Differential Diagnosis of Autoimmune Pancreatitis From Pancreatic Cancer by Analysis of Serum Gelatinase Levels

Felix, Klaus; Dobiasch, Sophie; Gaida, Matthias M.; Schneider, Kathrin; Werner, Jens; Martens, Erik; Vandooren, Jennifer; Opdenakker, Ghislain

doi:10.1097/mpa.0000000000000576

Cited by 6 publications

(2 citation statements)

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“…1c ) were significantly altered in achalasia versus control. In many inflammatory diseases, the ratio of MMP-9 versus MMP-2 is a useful marker 23 , 25 , 27 , 28 , as was corroborated here in achalasia versus controls (Fig. 1d ).…”

Section: Resultssupporting

confidence: 78%

Gelatinase B/Matrix Metalloproteinase-9 as Innate Immune Effector Molecule in Achalasia

Furuzawa‐Carballeda

Boon

Torres‐Villalobos

et al. 2018

Clinical and Translational Gastroenterology

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ObjectivesAchalasia is a primary esophageal motility disorder resulting from selective loss of inhibitory neurons in the esophageal myenteric plexus, likely due to an autoimmune response with involvement of the adaptive immune system. Innate immune processes of the host constitute the bridge between environmental etiological factors and the adaptive immune system. Although these remain poorly investigated, they might be of diagnostic and therapeutic relevance. In view of the role of extracellular proteolysis in organ-specific autoimmunity, we studied gelatinases of the matrix metalloproteinase (MMP) family in achalasia patients.MethodsThe presence of MMP-2 and MMP-9 proteoforms was analyzed in sera of two cohorts of achalasia patients. Additionally, with the use of immunohistopathological analysis, in situ MMP-2 and MMP-9 expression was investigated. Finally, we tested the paradigm of remnant epitopes generating autoimmunity (REGA) for achalasia-associated autoantigens by evaluating whether autoantigenic proteins are cleaved by MMP-9 into remnant epitopes.ResultsWe showed significantly increased ratios of MMP-9/MMP-2 and activated MMP-9/proMMP-9 in sera of achalasia patients (n = 88) versus controls (n = 60). MMP-9-positive and MMP-2-positive cells were more abundant in achalasia (n = 49) versus control biopsies from transplant donors (n = 10). Furthermore, extensive damage within the plexus was found in the tissues with more MMP-9-positive cells. Additionally, we documented achalasia-associated autoantigens PNMA2, Ri, GAD65, and VIP as novel MMP-9 substrates.ConclusionsWe provide new biomarkers and insights into innate immune mechanisms in the autoimmune pathology of achalasia. Our results imply that extracellular protease inhibition is worthwhile to test as therapeutic intervention in achalasia.

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Section: Resultssupporting

confidence: 78%

Gelatinase B/Matrix Metalloproteinase-9 as Innate Immune Effector Molecule in Achalasia

Furuzawa‐Carballeda

Boon

Torres‐Villalobos

et al. 2018

Clinical and Translational Gastroenterology

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“…Applying a multiplex ELISA for IL-1β, IL-7, and G-CSF on patients’ serum would also allow AIP-2 to be distinguished from PDAC. Combining them with the recently identified gelatinases A and B and apolipoproteins Apo-AI and Apo-AII as discriminatory parameters [50–52] in a multiplex format, this could form the basis for a clinically applicable blood test, allowing reliable distinction between AIP and PDAC. This test would warrant immune-suppressive therapy without surgery for AIP patients and immediate surgical and chemotherapeutical treatment of PDAC patients.…”

Section: Discussionmentioning

confidence: 99%

Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma

et al. 2017

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BackgroundDiscriminating 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.MethodsTo 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.ResultsComparing 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1227-3) contains supplementary material, which is available to authorized users.

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Serum apolipoprotein A2 isoforms in autoimmune pancreatitis

Kobayashi

Sato

Nishiumi

et al. 2018

Biochemical and Biophysical Research Communications

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Recently, apolipoprotein A2 (apoA2) isoforms have been reported as candidate serum/plasma biomarkers of pancreatic cancer. However, the distribution of apoA2 isoforms in patients with autoimmune pancreatitis (AIP) has not been investigated yet. In this study, we evaluated the distribution of serum apoA2 isoforms; i.e., homodimer apoA2-ATQ/ATQ, heterodimer apoA2-ATQ/AT, and homodimer apoA2-AT/AT, in AIP patients and healthy volunteers (HV) using enzyme-linked immunosorbent assays, and the clinical characteristics and serum levels of each apoA2 isoform in 32 AIP patients and 38 HV were investigated. The calculated apoA2-ATQ/AT levels of the AIP patients were significantly lower than those of the HV, which agreed with results obtained for patients with pancreatic cancer. Interestingly, most of the AIP patients exhibited high levels of apoA2-ATQ along with low levels of apoA2-AT, indicating that the processing of the C-terminal regions of apoA2 dimer was inhibited in the AIP patients. This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer.

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Differential Diagnosis of Autoimmune Pancreatitis From Pancreatic Cancer by Analysis of Serum Gelatinase Levels

Abstract: Differential gelatinase serum profiles as AIP markers, together with other clinical tests, help to assure the diagnosis of PDAC or AIP.

Cited by 6 publications

References 44 publications

Gelatinase B/Matrix Metalloproteinase-9 as Innate Immune Effector Molecule in Achalasia

Gelatinase B/Matrix Metalloproteinase-9 as Innate Immune Effector Molecule in Achalasia

Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma

Serum apolipoprotein A2 isoforms in autoimmune pancreatitis

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