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1
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Kudo T, Nakazawa D, Nishio S, Hattanda F, Ueda Y, Yoshikawa J, Shiratori-Aso S, Iwasaki S, Tsuji T, Nakanuma Y, Suda G, Ogawa K, Sakamoto N, Atsumi T. Tubulointerstitial nephritis with IgM-positive plasma cells complicated by liver failure. CEN Case Rep 2025; 14:253-260. [PMID: 39438434 PMCID: PMC11958902 DOI: 10.1007/s13730-024-00932-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 09/16/2024] [Indexed: 10/25/2024] Open
Abstract
Tubulointerstitial nephritis (TIN) is characterized by inflammation of the renal interstitium with the infiltration of immune cells, mainly consisting of T cells. Recently, patients with TIN with the predominant infiltration of immunoglobulin M (IgM)-positive plasma cells were reported, coined IgMPC-TIN. Here we report the case of a 70-year-old woman diagnosed with Fanconi syndrome and renal tubular acidosis. Renal biopsy revealed IgMPC-TIN. Her renal dysfunction and clinical findings improved after corticosteroid therapy. However, the patient died of progressive liver failure and spontaneous bacterial peritonitis. In laboratory tests, viral hepatitis was excluded, and autoantibodies associated with liver diseases were negative. Generally, IgMPC-TIN is often complicated by primary biliary cholangitis (PBC), whereas her autopsy revealed the local infiltration of IgM-positive plasma cells, obliterative portal venopathy, and nodular regenerative hyperplasia in liver. This case is the first demonstration that IgMPC-TIN is also seen in liver disease with nodular regenerative hyperplasia, although IgMPC-TIN is more common in anti-M2 antibody-positive disease.
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Affiliation(s)
- Takashi Kudo
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
| | - Daigo Nakazawa
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan.
| | - Saori Nishio
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
| | - Fumihiko Hattanda
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
| | - Yusho Ueda
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
| | - Junpei Yoshikawa
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
| | - Satoka Shiratori-Aso
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
| | - Sari Iwasaki
- Department of Pathology, Sapporo City General Hospital, 13-1-1, Kita 11, Nishi 13, Chuo-ku, Sapporo, Japan
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, 13-1-1, Kita 11, Nishi 13, Chuo-ku, Sapporo, Japan
| | - Yasuni Nakanuma
- Department of Diagnostic Pathology, Fukui Prefecture Saiseikai Hospital, Funabashi 7-1, Wadanaka-cho, Fukui, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita 14, Nishi 5, Kita-ku, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita 14, Nishi 5, Kita-ku, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita 14, Nishi 5, Kita-ku, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan
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2
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Pham HN, Pham L, Sato K. Deconvolution analysis identified altered hepatic cell landscape in primary sclerosing cholangitis and primary biliary cholangitis. Front Med (Lausanne) 2024; 11:1327973. [PMID: 38818402 PMCID: PMC11138208 DOI: 10.3389/fmed.2024.1327973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Introduction Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are characterized by ductular reaction, hepatic inflammation, and liver fibrosis. Hepatic cells are heterogeneous, and functional roles of different hepatic cell phenotypes are still not defined in the pathophysiology of cholangiopathies. Cell deconvolution analysis estimates cell fractions of different cell phenotypes in bulk transcriptome data, and CIBERSORTx is a powerful deconvolution method to estimate cell composition in microarray data. CIBERSORTx performs estimation based on the reference file, which is referred to as signature matrix, and allows users to create custom signature matrix to identify specific phenotypes. In the current study, we created two custom signature matrices using two single cell RNA sequencing data of hepatic cells and performed deconvolution for bulk microarray data of liver tissues including PSC and PBC patients. Methods Custom signature matrix files were created using single-cell RNA sequencing data downloaded from GSE185477 and GSE115469. Custom signature matrices were validated for their deconvolution performance using validation data sets. Cell composition of each hepatic cell phenotype in the liver, which was identified in custom signature matrices, was calculated by CIBERSORTx and bulk RNA sequencing data of GSE159676. Deconvolution results were validated by analyzing marker expression for the cell phenotype in GSE159676 data. Results CIBERSORTx and custom signature matrices showed comprehensive performance in estimation of population of various hepatic cell phenotypes. We identified increased population of large cholangiocytes in PSC and PBC livers, which is in agreement with previous studies referred to as ductular reaction, supporting the effectiveness and reliability of deconvolution analysis in this study. Interestingly, we identified decreased population of small cholangiocytes, periportal hepatocytes, and interzonal hepatocytes in PSC and PBC liver tissues compared to healthy livers. Discussion Although further studies are required to elucidate the roles of these hepatic cell phenotypes in cholestatic liver injury, our approach provides important implications that cell functions may differ depending on phenotypes, even in the same cell type during liver injury. Deconvolution analysis using CIBERSORTx could provide a novel approach for studies of specific hepatic cell phenotypes in liver diseases.
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Affiliation(s)
- Hoang Nam Pham
- Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University—Central Texas, Killeen, TX, United States
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
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Hsu M, Ju JY, Pearson MM, Yu L, Swanson PE, Yeh MM. IgG and IgM Immunohistochemistry in Primary Biliary Cholangitis (PBC) and Autoimmune Hepatitis (AIH) Liver Explants. Am J Clin Pathol 2022; 158:770-773. [PMID: 36048887 DOI: 10.1093/ajcp/aqac101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 07/22/2022] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) can be difficult to distinguish in end-stage liver disease. Previous studies have shown that immunoglobulin G (IgG) and immunoglobulin M (IgM) immunostaining can differentiate AIH from PBC in needle core biopsy specimens, and we seek to extend these data to cirrhotic liver explants, in which the histology of AIH or PBC may be indiscernible. METHODS Clinical data were reviewed for 20 patients with PBC cirrhosis and 16 with AIH cirrhosis. Immunohistochemistry for IgM and IgG was performed on representative blocks of explanted livers. Three high-power fields with the highest concentration of IgG- and IgM-positive plasma cells were counted and compared. RESULTS The average number of IgM-positive plasma cells was significantly higher in PBC explants (7.3) than in AIH (1.8) (P = .001). There was no significant difference in the average number of IgG-positive plasma cells in PBC (2.5) and AIH (2.8) (P = .8). The IgG/IgM ratio was more likely to be less than 1.0 in PBC (17/20, 85%) compared with AIH (7/16, 44%) (P = .01). CONCLUSIONS Our study demonstrates that the absolute number of IgM plasma cells is greater in explants of cirrhotic PBC compared with AIH. These findings may be helpful in the evaluation of cryptogenic cirrhosis.
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Affiliation(s)
- Maylee Hsu
- Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, WA, USA.,Department of Pathology, Veterans Affairs Medical Center, Portland, OR, USA
| | - Jennifer Y Ju
- Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, WA, USA
| | - Meredith M Pearson
- Department of Medicine, University of Washington Medical Center, Seattle, WA, USA
| | - Lei Yu
- Department of Medicine, University of Washington Medical Center, Seattle, WA, USA
| | - Paul E Swanson
- Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, WA, USA.,Department of Medicine, University of Washington Medical Center, Seattle, WA, USA
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, WA, USA.,Department of Medicine, University of Washington Medical Center, Seattle, WA, USA
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4
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Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease. Semin Immunopathol 2022; 44:461-474. [PMID: 35641679 PMCID: PMC9256571 DOI: 10.1007/s00281-022-00940-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/15/2022] [Indexed: 12/29/2022]
Abstract
Autoimmune liver diseases (AILD) include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These immune-mediated liver diseases involve a break down in peripheral self-tolerance with largely unknown aetiology. Regulatory T cells (Treg) are crucial in maintaining immunological tolerance. Hence, Treg immunotherapy is an attractive therapeutic option in AILD. Currently, AILD do not have a curative treatment option and patients take life-long immunosuppression or bile acids to control hepatic or biliary inflammation. Clinical investigations using good manufacturing practice (GMP) Treg in autoimmune liver disease have thus far demonstrated that Treg therapy is safe and that Treg migrate to inflamed liver tissue. For Treg immunotherapy to achieve efficacy in AILD, Treg must be retained within the liver and maintain their suppressive phenotype to dampen ongoing immune responses to hepatocytes and biliary epithelium. Therefore, therapeutic Treg subsets should be selected for tissue residency markers and maximal functionality. Optimisation of dosing regime and understanding longevity of Treg in vivo are critical to successful Treg therapy. It is also essential to consider combination therapy options to complement infused Treg, for instance low-dose interleukin-2 (IL-2) to support pre-existing and infused Treg survival and suppressive function. Understanding the hepatic microenvironment in both early- and late-stage AILD presents significant opportunity to better tailor Treg therapy in different patient groups. Modification of a hostile microenvironment to a more favourable one either prior to or during Treg therapy could enhance the efficacy and longevity of infused GMP-Treg. Applying recent technology to discovery of autoantigen responses in AILD, T cell receptor (TCR) sequencing and use of chimeric antigen receptor (CAR) technology represents the next frontier for disease-specific CAR-Treg therapies. Consideration of all these aspects in future trials and discovery research would position GMP Treg immunotherapy as a viable personalised-medicine treatment option for effective control of autoimmune liver diseases.
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5
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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6
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Minato M, Murakami T, Takahashi N, Ono H, Nishimura K, Tamaki M, Nagai K, Abe H, Iwano M, Joh K, Doi T. Glucocorticoid-dependent Tubulointerstitial Nephritis with IgM-positive Plasma Cells Presenting with Intracellular Crystalline Inclusions within the Rough Endoplasmic Reticulum. Intern Med 2021; 60:3129-3136. [PMID: 33840699 PMCID: PMC8545643 DOI: 10.2169/internalmedicine.7118-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Tubulointerstitial nephritis (TIN) with IgM-positive plasma cells (IgMPC-TIN) is an autoimmune kidney disease characterized by IgM/CD138-double-positive plasma cell infiltration in the tubulointerstitium. A 50-year-old man developed IgMPC-TIN and presented with crystalline inclusions in the rough endoplasmic reticulum. Intracellular crystal formation is a rare finding in paraprotein-related kidney diseases, but this case showed no pathogenic monoclonal immunoglobulin. Prednisolone (PSL, 30 mg) improved the TIN, but PSL tapering resulted in the recurrence of TIN. Combination therapy with 15 mg PSL and 150 mg mizoribine ultimately stabilized TIN. This case offers original evidence concerning the pathophysiology and treatment strategy of IgMPC-TIN.
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Affiliation(s)
- Masanori Minato
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
| | - Taichi Murakami
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
- Department of Nephrology, Ehime Prefectural Central Hospital, Japan
| | - Naoki Takahashi
- Department of Nephrology, Faculty of Medical Science, University of Fukui, Japan
| | - Hiroyuki Ono
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
| | - Kenji Nishimura
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
| | - Masanori Tamaki
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
| | - Kojiro Nagai
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
| | - Hideharu Abe
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
| | - Masayuki Iwano
- Department of Nephrology, Faculty of Medical Science, University of Fukui, Japan
| | - Kensuke Joh
- Department of Pathology, The Jikei University School of Medicine, Japan
| | - Toshio Doi
- Department of Nephrology, Tokushima University Graduate School of Biomedical Science, Japan
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7
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Cargill T, Culver EL. The Role of B Cells and B Cell Therapies in Immune-Mediated Liver Diseases. Front Immunol 2021; 12:661196. [PMID: 33936097 PMCID: PMC8079753 DOI: 10.3389/fimmu.2021.661196] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Abstract
B cells form a branch of the adaptive immune system, essential for the body’s immune defense against pathogens. B cell dysfunction has been implicated in the pathogenesis of immune mediated liver diseases including autoimmune hepatitis, IgG4-related hepatobiliary disease, primary biliary cholangitis and primary sclerosing cholangitis. B cells may initiate and maintain immune related liver diseases in several ways including the production of autoantibodies and the activation of T cells via antigen presentation or cytokine production. Here we comprehensively review current knowledge on B cell mechanisms in immune mediated liver diseases, exploring disease pathogenesis, B cell therapies, and novel treatment targets. We identify key areas where future research should focus to enable the development of targeted B cell therapies.
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Affiliation(s)
- Tamsin Cargill
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Emma L Culver
- Oxford Liver Unit, John Radcliffe Hospital, Oxford, United Kingdom
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8
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Lee BT, Wang Y, Yang A, Han H, Yuan L, Donovan J, Kaplowitz N, Kanel G, Kahn J, Dara L. IgG:IgM Ratios of Liver Plasma Cells Reveal Similar Phenotypes of Primary Biliary Cholangitis With and Without Features of Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2021; 19:397-399. [PMID: 31751773 PMCID: PMC7231645 DOI: 10.1016/j.cgh.2019.11.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/09/2019] [Accepted: 11/10/2019] [Indexed: 02/07/2023]
Abstract
Within the spectrum of autoimmune liver diseases, there are patients who manifest features of more than one disease, which was previously identified as having overlap syndrome1,2 and is now referred to as variant syndromes. The most common variant syndrome is between primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). Typically, AIH presents with elevated serum immunoglobulin (Ig) G, whereas PBC is associated with elevated serum IgM.3,4 Previous studies have suggested that plasma cells in liver biopsies of AIH patients are predominantly IgG+, whereas in PBC, there is an abundance of IgM+ cells.5,6 We wanted to determine the immunostaining pattern for IgG and IgM of liver plasma cells among Hispanic patients in Los Angeles with features of both PBC-AIH compared with those with PBC or AIH alone.
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Affiliation(s)
- Brian T. Lee
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Yun Wang
- Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Alexander Yang
- Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Hyosun Han
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California,USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Liyun Yuan
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California,USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - John Donovan
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California,USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Neil Kaplowitz
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California,USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Gary Kanel
- Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, California,USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Jeffrey Kahn
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California,USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Lily Dara
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California; USC Research Center for Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, California.
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9
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Floreani A, De Martin S, Ikeura T, Okazaki K, Gershwin ME. Gut microbial profiling as a therapeutic and diagnostic target for managing primary biliary cholangitis. Expert Opin Orphan Drugs 2020. [DOI: 10.1080/21678707.2020.1865917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Annarosa Floreani
- Scientific Consultant, IRCCS Negrar, Verona, Italy
- Studiosa Senior, University of Padova, Padova, Italy
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Tsukasa Ikeura
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Merrill Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
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10
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Nakamori A, Akagaki F, Yamaguchi Y, Sugiura T. Relapsing Tubulointerstitial Nephritis with Antimitochondrial M2 Antibody Accompanied by Pulmonary Involvement. Intern Med 2020; 59:1179-1187. [PMID: 32051384 PMCID: PMC7270750 DOI: 10.2169/internalmedicine.4048-19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
We herein report a 50-year-old woman who suffered from tubulointerstitial nephritis with antimitochondrial M2 antibody, distal renal tubular acidosis, and Fanconi syndrome. Our case also had interstitial pneumonia. After initially successful glucocorticoid therapy, tubulointerstitial nephritis and interstitial pneumonia relapsed. After the second successful round of glucocorticoid therapy, tubulointerstitial nephritis relapsed again and responded to glucocorticoid and azathioprine. This case might indicate (1) the association between pulmonary involvement and tubulointerstitial nephritis with antimitochondrial antibodies and (2) the need for a maintenance dose of glucocorticoid and immunosuppressants in tubulointerstitial nephritis with antimitochondrial antibodies.
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MESH Headings
- Acidosis, Renal Tubular/complications
- Acidosis, Renal Tubular/diagnosis
- Acidosis, Renal Tubular/drug therapy
- Autoantibodies/blood
- Diagnosis, Differential
- Fanconi Syndrome/complications
- Fanconi Syndrome/diagnosis
- Fanconi Syndrome/drug therapy
- Female
- Glucocorticoids/therapeutic use
- Humans
- Lung Diseases, Interstitial/complications
- Lung Diseases, Interstitial/diagnosis
- Lung Diseases, Interstitial/drug therapy
- Middle Aged
- Mitochondria/immunology
- Nephritis, Interstitial/complications
- Nephritis, Interstitial/diagnosis
- Nephritis, Interstitial/drug therapy
- Recurrence
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Affiliation(s)
- Aya Nakamori
- Department of Nephrology, Otemae Hospital, Japan
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11
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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12
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Takahashi N, Saeki T, Komatsuda A, Munemura C, Fukui T, Imai N, Homma N, Hatta T, Samejima KI, Fujimoto T, Omori H, Ito Y, Nishikawa Y, Kobayashi M, Morikawa Y, Fukushima S, Yokoi S, Mikami D, Kasuno K, Kimura H, Nemoto T, Nakamoto Y, Sada K, Sugai M, Naiki H, Yoshida H, Narita I, Saito Y, Iwano M. Tubulointerstitial Nephritis with IgM-Positive Plasma Cells. J Am Soc Nephrol 2017; 28:3688-3698. [PMID: 28794148 DOI: 10.1681/asn.2016101074] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 06/23/2017] [Indexed: 12/17/2022] Open
Abstract
Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.
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Affiliation(s)
| | - Takako Saeki
- Department of Internal Medicine, Nagaoka Red Cross Hospital, Niigata, Japan
| | - Atsushi Komatsuda
- Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Chishio Munemura
- Division of Medicine and Clinical Science, Tottori University Faculty of Medicine, Tottori, Japan
| | - Takeaki Fukui
- Division of Medicine and Clinical Science, Tottori University Faculty of Medicine, Tottori, Japan
| | - Naofumi Imai
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Noriyuki Homma
- Internal Medicine, Niigata Prefectural Shibata Hospital, Niigata, Japan
| | - Tsuguru Hatta
- Department of Nephrology, Omihachiman Community Medical Center, Shiga, Japan
| | | | - Takashi Fujimoto
- The Center for Rheumatic Diseases, Nara Medical University, Nara, Japan
| | - Hiroki Omori
- Division of Nephrology, Department of Internal Medicine, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan; and
| | - Yumi Ito
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | | | | | | | | | | | | | | | | | - Tomoyuki Nemoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | | | | | | | - Haruyoshi Yoshida
- Department of Internal Medicine, Sugita Genpaku Memorial Obama Municipal Hospital, Fukui, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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13
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Abstract
Histochemical and immunostains are routinely used to evaluate medical liver biopsy specimens. The use of these special stains allows the identification of more clinically important information than is available on hematoxylin and eosin stains alone. These special stains are important for evaluating active and chronic injury and for establishing a specific diagnosis. The skillful use of these stains greatly improves patient care. Information on the use of special stains can be scattered in different sources, making the information hard to access. In this article, the use of special stains in medical liver biopsies is concisely reviewed.
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14
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Mattner J. Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC). Int J Mol Sci 2016; 17:1864. [PMID: 27834858 PMCID: PMC5133864 DOI: 10.3390/ijms17111864] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 02/07/2023] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent the major clinical entities of chronic cholestatic liver diseases. Both disorders are characterized by portal inflammation and slowly progress to obliterative fibrosis and eventually liver cirrhosis. Although immune-pathogenic mechanisms have been implicated in the pathogenesis of PBC and PSC, neither disorder is considered to be a classical autoimmune disease, as PSC and PBC patients do not respond to immune-suppressants. Furthermore, the decreased bile flow resulting from the immune-mediated tissue assault and the subsequent accumulation of toxic bile products in PBC and PSC not only perpetuates biliary epithelial damage, but also alters the composition of the intestinal and biliary microbiota and its mutual interactions with the host. Consistent with the close association of PSC and inflammatory bowel disease (IBD), the polyclonal hyper IgM response in PBC and (auto-)antibodies which cross-react to microbial antigens in both diseases, an expansion of individual microbes leads to shifts in the composition of the intestinal or biliary microbiota and a subsequent altered integrity of epithelial layers, promoting microbial translocation. These changes have been implicated in the pathogenesis of both devastating disorders. Thus, we will discuss here these recent findings in the context of novel and alternative therapeutic options.
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MESH Headings
- Anti-Bacterial Agents/therapeutic use
- Antibodies, Bacterial/biosynthesis
- Bacterial Translocation
- Bile/drug effects
- Bile/microbiology
- Cholangiopancreatography, Endoscopic Retrograde
- Cholangitis, Sclerosing/diagnostic imaging
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/microbiology
- Gastrointestinal Microbiome/drug effects
- Host-Pathogen Interactions
- Humans
- Immunoglobulin M/biosynthesis
- Liver Cirrhosis, Biliary/diagnostic imaging
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/microbiology
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Affiliation(s)
- Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, D-91054 Erlangen, Germany.
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15
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Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: A comprehensive review. J Autoimmun 2015; 64:42-52. [PMID: 26250073 PMCID: PMC5014907 DOI: 10.1016/j.jaut.2015.07.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 07/06/2015] [Indexed: 12/20/2022]
Abstract
Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.
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Affiliation(s)
- G J Webb
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - K A Siminovitch
- Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto General Research Institute, and Departments of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - G M Hirschfield
- NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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16
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Reshetnyak VI. Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21:7683-7708. [PMID: 26167070 PMCID: PMC4491957 DOI: 10.3748/wjg.v21.i25.7683] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/07/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.
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17
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Kikuchi K, Tsuneyama K, Yamada H, Kajiyama Y, Matsumoto K, Tsunashima H, Yamashita R, Takai A, Negishi M, Hara M, Moritoki Y, Miyakawa H. Splenic lymph follicles generate immunoglobulin M-producing B cells in primary biliary cirrhosis. Hepatol Res 2014; 44:E253-E256. [PMID: 24033874 DOI: 10.1111/hepr.12231] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 08/21/2013] [Accepted: 08/21/2013] [Indexed: 01/24/2023]
Abstract
AIM To reveal the site of immunoglobulin (Ig)M production in primary biliary cirrhosis (PBC) we performed immunohistochemical analysis on spleens collected from patients with PBC. METHODS Splenic tissue samples were collected at the time of the autopsy from patients with hepatic failure. Immunostaining for IgM, CD21 and CXCL13 were performed using the splenic tissue samples. RESULTS The samples from five out of eight cases with PBC but not in eight cases of chronic hepatitis C virus infection showed accumulation of IgM positive cells in CD21 positive lymph follicles. The CXCL13 positive cells also accumulated in the center of the lymph follicles where the IgM positive cells accumulated. CONCLUSION The present results suggest that excess IgM is produced from the spleen of PBC. Furthermore, it was suggested that CXCL13 positive follicular dendritic cells possibly contribute to this process.
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Affiliation(s)
- Kentaro Kikuchi
- The Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan
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18
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The utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of autoimmune liver diseases. Med Mol Morphol 2014; 47:162-8. [PMID: 24969678 DOI: 10.1007/s00795-014-0082-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 05/20/2014] [Indexed: 12/11/2022]
Abstract
Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) present with distinct clinical features. The term "PBC-AIH overlap syndrome (OS)" has been adopted to describe the condition characterized by occurrence of both PBC and AIH, although this clinical entity is difficult to define. This study aimed to assess the utility of IgG, IgM, and CD138 immunohistochemistry in the evaluation of AIH, PBC, and OS. Immunohistochemistry was performed with anti-human IgG, IgM, and CD138 to detect specific plasma cells in the liver. Predominant IgG staining was observed in AIH (85.7 %), while equivocal (46.1 %) or predominant (38.5 %) IgM staining was observed in PBC. In OS, equivocal (20 %) or predominant (80 %) IgG staining was observed. The IgM/IgG ratio was significantly higher in PBC than in AIH or OS (P < 0.005). Histological findings revealed significantly higher IgM expression in PBC at cholangitis activity grades 2-3 compared to those at cholangitis activity grades 0-1. In contrast, a significantly higher IgG expression was observed in PBC at hepatitis activity and fibrosis grades 2-3 compared to those at hepatitis activity and fibrosis grades 0-1. Taken together, periportal plasmacytic infiltrates with variable immunohistochemistry patterns of IgG and IgM expression characterized different autoimmune liver diseases.
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19
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Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic autoimmune liver disease characterized by the destruction of small intrahepatic bile ducts and the presence of highly specific serum antimitochondrial antibodies (AMAs). In this article, we will review the clinical, serological and histopathological features of PBC as well as the advances in the diagnosis and differential diagnosis of PBC. In addition, this article systematically describes the advances in the treatment of PBC, and the treatments include ursodeoxycholic acid (UDCA), budesonide, methotrexate (MTX), farnesoid X receptor (FXR) agonists, cyclosporine A, bezafibrate, rituximab, bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation, and liver transplantation. At present, liver transplantation is the only option with known therapeutic benefit for end-stage PBC patients.
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20
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Kobayashi M, Kakuda Y, Harada K, Sato Y, Sasaki M, Ikeda H, Terada M, Mukai M, Kaneko S, Nakanuma Y. Clinicopathological study of primary biliary cirrhosis with interface hepatitis compared to autoimmune hepatitis. World J Gastroenterol 2014; 20:3597-3608. [PMID: 24707143 PMCID: PMC3974527 DOI: 10.3748/wjg.v20.i13.3597] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 07/16/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features.
METHODS: Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions.
RESULTS: Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgG-equal, and IgG-predominant types, with the latter sharing several features with AIH.
CONCLUSION: These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.
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21
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Sasaki M, Kakuda Y, Miyakoshi M, Sato Y, Nakanuma Y. Infiltration of inflammatory cells expressing mitochondrial proteins around bile ducts and in biliary epithelial layer may be involved in the pathogenesis in primary biliary cirrhosis. J Clin Pathol 2014; 67:470-6. [PMID: 24407434 DOI: 10.1136/jclinpath-2013-201917] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIMS Serum antimitochondrial antibodies are characteristic in most patients with primary biliary cirrhosis (PBC); however, the significance of antimitochondrial antibodies in the pathogenesis of PBC remains unclear. We examined the extent and types of mitochondrial protein-expressing inflammatory cells and its association with deregulated autophagy of mitochondria in biliary epithelial lesions in PBC. METHODS We examined the expression of pyruvate dehydrogenase complex-E2 component and a mitochondrial protein cytochrome c oxidase, subunit I in inflammatory cells in livers taken from patients with PBC (n=35) and control livers (n=64) including primary sclerosing cholangitis. Mitochondrial protein-expressing inflammatory cells were characterised by double immunofluorescence with surface markers. RESULTS Infiltration of mitochondrial protein-expressing inflammatory cells was mainly observed in portal tracts and in the biliary epithelial layer and around the damaged small bile ducts in PBC. The extent of infiltration in portal tracts was significantly higher in PBC and early stage of chronic viral hepatitis than normal livers. The extent of infiltration around bile ducts and in biliary epithelial layer was significantly higher in early stage of PBC than control livers. Mitochondrial protein-expressing inflammatory cells included (1) CD68 and/or myeloperoxidase -positive monocytes/macrophages and (2) CD79a, CD38, CD138, IgM-positive and/or IgG-positive plasma cells. Colocalised expression of pyruvate dehydrogenase complex-E2 component and autophagy marker light chain 3β was observed in the inflammatory cells. CONCLUSIONS Mitochondrial protein-expressing inflammatory cells infiltrating around the damaged bile ducts and in biliary epithelial layers may be closely associated with the pathogenesis of bile duct lesion in PBC.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yuko Kakuda
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masami Miyakoshi
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yasuni Nakanuma
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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22
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Sfakianaki O, Tzardi M, Voumvouraki A, Afgoustaki A, Koulentaki M, Kouroumalis E. Presence of disease specific autoantibodies against liver sinusoidal cells in primary biliary cirrhosis. World J Hepatol 2013; 5:568-576. [PMID: 24179616 PMCID: PMC3812459 DOI: 10.4254/wjh.v5.i10.568] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 07/20/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis (PBC).
METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B (HBV) virus, 3 patients with hepatitis C virus (HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis (AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targeted by autoantibodies present in the patients sera was performed by indirect immunofluorescence (IIF) analysis using paraffin-embedded liver sections as a substrate. Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy.
RESULTS: In total, 18/21 (85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21 (47.6%) in lymphocytes, 8/21 (38%) in cholangiocytes and 7/21 (33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G (IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining (20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody, positive staining was observed in 75% of lymphocytes, 62.5% of cholangiocytes, 37.5% of hepatocytes and 50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections, weak positive staining of cholangiocytes was observed in 3/21 (14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients.
CONCLUSION: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.
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23
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Abstract
Autoimmune hepatitis is a chronic necroinflammatory disease of unknown etiology that is characterized by increased aminotransferases, serum autoantibodies, increased immunoglobulin G levels, and histological interface hepatitis. The disease does not have a pathognomonic clinical, laboratory, or histological feature; diagnosis depends on a combination of clinical and pathologic criteria which also form the basis for a weighted scoring system to aid diagnosis. Liver biopsy is an essential part of the diagnostic criteria and is also crucial to the management of the disease. This review focuses on the diagnosis, microscopic features, differential diagnosis and overlap syndromes of autoimmune hepatitis.
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Affiliation(s)
- Cristina D Cole
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Indianapolis, IN 46202, USA
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Indianapolis, IN 46202, USA.
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24
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Danzer C, Mattner J. Impact of microbes on autoimmune diseases. Arch Immunol Ther Exp (Warsz) 2013; 61:175-186. [PMID: 23417246 PMCID: PMC4134873 DOI: 10.1007/s00005-013-0216-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 02/01/2013] [Indexed: 12/15/2022]
Abstract
Autoimmune and autoinflammatory diseases arise as a consequence of complex interactions of environmental factors with genetic traits. Although specific allelic variations cluster in predisposed individuals and promote the generation and/or expansion of autoreactive T and B lymphocytes, autoimmunity appears in various disease phenotypes and localizes to diverging tissues. Furthermore, the discovery that allelic variations within genes encoding components of the innate immune system drive self-reactive immune responses as well, led to the distinction of immune responses against host tissues into autoimmune and autoinflammatory diseases. In both categories of disorders, different pathogenic mechanisms and/or subsequent orders of tissue assaults may underlie the target cell specificity of the respective autoimmune attack. Furthermore, the transition from the initial tissue assault to the development of full-blown disease is likely driven by several factors. Thus, the development of specific forms of autoimmunity and autoinflammation reflects a multi-factorial process. The delineation of the specific factors involved in the pathogenic process is hampered by the fact that certain symptoms are assembled under the umbrella of a specific disease, although they might originate from diverging pathogenic pathways. These multi-factorial triggers and pathogenic pathways may also explain the inter-individual divergent courses and outcomes of diseases among humans. Here, we will discuss the impact of different environmental factors in general and microbial pathogens in particular on the regulation/expression of genes encoded within susceptibility alleles, and its consequences on subsequent autoimmune and/or autoinflammatory tissue damage utilizing primarily the chronic cholestatic liver disease primary biliary cirrhosis as model.
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Affiliation(s)
- Claudia Danzer
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie Und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054 Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut, Klinische Mikrobiologie, Immunologie Und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054 Erlangen, Germany. Division of Cellular and Molecular Immunology, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA
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25
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Shi TY, Zhang FC. Role of autoimmunity in primary biliary cirrhosis. World J Gastroenterol 2012; 18:7141-8. [PMID: 23326118 PMCID: PMC3544015 DOI: 10.3748/wjg.v18.i48.7141] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Revised: 07/16/2012] [Accepted: 08/14/2012] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of serum autoantibodies and chronic nonsuppurative destructive cholangitis. The pathogenesis of PBC involves environmental factors, genetic predisposition and loss of immune tolerance. In recent years, it has become univocally accepted that an inappropriately activated immune response is one of the most important factors in PBC. In this study, the role of autoimmunity in PBC is summarized and a feasible research orientation is recommended.
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26
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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.
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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
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27
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Cavazza A, Rossi G, Corradi D, Luppi F, Cervi G, Spaggiari L, Falco F, Roggeri A. Cellular non-specific interstitial pneumonia as a pulmonary manifestation of primary biliary cirrhosis. Pathology 2011; 42:596-8. [PMID: 20854086 DOI: 10.3109/00313025.2010.508779] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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28
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Abstract
Recent publications on hepatology and hepatic pathology provide a wealth of new information on wideranging topics. Morphologic aspects of liver disease associated with hepatitis B and C viruses, autoimmune hepatitis, and HIV infection were addressed, as was the prevalent problem of nonalcoholic fatty liver disease. Advances in diagnosis and pathogenesis of primary biliary cirrhosis, primary sclerosing cholangitis, and the increasingly complex spectrum of IgG4 hepatobiliary diseases were also reported. The histologic and immunohistochemical features of the rare "calcifying nested stromal-epithelial tumor" of the liver were described in a 9-case series. For benign and malignant liver tumors, immunohistochemistry plays a major diagnostic role, and several recent studies demonstrate the value of immunostains in distinguishing between liver-cell adenoma and focal nodular hyperplasia.
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Affiliation(s)
- Jay H Lefkowitch
- Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street-PH 15 West, Room 1574, New York, NY 10032, USA.
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29
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Moreira RK, Lee H, Stapp R, Ormsby A, Shah V. Immunohistochemical staining of inflammatory cells in liver biopsy specimens of patients with autoimmune hepatitis, primary biliary cirrhosis, and overlap syndromes. Am J Clin Pathol 2010; 134:852-3. [PMID: 20959674 DOI: 10.1309/ajcpce4iztna4ssz] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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30
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Cabibi D, Tarantino G, Barbaria F, Campione M, Craxì A, Di Marco V. Intrahepatic IgG/IgM plasma cells ratio helps in classifying autoimmune liver diseases. Dig Liver Dis 2010; 42:585-92. [PMID: 20060371 DOI: 10.1016/j.dld.2009.12.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2009] [Revised: 11/25/2009] [Accepted: 12/13/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM Plasma cells infiltrate in the liver is a prototype lesion of autoimmune liver diseases. The possible role of plasma cells isotyping (IgM and IgG) in the liver in the diagnostic definition of autoimmune liver disease, and particularly in variant syndromes such as autoimmune cholangitis and the primary biliary cirrhosis/autoimmune hepatitis overlap syndrome, is less defined. METHODS We analysed the clinical, serological and histological features of 83 patients with autoimmune liver disease (40 primary biliary cirrhosis, 20 autoimmune hepatitis, 13 primary sclerosing cholangitis, 4 autoimmune cholangitis and 6 overlap syndrome) compared to 34 patients with chronic hepatitis C and evaluated the expression of IgM and IgG plasma cells in their liver by immunostaining. RESULTS By Spearman's correlation, the mean-counts of IgM plasma cells in portal tracts were significantly correlated with female gender, serum alkaline phosphatase, gamma-glutamyl transferase and IgM values, positivity for anti-mitochondrial antibody-M2 and, on liver biopsy, with bile duct changes, orcein-positive granules and granulomas. Whereas IgG plasma cells resulted more correlated with alanine aminotransferase levels. IgG/IgM ratio lower than 1 was found no only in primary biliary cirrhosis but also in all patients with autoimmune cholangitis. Conversely, all patients with overlap syndrome showed IgG/IgM ratio higher than 1. CONCLUSION Immunostaining for IgM and IgG plasma cells on liver tissue can be a valuable parameter for better diagnosis of autoimmune liver disease and also for variant or mixed syndromes.
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Affiliation(s)
- Daniela Cabibi
- Dipartimento di Patologia Umana, University of Palermo, Italy.
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Lee H, Stapp RT, Ormsby AH, Shah VV. The usefulness of IgG and IgM immunostaining of periportal inflammatory cells (plasma cells and lymphocytes) for the distinction of autoimmune hepatitis and primary biliary cirrhosis and their staining pattern in autoimmune hepatitis-primary biliary cirrhosis overlap syndrome. Am J Clin Pathol 2010; 133:430-7. [PMID: 20154281 DOI: 10.1309/ajcpe93gzshuntai] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome (OS) is a vaguely defined entity demonstrating features of AIH and PBC. We investigated the usefulness of IgG and IgM immunostaining for the distinction of AIH and PBC and their staining pattern in cases of possible OS. The approximate quantity of IgG+ and IgM+ periportal inflammatory cells in immunohistochemical analysis were compared in cases of AIH, PBC, and OS. AIH cases showed predominant IgG immunostaining of periportal inflammatory cells. A significant number of PBC cases also demonstrated IgG predominance rather than IgM. Six OS cases had IgG predominance, 4 had IgM predominance, and 1 was equivocal. The usefulness of IgG and IgM immunostaining is limited in PBC cases with IgM predominance for excluding AIH. IgG predominance is not specific for AIH. OS does not demonstrate either IgG or IgM predominance (P > .2) and does not help classify OS into either category.
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Moreira RK, Revetta F, Koehler E, Washington MK. Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease. World J Gastroenterol 2010; 16:453-7. [PMID: 20101770 PMCID: PMC2811797 DOI: 10.3748/wjg.v16.i4.453] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the role of IgM and IgG immunohistochemistry (IHC) in the evaluation of autoimmune liver conditions - autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).
METHODS: Forty one biopsies from untreated patients diagnosed with autoimmune liver disease (AIH, n = 20; PBC, n = 13; PSC, n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected. IgM and IgG-positive plasma cells were counted in each sample.
RESULTS: A predominance of IgG-positive plasma cells was seen in AIH (90% of cases), PSC (75% of cases), and chronic hepatitis C (100% of cases), while IgM-positive plasma cells predominated in PBC (92.8% of cases). The IgM /IgG ratio (< 1 or ≥ 1) accurately distinguished PBC from AIH in 90.9% of cases (sensitivity = 92.3%, specificity = 90%), and PBC from either AIH or PSC in 87.8% of cases (sensitivity = 92.3%, specificity = 85.7%).
CONCLUSION: Plasmacytic infiltrates expressing predominantly IgM are characteristic of PBC, while other forms of liver disease analyzed in this study, including AIH, typically show an IgG-predominant plasma cell infiltrate. Our data indicate that IgM and IgG IHC may be a useful tool when PBC is a diagnostic consideration.
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