Adjuvants and autoimmunity
Authors: M Blank
E Israeli
N Agmon-Levin
Y Shoenfeld
Journal: Lupus (2009)
Discipline: CLINICAL MEDICINE
Keywords: adjuvants; immunological reaction; toll-like receptors; autoimmune; silicone
Affiliations: Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel.

Abstract:  Some adjuvants may exert adverse effects upon injection or, on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of the enormous implications for vaccine development. In the search for new and safer adjuvants, several new adjuvants were developed by pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special immune receptors called toll-like receptors (TLRs) that are expressed on leukocyte membranes. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. Alongside their supportive role, adjuvants were found to inflict by themselves an illness of autoimmune nature, defined as 'the adjuvant diseases'. The debatable question of silicone as an adjuvant and connective tissue diseases, as well as the Gulf War syndrome and macrophagic myofaciitis which followed multiple injections of aluminium-based vaccines, are presented here. Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants need to be developed and incorporated into future vaccines. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. More adjuvants were approved to date besides alum for human vaccines, including MF59 in some viral vaccines, MPL, AS04, AS01B and AS02A against viral and parasitic infections, virosomes for HBV, HPV and HAV, and cholera toxin for cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely in order to circumvent common side effects of adjuvant-activated TLRs such as local inflammation and the general malaise felt because of the costly whole-body immune response to antigen. 

Retracted: No

PubPeer comments:
 ![file]  Multiple vaccinations performed over a short period of time in the Persian Gulf area have been recognized as the main risk factor for GWS. This was a contentious claim in 2009 and has only become more contentious: https: en.wikipedia.org wiki Gulf_War_syndrome#Probable_causes . If I had been a reviewer of this paper, or an editor at Lupus, I would have asked for at least one citation rather than an invocation of the authority of Passive Voice. Is there any reason why the authors quote at length from Asa et al. (2000) to support the  squalene in anthrax vaccine claim, while ignoring all the subsequent failures to replicate like [Matyas et al (2004)] , or the arguments that Asa et al. were misled by laboratory contaminants? It seems like extreme cherry-picking. The US armed forces and the manufacturers of vaccines were united in denying that squalene had been used as an adjuvant. If one chooses to dismiss these denials, their unanimous nature presupposes some manner of conspiracy to conceal the truth. , 
 Page 1221: ![file] [Bashyam, 2008] : ![file] An acknowledgement of the source would have been nice. , 
 Page 1219: ![file] Here is an excerpt from the Wikipedia article on [ Immunologic adjuvant ](23 November 2007) (as edited and structured by  Waterspyder on 23rd October 2007): **Adjuvants and the adaptive immune response** [...] In order to understand the links between the innate immune response and the adaptive immune response to help substantiate an adjuvant function in enhancing adaptive immune responses to the specific antigen of a vaccine, the following points should be considered: u25cf Innate immune response cells such as DCs engulf pathogens through a process called phagocytosis. DCs then migrate to the lymph nodes where T cells (adaptive immune cells) wait for signals to trigger their activation.[8] u25cf In the lymph nodes, DCs mince the engulfed pathogen and then express the pathogen clippings as antigen on their cell surface by coupling them to a special receptor known as a major histocompatibility complex (MHC). u25cf T cells can then recognize these clippings and undergo a cellular transformation resulting in its own activation.[9] u25cf [[u03b3u03b4 T cells]] possess characteristics of both the innate and adaptive immune responses. u25cf Macrophages can also activate T cells in a similar approach. This process carried out by both DCs and macrophages is termed antigen presentation and represents a physical link between the innate and adaptive immune responses. Upon activation, mast cells release heparin and histamine to effectively increase trafficking to and seal off the site of infection to allow immune cells of both systems to clear the area of pathogens. In addition, mast cells also release chemokines which result in the positive chemotaxis of other immune cells of both the innate and adaptive immune responses to the infected area.[10][11] Due to the variety of mechanisms and links between the innate and adaptive immune response, an adjuvant-enhanced innate immune response results in an enhanced adaptive immune response. ---------------------------------------------------------------------------------------- An acknowledgement of the source would have been nice. , 
 The paper continues on Page 1220: ![file] The Wikipedia [entry continues] : **Adjuvants and toll-like receptors** The ability of immune system to recognize molecules that are broadly shared by pathogens is believed to be due to TLRs expressed in leukocyte membranes. TLRs were first discovered in drosophila[13] as membrane bound PRRs and are proposed to be responsible for most (although certainly not all) antigen-mediated infections, no matter how complex those antigens may be.[14] In fact, some studies have shown that in the absence of TLR, leukocytes become unresponsive (no inflammatory responses) to some microbial components such as LPS.[15] There are believed to be up to thirteen different forms of the TLR, each of which possesses its own characteristic affinities for varying types of ligand. Prevailing TLR ligands described to date (all of which eliciting adjuvant effects[16][17][18][19][20][21] include many of the evolutionarily conserved molecules already mentioned such as LPS, lipoproteins, lipopeptides, flagellin, double-stranded RNA, unmethylated CpG islands as well as various other forms of DNA and RNA classically released by bacteria and viruses. It is the binding of ligand (either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection) to the TLR that marks the key molecular event ultimately leading to innate immune responses and the development of antigen-specific acquired immunity.[22][23]The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. It is believed that upon activation, TLRs recruit adapter proteins (proteins that mediate other protein-protein interactions) within the cytosol of the immune cell in order to propagate the antigen-induced [[signal transduction pathway]]. To date, four adapter proteins have been well-characterized. These proteins are known as MyD88, Trif, Tram and Tirap (also called Mal).[24][25][26][27]These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases (IKKi, IRAK1, IRAK4, and TBK1) that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events. Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity.[23] The high sensitivity of TLR for microbial ligands is what makes adjuvants that mimic TLR ligands such a prime candidate for enhancing the overall effects of antigen specific vaccinations on immunological memory. , 
 ![file] Wikipedia, [as of 23 November 2007] : **Overview** [...] Adjuvants accomplish this task by mimicking specific sets of evolutionarily conserved molecules which include liposomes, lipopolysaccharide (LPS), molecular cages for antigen, components of bacterial cell walls, and endocytosed nucleic acids such as double-stranded RNA (dsRNA), single-stranded DNA (ssDNA), and unmethylated CpG dinucleotide-containing DNA. [2] Because immune systems have evolved to recognize these specific antigenic moieties, the presence of adjuvant in conjunction with the vaccine can greatly increase the [[innate immune response to the antigen by augmenting the activities of dendritic cells (DCs), lymphocytes and macrophages by by mimicking what a natural infection. [3] Furthermore, because adjuvants are attenuated beyond any function of virulence, they pose little or no independent threat to a host organism. ![file] Due to the variety of mechanisms and links between the innate and adaptive immune response, an adjuvant-enhanced innate immune response results in an enhanced adaptive immune response. Specifically, a recent study has observed that adjuvants may exert their immune-enhancing effects according to five immune-functional activities.[12] First, it was found that adjuvants all help in the **translocation of antigens to the lymph nodes where they can be recognized by T cells**. This will ultimately lead to *greater T cell activity resulting in a heightened clearance of pathogen throughout the organism*. Second, adjuvants provide physical **protection to antigens which grants the antigen a prolonged delivery. This means that the organism will be exposed to the antigen for a longer duration**, making the immune system more robust as it makes use of the additional time by *upregulating the production of B and T cells needed for greater immunological memory in the adaptive immune response*. Third, adjuvants help to **increase the capacity to cause local reactions at the injection site** (during vaccination), inducing *greater release of danger signals by chemokine releasing cells such as helper T cells and mast cells*. Fourth, they **induce the release of inflammatory cytokines** which helps to not only *recruit B and T cells at sites of infection but also to increase transcriptional events leading to a net increase of immune cells as a whole*. Finally, adjuvants are believed to *increase the innate immune response to antigen* by **interacting with pattern recognition receptors (PRRs), specifically Toll-like receptors (TLRs), on accessory cells**. , 
 I cannot find [Rovere-Querini et al (2005)] in the References. ![file] ![file] [McAnally et al (2001)] **are** cited, which is commendable. ![file]  **Abstract** Myasthenia gravis (MG) and its animal model, experimental autoimmune (EA) MG, are caused by interference with neuromuscular transmission by autoantibodies against the nicotinic acetylcholine receptor (AChR) on muscle. Previously, we have shown that two peptides, denoted RhCA 67-16 and RhCA 611-001, designed to be complementary in structure to the main immunogenic region and the dominant Lewis rat T cell epitope (u03b1-chain residues 100-116) of the AChR, respectively, are effective vaccines that prevent EAMG in rats by inducing anti-idiotypic clonotypic antibodies (Ab) and lowering levels of AChR Ab. These studies employed keyhole limpet hemocyanin (KLH) as a carrier and complete Freunds adjuvant (CFA). In advance of a clinical trial the present study tested the efficacy of RhCA 611-001 when combined with different adjuvants that are approved for use in humans. Adjuvants chosen for comparison were incomplete Freunds adjuvant (IFA) and aluminum hydroxide (Alum). As a second goal we evaluated diphtheria toxin (DT) as an alternative carrier protein to KLH. Alum was found to be an effective adjuvant, particularly when used with the peptide conjugated to DT. This combination of carrier and adjuvant provided protection against EAMG comparable with that observed with CFA and KLH. Using enzyme-linked immunosorbent assays for Ab against RhCA 611-001, it was found that disease protection is qualitatively, but not quantitatively, related to the anti-peptide Ab response. Our results demonstrate a vaccine formulation that should be useful in the first soon-to-be-conducted clinical trials of peptide vaccines to specifically correct aberrant T and B cell responses in an autoimmune disease. ,