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, 17 (3), 395-402

No Evidence to Support a Role for Helicobacter Pylori Infection and Plasminogen Binding Protein in Autoimmune Pancreatitis and IgG4-related Disease in a UK Cohort

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No Evidence to Support a Role for Helicobacter Pylori Infection and Plasminogen Binding Protein in Autoimmune Pancreatitis and IgG4-related Disease in a UK Cohort

Emma L Culver et al. Pancreatology.

Abstract

Background and objectives: Helicobacter pylori (H.pylori) plasminogen binding protein (PBP) has been proposed as an antigen triggering autoimmune pancreatitis (AIP), the pancreatic manifestation of IgG4-related disease (IgG4-RD). We investigated exposure to H. pylori infection, cytokine response and immunological memory to H. pylori PBP in a prospective IgG4-RD cohort in the UK.

Methods: Clinical and endoscopic evidence of peptic ulceration, serological H. pylori exposure and serum IgG4 levels were obtained in 55 IgG4-RD patients and 52 disease controls (DC) with autoimmune or inflammatory conditions with an elevated serum IgG4. Gastric and duodenal tissues were assessed for H. pylori and immunostained for IgG4. B and T cell ELISpot and cytokine luminex assays were used to detect immune responses to H. pylori PBP.

Results: 85% of IgG4-RD patients had pancreatic and/or biliary disease, 89% had extra-pancreatic manifestations, and 84% had an increased serum IgG4. Clinical dyspepsia (35.2%), gastritis (58%), peptic ulceration (7.4%) and H. pylori colonisation (24%) in IgG4-RD was similar to DC. In IgG4-RD, gastric tissue contained a chronic inflammatory infiltrate with a low IgG4+ plasma-cell count (<10/HPF; range 1-4/HPF), and duodenal specimens had an increased IgG4 count (>10/HPF; range 7-54) compared with DC (p < 0.01). Th1 and Th2 cytokine response and immunological B-cell memory to H. pylori PBP did not differ between IgG4-RD and DC.

Conclusions: In a prospective UK cohort, the prevalence of gastric ulceration, exposure to H. pylori, cytokine response and immunological memory to H. pylori PBP did not differ in IgG4-RD patients compared with DC. This study does not support a role for H. pylori PBP as a microbial antigen in IgG4-RD.

Keywords for abstract: Peptic ulceration, Antigens, B cells, T cells, Interleukins, Helicobacter pylori.

Keywords: Adaptive immunity; Autoimmune pancreatitis; Helicobacter pylori; IgG4; IgG4-related disease.

Figures

Fig. 1.
Fig. 1.
Total INF-γ T cell response to PBP in IgG4-RD patients and disease controls. Errors bars show the SEM. Mann-Whitney p values; ns ≥ 0.05. SFU: spot-forming units (per 106 PBMCs).
Fig. 2.
Fig. 2.
Mean IFN-γ T cell response to individual PBP peptide pools in IgG4-RD patients and disease controls. Peptide pools 1 to 8, positive controls (Con A, FEC and H. pylori lysate) and negative controls (R10-medium and DMSO) are shown on the X-axis. Con A: Concanavalin A; FEC: mixed HLA class I restricted peptides from cytomegalovirus, Epstein Barr virus and influenza; SFU: spot-forming units (per 106 PBMCs).
Fig. 3
Fig. 3
IFN-γ T cell response to H. pylori lysate in individuals with positive and negative anti-H. pylori IgG serology. Patients and disease controls were grouped and divided into those with positive and negative anti-H. pylori IgG serology. The dashed line represents the cut-off for a positive response: >10 spot-forming units (SFU) per 106 PBMCs. Median values are given for both groups. Mann-Whitney p value; ****p < 0.0001.
Fig. 4
Fig. 4
Th2 cytokine response in IgG4-RD patients, disease controls and healthy controls. Dot plots of the concentrations of the Th2 cytokines IL4, IL5 and IL13 in supernatants derived from cultured B cell ELISpots. In this assay PBMCs were stimulated non-specifically for 6 days, which elicits lymphocyte expansion and cytokine production. Kruskal-Wallis test with multiple comparisons p values; ns p ≥ 0.05.
Fig. 5
Fig. 5
Total IgG responses in IgG4-RD patients and disease controls. A (Left): Total IgG response in IgG4-RD patients and disease controls with elevated serum IgG4. Errors bars show the SEM. Mann-Whitney p values; ns p ≥ 0.05. B (Right): IgG response to PBP peptide pools 1–4 and 5–8, and H. pylori whole lysate in IgG4-RD patients and disease controls with an elevated serum IgG4. Errors bars show the median. SFU: spot-forming units (per 106 PBMCs).
Fig. 6
Fig. 6
(A): DAB-positive (brown) IgG4-positive plasma cells in gastric tissue of an AIP patient. (B):H. pylori-associated gastritis with lymphocytes and neutrophils in an AIP patient. (C): DAB-positive (brown) IgG4-positive plasma cells in a duodenal biopsy in a patient with AIP (IgG4 cells >10 per high power field).

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