti.2022.10590
Received: 22 April 2022; Accepted: 21 June 2022;
Published: 05 August 2022.
Copyright © 2022 Aguilera and Sousa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Isabel Aguilera, isabelaguilera1@gmail.com