DNA released from dying host cells mediates aluminum adjuvant activity

Marichal, Thomas; Ohata, Keiichi; Bedoret, Denis; Mesnil, Claire; Sabatel, Catherine; Kobiyama, Kouji; Lekeux, Pierre; Coban, Cevayir; Akira, Shizuo; Ishii, Ken J.; Bureau, Fabrice; Desmet, Christophe

doi:10.1038/nm.2403

Cited by 466 publications

(470 citation statements)

References 51 publications

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“…How particles induce Th2 responses is a complex subject for immunologists (26). The lipid mediator PGE 2 (57), self nucleic acids (58), and uric acid (59) are considered to be involved in alum-induced Th2 responses. It would be FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

Matsushita

Yoshimoto

2014

The Journal of Immunology

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Allergen-specific IgE is linked to asthma pathogenesis, but the underlying mechanisms of IgE production in response to allergen exposure are poorly understood. In this article, we show that B cell–intrinsic MyD88 is essential for IgE/IgG1 production evoked by ragweed pollen instilled into lungs. MyD88-deficient mice showed defective IgE/IgG1 production and germinal center responses to lung instillation of ragweed pollen. However, MyD88 was dispensable for dendritic cell activation and Th2 cell development. B cell–specific deletion of MyD88 replicated the defective Ab production observed in MyD88-deficient mice. Although ragweed pollen contains TLR ligands, TLR2/4/9-deficient mice developed normal allergic responses to ragweed pollen. However, anti–IL-1R1 Ab-treated mice and IL-18–deficient mice showed decreased IgE/IgG1 production with normal Th2 development. Furthermore, B cell–specific MyD88-deficient mice showed reduced IgE/IgG1 production in response to lung instillation of OVA together with IL-1α, IL-1β, or IL-18. Thus, pollen instillation into lungs induces IL-1α/β and IL-18 production, which activates B cell–intrinsic MyD88 signaling to promote germinal center responses and IgE/IgG1 production.

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Section: Discussionmentioning

confidence: 99%

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

Matsushita

Yoshimoto

2014

The Journal of Immunology

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“…Two papers suggested that these factors might be involved (7,9). However, a number of studies have shown that T-cell priming and Ab responses are intact in mice that are genetically deficient in caspase-1, Nlrp3, MyD88, or the IL-1 receptor (6,(10)(11)(12)(13)(14), and thus indicate that IL-1β and related cytokines are not required for alum to act as an adjuvant.…”

mentioning

confidence: 99%

Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells

McKee

Burchill

Munks

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

129

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Many vaccines include aluminum salts (alum) as adjuvants despite little knowledge of alum's functions. Host DNA rapidly coats injected alum. Here, we further investigated the mechanism of alum and DNA's adjuvant function. Our data show that DNase coinjection reduces CD4 T-cell priming by i.m. injected antigen + alum. This effect is partially replicated in mice lacking stimulator of IFN genes, a mediator of cellular responses to cytoplasmic DNA. Others have shown that DNase treatment impairs dendritic cell (DC) migration from the peritoneal cavity to the draining lymph node in mice immunized i.p. with alum. However, our data show that DNase does not affect accumulation of, or expression of costimulatory proteins on, antigen-loaded DCs in lymph nodes draining injected muscles, the site by which most human vaccines are administered. DNase does inhibit prolonged T-cell-DC conjugate formation and antigen presentation between antigen-positive DCs and antigen-specific CD4 T cells following i.m. injection. Thus, from the muscle, an immunization site that does not require host DNA to promote migration of inflammatory DCs, alum acts as an adjuvant by introducing host DNA into the cytoplasm of antigenbearing DCs, where it engages receptors that promote MHC class II presentation and better DC-T-cell interactions.interaction time | multiphoton imaging | lymph node

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“…Alum crystals can activate the nucleotide binding oligomerization domain-like receptor protein 3 inflammasome leading to the release of mature bioactive IL-1b and IL-18, whose effects could combine with those of IL-36b. At the site of injection, Alum causes tissue damage and cell death that indirectly stimulate nucleotide binding oligomerization domainlike receptor protein 3 via the release of danger-associated molecular patterns such as uric acid, DNA, and alarmins (45,46). These local effects of Alum did not lead to any detectable circulating cytokine levels in AD or NN mice.…”

Section: Discussionmentioning

confidence: 97%

IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

Palomo

Mastelic-Gavillet

Woldt

et al. 2016

The Journal of Immunology

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Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36β to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36β with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates. This neonatal toxicity was associated with high Il36r mRNA expression in neonatal liver, resulting in increased cytokine production. Liver Il36r mRNA expression decreased with the termination of fetal liver hematopoiesis, and this decrease correlated with a complete protection from TT/Alum/IL-36β–induced mortality. The combination of IL-36β and TT/Alum induced the rapid production of TNF-α and IFN-γ by liver myeloid and lymphoid cells, respectively. These responses were less marked when IL-36β was used alone, with no adverse effect. The toxicity of IL-36β + TT/Alum was abrogated by the administration of a neutralizing anti–TNF-α Ab, confirming causality. In conclusion, liver myeloid cells in neonatal mice are an important source of proinflammatory cytokines that may lead to TNF-α–mediated toxicity and even lethality.

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DNA released from dying host cells mediates aluminum adjuvant activity

Cited by 466 publications

References 51 publications

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells

IL-36–Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells

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