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Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity.
Nat Med. 2011 Apr; 17(4):479-87
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18 Mar 2011
DOI: 10.3410/f.9099956.9680054
In this manuscript, Flach et al. propose a novel model of action for alum. Alum is a potent adjuvant, but the mechanism by which it interacts with and activates antigen-presenting cells has been controversial, and the community has not settled on any particular favored model.
This study suggests that...Continue reading
This study suggests that...Continue reading
In this manuscript, Flach et al. propose a novel model of action for alum. Alum is a potent adjuvant, but the mechanism by which it interacts with and activates antigen-presenting cells has been controversial, and the community has not settled on any particular favored model.
This study suggests that alum interacts directly with dendritic cell lipids and triggers phagocytosis of associated antigens, but not of the alum crystals themselves. Alum binding was specific to dendritic cells and depended both on binding to membrane lipids and activation of signals in the cell. The study will, no doubt, raise questions as this mechanism of action is compared to other adjuvants, but it will have to be taken into consideration.
This study suggests that alum interacts directly with dendritic cell lipids and triggers phagocytosis of associated antigens, but not of the alum crystals themselves. Alum binding was specific to dendritic cells and depended both on binding to membrane lipids and activation of signals in the cell. The study will, no doubt, raise questions as this mechanism of action is compared to other adjuvants, but it will have to be taken into consideration.
Disclosures
None declared
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Underhill D: F1000Prime Recommendation of [Flach TL et al., Nat Med 2011, 17(4):479-87]. In F1000Prime, 18 Mar 2011; DOI: 10.3410/f.9099956.9680054. F1000Prime.com/9099956#eval9680054
21 Apr 2011
New Finding
DOI: 10.3410/f.9099956.10567056
In the field of vaccinology, adjuvants have taken prominence as a hot field of research. This publication potentially answers a vexatious question -- the mechanism of action of alum, the grand-daddy of human adjuvants, which until now has remained unknown.
The adjuvant alum (potassium aluminum sulfate)...Continue reading
The adjuvant alum (potassium aluminum sulfate)...Continue reading
In the field of vaccinology, adjuvants have taken prominence as a hot field of research. This publication potentially answers a vexatious question -- the mechanism of action of alum, the grand-daddy of human adjuvants, which until now has remained unknown.
The adjuvant alum (potassium aluminum sulfate) has been used in human vaccines since the 1930s, yet its mechanism of action has remained obscure. Originally used simply to help solubilise/stabilise the vaccine components, it was soon recognised that it increased the potency of the vaccine. The general assumption has been that it acted as an irritant, attracting antigen-presenting cells (APCs) by stimulating chemokine release {1,2}.
This new publication suggests a different mechanism: that alum binds directly to lipids in the plasma membrane of dendritic cells (DCs), leading to increased -- if abortive -- phagocytic activity and, thereby, (presumably) antigen uptake. Interestingly, this mechanism appears to be specific to DCs, and leads to their activation via the Src-ITAM-Syk-PI3k pathway. These activated DCs thereafter interact much more strongly with CD4+ T cells via ICAM-1 and LFA-1, accounting for their enhanced APC ability.
There are still unanswered questions -- most importantly, which lipids confer the DC specificity of alum -- but this manuscript opens up a new line of inquiry in adjuvant research.
The adjuvant alum (potassium aluminum sulfate) has been used in human vaccines since the 1930s, yet its mechanism of action has remained obscure. Originally used simply to help solubilise/stabilise the vaccine components, it was soon recognised that it increased the potency of the vaccine. The general assumption has been that it acted as an irritant, attracting antigen-presenting cells (APCs) by stimulating chemokine release {1,2}.
This new publication suggests a different mechanism: that alum binds directly to lipids in the plasma membrane of dendritic cells (DCs), leading to increased -- if abortive -- phagocytic activity and, thereby, (presumably) antigen uptake. Interestingly, this mechanism appears to be specific to DCs, and leads to their activation via the Src-ITAM-Syk-PI3k pathway. These activated DCs thereafter interact much more strongly with CD4+ T cells via ICAM-1 and LFA-1, accounting for their enhanced APC ability.
There are still unanswered questions -- most importantly, which lipids confer the DC specificity of alum -- but this manuscript opens up a new line of inquiry in adjuvant research.
References
1.
Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes.
Vaccine 2011 Feb 17; 9(29):1812-23
PMID: 21215831
2.
Immunology of TLR-independent vaccine adjuvants.
Curr Opin Immunol 2009 Jun; 3(21):339-45
PMID: 19493664
Disclosures
None declared
Doherty M: F1000Prime Recommendation of [Flach TL et al., Nat Med 2011, 17(4):479-87]. In F1000Prime, 21 Apr 2011; DOI: 10.3410/f.9099956.10567056. F1000Prime.com/9099956#eval10567056
F1000Prime Recommendations, Dissents and Comments for [Flach TL et al., Nat Med 2011, 17(4):479-87]. In F1000Prime, 25 May 2013; F1000Prime.com/9099956
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As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4(+) T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.
DOI: 10.1038/nm.2306
PMID: 21399646
