Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

Longhi, Maria Serena; Vuerich, Marta; Kalbasi, Alireza; Kenison, Jessica E.; Yeste, Ada; Csizmadia, Eva; Vaughn, Byron P.; Feldbrügge, Linda; Mitsuhashi, Shuji; Węgiel, Barbara; Otterbein, Leo E.; Moss, Alan C.; Quintana, Francisco J.; Robson, Simon C.

doi:10.1172/jci.insight.92791

Cited by 67 publications

(79 citation statements)

References 55 publications

(78 reference statements)

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“…Furthermore, bilirubin could protect against EAE by inhibiting CD4 + T cell reactivity through the inhibition of costimulator activities, suppression of immune transcription factor activation, and downregulation of inducible MHC class II expression [21]. Besides EAE, experimental colitis has also been shown to be regulated by bilirubin in a recent study in which Longhi et al [22] found that bilirubin suppressed immune responses of Th17 cells by upregulating CD139. In addition, Trujillo-Ochoa et al [23] demonstrated that bilirubin might exhibit an anti-inflammatory role by regulating regulatory T cell activity via the T cell immunoglobulin domain and mucin domain 3 (TIM-3) during acute hepatitis A virus infection.…”

Section: Discussionmentioning

confidence: 99%

Serum Bilirubin and Albumin in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Shu

Chen

et al. 2018

Neuroimmunomodulation

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Background and Objective: Low serum levels of bilirubin and albumin are associated with multiple autoimmune diseases, but their role in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. Methods: Serum bilirubin and albumin levels were evaluated in 60 patients with anti-NMDAR encephalitis, 50 cryptococcal encephalitis, and 145 healthy controls (CTLs). Of the 60 anti-NMDAR encephalitis patients, 30 had a follow-up evaluation at 3 months after admission. Results: Serum bilirubin and albumin levels were both significantly lower in anti-NMDAR encephalitis than in CTLs, and serum bilirubin levels were significantly lower in anti-NMDAR encephalitis than in cryptococcal encephalitis. Serum bilirubin levels were significantly lower in patients with psychiatric symptoms, with severe impairment, and with limited responses to treatment than those without psychiatric symptoms, with mild impairment, and with favorable responses to treatment, respectively. A follow-up evaluation of 30 patients revealed that the modified Rankin Scale scores were significantly decreased after treatment. Serum bilirubin significantly associated with serum albumin, and plasma hemoglobin. Conclusions: Our results revealed for the first time an association between the serum levels of bilirubin in the anti-NMDAR encephalitis. Further studies investigating the role of bilirubin and albumin in anti-NMDAR encephalitis are required.

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Section: Discussionmentioning

confidence: 99%

Serum Bilirubin and Albumin in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Shu

Chen

et al. 2018

Neuroimmunomodulation

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“…In a model of experimental colitis in Rag −/− mice, Th17 cells polarized in vitro were able to produce IL-10 because they expressed CD39 ( 31 ). Furthermore, unconjugated bilirubin (UCB) did not protect mice from experimental colitis if CD39 was deleted in vivo ( 32 ). CD39 and CD73 are two ectonucleotidases: CD39 is highly expressed on endothelial cells and immune cells in many organs and can hydrolyze ATP to AMP; CD73 is mainly expressed on leukocytes in various tissues and can cleave AMP to adenosine to inhibit ATP-induced cell death ( 33 ).…”

Section: Mechanisms Involved In Modulating Il-10 + mentioning

confidence: 99%

Insight Into Non-Pathogenic Th17 Cells in Autoimmune Diseases

Tian

Wang

2018

Front. Immunol.

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Th17 cells are generally considered to be positive regulators of immune responses because they produce pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22. Cytokine production not only promotes accumulation of immune cells, such as macrophages, neutrophils and lymphocytes, at inflammatory sites but can also cause tissue pathologies. Conversely, certain Th17 cells can also negatively regulate immune responses by secreting immunosuppressive factors, such as IL-10; these cells are termed non-pathogenic Th17 cells. In this review, we summarize recent advances in the development and regulatory functions of non-pathogenic Th17 cells in autoimmune diseases.

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“…Primary suppression, theoretically, can be the result of a number of non-EV and EV-associated factors. Non-EV associated factors can include IL-10, TGF-β (currently under investigation for EV-association) cell membrane bound activity of the ecto-nucleotidases CD39 and CD73 on myeloid and lymphoid cells to drive hydrolysis of ATP down to adenosine, and other classically secreted cytokines (52)(53)(54)(55)(56)(57). EV associated factors include IL-35, and the manipulation of the inflammatory milieu by decreasing extracellular ATP concentrations through EV-associated CD39/CD73 (19,58).…”

Section: Non-t Cell Sources Of Il-35mentioning

confidence: 99%

Infectious Tolerance as Seen With 2020 Vision: The Role of IL-35 and Extracellular Vesicles

et al. 2020

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Originally identified as lymphocyte regulation of fellow lymphocytes, our understanding of infectious tolerance has undergone significant evolutions in understanding since being proposed in the early 1970s by Gershon and Kondo and expanded upon by Herman Waldman two decades later. The evolution of our understanding of infectious tolerance has coincided with significant cellular and humoral discoveries. The early studies leading to the isolation and identification of Regulatory T cells (Tregs) and cytokines including TGFβ and IL-10 in the control of peripheral tolerance was a paradigm shift in our understanding of infectious tolerance. More recently, another potential, paradigm shift in our understanding of the "infectious" aspect of infectious tolerance was proposed, identifying extracellular vesicles (EVs) as a mechanism for propagating infectious tolerance. In this review, we will outline the history of infectious tolerance, focusing on a potential EV mechanism for infectious tolerance and a novel, EV-associated form for the cytokine IL-35, ideally suited to the task of propagating tolerance by "infecting" other lymphocytes.

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Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

Cited by 67 publications

References 55 publications

Serum Bilirubin and Albumin in Anti-<b><i>N</i></b>-Methyl-D-Aspartate Receptor Encephalitis

Serum Bilirubin and Albumin in Anti-<b><i>N</i></b>-Methyl-D-Aspartate Receptor Encephalitis

Insight Into Non-Pathogenic Th17 Cells in Autoimmune Diseases

Infectious Tolerance as Seen With 2020 Vision: The Role of IL-35 and Extracellular Vesicles

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