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The role of adjuvants in autoimmunity and infection — Vaccines and Autoimmunity
The role of adjuvants in autoimmunity and infection. Compared with the treatment of acute or chronic diseases, injection of commonly used vaccines is a cost-effective and healthy prevention method. However, not all vaccines are as effective and easy to administer as the vaccine against smallpox (vaccinia). Usually, when a pure antigen is injected, the antigen is not absorbed at the injection site, and the immune response fails. In order to help the immune system recognize the antigen, adjuvants are added to the antigen during vaccine development and production.
In recent years, researchers have been working to clarify the mechanism by which adjuvants play a role in immune effects. As of 2013, the mechanism of action of the most commonly used “senior” adjuvant alum has been discovered. Alum seems to have multiple pathways of action, and each pathway of action can independently increase the immune response of the antigen. Oil-based adjuvants Oil-based adjuvants (such as Freund’s adjuvant, original type, etc.) are usually present in the preparation of some veterinary vaccines. Incomplete Freund’s adjuvant (IFA) contains an oil-in-water emulsion, while complete Freund’s adjuvant (CFA) contains killed mycobacteria.
Mycobacteria added to the adjuvant can attract macrophages and other cells to the injection site, which enhances the immune response. Therefore, complete Freund’s adjuvant is usually used for the initial vaccination, and incomplete Freund’s adjuvant is suitable for booster immunization. Pharmaceutical companies are developing some new oil-in-water emulsions, such as MF59 (Novartis), AS03 (galxosmithkline), Advax (Vaxine Pty), and QS-21/immunostimulatory complex (see below).
Virosomes can induce local inflammation due to the widespread use of alum adjuvants. In the past two decades, a variety of techniques for improving the application ability of alum adjuvants have been studied (holzeret et al., 1996).
Therefore, other novel adjuvants-virus particles that can be used as antigen carrier systems have been developed. The virion contains membrane-bound hemagglutinin and neuraminidase derived from influenza virus, both of which promote the uptake of antigens by antigen-presenting cells (APC) and mimic natural immune responses (Gluck, 1999). New experimental adjuvants In the search for new and safer adjuvants, pharmaceutical companies have used new immunological and chemical innovations to develop several new adjuvants.
The following is a detailed introduction to the role of related adjuvants in the process of infection and autoimmunity:
TLRS related adjuvant
IC31 is a two-component synthetic adjuvant that conducts signals through toll-like receptor (TLR)-9. This new adjuvant was tested in the flu vaccine combination in 2008 (riedlet et al., 2008). The other four, ASO4, ASO2A, CPG 7907 and GM-CSF are used in some highly related vaccines, such as vaccines against papillomavirus, hepatitis B, and malaria (pichichero, 2008). Other TLRS-dependent adjuvant candidates are still in clinical development, such as rc-529, ISS, flagellin and TLRS antagonists. ASO4 and ASO2A are special adjuvants of GlaxoSmithKline (GSK).
AS02 oil-in-water emulsion contains MPL and QS-21. ASO4 can combine MPL and alum. MPL is a series of 4’monophosphoryl lipid A, which differ in the degree and position of fatty acid substitution. It is prepared from lipopolysaccharide (LSP) of Salmonella Minnesota R595 through weak acid and alkali hydrolysis, followed by purification. The abundance of unmethylated CpG dinucleotides is the reason why bacterial DNA becomes immune stimulus. Compared with bacterial DNA, vertebrate DNA contains relatively low unmethylated CpG, so vertebrate DNA does not stimulate immune response. When protein antigens are conjugated, the adjuvant effect of CpG is enhanced.
cpg7909 is an adjuvant developed by Coley Pharmaceuticals, which has been tested in some vaccines against infectious agents (such as hepatitis B allergens: Creticos et al., 2006) and tumor cells (alexeevet et al., 2008; Kirkwood et al., 2009) . The new adjuvant MF59 is a submicron oil-in-water emulsion of squalene, polyoxyethylene sorbitan monooleate (Tween 80), and sorbitan oleate. MF59 is approved for use in Europe and is found in several vaccines, including influenza vaccines.
It is also allowed to be used by other companies and is being actively tested in vaccine trials. Other oil-in-water emulsions include Sepic oil adjuvant, adjuvant 65 (used since the 1960s), and lipovant. QS-21, an adjuvant for the natural product of Quillaja bark (ghochikyan, 2006) native to Chile and Argentina, is currently under study. Immune stimulating complexes (ISCOMs) have a honeycomb-like structure, which is mainly composed of saponins, cholesterol, phospholipids and antigens.
Recently, people’s interest has focused on another clear natural structure endowed with adjuvant properties: bacterial DNA. Studies on bacterial DNA have shown that the unmethylated CpG motif shows the nucleotide sequence of 5’purine-purine-CpG-pyrimidine-pyrimidine 3′(pu: purine, A or G; Pyr: pyrimidine, C or T). Cells that are recognized and able to activate the immune system (Krieget et al., 1995). Such motifs allow the immune system to distinguish its own DNA from pathogen-derived foreign DNA.
CpG motifs were found to activate antigen-presenting cells, leading to the upregulation of major histocompatibility complex (MHC) and costimulatory molecules, and pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, interleukin-1 , Interleukin-6, interleukin-12, interleukin-18) secretion, and turn on T helper 1 (Th1) immunity. (Lipfordet et al., 1997; Millan, 1998; Zimmerman, 1998).
Tefsu’s own adjuvant, Tefsu A fragment cleaved by an enzyme. Due to genetics or deficiencies in Teferin after spleenectomy, it has increased susceptibility to certain infections caused by sandwiched organisms such as Haemophilus influenzae, Streptococcus pneumoniae, meningococcus and Salmonella. As an autoimmune stimulating molecule, Tefersu can be called “self adjuvant” based on its biological function.
Adjuvant and adaptive and innate immunity
In order to understand the connection between the innate immune response and the adaptive immune response, and to help confirm the function of adjuvants in enhancing the adaptive immune response to vaccine-specific antigens, the following points should be considered: Innate immune cells such as dendrites Cells engulf pathogens through phagocytosis. Dendritic cells then migrate to the lymph nodes, where T cells (adaptive immune cells) wait for signals to activate them (Bousso and Robey, 2003). In the lymph nodes, dendritic cells process the phagocytosed pathogen, and then express the pathogen cleavage as an antigen on the cell surface by coupling them to the major histocompatibility complex. Adjuvants can increase the adaptive immune response by enhancing the innate immune response.
Adjuvant and TLRS
The ability of the immune system to recognize molecules widely shared by pathogens is due in part to the presence of special immune receptors called TLRS expressed on the membrane of white blood cells. TLRS was first discovered in Drosophila and are membrane-bound pattern recognition receptors (PRRs), which are responsible for detecting most (though certainly not all) antigen-mediated infections (Beutler, 2004).
In fact, some studies have shown that in the absence of TLRS, white blood cells do not respond to some microbial components such as lipopolysaccharide (Poltoraket et al., 1998). There are at least 13 different forms of TLRS, each with its own characteristic ligand. The main ligands described so far (all of which cause adjuvant effects) include many evolutionarily conserved molecules.
The fact that TLRS activation results in an adaptive immune response to foreign entities explains why vaccine adjuvants used today are developed to mimic TLRS ligands. So far, scientists have characterized four adaptor proteins: MyD88, Trif, Tram, and Tirap (also known as “Mal”) (Shizuo, 2003). These mobilized proteins are responsible for the subsequent activation of other downstream proteins, including Protein kinases (ikki, IRAK1, IRAK4, and TBK1) further amplify the signal and ultimately lead to the up-regulation or suppression of genes that coordinate inflammation and other transcription events.
Adjuvants induce autoimmune (auto-inflammation) syndromes-silicone disease, Gulf War syndrome, macrophage myofascial inflammation, and post-vaccination phenomena are all related to an adjuvant previously exposed. In addition, these four diseases have similar complex symptoms and signs, further supporting a common characteristic. Shoenfeld and Agmon–Levin (2011) recently suggested that these four mysterious diseases should be included in a common syndrome called “adjuvant-induced autoimmune (auto-inflammatory) syndrome” (ASIS).
The author further proposed several major and minor criteria (although they need to be further verified) that may help the diagnosis of this newly defined syndrome. Therefore, ASIA may be a common syndrome of the five diseases mentioned. The accumulated data for each disease can provide a new perspective on the immune response to environmental adjuvants, as well as a better definition and diagnosis of these diseases. In addition, uncovering the pathogenesis of this newly defined syndrome may help to find preventive and therapeutic interventions.
Conclusion Due to the side effects of adjuvants, there is undoubtedly a need for safer adjuvants to be included in future vaccines. The problem with the pure recombinant or synthetic antigens used in modern vaccines is that their immunogenicity is usually much worse than the old live or dead vaccines. This has created a need for improved and more effective adjuvants in these vaccines (Petrovsky and Aguilar, 2004).
Without exception, alum is still a human adjuvant approved for use in most countries in the world. Fortunately, most of the more serious side effects are relatively rare. Therefore, humans are in urgent need of safer and more effective adjuvants, especially safe and non-toxic adjuvants that can stimulate cellular (Th1 cell) immunity.
In addition to alum, other human vaccine adjuvants have been approved so far. Among them, MF59 is a viral vaccine, MPL, AS04, As01B and AS02A are for virus and parasite infections, as well as viral particles hepatitis B virus, human papilloma virus and Hepatitis A virus, and cholera toxin for cholera.
Other needs according to the new vaccine technology are other adjuvants suitable for use with mucosal delivered vaccines, DNA vaccines, cancer and autoimmunity. Each of these areas is highly specialized, with unique requirements for suitable adjuvant technology.
Although controversial, the high sensitivity of TLRS to microbial ligands makes adjuvants that mimic TLRS ligands the main candidates for enhancing the overall effect of antigen-specific vaccines on immune memory. In short, all TLRS ligands are adjuvants but not all adjuvants are TLRS ligands.
We can conclude that in addition to TLRS, there are likely to be other uncharacterized adjuvants that will open up future research areas. Perhaps in the future, adjuvants occupying these hypothetical receptors will completely bypass the TLRS signaling pathway to avoid the common side effects of adjuvant activation of TLRS, such as local inflammation and general discomfort due to the systemic immune response to antigens. Of course, such issues will be the focus of debate among future researchers.
Vaccine injection and administration cannot be separated from the final good absorption. The immune system’s recognition of antigens directly affects the effect of vaccination, so the role of adjuvant is self-evident. As the old saying goes: Everything has two sides. Studies on the adverse mechanism of adjuvants have found that alum and other traditional adjuvants have greater toxicity and side effects. In response to this problem, in addition to the past three common adjuvants (aluminum) In addition to improving salt, oil-based agents, and viral agents), scientists discovered the existence and mechanism of TLRS and developed adjuvants that mimic this mechanism. They enhanced the immune response and improved the occurrence of adaptive immunity. Because of this, the TLRS adjuvant has attracted the attention of scientists, because it can greatly improve the safety of vaccines if it can be successfully applied.