Low Levels of Endotoxin Enhance Allergen-Stimulated Proliferation and Reduce the Threshold for Activation in Human Peripheral Blood Cells

Veličković, Tanja Ćirković; Thunberg, Sarah; Polović, Natalija; Neimert-Andersson, Theresa; Grönlund, Hans; Hage, Marianne van; Gafvelin, Guro

doi:10.1159/000112497

Cited by 13 publications

(4 citation statements)

References 67 publications

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“…Additional cytokine analysis (IL-6, IL-10, IL-17A, IFN-γ, and TNF) was performed with CBA, but no significant differences were observed between PBMCs from cat-allergic and healthy donors cocultured with the different exosome preparations (data not shown). Similar results for IL-10 and IFNγ have been previously observed for PBMCs treated with only Fel d 1 (5).…”

Section: Resultssupporting

confidence: 88%

Dendritic cell‐derived exosomes carry the major cat allergen Fel d 1 and induce an allergic immune response

Vallhov

Gutzeit

Hultenby

et al. 2015

Allergy

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Exosomes are nano-sized membrane vesicles (50-120 nm), which are released from a wide variety of cells. Depending on their cellular origin, they can induce immune stimulatory-, inhibitory-, or tolerance-inducing effects. However, it is still unclear what role exosomes play during human inflammatory diseases. It has not been studied whether exosomes derived from human dendritic cells (DCs), the first cells to encounter allergens in the mucosa, can carry aeroallergens and contribute to allergic immune responses. We therefore explored whether DC-derived exosomes can present the major cat allergen Fel d 1 and whether they thereby contribute to the pathogenesis of allergic disease. Our results demonstrate that exosomes are able to present aeroallergens and thereby induce T-cell T(H)2-like cytokine production in allergic donors. Thus, these exosomes may be important immune-stimulatory factors in allergic immune responses and important targets or engineered tools in immunotherapy.

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Section: Resultssupporting

confidence: 88%

Dendritic cell‐derived exosomes carry the major cat allergen Fel d 1 and induce an allergic immune response

Vallhov

Gutzeit

Hultenby

et al. 2015

Allergy

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“…It is well known that at LPS concentrations lower than 1 ng/ml the system responds digitally or does not respond at all, thus representing an activation threshold 45,46 . We observed a clear non-linear activation curve (phosphorylation) in both systems of NF-κB and MAPK cascades (Fig.…”

Section: Discussionmentioning

confidence: 99%

Elevated pre-activation basal level of nuclear NF-κB in native macrophages accelerates LPS-induced translocation of cytosolic NF-κB into the cell nucleus

Bagaev

Garaeva

Лебедева

et al. 2019

Sci Rep

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Signaling via Toll-like receptor 4 (TLR4) in macrophages constitutes an essential part of the innate immune response to bacterial infections. Detailed and quantified descriptions of TLR4 signal transduction would help to understand and exploit the first-line response of innate immune defense. To date, most mathematical modelling studies were performed on transformed cell lines. However, properties of primary macrophages differ significantly. We therefore studied TLR4-dependent activation of NF-κB transcription factor in bone marrow-derived and peritoneal primary macrophages. We demonstrate that the kinetics of NF-κB phosphorylation and nuclear translocation induced by a wide range of bacterial lipopolysaccharide (LPS) concentrations in primary macrophages is much faster than previously reported for macrophage cell lines. We used a comprehensive combination of experiments and mathematical modeling to understand the mechanisms of this rapid response. We found that elevated basal NF-κB in the nuclei of primary macrophages is a mechanism increasing native macrophage sensitivity and response speed to the infection. Such pre-activated state of macrophages accelerates the NF-κB translocation kinetics in response to low agonist concentrations. These findings enabled us to refine and construct a new model combining both NF-κB phosphorylation and translocation processes and predict the existence of a negative feedback loop inactivating phosphorylated NF-κB.

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“…Such property provided the possibility for further purification of the vaccine. Moreover, amebocyte lysate analysis showed that both Der f 36 and hypoallergenic Der f 36 were almost endotoxin-free molecules according to a previous study ( 45 ), which is crucial for animal experiment and PBMC cytokine expression.…”

Section: Discussionmentioning

confidence: 73%

Construction by artificial intelligence and immunovalidation of hypoallergenic mite allergen Der f 36 vaccine

Qin,

Tang,

Wang

et al. 2024

Front. Immunol.

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BackgroundThe house dust mite (HDM) is widely recognized as the most prevalent allergen in allergic diseases. Allergen-specific immunotherapy (AIT) has been successfully implemented in clinical treatment for HDM. Hypoallergenic B-cell epitope-based vaccine designed by artificial intelligence (AI) represents a significant progression of recombinant hypoallergenic allergen derivatives.MethodThe three-dimensional protein structure of Der f 36 was constructed using Alphafold2. AI-based tools were employed to predict B-cell epitopes, which were subsequently verified through IgE-reaction testing. Hypoallergenic Der f 36 was then synthesized, expressed, and purified. The reduced allergenicity was assessed by enzyme-linked immunosorbent assay (ELISA), immunoblotting, and basophil activation test. T-cell response to hypoallergenic Der f 36 and Der f 36 was evaluated based on cytokine expression in the peripheral blood mononuclear cells (PBMCs) of patients. The immunogenicity was evaluated and compared through rabbit immunization with hypoallergenic Der f 36 and Der f 36, respectively. The inhibitory effect of the blocking IgG antibody on the specific IgE-binding activity and basophil activation of Der f 36 allergen was also examined.ResultsThe final selected non-allergic B-cell epitopes were 25–48, 57–67, 107–112, 142–151, and 176–184. Hypoallergenic Der f 36 showed significant reduction in IgE-binding activity. The competitive inhibition of IgE-binding to Der f 36 was investigated using the hypoallergenic Der f 36, and only 20% inhibition could be achieved, which is greatly reduced when compared with inhibition by Der f 36 (98%). The hypoallergenic Der f 36 exhibited a low basophil-stimulating ratio similar to that of the negative control, and it could induce an increasing level of IFN‐γ but not Th2 cytokines IL-5 and IL-13 in PBMCs. The vaccine-specific rabbit blocking IgG antibodies could inhibit the patients’ IgE binding and basophil stimulation activity of Derf 36.ConclusionThis study represents the first application of an AI strategy to facilitate the development of a B-cell epitope-based hypoallergenic Der f 36 vaccine, which may become a promising immunotherapy for HDM-allergic patients due to its reduced allergenicity and its high immunogenicity in inducing blocking of IgG.

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Low Levels of Endotoxin Enhance Allergen-Stimulated Proliferation and Reduce the Threshold for Activation in Human Peripheral Blood Cells

Cited by 13 publications

References 67 publications

Dendritic cell‐derived exosomes carry the major cat allergen Fel d 1 and induce an allergic immune response

Dendritic cell‐derived exosomes carry the major cat allergen Fel d 1 and induce an allergic immune response

Elevated pre-activation basal level of nuclear NF-κB in native macrophages accelerates LPS-induced translocation of cytosolic NF-κB into the cell nucleus

Construction by artificial intelligence and immunovalidation of hypoallergenic mite allergen Der f 36 vaccine

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