The Biological Effects of IL-21 Signaling on B-Cell-Mediated Responses in Organ Transplantation

Wu, Yongkang; Besouw, Nicole M. van; Shi, Yunying; Hoogduijn, Martin J.; Wang, Lanlan; Baan, Carla C.

doi:10.3389/fimmu.2016.00319

Cited by 25 publications

(24 citation statements)

References 100 publications

(158 reference statements)

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“…IL-21 is a cytokine with pleiotropic effects; it maintains the immune homeostasis including in patients after solid organ transplantation [ 25 ]. It is identified as the most potent plasma cell inducer in vitro [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Elevated serum IL-21 levels are associated with stable immune status in kidney transplant recipients and a mouse model of kidney transplantation

Guo

Zhang

et al. 2020

Aging

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Allograft rejection after renal transplantation remains a challenge to overcome. Interleukin (IL)-21, a cytokine with pleiotropic effects, maintains immune homeostasis post-transplantation. Here, we report higher levels of IL-21 in kidney transplant recipients with non-rejection (NR) than in recipients with T cell-mediated rejection (TCMR, P < 0.001) and antibody-mediated rejection (ABMR, P = 0.005). We observed a negative correlation between IL-21 and creatinine (Cr) levels ( P = 0.016). The receiving operating characteristic (ROC) curve showed a promising diagnostic value of IL-21 to identify acute rejection with an area under the curve (AUC) of 0.822 ( P < 0.001). In contrast, exogenous administration of IL-21 accelerated acute rejection in a comparative translational kidney transplant (KT) mouse model. Reduced IL-21 levels in the peripheral blood were observed in KT mice after IL-21 injection. Further analysis revealed that increased IL-21 levels in the spleen induced proliferation of CD4+ T cells and CD19+ B cells after IL-21 treatment. Our findings suggest a critical function of IL-21 in kidney transplantation and the potential involvement of the IL-21/IL-21R pathway in acute rejection management.

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Section: Discussionmentioning

confidence: 99%

Elevated serum IL-21 levels are associated with stable immune status in kidney transplant recipients and a mouse model of kidney transplantation

Guo

Zhang

et al. 2020

Aging

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“…It is well-known that local ectopic GCF is a key event in plasma cell differentiation, in which interlukin-6 (IL-6) and Tfh cells play a central role (12,15,16). With the stimulation of IL-6, Tfh cells could be activated and promote antibody secretion of B cells and its differentiation into plasma cells with the collaboration of BAFF, CD40L, IL-21, and IL-4 (17)(18)(19)(20)(21)(22). In patients with IgG4-RD, a significantly increased number of Tfh cells was seen in the peripheral blood, tissue, tertiary lymphoid organs, and secondary lymphoid organs (18,(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

Chen

Cui

et al. 2020

Front. Immunol.

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Background: The remarkable mechanisms of storiform fibrosis and the formation of high levels of IgG4 with a pathogenic germinal center (GC) in the inflammatory tissue of IgG4-RD remains unknown and may be responsible for the unsatisfactory therapeutic effect on IgG4-related diseases when using conventional therapy. Objectives: To investigate the mechanisms of interleukin 6 (IL-6) inducing fibroblasts to produce cytokines for pathogenic GC formation in the development of IgG4-related disease (IgG4-RD). Methods: The clinical data and laboratory examinations of 56 patients with IgG4-RD were collected. IL-6 and IL-6R expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by Luminex assays. Results: The serum IL-6 and IL-6R levels were elevated in active IgG4-RD patients and IL-6 was positively correlated with the disease activity (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and IgG4-RD responder index). IL-6 and IL-6R expression in the tissue lesions of IgG4-related retroperitoneal fibrosis and IgG4-related sialadenitis patients were also significantly higher than that in the normal tissues. In addition, there is a relative abundance of myofibroblasts as well as IgG4 + plasma cells in the tissues of IgG4-related retroperitoneal fibrosis. α-SMA and B cell differentiation cytokines (i.e., B cell activating factor), and α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were co-expressed in the local lesions. In vitro, IL-6/IL-6R significantly promoted the production of B cell activating factor, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was partially blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively. Conclusions: In vitro IL-6/IL-6R trans-signaling in fibroblasts releases Tfh and B cell differentiation factors partially via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt Zongfei et al. IL-6 and Fibroblast Induced IgG4-RD pathways, which may be linked to the pathogenesis of IgG4-RD. This indicated that IL-6 and fibroblasts may be responsible for GC formation and fibrosis in the development of IgG4-RD. Blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might be beneficial for IgG4-RD treatment.

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“…(14) B-cell maturation into plasma cells within the germinal centre is facilitated by Th 2 -type cytokines IL-4 (15) and IL-6 (16,17) and T FH -derived IL-21. (18) Matured plasma cells produce antibody directed against the inciting donor antigen, and this donor-specific antibody (DSA) results in humoral rejection.…”

Section: The Immunobiology Of Rejectionmentioning

confidence: 99%

Murder in the Cathedral: Antibodies and the Limits of Transplantation

Davies¹

2019

Wits Journal of Clinical Medicine

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Although transplantation is the optimal therapy for end-stage renal disease, long-term survival of kidney allografts remains elusive. Antibody-mediated rejection has been implicated as a major factor in late period graft loss. The refractory nature of late period antibody-mediated rejection is the evidence of an important immunological process with implications for other solid organ transplants and for other diseases. This review details advances in the understanding of late period antibody-mediated rejection in the context of local experience.

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The Biological Effects of IL-21 Signaling on B-Cell-Mediated Responses in Organ Transplantation

Cited by 25 publications

References 100 publications

Elevated serum IL-21 levels are associated with stable immune status in kidney transplant recipients and a mouse model of kidney transplantation

Elevated serum IL-21 levels are associated with stable immune status in kidney transplant recipients and a mouse model of kidney transplantation

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease

Murder in the Cathedral: Antibodies and the Limits of Transplantation

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