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Immunoglobulin G4(+) B-cell Receptor Clones Distinguish Immunoglobulin G 4-related Disease From Primary Sclerosing Cholangitis and Biliary/Pancreatic Malignancies

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Immunoglobulin G4(+) B-cell Receptor Clones Distinguish Immunoglobulin G 4-related Disease From Primary Sclerosing Cholangitis and Biliary/Pancreatic Malignancies

Marieke E Doorenspleet et al. Hepatology.

Abstract

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) of the biliary tree and pancreas is difficult to distinguish from sclerosing cholangitis and biliary/pancreatic malignancies (CA). An accurate noninvasive test for diagnosis and monitoring of disease activity is lacking. We demonstrate that dominant IgG4(+) B-cell receptor (BCR) clones determined by next-generation sequencing accurately distinguish patients with IgG4-associated cholangitis/autoimmune pancreatitis (n = 34) from those with primary sclerosing cholangitis (n = 17) and CA (n = 17). A novel, more affordable, and widely applicable quantitative polymerase chain reaction (qPCR) protocol analyzing the IgG4/IgG RNA ratio in blood also achieves excellent diagnostic accuracy (n = 125). Moreover, this qPCR test performed better than serum IgG4 levels in sensitivity (94% vs. 86%) and specificity (99% vs. 73%) and correlates with treatment response (n = 20).

Conclusions: IgG4(+) BCR clones and IgG4/IgG RNA ratio markedly improve delineation, early diagnosis, and monitoring of IgG4-RD of the biliary tree and pancreas. (Hepatology 2016;64:501-507).

Figures

Figure 1
Figure 1
BCR repertoire in IgG4‐related disease and disease controls (A,B) scatterplot showing the IgG+ repertoires in 34 patients suffering from IgG4‐RD (IRD01‐IRD34; A) and disease controls (B), consisting of PSC (PSC01‐PSC17; n = 17) and CA (CA01‐CA17; n = 17). Every dot represents a unique IgG+ clone. IgG4+ clones are marked in red. (C) Bar chart showing the distribution of IgG1+, IgG2+, IgG3+, and IgG4‐positive clones of all IgG+ clones within the repertoire in IgG4‐RD, PSC, and CA. (D) Bar chart showing the part of the repertoire taken up by IgG4+ BCRs versus IgG4 BCRs in IgG4RD, PSC, and CA. (E) Ranks of the most dominant IgG4+ clones within the IgG+ repertoire in IgG4‐RD, PSC, and CA (P < 0.0001).
Figure 2
Figure 2
qPCR test in IgG4‐RD and disease controls (A) dot plot showing the percentage specific IgG4 RNA molecules of total IgG RNA molecules in 50 IgG4‐RD patients, 48 PSC patients, and 27 patients suffering from CA. The red dotted line delineates the cut‐off value of 5%; *** P < 0.001. (B) ROC curve of the qPCR test for the prediction of IgG4‐RD (50 cases vs. 75 controls). The arrow points to the cut‐off value and denotes this value. (C) Before‐after dot plot showing the qPCR test values in 20 IgG4‐RD patients at baseline, and 4 and 8 weeks after high‐dose corticosteroid therapy. The red dotted line delineates the cut‐off value of 5%; *** P < 0.001.

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