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Houillier P, Prot-Bertoye C. Autoimmune Tubulopathies. J Am Soc Nephrol 2025; 36:706-712. [PMID: 39786900 DOI: 10.1681/asn.0000000628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025] Open
Abstract
The renal tubule and collecting duct express a large number of proteins, all having putative immunoreactive motives. Therefore, all can be the target of pathogenic autoantibodies. However, autoimmune tubulopathies seem to be rare, and we hypothesize that they are underdiagnosed. This review summarizes the current knowledge on autoimmune tubulopathies. We elected to classify tubulopathies according to the segment that is targeted because this determines, at least in part, the phenotypic presentation. In the proximal tubule, autoantibodies can cause anti-brush border antibody disease, renal Fanconi syndrome, renal proximal tubular acidosis, or tubulointerstitial nephritis and uveitis syndrome. Autoantibodies targeting the thick ascending limb of the loop of Henle can cause either acquired Bartter syndrome or hypomagnesemia with hypercalciuria, whereas autoantibodies targeting the distal convoluted tubule can cause acquired Gitelman syndrome. Finally, renal distal tubular acidosis or nephrogenic diabetes insipidus can be caused by autoantibodies targeting the collecting duct. In most instances, the characterization of the autoantibodies remains incomplete and the pathogenesis of the disease obscure. We believe it is important to increase the awareness of physicians regarding autoantibody-mediated tubular diseases to have a better estimation of the prevalence and to improve the care to patients. A research effort to increase the understanding of the pathogenesis of autoantibodies-mediated tubular diseases is also hoped for.
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Affiliation(s)
- Pascal Houillier
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France; CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France; Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France; Centre de Référence des Maladies Rares du Calcium et du Phosphate, Paris, France; and Faculté de Médecine, Université Paris Cité, Paris, France
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2
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Wallace ZS, Katz G, Hernandez-Barco YG, Baker MC. Current and future advances in practice: IgG4-related disease. Rheumatol Adv Pract 2024; 8:rkae020. [PMID: 38601138 PMCID: PMC11003820 DOI: 10.1093/rap/rkae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 12/28/2023] [Indexed: 04/12/2024] Open
Abstract
IgG4-related disease (IgG4-RD) is an increasingly recognized cause of fibroinflammatory lesions in patients of diverse racial and ethnic backgrounds and is associated with an increased risk of death. The aetiology of IgG4-RD is incompletely understood, but evidence to date suggests that B and T cells are important players in pathogenesis, both of which are key targets of ongoing drug development programmes. The diagnosis of IgG4-RD requires clinicopathological correlation because there is no highly specific or sensitive test. Glucocorticoids are highly effective, but their use is limited by toxicity, highlighting the need for studies investigating the efficacy of glucocorticoid-sparing agents. B cell-targeted therapies, particularly rituximab, have demonstrated benefit, but no randomized clinical trials have evaluated their efficacy. If untreated or under-treated, IgG4-RD can cause irreversible organ damage, hence close monitoring and consideration for long-term immunosuppression is warranted in certain cases.
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Affiliation(s)
- Zachary S Wallace
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Guy Katz
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Yasmin G Hernandez-Barco
- Harvard Medical School, Harvard University, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Matthew C Baker
- Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA, USA
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3
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Lee JY, Reichl A, O'Brien C, Ayoub M. A Diagnostic Paradox: Identifying IgG4-Related Disease in a Patient Previously Diagnosed with Sjogren's Syndrome. JOURNAL OF BROWN HOSPITAL MEDICINE 2024; 3:94450. [PMID: 40026799 PMCID: PMC11864382 DOI: 10.56305/001c.94450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 02/28/2024] [Indexed: 03/05/2025]
Abstract
We present the case of a 77-year-old male with a history of rectal adenocarcinoma and Sjogren's disease who was admitted for severely elevated liver function tests. Cross-sectional imaging demonstrated a dilated bile duct, and eventual biopsy of the area showed fibrosis and lymphocytic infiltrate consistent with IgG4-related disease. The patient was treated with rituximab and a prednisone taper. This case discusses the clinical, laboratory, and imaging hallmarks of this rare disease and illustrates the practical challenges of distinguishing it from other rheumatologic conditions.
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Affiliation(s)
- Ju Young Lee
- Department of Medicine David Geffen School of Medicine at University of California, Los Angeles
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4
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Wang BC, Fan JG. Unmet needs in biomarkers for autoimmune pancreatitis diagnosis. World J Gastroenterol 2024; 30:523-526. [PMID: 38463027 PMCID: PMC10921148 DOI: 10.3748/wjg.v30.i6.523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/10/2024] [Accepted: 01/15/2024] [Indexed: 02/05/2024] Open
Abstract
Autoimmune pancreatitis (AIP) is a rare chronic autoimmune disorder. The diagnosis of AIP mainly depends on histopathology, imaging and response to treatment. Serum immunoglobulin 4 (IgG4) is used only as collateral evidence in diagnostic criteria for AIP because of its moderate sensitivity. Serum IgG4 levels are normal in 15%-37% of type 1 AIP and most of type 2 AIP patients. In these patients, the indeterminate imaging and histopathology may lead to the difficulty in definitive diagnosis of AIP. Therefore, discovery of new biomarkers is important for AIP diagnosis. Here, we provide some views on the progression and challenges in identifying novel serological biomarkers in AIP diagnosis.
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Affiliation(s)
- Bao-Can Wang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
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Lakota J. Spontaneous regression of tumours. Possible cross reactivity of autoantibodies against carbonic anhydrase I. J Cell Mol Med 2023; 27:3637-3640. [PMID: 37776059 PMCID: PMC10660616 DOI: 10.1111/jcmm.17970] [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: 06/28/2023] [Revised: 09/11/2023] [Accepted: 09/16/2023] [Indexed: 10/01/2023] Open
Abstract
Spontaneous tumour regression in patients after high dose therapy and autologous stem cell transplantation or patients with standard therapy is accompanied with the presence of high titers autoantibodies against carbonic anhydrase I (CA I). The concomitant presence of aplastic anaemia-like syndrome in these patients points to parallel bone marrow suppression during this period. It seems that CA I, an 'obscure' enzyme, does not have any significant physiological role in humans. One possible explanation points to the fact that autoantibodies against CA I may target another antigen(s) which is(are) important in tumour growth as well as in normal haematopoiesis. One of the candidates for such a target is the DNA polymerase theta.
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Affiliation(s)
- Ján Lakota
- Centre of Experimental Medicine, SASBratislavaSlovakia
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Wagner CA, Unwin R, Lopez-Garcia SC, Kleta R, Bockenhauer D, Walsh S. The pathophysiology of distal renal tubular acidosis. Nat Rev Nephrol 2023; 19:384-400. [PMID: 37016093 DOI: 10.1038/s41581-023-00699-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2023] [Indexed: 04/06/2023]
Abstract
The kidneys have a central role in the control of acid-base homeostasis owing to bicarbonate reabsorption and production of ammonia and ammonium in the proximal tubule and active acid secretion along the collecting duct. Impaired acid excretion by the collecting duct system causes distal renal tubular acidosis (dRTA), which is characterized by the failure to acidify urine below pH 5.5. This defect originates from reduced function of acid-secretory type A intercalated cells. Inherited forms of dRTA are caused by variants in SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, WDR72 and probably in other genes that are yet to be discovered. Inheritance of dRTA follows autosomal-dominant and -recessive patterns. Acquired forms of dRTA are caused by various types of autoimmune diseases or adverse effects of some drugs. Incomplete dRTA is frequently found in patients with and without kidney stone disease. These patients fail to appropriately acidify their urine when challenged, suggesting that incomplete dRTA may represent an intermediate state in the spectrum of the ability to excrete acids. Unrecognized or insufficiently treated dRTA can cause rickets and failure to thrive in children, osteomalacia in adults, nephrolithiasis and nephrocalcinosis. Electrolyte disorders are also often present and poorly controlled dRTA can increase the risk of developing chronic kidney disease.
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Affiliation(s)
- Carsten A Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland.
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK.
| | - Robert Unwin
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Sergio C Lopez-Garcia
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Robert Kleta
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Detlef Bockenhauer
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Stephen Walsh
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
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Osman O, Manzi S, Wasko MC, Clark BA. Case report: disease mechanisms and medical management of calcium nephrolithiasis in rheumatologic diseases. BMC Urol 2023; 23:42. [PMID: 36959633 PMCID: PMC10035194 DOI: 10.1186/s12894-023-01203-y] [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: 08/16/2021] [Accepted: 02/19/2023] [Indexed: 03/25/2023] Open
Abstract
Background Nephrolithiasis as a feature of rheumatologic diseases is under recognized. Understanding presenting features, diagnostic testing is crucial to proper management. Case presentation A 32 year old woman with a history of recurrent complicated nephrolithiasis presented to a rheumatologist for a several month history of fatigue, dry eyes, dry mouth, arthralgias. She had a positive double-stranded DNA, positive SSA and SSB antibodies. She was diagnosed with Systemic Lupus erythematosus (SLE) and Sjogren's syndrome and was started on mycophenalate mofetil. Of relevance was a visit to her local emergency room 4 years earlier with profound weakness with unexplained marked hypokalemia and a non-anion gap metabolic acidosis. Approximately one year after that episode she developed flank pain and nephrocalcinosis. She had multiple issues over the ensuing years with stones and infections on both sides. Interventions included extracorporeal shockwave lithotripsy as well as open lithotomy and eventual auto-transplantation of left kidney for recurrent ureteric stenosis. 24 h stone profile revealed marked hypocitraturia, normal urine calcium, normal urine oxalate and uric acid. She was treated with potassium citrate. Mycophenolate was eventually stopped due to recurrent urinary tract infections and she was started on Belimumab. Because of recurrent SLE flares, treatment was changed to Rituximab (every 6 months) with clinical and serologic improvement. Her kidney stone frequency gradually improved and no further interventions needed although she continued to require citrate repletion for hypocitraturia. Conclusions Nephrolithiasis can be a prominent and even presenting feature in Sjogrens syndrome as well as other rheumatologic diseases. Prompt recognition and understanding disease mechanisms is important for best therapeutic interventions for kidney stone prevention as well as treatment of underlying bone mineral disease.
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Affiliation(s)
- Omar Osman
- grid.417046.00000 0004 0454 5075Department of Medicine, Allegheny Health Network, 320 East North Ave, Pittsburgh, PA 15212 USA
| | - Susan Manzi
- grid.417046.00000 0004 0454 5075Department of Medicine, Allegheny Health Network, 320 East North Ave, Pittsburgh, PA 15212 USA
| | - Mary Chester Wasko
- grid.417046.00000 0004 0454 5075Department of Medicine, Allegheny Health Network, 320 East North Ave, Pittsburgh, PA 15212 USA
| | - Barbara A. Clark
- grid.417046.00000 0004 0454 5075Department of Medicine, Allegheny Health Network, 320 East North Ave, Pittsburgh, PA 15212 USA
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Goni E, Regel I, Mahajan UM, Amodio A, De Marchi G, Beyer G, Zuppardo RA, Di Leo M, Lanzillotta M, Bonatti F, Kauke T, Dick A, Weiss FU, Schönermarck U, Lerch MM, Frulloni L, Cavestro GM, Mayerle J. HLA-DRB1∗16 and -DQB1∗05 alleles are strongly associated with autoimmune pancreatitis in a cohort of hundred patients. Pancreatology 2022; 22:466-471. [PMID: 35379557 DOI: 10.1016/j.pan.2022.03.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Autoimmune diseases are often associated with human leukocyte antigen (HLA) haplotypes, indicating that changes in major histocompatibility complex (MHC)-dependent self-peptide or antigen presentation contribute to autoimmunity. In our study, we aimed to investigate HLA alleles in a large European cohort of autoimmune pancreatitis (AIP) patients. METHODS Hundred patients with AIP, diagnosed and classified according to the International Consensus Diagnostic Criteria (ICDC), were prospectively enrolled in the study. Forty-four patients with chronic pancreatitis (CP) and 254 healthy subjects served as control groups. DNA was isolated from blood samples and two-digit HLA typing was performed with sequence-specific primer (SSP-) PCR. HLA allele association strength to AIP was calculated as odds ratio. RESULTS We uncovered a strong enrichment of HLA-DQB1 homozygosity in type 1 and type 2 AIP patients. Moreover, a significantly increased incidence of the HLA-DRB1∗16 and HLA-DQB1∗05 alleles and a concomitant lack of the HLA-DRB1∗13 allele was detected in AIP type 1 and type 2 patients. In contrast, the HLA-DQB1∗02 allele was underrepresented in the 'not otherwise specified' (NOS) AIP subtype. We detected no significant difference in the HLA-DRB3, HLA-DRB4 and HLA-DRB5 allele frequency in our cohort. CONCLUSIONS Although AIP type 1 and type 2 are characterized by distinct histopathological characteristics, both subtypes are associated with the same HLA alleles, indicating that the disease might rely on similar immunogenic mechanisms. However, AIP NOS represented another subclass of AIP.
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Affiliation(s)
- Elisabetta Goni
- Department of Medicine II, University Hospital, LMU, Munich, Germany
| | - Ivonne Regel
- Department of Medicine II, University Hospital, LMU, Munich, Germany.
| | | | - Antonio Amodio
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Giulia De Marchi
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Georg Beyer
- Department of Medicine II, University Hospital, LMU, Munich, Germany
| | - Raffaella Alessia Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy, Division of Experimental Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Milena Di Leo
- Gastroenterology and Gastrointestinal Endoscopy, Division of Experimental Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Marco Lanzillotta
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, uniRAR, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Bonatti
- Department of Medicine and Surgery, Medical Genetics Unit, University of Parma, Italy
| | - Teresa Kauke
- Division of Transfusion Medicine, Cellular Therapeutics and Hemostaseology, University Clinic LMU, Munich, Germany
| | - Andrea Dick
- Division of Transfusion Medicine, Cellular Therapeutics and Hemostaseology, University Clinic LMU, Munich, Germany
| | - Frank Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ulf Schönermarck
- Department of Medicine IV, University Hospital, LMU, Munich, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Luca Frulloni
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy, Division of Experimental Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU, Munich, Germany
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9
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Notohara K. Histological features of autoimmune pancreatitis and IgG4-related sclerosing cholangitis with a correlation with imaging findings. J Med Ultrason (2001) 2021; 48:581-594. [PMID: 34669070 DOI: 10.1007/s10396-021-01148-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022]
Abstract
Autoimmune pancreatitis (AIP) is characterized by a tumefactive inflammatory lesion resembling pancreatic carcinoma. Type 1 AIP is a pancreatic manifestation of IgG4-related disease characterized by unique histological features that can be identified on imaging. The capsule-like rim, which is a collar of hypertrophic lesion surrounding the pancreas, consists of lymphoplasmacytic infiltration and fibrosis, and storiform fibrosis is often identified. Hypertrophic lesions of various microscopic architectures such as the ducts, veins (obliterative phlebitis), arteries (periarteritis), and nerves are observed without parenchymal damage. The pancreatic lobules keep their contours, but the acinar cells are diminished and replaced by numerous inflammatory cells. These features provide clues to arrive at a diagnosis of type 1 AIP and to distinguish it from pancreatic carcinoma on imaging. In contrast, type 2 AIP is an epithelium-centered inflammation involving the ducts and lobules. Neutrophilic infiltration in the epithelium and/or lumens (granulocytic epithelial lesion) is a characteristic finding. Lobular swelling due to inflammation is the cause of pancreatic enlargement. IgG4-related sclerosing cholangitis is histologically similar to the hypertrophic ductal lesion in type 1 AIP and characterized by wall thickening due to inflammation and luminal stenosis. The epithelium is intact, which is different from bile duct carcinomas and primary sclerosing cholangitis, the latter of which is characterized by inflammation targeting the epithelium. Although the histological features of type 1 AIP and IgG4-related sclerosing cholangitis are unique, the biopsy diagnosis of these diseases has limitations, which should be recognized by clinicians.
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Affiliation(s)
- Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.
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Thatayatikom A, Jun I, Bhattacharyya I, Berg K, Lee YJ, Kim Y, Adewumi A, Zhang W, Thatayatikom S, Shah A, Beal C, Modica R, Elder ME, Cha S. The Diagnostic Performance of Early Sjögren's Syndrome Autoantibodies in Juvenile Sjögren's Syndrome: The University of Florida Pediatric Cohort Study. Front Immunol 2021; 12:704193. [PMID: 34249010 PMCID: PMC8267463 DOI: 10.3389/fimmu.2021.704193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/02/2021] [Indexed: 11/13/2022] Open
Abstract
Objectives The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in a recently identified pediatric cohort. Methods A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria. Demographic/clinical/laboratory parameters were compared between JSS (n = 27) and non-JSS (n = 78) for % positivity, sensitivity, and specificity of eSjA (SP1, anti-salivary protein; CA6, anti-carbonic anhydrase VI; PSP, anti-parotid secretory protein) and classic SS-autoantibodies (cSjA; ANA, SSA/SSB, RF, and others) either alone or in combination. Associations between eSjA and diagnostic/glandular parameters were also determined by Fisher's exact test. Results Compared to non-JSS, JSS patients exhibited sicca symptoms demonstrating reduced unstimulated salivary flow rate (USFR) and abnormal glandular features revealed by salivary gland ultrasound (SGUS). Among cSjA, ANA demonstrated the highest sensitivity of 69.2%, while SSA, SSB, and RF showed around 95% specificities for JSS diagnosis. The % positive-SSA was notably higher in JSS than non-JSS (56% vs. 5%). Of eSjA, anti-CA6 IgG was the most prevalent without differentiating JSS (37%) from non-JSS (32%). Sensitivity and specificity of eSjA were 55.6 and 26.9%, respectively. Autoantibodies with potentially applicable specificity/sensitivity for JSS were seen only in cSjA without a single eSjA included. There were no associations detected between eSjA and focus score (FS), USFR, SSA, SGUS, and parotitis/glandular swelling analyzed in the entire cohort, JSS, and non-JSS. However, a negative association between anti-PSP and parotitis/glandular swelling was found in a small group of positive-SSA (n = 19, p = 0.02) whereas no such association was found between anti-PSP-positive compared to anti-PSP-negative. JSS and non-JSS groups differed in FS, USFR, and EULAR SS Patient Reported Index Dryness/Mean in CA6/PSP/ANA, SP1, and SSA-positive groups, respectively. Additionally, a higher FS was found in RF-positive than RF-negative individuals. Conclusions eSjA underperformed cSjS in differentiating JSS from non-JSS. The discovery of clinical impact of eSjA on early diagnosis of JSS necessitates a longitudinal study.
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Affiliation(s)
- Akaluck Thatayatikom
- Department of Pediatrics, Division of Allergy, Immunology, Rheumatology, College of Medicine, University of Florida, Gainesville, FL, United States.,Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States
| | - Inyoung Jun
- Department of Epidemiology, College of Public Health and Health Professions & College of Medicine, University of Florida, Gainesville, FL, United States
| | - Indraneel Bhattacharyya
- Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States.,Division of Oral Pathology, Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL, United States
| | - Kathleen Berg
- Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States.,Division of Oral Medicine, Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL, United States
| | - Yun Jong Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Yoosik Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Abi Adewumi
- Department of Pediatric Dentistry, College of Dentistry, University of Florida, Gainesville, FL, United States
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Sthorn Thatayatikom
- Department of Pediatrics, Division of Allergy, Immunology, Rheumatology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Ankit Shah
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Casey Beal
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Renee Modica
- Department of Pediatrics, Division of Allergy, Immunology, Rheumatology, College of Medicine, University of Florida, Gainesville, FL, United States.,Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States
| | - Melissa E Elder
- Department of Pediatrics, Division of Allergy, Immunology, Rheumatology, College of Medicine, University of Florida, Gainesville, FL, United States.,Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States
| | - Seunghee Cha
- Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States.,Division of Oral Medicine, Department of Oral and Maxillofacial Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, FL, United States
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Review of Diagnostic Biomarkers in Autoimmune Pancreatitis: Where Are We Now? Diagnostics (Basel) 2021; 11:diagnostics11050770. [PMID: 33923064 PMCID: PMC8146865 DOI: 10.3390/diagnostics11050770] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/16/2022] Open
Abstract
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of an IgG4-related disease (IgG4-RD). AIP lacks disease-specific biomarkers, and therefore, it is difficult to distinguish AIP from malignancies, especially pancreatic cancer. In this review, we have summarized the latest findings on potential diagnostic biomarkers for AIP. Many investigations have been conducted, but no specific biomarkers for AIP are identified. Therefore, further studies are required to identify accurate diagnostic biomarkers for AIP.
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12
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Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol 2020; 16:702-714. [PMID: 32939060 DOI: 10.1038/s41584-020-0500-7] [Citation(s) in RCA: 200] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 12/14/2022]
Abstract
IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years.
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Affiliation(s)
- Cory A Perugino
- Massachusetts General Hospital, Division of Rheumatology, Allergy and Immunology, Boston, MA, USA.,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - John H Stone
- Massachusetts General Hospital, Division of Rheumatology, Allergy and Immunology, Boston, MA, USA.
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Hsieh SC, Shen CY, Liao HT, Chen MH, Wu CH, Li KJ, Lu CS, Kuo YM, Tsai HC, Tsai CY, Yu CL. The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease. Int J Mol Sci 2020; 21:ijms21145082. [PMID: 32708432 PMCID: PMC7404109 DOI: 10.3390/ijms21145082] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/09/2020] [Accepted: 07/14/2020] [Indexed: 12/16/2022] Open
Abstract
IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato–hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part.
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Affiliation(s)
- Song-Chou Hsieh
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
| | - Chieh-Yu Shen
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
| | - Hsien-Tzung Liao
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, Taipei 11217, Taiwan; (H.-T.L.); (M.-H.C.); (H.-C.T.)
| | - Ming-Han Chen
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, Taipei 11217, Taiwan; (H.-T.L.); (M.-H.C.); (H.-C.T.)
| | - Cheng-Han Wu
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
| | - Ko-Jen Li
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
| | - Cheng-Shiun Lu
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
| | - Yu-Min Kuo
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
| | - Hung-Cheng Tsai
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, Taipei 11217, Taiwan; (H.-T.L.); (M.-H.C.); (H.-C.T.)
| | - Chang-Youh Tsai
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, Taipei 11217, Taiwan; (H.-T.L.); (M.-H.C.); (H.-C.T.)
- Correspondence: (C.-Y.T.); (C.-L.Y.); Tel.: +886-2-28712121 (ext. 3366) (C.-Y.T.); +886-2-23123456 (ext. 65011) (C.-L.Y.)
| | - Chia-Li Yu
- Division of Rheumatology, Immunology & Allergy, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan; (S.-C.H.); (C.-Y.S.); (C.-H.W.); (K.-J.L.); (C.-S.L.); (Y.-M.K.)
- Correspondence: (C.-Y.T.); (C.-L.Y.); Tel.: +886-2-28712121 (ext. 3366) (C.-Y.T.); +886-2-23123456 (ext. 65011) (C.-L.Y.)
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Mentese A, Erkut N, Demir S, Yaman SO, Sumer A, Erdem M, Alver A, Sonmez M. Serum carbonic anhydrase I and II autoantibodies in patients with chronic lymphocytic leukaemia. Cent Eur J Immunol 2018; 43:276-280. [PMID: 30588172 PMCID: PMC6305617 DOI: 10.5114/ceji.2018.80046] [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] [Received: 09/29/2016] [Accepted: 12/18/2016] [Indexed: 01/09/2023] Open
Abstract
Cancer is the second most important cause of mortality, and millions of people either have or have had the disease. Leukaemia is one of the most common forms of cancer. Autoantibodies that have developed against the organism's self-antigens are detected in the sera of subjects with cancer. In recent years carbonic anhydrase (CA) autoantibodies have been determined in some autoimmune diseases and carcinomas, but the mechanisms underlying this immune response have not yet been fully explained. The purpose of this study was to determine CA I and II autoantibodies in subjects with chronic lymphocytic leukaemia (CLL) and to provide a novel perspective regarding the autoimmune basis of the disease. Autoantibody levels were investigated using enzyme-linked immunosorbent assay (ELISA) in serum samples from 37 patients with CLL and 37 healthy peers. Anti-CA I titres in the CLL group were significantly higher compared with the control group (p = 0.0001). However, there was no significant difference between CLL and control groups in terms of anti-CA II titres (p = 0.278). The prevalences of CA I and II autoantibodies in patients with CLL in this study were 27% and 24.3%, respectively. Our results suggest that these autoantibodies may be involved in the pathogenesis of CLL. More extensive studies are now needed to reveal the entire mechanism.
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Affiliation(s)
- Ahmet Mentese
- Program of Medical Laboratory Techniques, Vocational School of Health Sciences, Karadeniz Technical University, Trabzon, Turkey
| | - Nergiz Erkut
- Department of Haematology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Selim Demir
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, Trabzon, Turkey
| | - Serap Ozer Yaman
- Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Aysegul Sumer
- Department of Nursing, School of Health Services, Recep Tayyip Erdog¡an University, Rize, Turkey
| | - Mehmet Erdem
- Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Ahmet Alver
- Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Mehmet Sonmez
- Department of Haematology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
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Abstract
Type 1 autoimmune pancreatitis (AIP) is an IgG-4-related systemic disease that can manifest as a pancreatic disorder or another disorder of presumed autoimmune origin. Type 2 disease is typically characterized by absent IgG-4-positive cells. As patients often present with acute pancreatitis, obstructive jaundice, or pancreatic mass, it is imperative to exclude malignancy, a more common diagnosis. AIP may respond to corticosteroids, and has a strong association with other immune-mediated diseases. Recent literature suggests the benefit of immune-modulating therapy, including rituximab, although no consensus exists. This review covers the essentials of diagnosis, but focuses primarily on management of AIP.
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Affiliation(s)
- Kamraan Madhani
- Department of Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Department of Medicine, Waterbury Internal Medicine Residency Program, Waterbury Hospital, Yale New Haven Hospital, Main 3, 64 Robbins Street, Waterbury, CT 06708, USA
| | - James J Farrell
- Section of Digestive Diseases, Yale University School of Medicine, Yale Center for Pancreatic Disease, Yale University, LMP 1080, 15 York Street, New Haven, CT 06510, USA.
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Nagpal SJS, Sharma A, Chari ST. Autoimmune Pancreatitis. Am J Gastroenterol 2018; 113:1301. [PMID: 29910463 DOI: 10.1038/s41395-018-0146-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 05/04/2018] [Indexed: 12/11/2022]
Abstract
Over the course of the last 2 decades our knowledge of autoimmune pancreatitis has increased exponentially. In this review, we summarize the clinical presentation, diagnosis and treatment of AIP, to better allow general gastroenterologists and primary care providers to consider AIP as a as a rare but important cause of painless obstructive jaundice and recurrent acute pancreatitis. While steroids remain the mainstay of first line therapy, a number of patients with type 1 AIP require immunomodulators or rituximab to maintain remission; recommendations on the management of relapses continue to evolve.
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Affiliation(s)
| | - Ayush Sharma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Effect of anti-muscarinic autoantibodies on leukocyte function in Sjögren's syndrome. Mol Immunol 2017; 90:136-142. [PMID: 28750255 DOI: 10.1016/j.molimm.2017.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 07/04/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Patients with primary Sjögren's syndrome, a systemic autoimmune disease, have been shown to have serum autoantibodies that react with the muscarinic acetylcholine type 3 receptor (M3R).Primary Sjögren's syndrome is a systemic autoimmune disease. Patients with primary Sjögren's syndrome have been shown to have serum autoantibodies that react with the muscarinic acetylcholine type 3 receptor (M3R). Leukopenia has been reported to be significantly more common in primary Sjögren's syndrome patients who have anti-M3R-autoantibodies in their sera. In this study, we investigated whether these anti-M3R autoantibodies have effects on M3R and MHCI expression in Jurkat T cells. Purified IgG antibodies were isolated from the serum of healthy individuals and primary Sjögren's syndrome patients. Jurkat cell line was used to represent T lymphocytes. In situ immunofluorescence confocal microscopy was used to confirm the binding reactivity of primary Sjögren's syndrome IgG antibodies to M3R. Co-immunoprecipitation and immunofluorescence results suggested a direct interaction between M3R and MHC I. Co-internalization of M3R and MHC I was observed when Jurkat cells were exposed to the primary Sjögren's syndrome IgG, but this primary Sjögren's syndrome IgG-induced co-internalization of M3R and MHC I was prevented by the presence of exogenous IFN-γ. Primary Sjögren's syndrome IgG itself did not affect the viability of Jurkat cells, but Jurkat cells exposed to primary Sjögren's syndrome IgG were observed to undergo significant cell death when co-cultured with primary Natural Killer cells. Our results suggest that anti-M3R autoantibodies in primary Sjögren's syndrome induce downregulation of plasma membrane-resident M3R and MHC class I molecules in leukocytes followed by NK cell-mediated cell death. This mechanism may explain the frequency of leukopenia occurrence in patients with primary Sjögren's syndrome.
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18
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Ghassem-Zadeh S, Gaida MM, Szanyi S, Acha-Orbea H, Frossard JL, Hinz U, Hackert T, Strobel O, Felix K. Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma. J Transl Med 2017; 15:126. [PMID: 28578701 PMCID: PMC5457650 DOI: 10.1186/s12967-017-1227-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 05/27/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. METHODS To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. RESULTS Comparing AIP and PDAC patients' serum, significantly higher concentrations were found in AIP for interleukins IL-1β, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1β when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. CONCLUSIONS The cytokines IL-1β, IL-7, and G-CSF can be routinely measured in patients' serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment.
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Affiliation(s)
- Sahar Ghassem-Zadeh
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Matthias M. Gaida
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Szilard Szanyi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Hans Acha-Orbea
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Jean-Louis Frossard
- Department of Medical Specialties, Gastroenterology and Hepatology Division, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland
| | - Ulf Hinz
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Klaus Felix
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
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Detection of autoantibodies against carbonic anhydrase I and II in the plasma of patients with gastric cancer. Cent Eur J Immunol 2017; 42:73-77. [PMID: 28680333 PMCID: PMC5470616 DOI: 10.5114/ceji.2017.67320] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 06/06/2016] [Indexed: 12/18/2022] Open
Abstract
Cancer is the second leading cause of death and gastric cancer is the fourth most common cancer type worldwide. Investigation of autoantibodies in cancer patients has been a popular research area in recent years. The aim of the current study was to investigate carbonic anhydrase I and II (CA I and II) autoantibodies in the plasma of subjects with gastric cancer based on the information and considerations of autoimmune relation of gastric cancer. Anti-CA I and II antibody levels were investigated by ELISA in plasma samples of fifty two patients with gastric cancer and thirty five healthy peers. Anti-CA I and II antibody titers of the gastric cancer group were significantly higher compared with the control group (p = 0.004, p = 0.0001, respectively). Plasma anti-CA I levels of the metastatic group were lower than the non-metastatic group and this difference was found statistically significant (p < 0.05), but there was no statistical difference between plasma anti-CA II levels of the groups. CA I and II autoantibody titers in patients with gastric cancer were found higher compared to healthy subjects and the results suggest that these autoantibodies may be involved in the pathogenesis of gastric cancer.
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20
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Menteşe A, Erkut N, Demir S, Özer Yaman S, Sümer A, Doğramacı Ş, Alver A, Sönmez M. Autoantibodies Against Carbonic Anhydrase I and II in Patients with Acute Myeloid Leukemia. Turk J Haematol 2017; 34:307-313. [PMID: 28270370 PMCID: PMC5774362 DOI: 10.4274/tjh.2016.0341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
OBJECTIVE Cancer, one of the principal causes of death, is a global social health problem. Autoantibodies developed against the organism's self-antigens are detected in the sera of subjects with cancer. In recent years carbonic anhydrase (CA) I and II autoantibodies have been shown in some autoimmune diseases and carcinomas, but the mechanisms underlying this immune response have not yet been explained. The aim of this study was to evaluate CA I and II autoantibodies in patients with acute myeloid leukemia (AML) and to provide a novel perspective regarding the autoimmune basis of the disease. MATERIALS AND METHODS Anti-CA I and II antibody levels were investigated using ELISA in serum samples from 30 patients with AML and 30 healthy peers. RESULTS Anti-CA I and II antibody titers in the AML group were significantly higher compared with the control group (p=0.0001 and 0.018, respectively). A strong positive correlation was also determined between titers of anti-CA I and II antibodies (r=0.613, p=0.0001). CONCLUSION Our results suggest that these autoantibodies may be involved in the pathogenesis of AML. More extensive studies are now needed to reveal the entire mechanism.
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Affiliation(s)
- Ahmet Menteşe
- Karadeniz Technical University Vocational School of Health Sciences, Program of Medical Laboratory Techniques, Trabzon, Turkey
| | - Nergiz Erkut
- Karadeniz Technical University Faculty of Medicine, Department of Hematology, Trabzon, Turkey
| | - Selim Demir
- Karadeniz Technical University Faculty of Health Sciences, Department of Nutrition and Dietetics, Trabzon, Turkey
| | - Serap Özer Yaman
- Karadeniz Technical University Faculty of Medicine, Department of Medical Biochemistry, Trabzon, Turkey
| | - Ayşegül Sümer
- Recep Tayyip Erdoğan University Faculty of Health Services, Department of Nursing, Rize, Turkey
| | - Şeniz Doğramacı
- Karadeniz Technical University Faculty of Medicine, Department of Medical Biochemistry, Trabzon, Turkey
| | - Ahmet Alver
- Karadeniz Technical University Faculty of Medicine, Department of Medical Biochemistry, Trabzon, Turkey.,Recep Tayyip Erdoğan University Faculty of Medicine, Department of Medical Biochemistry, Rize, Turkey
| | - Mehmet Sönmez
- Karadeniz Technical University Faculty of Medicine, Department of Hematology, Trabzon, Turkey
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Lakota J, Vulic R, Dubrovcakova M, Tyciakova S. Sera of patients with spontaneous tumour regression and elevated anti-CA I autoantibodies change the gene expression of ECM proteins. J Cell Mol Med 2016; 21:543-551. [PMID: 27704726 PMCID: PMC5323822 DOI: 10.1111/jcmm.13000] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 08/29/2016] [Indexed: 12/20/2022] Open
Abstract
Spontaneous tumour regression after high‐dose therapy and autologous stem cell transplantation is associated with the aplastic anaemia‐like syndrome and the presence of polyclonal autoantibodies against carbonic anhydrase I (CA I). When tumour cells were grown in vitro in the presence of patients’ sera positive for anti‐CA I autoantibodies, their morphological pattern was altered. These changes were accompanied by modifications in the gene expression profile. We observed downregulation of genes of the basal lamina assembly (collagen type IV alpha 4, the laminin subunit gamma 2), the extracellular matrix (collagen type I alpha 1), the cytoskeleton (keratin 14 type I), the collagen triple helix repeat containing 1 and the proto‐oncogene WNT7B. On the other hand, the expression of the CA 1 gene was increased in the tumour cells. It was also noticed that the presence of anti‐CA I autoantibodies did not impair tumour cell proliferation and cell viability in vitro. These findings were observed only in the presence of patients’ sera positive for anti‐CA I autoantibodies.
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Affiliation(s)
- Jan Lakota
- Cancer Research Institute BMC SAS, Bratislava, Slovakia.,Institute of Normal and Pathological Physiology, SAS, Bratislava, Slovakia.,St. Elizabeth Cancer Institute, Bratislava, Slovakia
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22
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Nishita T, Miyazaki R, Miyazaki T, Ochiai H, Orito K. Antibodies reacting to carbonic anhydrase isozymes (I and II) and albumin in sera from dogs. Res Vet Sci 2016; 106:180-2. [PMID: 27234558 DOI: 10.1016/j.rvsc.2016.04.010] [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: 07/24/2015] [Revised: 04/26/2016] [Accepted: 04/29/2016] [Indexed: 11/19/2022]
Abstract
IgGs to carbonic anhydrase isozymes (CA-I and CA-II) and albumin were identified in dog serum. IgG titers were determined in the sera of asymptomatic dogs, and in dogs with atopic dermatitis, diarrhea and/or vomiting, diabetes and/or pancreatitis, kidney disease, hepatic disease, and thyroid gland disease, using ELISA. Low titres of IgG-reactive CA-I, CA-II, BSA, and CSA were found in the sera of healthy beagles. Compared with healthy beagles, there was a significant difference in the titers of antibodies against CA-I in asymptomatic dogs, dogs with diabetes and/or pancreatitis, or thyroid gland disease, or hepatic disease. Compared with healthy beagles, there was a significant difference in the antibody titer of anti-CA-II IgG in asymptomatic dogs and in those with hepatic disease. There was a significant difference in the antibody titer of anti-BSA IgG between healthy beagles and dogs with hepatic disease.
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Affiliation(s)
- Toshiho Nishita
- Laboratory of Physiology I, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 252-5201, Japan.
| | - Rui Miyazaki
- Laboratory of Physiology I, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 252-5201, Japan
| | - Takae Miyazaki
- Laboratory of Physiology I, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 252-5201, Japan
| | - Hideharu Ochiai
- Research Institute of Biosciences, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 252-5201, Japan
| | - Kensuke Orito
- Laboratory of Physiology II, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Sagamihara, Kanagawa 252-5201, Japan
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Madhani K, Farrell JJ. Autoimmune Pancreatitis: An Update on Diagnosis and Management. Gastroenterol Clin North Am 2016; 45:29-43. [PMID: 26895679 DOI: 10.1016/j.gtc.2015.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
There is an evolving understanding that autoimmune pancreatitis (AIP) is an immunoglobulin (Ig) G4 systemic disease. It can manifest as primarily a pancreatic disorder or in association with other disorders of presumed autoimmune cause. Classic clinical characteristics include obstructive jaundice, abdominal pain, and acute pancreatitis. Thus, AIP can be difficult to distinguish from pancreatic malignancy. However, AIP may respond to therapy with corticosteroids, and has a strong association with other immune mediated diseases. Although primarily a pathologic diagnosis, attempts have been made to reliably diagnose AIP clinically. AIP can be classified as either type 1 or type 2.
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Affiliation(s)
- Kamraan Madhani
- Yale-Waterbury Internal Medicine Residency Program, Yale University School of Medicine, New Haven, CT 06510, USA
| | - James J Farrell
- Yale Center for Pancreatic Disease, Section of Digestive Disease, Yale University, LMP 1080, 15 York Street, New Haven, CT 06510, USA.
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Regenerating Gene Protein as a Novel Autoantigen in the Pathogenesis of Sjögren’s Syndrome. Antibodies (Basel) 2015. [DOI: 10.3390/antib4040409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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25
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Tomoda T, Nouso K, Kato H, Miyahara K, Dohi C, Morimoto Y, Kinugasa H, Akimoto Y, Matsumoto K, Yamamoto N, Noma Y, Horiguchi S, Tsutsumi K, Amano M, Nishimura SI, Yamamoto K. Alteration of serum N-glycan profile in patients with autoimmune pancreatitis. Pancreatology 2015; 16:44-51. [PMID: 26723536 DOI: 10.1016/j.pan.2015.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 10/06/2015] [Accepted: 11/10/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aims of this study were to determine the change in whole-serum N-glycan profile in autoimmune pancreatitis (AIP) patients and to investigate its clinical utility. METHODS We collected serum from 21 AIP patients before any treatment, and from 60 healthy volunteers (HLTs). Serum glycan profile was measured by comprehensive and quantitative high-throughput glycome analysis. RESULTS Of the 53 glycans detected, 14 were differentially expressed in AIP patients. Pathway analysis demonstrated that agalactosyl and monogalactosyl bi-antennary glycans were elevated in AIP patients. Among the 14 glycans, #3410, #3510, and #4510 showed high area under receiver operating characteristic (AUROC) values (0.955, 0.964, and 0.968 respectively) for the diagnosis of AIP. These three glycans were mainly bound to immunoglobulin G; however, their serum levels were significantly higher, even in AIP patients who showed lower serum IgG4 levels, than in HLTs. CONCLUSIONS We demonstrated, for the first time, whole-serum glycan profiles of AIP patients and showed that the levels of glycans #3410, #3510, and #4510 were increased in AIP patients. These glycans might be valuable biomarkers of AIP.
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Affiliation(s)
- Takeshi Tomoda
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
| | - Kazuhiro Nouso
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hironari Kato
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Koji Miyahara
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Chihiro Dohi
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Yuki Morimoto
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Hideaki Kinugasa
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Yutaka Akimoto
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuyuki Matsumoto
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Naoki Yamamoto
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Yasuhiro Noma
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Shigeru Horiguchi
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Koichiro Tsutsumi
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Maho Amano
- Field of Drug Discovery Research, Faculty of Advanced Life Science & Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan; Medicinal Chemistry Pharmaceuticals, Co., Ltd., Sapporo, Hokkaido, Japan
| | - Shin-Ichiro Nishimura
- Field of Drug Discovery Research, Faculty of Advanced Life Science & Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan; Medicinal Chemistry Pharmaceuticals, Co., Ltd., Sapporo, Hokkaido, Japan
| | - Kazuhide Yamamoto
- Departments of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Loos M, Lauffer F, Schlitter AM, Kleeff J, Friess H, Klöppel G, Esposito I. Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis. Virchows Arch 2015; 467:641-648. [PMID: 26427656 DOI: 10.1007/s00428-015-1850-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 09/03/2015] [Accepted: 09/16/2015] [Indexed: 12/18/2022]
Abstract
Th17 cells have been shown to play an important role in the pathogenesis of a variety of autoimmune diseases. The aim of this study was to investigate the potential role of Th17 cells in autoimmune pancreatitis (AIP). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine gene expression of the signature cytokines of Th17 cells IL-17A and IL-21 and of the Th17 lineage-specific transcription factor retinoic acid receptor-related orphan receptor C (RORC) in human tissue specimens of AIP, classical chronic pancreatitis (CP), and normal pancreas (NP). Infiltrating immune cells were characterized by immunohistochemistry (IHC). Gene expression of IL-17A, IL-21, and RORC were found to be significantly increased in AIP. Accordingly, the number of Th17 cells was significantly increased in AIP compared to NP or CP. Both gene expression analysis and IHC revealed a clear difference between type 1 and 2 AIP. In the periductal compartment of type 2 AIP, which is characterized by granulocytic epithelial lesions (GELs), the number of infiltrating Th17 cells and neutrophilic granulocytes was significantly increased compared to type 1 AIP. Our data suggest that Th17 cells play a role in the pathogenesis of AIP, in particular of type 2 AIP. Cross-talk between Th17 cells and neutrophilic granulocytes mediated via IL-17A may be a potential mechanism by which neutrophils are recruited to the duct and acinar cells with subsequent destruction, a process that is pathognomonic for type 2 AIP.
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Affiliation(s)
- M Loos
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. .,Department of General, Visceral and Transplantation Surgery, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - F Lauffer
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.,Department of Dermatology and Allergy, Technische Universität München, Munich, Germany
| | - A M Schlitter
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - J Kleeff
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - H Friess
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - G Klöppel
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - I Esposito
- Institute of Pathology, Technische Universität München, Munich, Germany.,Institute of Pathology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
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Menteşe A, Erkut N, Sümer A, Us Altay D, Alver A, Sönmez M. Anti-carbonic anhydrase antibodies in iron deficiency anemia. Hematology 2014; 20:363-7. [DOI: 10.1179/1607845414y.0000000204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Ahmet Menteşe
- Department of Medical BiochemistryFaculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Nergiz Erkut
- Internal Medicine Division of HematologyFaculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
- Department of Hematology, Trabzon Kanuni Training and Research Hospital, Trabzon, Turkey
| | - Ayşegül Sümer
- Department of Medical BiochemistryFaculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Diler Us Altay
- Department of Medical BiochemistryFaculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Ahmet Alver
- Department of Medical BiochemistryFaculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Mehmet Sönmez
- Internal Medicine Division of HematologyFaculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
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Talar-Wojnarowska R, Gąsiorowska A, Olakowski M, Dranka-Bojarowska D, Lampe P, Śmigielski J, Kujawiak M, Grzegorczyk J, Małecka-Panas E. Utility of serum IgG, IgG4 and carbonic anhydrase II antibodies in distinguishing autoimmune pancreatitis from pancreatic cancer and chronic pancreatitis. Adv Med Sci 2014; 59:288-92. [PMID: 25194335 DOI: 10.1016/j.advms.2014.08.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Revised: 08/02/2014] [Accepted: 08/12/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE Autoimmune pancreatitis (AIP) can mimic pancreatic cancer in its clinical presentation, imaging features and laboratory parameters. The aim of our study was to compare IgG, IgG4 and anti-CAIIAb serum levels in patients with AIP, pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP) and to assess their clinical significance and utility in differential diagnosis of pancreatic diseases. PATIENT/METHODS The study included 124 patients: 45 with PA, 24 with AIP and 55 with CP. Peripheral venous blood samples were obtained from all analyzed patients at the time of hospital admission and total IgG, IgG4 and anti-CAIIAB serum levels were measured using ELISA tests. RESULTS Serum levels of IgG, IgG4 and anti-CAIIAb were significantly higher in patients with AIP compared to PA and CP patients (p<0.001). In AIP patients the median IgG levels were 19.7 g/l, IgG4 levels - 301.9 mg/dl and anti-CAIIAb - 81.82 ng/ml, compared to 10.61 g/l, 123.2mg/dl and 28.6 ng/ml, respectively, in PA patients. IgG4 for the cut-off 210 mg/dl showed the best sensitivity and specificity (83.8% and 89.5%) in AIP diagnosis compared to IgG (69.3% and 87.3%, respectively) and anti-CAIIAb (45.3% and 74.3%). However, 16 (35.5%) patients with PA and 14 (25.4%) patients with CP had IgG4 levels greater than 140 mg/dl. Moreover, in 3 (6.67%) patients with pancreatic cancer those values were greater than 280 mg/dl. No patients with CP had IgG4 more than 280 mg/dl. CONCLUSIONS IgG4 at cut-off 210 mg/dl showed the best sensitivity and specificity in AIP diagnosis compared to IgG and anti-CAIIAb, however elevations of serum IgG4 may be seen in subjects without AIP, including pancreatic cancer.
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Affiliation(s)
| | - Anita Gąsiorowska
- Department of Digestive Tract Diseases, Medical University of Lodz, Poland
| | - Marek Olakowski
- Department of Digestive Tract Surgery, Silesian Medical University, Katowice, Poland
| | | | - Paweł Lampe
- Department of Digestive Tract Surgery, Silesian Medical University, Katowice, Poland
| | - Jacek Śmigielski
- Department of Thoracic Surgery, General and Oncological Surgery, Medical University of Lodz, Poland
| | - Magdalena Kujawiak
- Department of Microbiology and Laboratory Medical Immunology, Faculty of Medicine, Medical University of Lodz, Poland
| | - Janina Grzegorczyk
- Department of Microbiology and Laboratory Medical Immunology, Faculty of Medicine, Medical University of Lodz, Poland
| | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Medical University of Lodz, Poland
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O’Reilly DA, Malde DJ, Duncan T, Rao M, Filobbos R. Review of the diagnosis, classification and management of autoimmune pancreatitis. World J Gastrointest Pathophysiol 2014; 5:71-81. [PMID: 24891978 PMCID: PMC4025075 DOI: 10.4291/wjgp.v5.i2.71] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 04/17/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, with as yet undetermined incidence and prevalence in the general population. Our understanding of it continues to evolve. In the last few years, 2 separate subtypes have been identified: type 1 AIP has been recognised as the pancreatic manifestation of a multiorgan disease, named immunoglobulin G4 (IgG4)-related disease while type 2 AIP is a pancreas specific disorder not associated with IgG4. International criteria for the diagnosis of AIP have been defined: the HISORt criteria from the Mayo clinic, the Japan consensus criteria and, most recently, the international association of pancreatology “International Consensus Diagnostic Criteria”. Despite this, in clinical practice it can still be very difficult to confirm the diagnosis and differentiate AIP from a pancreatic cancer. There are no large studies into the long-term prognosis and management of relapses of AIP, and there is even less information at present regarding the Type 2 AIP subtype. Further studies are necessary to clarify the pathogenesis, treatment and long-term outcomes of this disease. Critically for clinicians, making the correct diagnosis and differentiating the disease from pancreatic cancer is of the utmost importance and the greatest challenge.
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Jankovicova B, Skultety L, Dubrovcakova M, Stern M, Bilkova Z, Lakota J. Overlap of epitopes recognized by anti-carbonic anhydrase I IgG in patients with malignancy-related aplastic anemia-like syndrome and in patients with aplastic anemia. Immunol Lett 2013; 153:47-9. [PMID: 23892086 DOI: 10.1016/j.imlet.2013.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 07/17/2013] [Indexed: 11/16/2022]
Abstract
High titers of anti-carbonic anhydrase I (anti-CA I) autoantibodies were detected in the sera of patients with malignancies who developed an aplastic anemia-like (AA-like) syndrome after a high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). It was found, that the presence of these anti-CA I autoantibodies is associated with spontaneous tumor regression. The main immunodominant epitopes of carbonic anhydrase isoform I (CA I) have previously been identified using epitope extraction technique in combination with mass spectrometric detection and bioinformatic verification. Similarly, the sera of patients with bona fide aplastic anemia (AA) who poorly responded to immunosuppressive treatment with anti-thymocyte globulin (ATG) demonstrated high titers of anti-CA I antibodies. In order to reveal differences between these antibodies, we applied the same methodology of epitope mapping procedure. Surprisingly, the anti-CA I antibodies from the both groups of patients compatibly recognized the same four candidate CA I epitopes--DGLAV, NVGHS, SLKPI, SSEQL. This finding may indicate common pathophysiological mechanisms in these two syndromes. However, at this moment it remains unresolved if anti-CA I antibodies are implicated in marrow or tumor suppression or are just an epi-phenomenon.
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Affiliation(s)
- Barbora Jankovicova
- Department of Biological and Biochemical Sciences, University of Pardubice, Pardubice, Czech Republic
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Abstract
Autoimmune pancreatitis (AIP) is a rare, heterogeneous, fibroinflammatory disorder of the pancreas. It has gained increasing recognition due to a presentation that can mimic difficult-to-treat disorders such as pancreatic cancer, cholangiocarcinoma and primary sclerosing cholangitis. In contrast, autoimmune pancreatitis is a benign disease that is very responsive to therapy with corticosteroids. There are two types of AIP. Type 1 disease is the most common worldwide and is associated with extrapancreatic manifestations and elevated levels of IgG4-positive cells. Type 2 AIP is characterized by a paucity of IgG4-positive cells and is more difficult to diagnose. This review provides an update on the diagnosis, pathophysiology and treatment of AIP, with special emphasis on the two subtypes.
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Affiliation(s)
- Gyanprakash A. Ketwaroo
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Sunil Sheth
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Possible Involvement of Foxp3(+) Regulatory T Cells in the Development of Immune-Mediated Pancreatitis in MRL/Mp Mice Treated with Polyinosinic:Polycytidylic Acid. Int J Rheumatol 2013; 2013:367325. [PMID: 23781248 PMCID: PMC3678441 DOI: 10.1155/2013/367325] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Accepted: 04/29/2013] [Indexed: 12/24/2022] Open
Abstract
Objectives. This study was conducted to clarify whether or not Tregs are involved in the development of immune-mediated pancreatitis in MRL/Mp mice as an AIP (autoimmune pancreatitis) model, in order to understand more clearly the pathogenic mechanism of AIP. Methods. We compared the immunohistochemical features of pancreatic forkhead box P3 (Foxp3) in the administration of poly I:C in MRL/Mp mice and two types of control mice (BALB/c and C57BL/6). As a contrast, we analyzed three mouse models of pancreatitis without autoimmune mechanism (Cerulein-, Ligation-, and Ligation + Cerulein-treated mice). After staining these specimens, we compared the ratios of Foxp3-positive cells to infiltrated mononuclear cells (Foxp3/Mono). Results. Our immunohistochemical study of Foxp3 revealed that the infiltration of Foxp3-positive cells increased in poly I:C-treated MRL/Mp mice. The histopathological score of pancreatitis showed no difference among poly I:C-treated MRL/Mp, Ligation-, and Ligation + Cerulein-treated mice; however, the Foxp3/Mono ratio in poly I:C-treated MRL/Mp mice was significantly increased compared with Ligation- and Ligation + Cerulein-treated mice. Conclusions. MRL/Mp mice treated with poly I:C showed early development of pancreatitis with abundant infiltration of Foxp3-positive cells. There may be a possibility that Tregs are involved in the development of pancreatitis in these mice.
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Abstract
OBJECTIVES Type 1 autoimmune pancreatitis (AIP) is histologically characterized by dense lymphoplasmacytic infiltration and marked storiform fibrosis, manifestations associated with pancreatic ducts. Such periductal lymphocyte recruitment is thought to be elicited by dysregulation of mechanisms governing physiological lymphocyte homing. The present study was undertaken to determine whether vascular addressins including peripheral lymph node addressin and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) play a role in type 1 AIP histogenesis. METHODS Tissue sections of type 1 AIP and tumor-associated non-AIP chronic pancreatitis, as well as normal pancreas, were subjected to immunohistochemical analysis using vascular addressin-related antibodies. RESULTS The number of periductal mouse endothelial cell antigen 79-positive high endothelial venule (HEV)-like vessels was increased in type 1 AIP relative to that seen in non-AIP chronic pancreatitis, whereas the number of MAdCAM-1-positive HEV-like vessels did not differ between the 2 conditions. Mouse endothelial cell antigen 79 antigens are expressed on duct-forming epithelial cells not only in pancreas but also in salivary glands, which often harbor extrapancreatic lesions in type 1 AIP. CONCLUSIONS Type 1 AIP can be characterized by periductal induction of MECA-79-positive HEV-like vessels. MECA-79-positive 6-sulfo sialyl Lewis X-related carbohydrate antigens expressed on duct-forming epithelial cells could be associated with type 1 AIP pathogenesis.
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Abstract
This article reviews current understanding of the clinical manifestations, diagnosis and treatment of Sjögren's syndrome. Sjögren's syndrome is a chronic inflammatory disorder of the exocrine glands with multiple nonexocrine features. It is found predominantly in middle-aged women but exists throughout the population. The diagnosis of Sjögren's syndrome can be challenging because the cardinal sicca symptoms may be subclinical or attributed to other causes, such as medications or aging. Differential diagnosis of Sjögren's syndrome can be confounded by the multiple exocrine manifestations in the mouth, eyes, ears, nose, skin, vagina, and respiratory and gastrointestinal tracts, as well as seemingly unrelated nonexocrine involvement in the thyroid, liver, kidneys and the musculoskeletal, vascular and nervous systems. This article concludes that early diagnosis of Sjögren's syndrome is crucial to prevent and/or minimize potentially life-threatening complications. Periodic follow-up of patients' status and collaboration between the primary-care physician and the rheumatologist, dentist, ophthalmologist and other specialists are indispensable.
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Affiliation(s)
- Ibtisam Al-Hashimi
- Baylor College of Dentistry, Salivary Dysfunction Clinic, Department of Periodontics, 3302 Gaston Avenue, Dallas, TX 75246, USA and University of Texas Southwestern Medical Centre, Faculty of Surgery, Division of Oral Surgery, Dallas, TX, USA.
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Autoantibodies in autoimmune pancreatitis. Int J Rheumatol 2012; 2012:940831. [PMID: 22844291 PMCID: PMC3403403 DOI: 10.1155/2012/940831] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2011] [Revised: 04/19/2012] [Accepted: 04/21/2012] [Indexed: 12/24/2022] Open
Abstract
Autoimmune pancreatitis (AIP) was first used to describe cases of pancreatitis with narrowing of the pancreatic duct, enlargement of the pancreas, hyper-γ-globulinaemia, and antinuclear antibody (ANA) positivity serologically. The main differential diagnosis, is pancreatic cancer, which can be ruled out through radiological, serological, and histological investigations. The targets of ANA in patients with autoimmune pancreatitis do not appear to be similar to those found in other rheumatological diseases, as dsDNA, SS-A, and SS-B are not frequently recognized by AIP-related ANA. Other disease-specific autoantibodies, such as, antimitochondrial, antineutrophil cytoplasmic antibodies or diabetes-specific autoantibodies are virtually absent. Further studies have focused on the identification of pancreas-specific autoantigens and reported significant reactivity to lactoferrin, carbonic anhydrase, pancreas secretory trypsin inhibitor, amylase-alpha, heat-shock protein, and plasminogen-binding protein. This paper discusses the findings of these investigations and their relevance to the diagnosis, management, and pathogenesis of autoimmune pancreatitis.
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Alver A, Şentürk A, Çakirbay H, Menteşe A, Gökmen F, Keha E, Uçar F. Carbonic anhydrase II autoantibody and oxidative stress in rheumatoid arthritis. Clin Biochem 2011; 44:1385-9. [DOI: 10.1016/j.clinbiochem.2011.09.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Revised: 09/10/2011] [Accepted: 09/14/2011] [Indexed: 10/17/2022]
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Jin M, Hwang SM, Davies AJ, Shin Y, Bae JS, Lee JH, Lee EB, Song YW, Park K. Autoantibodies in primary Sjögren's syndrome patients induce internalization of muscarinic type 3 receptors. Biochim Biophys Acta Mol Basis Dis 2011; 1822:161-7. [PMID: 22137887 DOI: 10.1016/j.bbadis.2011.11.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 11/10/2011] [Accepted: 11/14/2011] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by lymphocyte infiltration into the salivary and lachrymal glands, leading to dry mouth and eyes. The presence of functional autoantibodies against muscarinic type 3 receptor (M3R) has been reported in pSS patients. However, the pathological role of anti-M3R autoantibodies in pSS salivary dysfunction remains controversial. METHODS Purified IgGs were obtained from normal (control) and primary SS patients' sera (pSS IgG). Internalization of M3R and clathrin was analyzed by biochemical assay and immunofluorescence confocal microscopy using human submandibular gland (hSMG) cells. Cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) was measured by microspectrofluorimetry. RESULTS Incubation of hSMG cells with pSS IgG (1mg/ml) significantly decreased M3R expression levels at the membrane. Carbachol-induced [Ca(2+)](i) transients (CICTs) in these cells were also inhibited by pSS IgG. In contrast to pSS IgG, control IgG had no effect on both the M3R expression level and CICTs. We found that binding of pSS IgG to M3R induces phosphorylation of the receptor, and that the pSS IgG-induced M3R internalization is prevented by the lysosomal inhibitor, chloroquine. In addition, pSS IgG decreased membrane clathrin expression, which was inhibited by atropine. Our immunofluorescence study further confirmed that pSS IgG induces a co-localization of M3R with clathrin and subsequent internalization of M3R. CONCLUSION pSS IgG induces internalization of M3R partly through a clathrin-mediated pathway. The results suggest M3R internalization as a potential mechanism to explain the exocrinopathy seen in pSS patients.
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Affiliation(s)
- Meihong Jin
- Department of Physiology, College of Medicine, Seoul National University and Dental Research Institute, Seoul 110-749, Republic of Korea
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Autoimmune pancreatitis mimicking pancreatic cancer. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:162-9. [PMID: 20811916 DOI: 10.1007/s00534-010-0321-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND/PURPOSE Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that can often be difficult to distinguish from pancreatic cancer. We describe the clinical and radiographic features of 23 patients with AIP whose presentations mimicked pancreatic cancer. METHODS A review of clinic, radiology, and endoscopy records from a 6-year period identified patients with AIP initially suspected of having pancreatic cancer. Abdominal computed tomography (CT) with intravenous contrast, endoscopic ultrasonography (EUS), and/or ERCP was performed in each patient. The diagnosis of AIP was made histologically and/or cytologically for each patient. RESULTS Nineteen of 23 patients (83%) presented with new-onset weight loss, jaundice, or both. Nineteen (83%) patients had CT findings worrisome for pancreatic cancer including: (1) pancreatic enlargement or focal mass, (2) regional lymphadenopathy, and/or (3) vascular invasion. Eighteen patients (78%) had common bile duct strictures on ERCP. EUS-guided fine-needle aspiration biopsies excluded pancreatic cancer in all 22 patients who had EUS (96%). Seven patients had surgery for continued suspicion of pancreatic cancer. CONCLUSIONS Although AIP commonly presents with features suggestive of pancreatic cancer, clinical recognition of AIP with appropriate diagnostic testing including EUS with fine-needle aspiration, ERCP, IgG4 levels, and pancreatic protocol CT expedites diagnosis and can spare patients unnecessary surgery.
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Pezzilli R, Vecchiarelli S, Di Marco MC, Serra C, Santini D, Calculli L, Fabbri D, Rojas Mena B, Imbrogno A. Pancreatic ductal adenocarcinoma associated with autoimmune pancreatitis. Case Rep Gastroenterol 2011; 5:378-85. [PMID: 21769291 PMCID: PMC3134062 DOI: 10.1159/000330291] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Autoimmune pancreatitis (AIP), in contrast to other benign chronic pancreatic diseases, can be cured with immunosuppressant drugs, thus the differentiation of AIP from pancreatic cancer is of particular interest in clinical practice. There is the possibility that some patients with AIP may develop pancreatic cancer, and this possibility contributes to increasing our difficulties in differentiating AIP from pancreatic cancer. We herein report the case of a 70-year-old man in whom pancreatic adenocarcinoma and AIP were detected simultaneously. We must carefully monitor AIP patients for the simultaneous presence of pancreatic cancer, even when a diagnosis of AIP is confirmed.
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Affiliation(s)
- Raffaele Pezzilli
- Pancreas Unit, Department of Digestive Diseases and Internal Medicine, University of Bologna, Bologna, Italy
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Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model. J Biomed Biotechnol 2011; 2011:407031. [PMID: 21660135 PMCID: PMC3110304 DOI: 10.1155/2011/407031] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Revised: 02/08/2011] [Accepted: 03/08/2011] [Indexed: 11/30/2022] Open
Abstract
Sjögren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS-B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity.
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Giday SA, Khashab MA, Buscaglia JM, Krishnamurty DM, Chen T, Kalloo AN, Canto MI, Okolo PI, Hruban RH, Jagannath SB. Autoimmune pancreatitis: current diagnostic criteria are suboptimal. J Gastroenterol Hepatol 2011; 26:970-3. [PMID: 21299615 DOI: 10.1111/j.1440-1746.2011.06683.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS The preoperative diagnosis of autoimmune pancreatitis (AIP) is difficult, given its similar clinical presentation to pancreatic cancer. The aims of the study are to describe our center's experience with AIP and apply the Japanese AIP diagnostic criteria to a cohort of patients with histologically-proven AIP in order to assess their performance characteristics. METHODS A prospective pathology database was queried for AIP patients who were evaluated and/or treated at Johns Hopkins Hospital from 2002 to 2009. AIP histology was defined by the presence of lymphoplasmacytic infiltration, periductal inflammation, fibrosis, and periphlebitis. Imaging, clinical, and biochemical data were analyzed. RESULTS Thirty patients had pancreatic resection with pathological confirmation of AIP. Imaging revealed pancreatic mass (45%), focal prominence without mass lesion (24%), diffuse enlargement (17%), and normal pancreas (14%). Twenty-four patients underwent an endoscopic retrograde cholangiopancreatography and/or magnetic resonance cholangiopancreatography, and 4/24 (17%) had pancreatic ductal narrowing or irregularity. Extrapancreaticobiliary organ involvement was found in 6% (n = 2) of patients. Biliary strictures were present in 87% of patients. Of 16 patients who underwent preoperative tissue biopsy, 10 had non-diagnostic pathology, five had cellular atypia, and one had AIP. Serum immunoglobulin G4 (IgG4) levels were elevated in 12 of 29 (41%) patients. Three (10%) patients had evidence of extrapancreatic manifestations of AIP. When applying the Japanese criteria to the 27 patients who had serum IgG4 measurement, preoperative biopsy, and cross-sectional abdominal imaging, only 44% of the patients would have been diagnosed accurately. CONCLUSIONS When applied to a highly-selected single-center referral population in the USA, current Japanese guidelines for the diagnosis of AIP are found to have suboptimal sensitivity.
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Affiliation(s)
- Samuel A Giday
- Department of Medicine and Division of Gastroenterology and Hepatology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
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Aliyazicioglu R, Guven S, Mentese A, Kolayli S, Cengiz S, Deger O, Alver A. Serum Anti-Carbonic Anhydrase II Antibodies and Oxidant-Antioxidant Balance in Pre-eclampsia. Am J Reprod Immunol 2011; 66:297-303. [DOI: 10.1111/j.1600-0897.2011.00981.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Current concepts: mouse models of Sjögren's syndrome. J Biomed Biotechnol 2010; 2011:549107. [PMID: 21253584 PMCID: PMC3018660 DOI: 10.1155/2011/549107] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 11/10/2010] [Indexed: 11/18/2022] Open
Abstract
Sjögren's syndrome (SjS) is a complex chronic autoimmune disease of unknown etiology which primarily targets the exocrine glands, resulting in eventual loss of secretory function. The disease can present as either primary SjS or secondary SjS, the latter of which occurs concomitantly with another autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or primary biliary cirrhosis. Current advancements in therapeutic prevention and treatment for SjS are impeded by lack of understanding in the pathophysiological and clinical progression of the disease. Development of appropriate mouse models for both primary and secondary SjS is needed in order to advance knowledge of this disease. This paper details important features, advantages, and pitfalls of current animal models of SjS, including spontaneous, transgenic, knockout, immunization, and transplantation chimera mouse models, and emphasizes the need for a better model in representing the human SjS phenotype.
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Nguyen CQ, Peck AB. Inflammation in dry eye diseases culminating in loss of ocular homeostasis. EXPERT REVIEW OF OPHTHALMOLOGY 2010. [DOI: 10.1586/eop.10.51] [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: 11/08/2022]
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Barth E, Savides TJ. Autoimmune pancreatitis. Expert Rev Clin Immunol 2010; 5:801-11. [PMID: 20477698 DOI: 10.1586/eci.09.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Autoimmune pancreatitis is becoming a more widely recognized form of pancreatitis that can mimic pancreatic or biliary malignancy. The combination of serological, histological and radiographic findings makes it unique among pancreatic diseases. The presence of autoantibodies, IgG4 and a lymphoplasmacytic infiltrate reflect its autoimmune etiology. The dramatic response to steroids is also a distinguishing feature and differentiates it from other pancreatic diseases.
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Affiliation(s)
- Erin Barth
- Department of Medicine, University of California, San Diego, CA, USA
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Devauchelle-Pensec V, Cagnard N, Pers JO, Youinou P, Saraux A, Chiocchia G. Gene expression profile in the salivary glands of primary Sjögren's syndrome patients before and after treatment with rituximab. ACTA ACUST UNITED AC 2010; 62:2262-71. [DOI: 10.1002/art.27509] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Alver A, Menteşe A, Erem C, Değer O, Koçak M, Keha EE. Serum carbonic anhydrase autoantibodies in metabolic syndrome. Diabetes Metab Syndr 2009. [DOI: 10.1016/j.dsx.2009.07.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Karahan SC, Guven S, Mentese A, Bacak A, Kopuz M, Ozeren M. Serum anti-carbonic anhydrase I and II antibodies and idiopathic recurrent pregnancy loss. Reprod Biomed Online 2009; 19:859-63. [DOI: 10.1016/j.rbmo.2009.09.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Frulloni L, Lunardi C, Simone R, Dolcino M, Scattolini C, Falconi M, Benini L, Vantini I, Corrocher R, Puccetti A. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med 2009; 361:2135-42. [PMID: 19940298 DOI: 10.1056/nejmoa0903068] [Citation(s) in RCA: 245] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Autoimmune pancreatitis is characterized by an inflammatory process that leads to organ dysfunction. The cause of the disease is unknown. Its autoimmune origin has been suggested but never proved, and little is known about the pathogenesis of this condition. METHODS To identify pathogenetically relevant autoantigen targets, we screened a random peptide library with pooled IgG obtained from 20 patients with autoimmune pancreatitis. Peptide-specific antibodies were detected in serum specimens obtained from the patients. RESULTS Among the detected peptides, peptide AIP(1-7) was recognized by the serum specimens from 18 of 20 patients with autoimmune pancreatitis and by serum specimens from 4 of 40 patients with pancreatic cancer, but not by serum specimens from healthy controls. The peptide showed homology with an amino acid sequence of plasminogen-binding protein (PBP) of Helicobacter pylori and with ubiquitin-protein ligase E3 component n-recognin 2 (UBR2), an enzyme highly expressed in acinar cells of the pancreas. Antibodies against the PBP peptide were detected in 19 of 20 patients with autoimmune pancreatitis (95%) and in 4 of 40 patients with pancreatic cancer (10%). Such reactivity was not detected in patients with alcohol-induced chronic pancreatitis or intraductal papillary mucinous neoplasm. The results were validated in another series of patients with autoimmune pancreatitis or pancreatic cancer: 14 of 15 patients with autoimmune pancreatitis (93%) and 1 of 70 patients with pancreatic cancer (1%) had a positive test for anti-PBP peptide antibodies. When the training and validation groups were combined, the test was positive in 33 of 35 patients with autoimmune pancreatitis (94%) and in 5 of 110 patients with pancreatic cancer (5%). CONCLUSIONS The antibody that we identified was detected in most patients with autoimmune pancreatitis but also in some patients with pancreatic cancer, making it an imperfect test to distinguish between these two conditions.
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Affiliation(s)
- Luca Frulloni
- Section of Gastroenterology, University of Verona, Verona, Italy
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