B- and T-lymphocyte attenuator stimulation protects against atherosclerosis by regulating follicular B cells

Douna, Hidde; Amersfoort, J.M.M. van; Schaftenaar, Frank H.; Kröner, Mara J.; Kiss, M.; Slütter, Bram; Depuydt, Marie A.C.; Kleijn, M.N.A. Bernabé; Wezel, Anouk; Smeets, H.J.; Yagita, Hideo; Binder, Christoph J.; Bot, Ilze; Kuiper, Johan; Foks, Amanda C.

doi:10.1093/cvr/cvz129

Cited by 17 publications

(20 citation statements)

References 42 publications

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“…Immune checkpoint proteins are extremely potent targets to modulate immunity in autoimmune diseases such as cardiovascular disease ( 23 , 24 , 27 ). In this study, we show that stimulation of signaling through the immune checkpoint protein PD-1 inhibits atherosclerotic lesion development in WTD-fed Ldlr −/− mice despite elevated serum cholesterol levels.…”

Section: Discussionmentioning

confidence: 99%

“…It is however unknown whether stimulation of PD-1 signaling can inhibit atherosclerosis. Previous studies have shown that stimulation of coinhibitory molecules, such as CTLA-4 and BTLA, suppressed pro-atherogenic T- and B cell immunity and decreased atherosclerosis development in ApoE −/− and Ldlr −/− mice, respectively ( 23 , 24 ). In addition, Seko et al showed that treatment of C3H/He mice with an agonistic PD-1 antibody protected against virus-induced myocarditis ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice

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Verwilligen

et al. 2021

Front. Cardiovasc. Med.

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Aim: Signaling through the coinhibitory programmed death (PD)-1/PD-L1 pathway regulates T cell responses and can inhibit ongoing immune responses. Inflammation is a key process in the development of atherosclerosis, the underlying cause for the majority of cardiovascular diseases. Dampening the excessive immune response that occurs during atherosclerosis progression by promoting PD-1/PD-L1 signaling may have a high therapeutic potential to limit disease burden. In this study we therefore aimed to assess whether an agonistic PD-1 antibody can diminish atherosclerosis development.Methods and Results: Ldlr−/− mice were fed a western-type diet (WTD) while receiving 100 μg of an agonistic PD-1 antibody or control vehicle twice a week. Stimulation of the PD-1 pathway delayed the WTD-induced monocyte increase in the circulation up to 3 weeks and reduced T cell activation and proliferation. CD4+ T cell numbers in the atherosclerotic plaque were reduced upon PD-1 treatment. More specifically, we observed a 23% decrease in atherogenic IFNγ-producing splenic CD4+ T cells and a 20% decrease in cytotoxic CD8+ T cells, whereas atheroprotective IL-10 producing CD4+ T cells were increased with 47%. Furthermore, we found an increase in regulatory B cells, B1 cells and associated atheroprotective circulating oxLDL-specific IgM levels in agonistic PD-1-treated mice. This dampened immune activation following agonistic PD-1 treatment resulted in reduced atherosclerosis development (p < 0.05).Conclusions: Our data show that stimulation of the coinhibitory PD-1 pathway inhibits atherosclerosis development by modulation of T- and B cell responses. These data support stimulation of coinhibitory pathways as a potential therapeutic strategy to combat atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice

Grievink

Smit

Verwilligen

et al. 2021

Front. Cardiovasc. Med.

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“…Tay et al, reported that mature B cell-specific Blimp-1 deficiency impaired plasma cell differentiation from FO B cells, resulting in decreased IgG levels and reduced atherosclerosis development in LDLr -/mice (212). In line with these findings, Douna et al discovered that specific FO B cell inhibition by BTLA stimulation resulted in significantly reduced atherosclerosis (213). In contrast to FO B cells, MZ B cells exhibit atheroprotective properties by suppressing the proatherogenic T FH response, thereby inhibiting atherosclerosis development (214).…”

Section: B Cell Aging In Atherosclerosismentioning

confidence: 91%

The Dynamics of B Cell Aging in Health and Disease

et al. 2021

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Aging is considered to be an important risk factor for several inflammatory diseases. B cells play a major role in chronic inflammatory diseases by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets have been implicated in infections and multiple autoimmune diseases. Since aging decreases B cell numbers, affects B cell subsets and impairs antibody responses, the aged B cell is expected to have major impacts on the development and progression of these diseases. In this review, we summarize the role of B cells in health and disease settings, such as atherosclerotic disease. Furthermore, we provide an overview of age-related changes in B cell development and function with respect to their impact in chronic inflammatory diseases.

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“…th1/th2 subsets: In the next stage of the immune responses, macrophages, monocytes, and dendritic cells known as the antigen-presenting cells (APCs) are observed in the inflamed tissue. Such imbalances may provide essential links to cardiovascular pathology [47]. Although the content of dendritic cells and macrophages in the periodontal tissue is decreased in comparison to healthy tissue [38], their role in capturing and presenting antigens to lymphocytes is essential.…”

Section: Immune Mechanisms Of Periodontitismentioning

confidence: 99%

Periodontitis as an inflammatory trigger in hypertension: From basic immunology to clinical implications

Szczepaniak¹,

Mikołajczyk²,

Cześnikiewicz-Guzik³

et al. 2021

Kardiol Pol

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Hypertension and periodontitis are both highly prevalent co-morbidities worldwide, and their occurrence increases with age. Multiple observational epidemiological studies have shown that periodontitis is associated with an increased cardiovascular disease (CVD) occurrence. Large systematic reviews and metanalyses further show that periodontitis increases the risk of hypertension and is associated with increased systolic and diastolic blood pressure. Genetic and clinical evidence, utilizing mendelian randomization and randomized clinical trials, support the causal role of periodontitis in hypertension. The mechanisms of this link remain unclear. Critical components of immune and inflammatory pathogenesis of periodontitis considerably overlap with immune mechanisms of hypertension. Clinical studies support that both C-reactive protein (CRP) levels and white blood cell counts (WBC) mediate the relationship between periodontal disease and high blood pressure. In particular, activation of Th1, Th17, T regulatory cells, and proinflammatory monocytes has been shown to be essential in both conditions. Immunosenescent dysregulated CD28null T cells have been implicated, along with key effector cytokines such as interleukin 6 (IL-6), TNF-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin 17 (IL-17). A better understanding of the relationships between hypertension and periodontitis is essential not only for possible utilization of this knowledge for a non-pharmacological approach to improving blood pressure control. It may also provide valuable pathogenetic clues linking inflammation and hypertension, which has become particularly relevant in the light of links between hypertension and autoimmune disorders or, more recently, COVID-19.

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B- and T-lymphocyte attenuator stimulation protects against atherosclerosis by regulating follicular B cells

Cited by 17 publications

References 42 publications

Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice

Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice

The Dynamics of B Cell Aging in Health and Disease

Periodontitis as an inflammatory trigger in hypertension: From basic immunology to clinical implications

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