IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis

Ghalamfarsa, Ghasem; Mahmoudi, Mahmoud; Mohammadnia‐Afrouzi, Mousa; Yazdani, Yaghoub; Anvari, Enayat; Hadinia, Abolghasem; Ghanbari, Amir; Setayesh, Maryam; Yousefi, Mehdi; Jadidi‐Niaragh, Farhad

doi:10.3109/1547691x.2015.1089343

Cited by 35 publications

(31 citation statements)

References 118 publications

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“…IL-21 expression is, in some cases, reported to be associated with MS, while in other cases it is reported to have no association. Likewise, in the EAE mouse model, its role remains controversial [ 35 ]. It is curious that CD3+CD40 stimulation induced IL-21 production by the T cells from un-induced control mice while cells from EAE-induced mice produced this cytokine in response to CD3+CD28.…”

Section: Discussionmentioning

confidence: 99%

Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

et al. 2017

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CD40-CD154 interaction is critically involved in autoimmune diseases, and CD4 T cells play a dominant role in the Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). CD4 T cells expressing CD40 (Th40) are pathogenic in type I diabetes but have not been evaluated in EAE. We demonstrate here that Th40 cells drive a rapid, more severe EAE disease course than conventional CD4 T cells. Adoptively transferred Th40 cells are present in lesions in the CNS and are associated with wide spread demyelination. Primary Th40 cells from EAE-induced donors adoptively transfer EAE without further in-vitro expansion and without requiring the administration of the EAE induction regimen to the recipient animals. This has not been accomplished with primary, non-TCR-transgenic donor cells previously. If co-injection of Th40 donor cells with Freund’s adjuvant (CFA) in the recipient animals is done, the disease course is more severe. The CFA component of the EAE induction regimen causes generalized inflammation, promoting expansion of Th40 cells and infiltration of the CNS, while MOG-antigen shapes the antigen-specific TCR repertoire. Those events are both necessary to precipitate disease. In MS, viral infections or trauma may induce generalized inflammation in susceptible individuals with subsequent disease onset. It will be important to further understand the events leading up to disease onset and to elucidate the contributions of the Th40 T cell subset. Also, evaluating Th40 levels as predictors of disease onset would be highly useful because if either the generalized inflammation event or the TCR-honing can be interrupted, disease onset may be prevented.

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Section: Discussionmentioning

confidence: 99%

Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

et al. 2017

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“…54 While IL-2 is predominantly produced by activated CD4 + T cells, IL-21 can be released by several cell types, such as T H 17, T H 2, and NKT cells. 32,55 IL-9 is predominantly released by T H 9 and in smaller amounts by T H 17. 23 IL-2 binds to a high-affinity receptor complex consisting of three subunits designated as IL-2Rα (CD25), IL-2Rβ (CD122), and the common γ-chain (CD132).…”

Section: Il-2 Il-9 and Il-21mentioning

confidence: 99%

“…However, contradictory studies also exist that reveal opposite results. 32 Nonetheless, therapeutic approaches in MS patients indicate a role for IL-21. For instance, treatment of MS patients with alemtuzumab (a CD52 antibody) or ultraviolet B (UVB) phototherapy led to decreased IL-21 levels.…”

Section: Il-2 Il-9 and Il-21mentioning

confidence: 99%

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Cytokine signaling in multiple sclerosis: Lost in translation

2018

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Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical studies delineate abnormal expression of specific cytokines over the course of disease. Preclinical studies using animal models of MS have yielded promising results in manipulating the activity of certain cytokines to improve the clinical outcome. However, the translation of these findings into the clinic is often disappointing. The reason for this might be the complex nature of cytokine networks and the pathogenesis of neuroinflammation, as well as an oversimplified interpretation of preclinical observations. This review presents an overview on cytokines that potentially contribute to the development of MS and provides examples of success and failure in translating basic science into clinical benefit for people with MS.

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“…In normal physiology, IL‐21 helps in promoting NK cells activation, CD4 + T cell effector function and B cell proliferation to plasma cells for antibody production (Davis et al, ; Spolski & Leonard, ). IL‐21/IL‐21R have been shown to mediate various autoimmune disorders such as Sjögren's syndrome, systemic lupus erythematosus (SLE), multiple sclerosis and type I diabetes (Ferreira et al, ; Ghalamfarsa et al, ; Huang et al, ; Kwok et al, ). In recent years, IL‐21 has been found to be a key player in RA pathogenesis and progression (Kwok et al, ; Xiang, Jin, et al, 2016; Xing, Yang, et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Multifaceted role of IL‐21 in rheumatoid arthritis: Current understanding and future perspectives

Dinesh

Rasool²

2017

Journal Cellular Physiology

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Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder designated with hyperplastic synovium, bone destruction and cartilage degradation. Current therapies involve targeting major cytokines and inflammatory mediators involved in RA to alleviate the pain and provide a temporary relief. Interleukin 21 (IL-21), a recently identified cytokine is known to possess a versatile role in modulating the cells of the RA synovium. Over the past decade, the pleiotropic role of IL-21 in RA pathogenesis has been implicated in several aspects. T helper 17 (Th17) and follicular T helper cells (Tfh), being the key immunomodulators of the RA synovium secrete high amounts of IL-21 during disease progression. Several studies have provided experimental evidences elucidating the multifaceted role of IL-21 in RA disease progression. IL-21 has the potential to activate T cells, B cells, monocytes/macrophages and synovial fibroblasts in RA pathogenesis through activation of JAK-STAT, MAPK and PI3K/Akt signaling pathways. Till date, therapies targeting Th17 cells and its inflammatory cytokines have been under investigation and are subjected to various clinical trials. This review showcases the role of IL-21 in RA pathogenesis and recent reports implicating its function in various immune cells, major signaling pathways, and in promoting osteoclastogenesis.

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IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis

Cited by 35 publications

References 118 publications

Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

Cytokine signaling in multiple sclerosis: Lost in translation

Multifaceted role of IL‐21 in rheumatoid arthritis: Current understanding and future perspectives

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