title: How aluminum adjuvants could promote and enhance non-target IgE synthesis in a genetically-vulnerable sub-population.
abstract: Aluminum-containing adjuvants increase the effectiveness of vaccination, but their ability to augment immune responsiveness also carries the risk of eliciting non-target responses, especially in genetically susceptible individuals. This study reviews the relevant actions of aluminum adjuvants and sources of genetic risk that can combine to adversely affect a vulnerable sub-population. Aluminum adjuvants promote oxidative stress and increase inflammasome activity, leading to the release of IL-1β, IL-18, and IL-33, but not the important regulatory cytokine IL-12. In addition, they stimulate macrophages to produce PGE₂, which also has a role in regulating immune responses. This aluminum-induced cytokine context leads to a T(H)2 immune response, characterized by the further release of IL-3, IL-4, IL-5, IL-9, IL-13, and IgE-potentiating factors such as sCD23. Genetic variants in cytokine genes, such as IL-4, IL-13, IL-33, and IL-18 influence the response to vaccines in children and are also associated with atopy. These genetic factors may therefore define a genetically-vulnerable sub-population, children with a family history of atopy, who may experience an exaggerated T(H)2 immune response to aluminum-containing vaccines. IL-4, sCD23, and IgE are common factors for both atopy and the immune-stimulating properties of aluminum adjuvants. IL-4 is critical in the production of IgE and total IgE up-regulation. IL-4 has also been reported to induce the production of sCD23 and trigger resting sIgM+, sIgD+ B-cells to switch to sIgE+ B-cells, making them targets for IgE-potentiating factors. Further, the actions of IgE-potentiating factors on sIgE+ B-cells are polyclonal and unrestricted, triggering their differentiation into IgE-forming plasma cells. These actions provide a mechanism for aluminum-adjuvant promotion and enhancement of non-target IgE in a genetically vulnerable sub-population. Identification of these individuals may decrease the risk of adverse events associated with the use of aluminum-containing vaccines.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, 148 TF, 360 Huntington Avenue, Boston, MA 02115, USA. toddterhune@comcast.net
authors.forename: Todd D
authors.initials: TD
authors.lastname: Terhune
authors.forename: Richard C
authors.initials: RC
authors.lastname: Deth
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000535:Aluminum / Q000008:administration & dosage*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects; D011110:Polymorphism, Genetic; D044382:Population Groups; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007073:Immunoglobulin E; D000535:Aluminum