Autoantibodies Against the Exocrine Pancreas in Autoimmune Pancreatitis: Gene and Protein Expression Profiling and Immunoassays Identify Pancreatic Enzymes as a Major Target of the Inflammatory Process

Löhr, Matthias; Faissner, Ralf; Koczan, Dirk; Bewerunge, Peter; Bassi, Claudio; Brors, Benedikt; Eils, Roland; Frulloni, Luca; Funk, A.; Halangk, Walter; Jesnowski, Ralf; Kaderali, Lars; Kleeff, Jörg; Krüger, Burkhard; Lerch, Markus M.; Lösel, Ralf; Magnani, Mauro; Neumaier, Michael; Nittka, Stefanie; Sahin–Tóth, Miklós; Sänger, Julian; Serafini, Sonja; Schnölzer, Martina; Thierse, Hermann‐Josef; Wandschneider, Silke; Zamboni, Giuseppe; Klöppel, Günter

doi:10.1038/ajg.2010.141

Cited by 142 publications

(94 citation statements)

References 48 publications

(67 reference statements)

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“…Moreover, HCO 3-and H+ are produced by a carbonic anhydrase, such as CA4, from CO 2 derived from the blood. The CA4 subfamily F member 1 (ABCF1) as well as the ATP-binding cassette have been reported to be antigens in the autoimmune pancreatitis that represents the 2%-4% of cases of CP (48,49) and two patients present a variant in one of these two genes. We also found variants in genes encoding proteins involved in calcium (Ca 2+ ) signaling and ZG exocytosis (ITPR3, STIM1, TRPC3, ATP2C2, PIK3CG, PRKCD, TRPV1, TRPV5, TRPV6, GP2, RAB27B and DMBT) in a total of 26 patients.…”

Section: Discussionmentioning

confidence: 99%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

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Genetic features of chronic pancreatitis (CP) have been investigated extensively, mainly by testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. A total of 80 patients with idiopathic chronic pancreatitis (ICP) were investigated using a Next-Generation Sequencing (NGS) approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen, modifier genes of cystic fibrosis phenotype, pancreatic secretion and ion homeostasis, calcium signaling and zymogen granules (ZG) exocytosis, autophagy and autoimmune pancreatitis-related genes. We detected mutations in 34 out of 70 genes examined; of the 80 patients, 64 (80.0%) were positive for mutations in one or more genes and 16 (20.0%) had no mutations. Mutations in CFTR were detected in 32 of the 80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38 (59.3%) of the 64 patients positive for mutations showed variants in two or more genes. Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in CP and that trans-heterozygosity may predispose to the ICP phenotype. online address: http://www.molmed.org

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Section: Discussionmentioning

confidence: 99%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

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“…Auto-antibodies have been detected in human AIP against carbonic anhydrase II (anti-CA-II), lactoferrin (anti-LF) and trypsinogen [8]. Current studies revealed that approximately 40% of AIP patients suffer from extra-pancreatic manifestations involving liver, salivary glands, retroperitoneum or kidneys [9].…”

Section: Introductionmentioning

confidence: 99%

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

Seleznik¹,

Reding²,

Romrig

et al. 2012

Gastroenterology

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BACKGROUND AIMS:: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to development of AIP and new therapeutic strategies. METHODS:: We used quantitative PCR, immunohistochemical and ELISA analyses to measure expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing LT and specifically in acinar cells ( Ela1-LTab mice). RESULTS:: mRNA levels of lymphotoxin (LT) and were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines ( CXCL13, CCL19, CCL21, CCL1 and BAFF) was increased in pancreatic and serum samples from patients. Upregulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LT (Ela1-LT) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LT did not cause autoimmunity in mice without lymphocytes(Ela1-LTab/Rag1(-/-)); moreover lack of pro-inflammatory monocytes (Ela1-LTab/Ccr2-/-) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as anti-pancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS:: Overexpression of LT specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LT R ligands might be used to treat patients with AIP.

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“…However, the primary etiology of this cell expansion is still unknown. Autoantigens (1,16,24,25), infection (4,15), and allergy may be responsible for the primary etiology of IgG4-RD, but the issue remains unresolved. + lymphoid follicle was also confirmed by multicolor staining (white arrow).…”

Section: Discussionmentioning

confidence: 99%

CD14+ follicular dendritic cells in lymphoid follicles may play a role in the pathogenesis of IgG4-related disease

et al. 2015

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Proliferated IgG4+ plasma cells are polyclonal, suggesting that the pathogenesis of IgG4-related disease (IgG4-RD) involves upstream events related to the regulation of IgG4 expansion. We hypothesized that lymphoid follicle formation may play an important role in the pathogenesis of IgG4-RD. Using various antibodies, especially against monocyte, macrophage, and follicular dendritic cell markers, we immunohistochemically assessed the distribution of immune cells in lymphoid follicles. Pathological findings of tissue samples from patients with IgG4-RD (n = 22), reactive hyperplasia (n = 3), multicentric Castleman's disease (n = 3), and Sjögren's syndrome (n = 13) were analyzed. CD14-positive lymphoid follicles were observed only in patients with IgG4-RD, and CD14-positive cells were identified as follicular dendritic cells by multicolor immunohistochemistry. There were few differences in the distributions of other cell types between the IgG4-RD and control groups. The presence of CD14 + follicular dendritic cells in lymphoid follicles may play a pathophysiological role in IgG4-RD.IgG4-related disease (IgG4-RD) is a newly established clinical entity with a relatively high incidence rate in Japan (7). Patients with IgG4-RD show organ enlargement or nodular/hyperplastic lesions in various organs concurrently or metachronously because of marked infiltration of lymphocytes and IgG4 + plasma cells, as well as fibrosis of unknown etiology. Symptoms are dependent on the organs involved and may include occlusion or compression due to organ enlargement or hypertrophy and organ function failure due to fibrosis, and some patients may develop severe complications (17,33,36). The diagnosis of IgG4-RD is based on the presence of hyper-IgG4-gammaglobulinemia (≥135 mg/dL) and an increased number of IgG4 + plasma cells, defined as an IgG4 + /IgG + cell ratio >40%, and >10 IgG4 + plasma cells per high power field. Some patients with other disorders such as cancer, lymphoma, vasculitis, sarcoidosis, and multicentric Castleman's disease also have hyper-IgG4-gammaglobulinemia and/ or elevated IgG4 + cell numbers in the affected tissues, making it necessary to distinguish among these disorders that differ in their clinical course and prognosis. Because IgG4-RD shows a good glucocorticoid responsiveness (2, 7, 10-13, 16-20, 28, 33, 36, 37, 40), diagnosis is directly related to therapeutic strategy. The histopathological characteristics of IgG4-RD are as follows (2,16,19,28): 1) massive lymphocyte and IgG4 + plasma cell infiltration forming lymphoid follicles is a typical feature, whereas duct destruction due to lymphoid cell infiltration into the duct epithelium (lymphoepithelial lesions) is very rare, and therefore organ swelling occurs without impaired secretion or dryness; 2) sclerotic changes or fibrosis

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Autoantibodies Against the Exocrine Pancreas in Autoimmune Pancreatitis: Gene and Protein Expression Profiling and Immunoassays Identify Pancreatic Enzymes as a Major Target of the Inflammatory Process

Cited by 142 publications

References 48 publications

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Lymphotoxin β Receptor Signaling Promotes Development of Autoimmune Pancreatitis

<b>CD14</b><sup><b>+</b></sup><b> follicular dendritic cells in lymphoid follicles may play a role in the pathogenesis of IgG4-related </b><b>disease </b>

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