Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common cholestatic liver diseases. While PBC is generally accepted to be an autoimmune disorder characterized by pathognomonic autoantibodies against mitochondrial antigens, the pathogenesis of PSC is less precisely defined; however, some degree of altered immunity toward autoantigens has been suggested. Follicular T helper (Tfh) cells, a distinct clusters of differentiation (CD)4 T‐cell subset specialized in facilitating antibody responses, have been shown to contribute to humoral autoimmunity in various disorders; yet, there is only limited information on possible alterations of Tfh cells in the context of cholestatic liver diseases. Thus, we addressed this important question by analyzing the frequency, activation status, and function of Tfh cells and frequencies of regulatory follicular T helper (Tfr) cells in well‐defined cohorts of patients with PBC and patients with PSC. Interestingly, we observed a significant increase in circulating chemokine (C‐X‐C motif) receptor 5 (CXCR5)+programmed death 1 (PD‐1) +CD4+ Tfh cells in patients with PBC but not in those with PSC. Although the frequency of potentially pathogenic chemokine (C‐C motif) receptor 7 (CCR7)lowCXCR5+PD‐1+CD4+ Tfh cells was increased in both disorders compared to healthy donors, the increase was significantly more pronounced in PBC. Furthermore, in patients with PBC, Tfh cells displayed stronger expression of the activation markers OX40 and inducible costimulator of T cells, correlated with anti‐anti‐mitochondrial antibody M2 and immunoglobulin M titers, and were most significantly increased in patients with cirrhosis. Tfr cell numbers were similarly increased; however, Tfh/Tfr ratios were unaltered in PSC and PBC. These alterations did not correlate with increased secretion of the Tfh signature cytokine interleukin‐21 in sorted CD4 T cells. Conclusion: Significant alterations occur in the Tfh cell compartment in cholestatic liver diseases, suggesting that Tfh cells influence the pathogenesis of PBC and to a lesser extend PSC.

CXCL13 and Its Receptor CXCR5 in Cancer: Inflammation, Immune Response, and Beyond

“…Indeed, circulating CXCR5+/CD4+ T-cells that resemble T FH cells have been identified in SLE patients, where they facilitate pathologic B cell differentiation and correlate with disease progression. Pathogenic roles for T FH cells have also been reported for many other autoimmune entities such as Sjögren's syndrome (50), primary biliary cholangitis (51), vitiligo (52), ankylosing spondylitis (53), and pemphigus vulgaris (54). Overall, dysregulation of the CXCL13:CXCR5 axis affecting both B- and T FH cell function is major player in autoimmune disorders, and potentially serves as a biomarker for disease progression and therapeutic response.…”

The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia

“…Cellular immune responses might be involved in the pathophysiology of PSC [8]. However, in contrast to primary biliary cholangitis (PBC), regulatory follicular T helper cells in patients with PSC appear to have less impact on the cholestatic pathophysiology [9].…”

Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn’s Disease

“… 25 In addition to these well-established CD4+ T cell populations, TFH cells have been implicated in the pathogenesis of several chronic inflammatory and autoimmune diseases. 26 , 27 , 28 , 29 , 30 However, it is still unclear whether TFH cells play a role in the pathogenesis of CD, which is not dependent on the formation of autoantibodies. Here, we demonstrate that TFH cell frequencies in the terminal ileum correlate with endoscopic CD activity in patients.…”