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Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients
Sachiyo Yoshio, … , Junko Tanaka, Tatsuya Kanto
Sachiyo Yoshio, … , Junko Tanaka, Tatsuya Kanto
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e122268. https://doi.org/10.1172/jci.insight.122268.
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Clinical Medicine Hepatology Immunology

Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients

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Abstract

BACKGROUND. The clearance of hepatitis B surface antigen (HBsAg) loss, defined as functional cure, is a clinical target in patients with chronic hepatitis B (CH). To understand the immune responses underlying functional cure, we evaluated cytokine and chemokine expression profiles from patients with resolving and nonresolving acute hepatitis B (AH). METHODS. We cross-sectionally evaluated 41 chemokines and cytokines at the peak of hepatitis in the sera from 41 self-limited AH patients who achieved HBsAg seroconversion, 8 AH patients who failed to clear HBsAg within 1 year after the diagnosis, 8 CH patients with hepatic flare, and 14 healthy volunteers. We longitudinally examined 41 chemokines and cytokines in the sera from 4 self-limited AH patients, 3 chimpanzees inoculated with hepatitis B virus (HBV), and 2 CH patients treated with nucleotide analogs and PEG–IFN-α, one resulting in functional cure. RESULTS. In AH patients and HBV-inoculated chimpanzees with HBsAg loss, CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 were elevated at hepatitis with subsequent decline of HBsAg. Interestingly, IL-21 elevation was observed only in resolving AH patients but not in nonresolvers. CXCL13 and IL-21 elevation was not observed in CH patients who failed to attain HBsAg loss, even at hepatic flare. A concomitant increase of CXCL13 and IL-21 was significant in CH patients who attained HBsAg seroconversion with a sequential therapy. CONCLUSION. Elevation of serum CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 might be a hallmark of functional cure of AH or CH patients.

Authors

Sachiyo Yoshio, Yohei Mano, Hiroyoshi Doi, Hirotaka Shoji, Tomonari Shimagaki, Yuzuru Sakamoto, Hironari Kawai, Michitaka Matsuda, Taizo Mori, Yosuke Osawa, Masaaki Korenaga, Masaya Sugiyama, Masashi Mizokami, Eiji Mita, Keiko Katayama, Junko Tanaka, Tatsuya Kanto

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Figure 4

Sequential analyses of serum chemokines in chronic hepatitis patients with a sequential therapy of nucleoside analogues and PEG–IFN-α.

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Sequential analyses of serum chemokines in chronic hepatitis patients wi...
Case S1 (50 years old, male) was HBsAg positive (HBsAg titer 156 IU/ml, genotype B), HBeAg negative, and HBeAb positive at the start of a sequential therapy consisting of a combination of nucleoside analogs (NAs) and subsequent PEG–IFN-α (48 weeks). Case S2 (36 years old, female) was HBsAg positive (HBsAg titer 1,130 IU/ml, genotype C), HBeAg negative, and HBeAb positive at the start of the sequential therapy. At the end of treatment, HBV DNA was negative but HBsAg was 876 IU/ml. Two months after the end of treatment, case S2 had hepatic flare (HBV DNA 5.5 log copies/ml, ALT 585 IU/l). The durations of NA and PEG–IFN-α treatments in cases S1 and S2 are shown as gray and black bars at the top of the panels. The left vertical axes are for ALT (bar chart), CX3CL1, CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 (solid black line). The right vertical axes are for HBsAg titers (dotted line) and anti-HBs (solid gray line). The additional right vertical axis is for HBV DNA titers (triangles) (case S2). n.d., not detected.

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