An Enhanced Level of LAMP-2A Participates in CD4+T Cell Hyperactivity in Patients with Primary Biliary Cholangitis.
ANNALS OF TRANSLATIONAL MEDICINE（2021）
Fourth Mil Med Univ
Abstract
Background: Primary biliary cholangitis (PBC) is an immune-mediated chronic cholestasis, in which T cell homeostasis plays an important role. Lysosomal-associated membrane protein 2 isoform A (LAMP-2A) has been implicated in the regulation of CD4(+)T cell responses. Methods: We comprehensively evaluated the immunobiology of CD4+T cells in patients with PBC (PBC, n=42), chronic hepatitis B (CHB, n=20), and healthy control subjects (HC, n=20) by flow cytometry including activation status and LAMP-2A expression. Additionally, we investigated the activation responses of PBC-naive CD4(+)T cells by stimulation in vitro and tested the changes caused by deleting the gene encoding LAMP-2A. Results: Firstly, we found an increased activation status of circulating CD4(+)T cells from PBC patients compared to the HC subjects, and PBC-naive CD4(+)T cells showed enhanced responses after stimulation in vitro. Secondly, PBC-naive CD4(+)T cells expressed a significantly higher level of LAMP-2A compared to the HC and CHB groups [PBC vs. HC, 1,954.74 (1,254.28-3,057.14) vs. 1,542.12 (961.18-2,277.98), P=0.03; vs. CHB, 1,153.59 (726.87-1,275.48), P=0.02], and the overreactions of PBC-naive CD4(+)T cells could be reversed by interfering with LAMP-2A expression in vitro. Thirdly, the LAMP-2A expression level of PBC-naive CD4(+)T cells was related to disease severity and drug response. Conclusions: An abnormally increased LAMP-2A expression of PBC-naive CD4(+)T cells might be related to excessive activation responses. LAMP-2A could be a novel therapeutic target for the treatment of PBC by reversing excessive responses and consequently reducing biliary injury.
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Primary Sclerosing Cholangitis
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