For years, adjuvants have been used by physicians and scientists to boost a desirable immune response, either in experimental models or during medical interventions, most classically, immunization. The adjuvant effects encompass physical protection of the antigen from degradation, stimulation of innate immunity by toll-like receptors (TLRs) and non-TLRs sensors, antigen translocation to regional lymph nodes, and activation of the complement system.10 Consequently, adjuvants enable a longer exposure of the immune system to the antigen and prime the system for the production and activation of B and T cells, resulting in a more robust response.
Despite their ability to boost immune responses, in the past, adjuvants were generally considered to be inert materials that posed little or no independent threat to the host. Alas, animal studies as well as reports of human diseases have clearly demonstrated the ability of adjuvants to inflict diseases by themselves.10 One of the most studied adjuvants in this context is pristane. This adjuvant was found to be capable of inducing an autoimmune disease like systemic lupus erythematosus (SLE) in a murine model.13 Replicating features of human disease, pristane-induced lupus is characterized by the production of autoantibodies as well as organ damage (e.g., renal disease) that depends on the interferon (IFN)-I receptor signaling pathway. The adjuvant, squalene, can also induce arthritis in rats and the production of SLE- associated autoantibodies in mice.13,14
Aluminum is a widely used adjuvant that may produce immune activation and induce autoimmunity.10 This metal is encountered extensively in daily life through the soil, water, food, and pharmaceutical agents. Aluminum may be present in high amounts in dialysate, intravenous solutions, antacids, buffered aspirins, antidiarrheal products, bone cement, and alum-containing vaccines. The widespread use of aluminum was enhanced by the belief that it is nontoxic and rapidly excreted in the urine. Regrettably, it turns out that aluminum has several pathologic effects such as postdialysis encephalopathy, degenerative brain disorders, osteomalacia, cholestasis, ototoxicity, normo- or microcytic anemia, hemolytic anemia, disturbed erythropoiesis process, and inhibition of macrophage and leukocyte defensive mechanisms.15 The widely used adjuvant alum is hydrated potassium aluminum sulfate.
In a series of experiments, Shaw and Petrik studied the potential toxicity of aluminum hydroxide in male CD-1 mice.16 Aluminum-treated mice showed significant impairments in a number of motor functions as well as diminished spatial memory capacity. Histology demonstrated increased apoptosis of motor neurons and increases in reactive astrocytes and microglial proliferation within the spinal cord and cortex. Aluminum was observed in the cytoplasm of motor neurons with some neurons also testing positive for the presence of tau protein, a pathological hallmark of Alzheimer’s disease. Recent studies have indicated that alum can initiate cellular damage following the release of uric acid, a known trigger of the inflammasome and the activation of caspase 1 mediated downstream targets such as interleukin (IL)-1β, IL-18, and IL-33.12,17