Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice

Oya, Yoshihiro; Watanabe, Norihiko; Kobayashi, Y.; Owada, Takayoshi; Oki, Mie; Ikeda, Kei; Suto, Akira; Kagami, Shin-ichiro; Hirose, Koichi; Kishimoto, Takashi; Nakajima, Hiroshi

doi:10.1093/intimm/dxr017

Cited by 27 publications

(23 citation statements)

References 34 publications

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“…Krieg et al noticed that the stimulation of murine T-cells in presence of an agonistic BTLA antibody results in decreased IL-2 production and diminished occurrence of CD25 + T-cells (27). There is evidence from animal studies that BTLA knockout leads to autoimmune diseases (20,28,29).…”

Section: Discussionmentioning

confidence: 99%

“…BTLA ligation with HVEM results in a reduction of T-cell proliferation (13,17,18). Mice with BTLA deficiency show increased T-cell activation and higher levels of circulating TNF-α, IFN-γ, IL-2, and IL-4 (19,20). However, BTLA as a co-inhibitor is scarcely studied in human autoimmune diseases and its role in disease pathogenesis is unclear.…”

Section: Introductionmentioning

confidence: 99%

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The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

et al. 2019

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Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor Band T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV). Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3 + CD4 − CD8 −. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied. Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3 + CD4 − CD8 −). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC. Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

et al. 2019

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“…BTLA (CD272) is another IgSF co-inhibitory receptor. Btla −/− MRL- lpr mice exhibited exacerbated lupus-associated disorders with elevated auto-Ab production and massive organ infiltration of inflammatory cells (Oya et al, 2011). These studies suggest that co-inhibitory pathways are utilized to protect against autoimmunity in SLE despite the malfunctioned co-stimulatory pathways.…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Co-stimulatory and Co-inhibitory Pathways in Autoimmunity

2016

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The immune system is guided by a series of checks and balances, a major component of which is a large array of co-stimulatory and co-inhibitory pathways that modulate the host response. While co-stimulation is essential to boost and shape the initial response following signaling through the antigen receptor, inhibitory pathways are also critical to modulate the immune response. Excessive co-stimulation and/or insufficient co-inhibition can lead to a breakdown of self-tolerance, leading to autoimmunity. In this review, we will focus on the role of co-stimulatory and co-inhibitory pathways in two systemic (Systemic Lupus Erythematosus and Rheumatoid Arthritis) and two organ-specific (Multiple Sclerosis and Type 1 Diabetes) autoimmune diseases that are emblematic. We will also discuss how mechanistic analysis of these pathways has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead.

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“…We have shown that the deficiency of BTLA also causes the breakdown of self-tolerance, resulting in the development of an autoimmune hepatitis- (AIH-) like disease and lymphocytic infiltration in multiple organs [75]. We have also shown that BTLA plays a protective role in autoimmune diseases in MRL-lpr mice and that AIH-like disease develops in BTLA-deficient mice even in the absence of Fas-dependent signaling [76]. …”

Section: Relevance Of Btla-hvem Pathway In Autoimmune Diseasesmentioning

confidence: 99%

Coinhibitory Molecules in Autoimmune Diseases

Watanabe

Nakajima

2012

Clinical and Developmental Immunology

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Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency or mutation of coinhibitory molecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e.g., CTLA-4 Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4 Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans.

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Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice

Cited by 27 publications

References 34 publications

The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

Co-stimulatory and Co-inhibitory Pathways in Autoimmunity

Coinhibitory Molecules in Autoimmune Diseases

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