Interleukin-21 plays a critical role in the pathogenesis and severity of type I autoimmune hepatitis

Abe, Kazumichi; Takahashi, Atsushi; Imaizumi, Hiromichi; Hayashi, Manabu; Okai, Ken; Kanno, Yukiko; Watanabe, Hiroshi; Ohira, Hiromasa

doi:10.1186/s40064-016-2512-y

Cited by 33 publications

(33 citation statements)

References 43 publications

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“…Similar to our findings, studies from HIV infected patients have shown impaired IL-21 during acute HIV infection when compared to uninfected controls [55] and that this impairment was partially rescued when ART was initiated [55]. Previous published IL-21 levels from the healthy donors were also similar to our IL-21 levels from our non-TB healthy controls cohort [56]. In mouse models, it has been reported that IL-21 signaling has a key role in promoting the protective capacity of T cells.…”

Section: Discussionsupporting

confidence: 91%

Diminished plasma levels of common γ-chain cytokines in pulmonary tuberculosis and reversal following treatment

et al. 2017

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BackgroundThe immune response to tuberculosis (TB) is T cell dependent. T cells are the major facilitators of protection and effector functions with CD4+ T cells being the most important players, followed by CD8+ T cells. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 play a vital role in peripheral T cell growth and survival. However, the role of common γ-chain cytokines in pulmonary TB (PTB) is poorly understood.Aim and methodsTo examine the association of circulating common γ-chain cytokines with TB disease or infection, we examined the systemic levels of IL-2, IL-7, IL-15, and IL-21 in individuals with PTB, latent TB (LTB) or no TB infection (NTB). We also examined the levels of these cytokines in PTB individuals before and after anti-tuberculosis treatment.ResultsCirculating levels of IL-2, IL-7 and IL-21 were significantly diminished in PTB compared to LTB or NTB individuals. Moreover, TB antigen stimulated whole blood also exhibited diminished levels of common γ-chain cytokines in PTB compared to LTB or NTB individuals. The plasma levels of common γ-chain cytokines exhibited no significant association with the severity or extent of TB disease or with bacterial burdens. However, upon standard anti-TB treatment, both the systemic as well as the TB antigen stimulated levels of IL-2, IL-7 and IL-21 were significantly increased in PTB individuals.ConclusionTherefore our data demonstrate that diminished levels of common γ-chain cytokines are a common characteristic of PTB and potentially highlight the importance of boosting these responses to improve treatment outcomes.

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Section: Discussionsupporting

confidence: 91%

Diminished plasma levels of common γ-chain cytokines in pulmonary tuberculosis and reversal following treatment

et al. 2017

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“…This population decreases significantly consecutively to prednisolone treatment, with the decrease of serum alanine transferase ( 201 ). Serum levels of IL-21 are higher in patients with AIH than in patients with other liver diseases or healthy volunteers ( 202 , 203 ), correlating with the numbers of cTfh cells. They are associated with the severity of the disease.…”

Section: Hepatological and Gastroenterological Diseasesmentioning

confidence: 95%

“…They are associated with the severity of the disease. Finally, they correlate positively with total serum bilirubin levels and negatively with serum albumin ( 203 ). Data obtained from immunohistochemistry studies and from flow cytometry on extracted cells from liver biopsies of patients with AIH have been also published: frequencies of activated Tfh cells are significantly increased in the liver from patients and positively correlate with their circulating counterparts in blood of patients ( 201 ).…”

Section: Hepatological and Gastroenterological Diseasesmentioning

confidence: 99%

T Follicular Helper Cells in Autoimmune Disorders

et al. 2018

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T follicular helper (Tfh) cells are a distinct subset of CD4+ T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity. Indeed, deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. In the present review, we briefly introduce the molecular factors involved in Tfh cell formation in the context of a normal immune response, as well as markers associated with their identification (transcription factor, surface marker expression, and cytokine production). We then consider in detail the role of Tfh cells in the pathogenesis of a broad range of autoimmune diseases, with a special focus on systemic lupus erythematosus and rheumatoid arthritis, as well as on the other autoimmune/inflammatory disorders. We summarize the observed alterations in Tfh numbers, activation state, and circulating subset distribution during autoimmune and some other inflammatory disorders. In addition, central role of interleukin-21, major cytokine produced by Tfh cells, is discussed, as well as the involvement of follicular regulatory T cells, which share characteristics with both Tfh and regulatory T cells.

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“…The complex interplay of several cytokines, especially proinflammatory and Th17 cytokines, and Treg suppression by IL‐12p40 play a pivotal role in the pathogenesis of AIH. We previously found that serum IL‐21 levels were significantly higher in severe AIH cases compared to nonsevere cases and that serum IL‐21 level correlated positively with TB level and necroinflammatory activity grade . Moreover, a recent study revealed that IL‐21 and IL‐33 are potent regulators of HBV clearance .…”

Section: Discussionmentioning

confidence: 96%

“…We previously found that serum IL-21 levels were significantly higher in severe AIH cases compared to nonsevere cases and that serum IL-21 level correlated positively with TB level and necroinflammatory activity grade. (48) Moreover, a recent study revealed that IL-21 and IL-33 are potent regulators of HBV clearance. (49) This relationship between IL-21 and IL-33 is also expected in the pathogenesis of AIH.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐33/ST2‐Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis

Abe¹,

Takahashi²,

Fujita³

et al. 2019

Hepatol Commun

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Interleukin (IL)‐33 was recently described as a new member of the IL‐1 family; members of this family have proinflammatory activity. IL‐33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL‐33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male‐to‐female ratio was 6:59. Serum IL‐33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL‐33 expression in liver sections from patients with AIH. In particular, serum IL‐33 and sST2 levels were significantly higher in acute‐onset AIH than in chronic‐onset AIH. Serum IL‐33 levels were positively correlated with serum total bilirubin (TB), alanine aminotransferase (ALT), and necroinflammatory activity in AIH. We performed multivariate logistic regression analysis and found serum IL‐33 levels to be independent factors for severe activity. Serum sST2 levels were positively correlated with serum TB and ALT and negatively correlated with serum albumin and prothrombin time in AIH. In particular, serum sST2 levels were significantly higher in severe symptoms of AIH. Serum IL‐33 and sST2 levels in patients with AIH responsive to treatment with prednisolone were significantly decreased after treatment. Interestingly, serum IL‐33 level was associated with a significantly increased risk of relapse. Conclusion: IL‐33/ST2 may play an important role in the pathogenesis and severity of AIH and may be a promising target for AIH therapy.

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Interleukin-21 plays a critical role in the pathogenesis and severity of type I autoimmune hepatitis

Cited by 33 publications

References 43 publications

Diminished plasma levels of common γ-chain cytokines in pulmonary tuberculosis and reversal following treatment

Diminished plasma levels of common γ-chain cytokines in pulmonary tuberculosis and reversal following treatment

T Follicular Helper Cells in Autoimmune Disorders

Interleukin‐33/ST2‐Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis

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