1. Introduction
Systemic lupus erythematosus is a systemic autoimmune disease hitting multiple tissues and organs due to deposition of immune complexes formed by auto-antibodies against multiple autoantigens, such as DNA, nuclear proteins, ribonucleoproteins, and phospholipids. Typical sites of damage are the renal glomeruli, the joint sinovias, the skin, and the blood vessels. Immune complexes deposition triggers local inflammation and damage through activation of the complement cascade, release of anaphylotoxins, and recruitment of inflammatory cells. According to a widely accepted etiologic model of autoimmune diseases, SLE is a multifactorial disease involving both environmental and genetic factors.
The genetic factors contemporarily involve multiple genes whose variants cooperate to constitute an autoimmunity-prone genetic background. A key role is played by alleles of the class-II major histocompatibility complex (MHC), but several other immune genes have been recently detected by genome wide association studies (GWAS). A genetic factor is also the gender, since SLE predominantly affects females, similarly to many other autoimmune diseases. This gender bias of autoimmunity has been ascribed to hormonal and reproductive factors, but other factors may concur such as the double dose of immune genes located in the X chromosomes (namely those genes that escape X chromosome inactivation or are reactivated), nonrandom X chromosome inactivation, and different susceptibility to genitourinary infections.
Discordance between identical twins and among dispersed people of the same ethnic group support the possibility that environmental factors may importantly contribute to development of autoimmune diseases. A key role has been ascribed to infections due to cross-reactions of the immune response specific for the infectious agent against structurally similar self molecules (molecular mimicry). According to this model, lymphocytes activated against an infectious agent would trigger the autoimmune disease by attacking self tissues expressing cross-reactive autoantigens. However, environmental factors may also act as predisposing factors. For instance, the vitamin D system (including Vitamin D, Ca, and light exposure) has been suggested to play a regulatory role in several autoimmune diseases. Low levels of vitamin D are associated with numerous autoimmune diseases such as multiple sclerosis, SLE, and psoriasis (Environmental pathways to autoimmune diseases: the cases of primary biliary cirrhosis and multiple sclerosis, 2011 Jun).
Two intriguing papers, one by Burry and the other by Wang et al, added a novel player in the field of the environmental factors involved in SLE (and possibly other autoimmune diseases): use of lipstick and, possibly, other cosmetics. This novel factor may partly account for the gender bias of several autoimmune reactions.
2.The hypothesis and the epidemiologic study
In 1969, Burry published a letter to the editor in The New England Journal of Medicine postulating that substances contained in lipsticks might be an environmental predisposing factor for systemic lupus erythematosus (SLE) and might have part in the gender bias of this disease toward females. In particular, he suggested that eosin, which strongly binds to tissues, may be retained in vivo and act as a persistent immunological trigger causing autoimmunity. This was a theoretical work lacking any experimental support (Lipstick and lupus erythematosus, 1969).
About forty years later, Wang et al published an ingenious Internet-based case–control epidemiologic study showing that the Burry’s hypothesis may indeed be true since lipstick use, 3 days or more per week, was associated with <1.5 fold increase of risk of SLE development. The risk increased further with young age of starting and frequency of use. Briefly, the authors created a study website and invited the access to all internet users entering SLE-related key terms in the Google™ search engine. The homepage of the study website provided information about the study and the relative questionnaires querying about gender, SLE status, and lipstick use.
Lipstick is one of the most commonly used cosmetic products, especially among women. Several chemicals commonly contained in the lipstick have been associated with autoimmune reactions. Eosin is a red dye that has been implicated in photosensitivity and lupus flares; phthalate can induce anti-DNA antibody responses and a SLE-like picture in lupus-prone mice; 2-Octynoic acid has been involved in induction of antimitochondrial antibodies (AMA) in primary biliary cirrhosis (PBC). Furthermore, the application of products to the lips confers a unique potential to increase the amount of chemical exposure through oral ingestion and proximity to the oral mucosa, a site of privileged absorption that evades “first-pass” hepatic metabolism.
(Is lipstick associated with the development of systemic lupus erythematosus (SLE)?, 2008.)
3. The molecular mimicry mechanisms
Among these chemicals, those that have been best studied for involvement in autoimmunity are 2-octynoic acid and phthalates that have been involved in PBC and SLE respectively.
a) 2-octynoic acid in primary biliary cirrhosis
Lipoic Acid 
2-Octynoic acid
PBC is a chronic progressive cholestatic liver disease associated with AMA production in 95% of the patients. In these patients, AMA can be found on routine screening many years before the clinical appearance of disease. AMA production has been suggested to be due to molecular mimicry between the self-Ag lipoylated E2 component of pyruvate dehydrogenase complexes (PDC- E2) and xenobiotically modified PDC-E2. This possibility is supported by the observation that antibodies to PDC-E2 Abs from patients with PBC were able to recognize xenobiotically modified PDC-E2 peptides mimicking lipoic acid. Moreover, experimental animals immunized with the lipoic acid mimic 6-bromohexanoate, conjugated to bovine serum albumin, produced AMA. Indeed, a microarray screening of 107 different organic compounds coupled to the lysine residue of an immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain detected multiple compounds which had a significantly higher reactivity against PBC sera compared with normal control sera. Several of these sera were crossreactive with the native lipoylated peptide and with lipoic acid. The best reacting compound was found to be 2-octynoic acid, which not only has the potential to modify PDC-E2 in vivo but it is widely used in in perfumes, soaps, detergents, lipsticks, toilet waters, facial creams, and perfumed cosmetics because of its violet scent. 2-Octynoic acid methyl ester also finds some use in flavor compositions mainly for cucumber, berry complexes, fruit blends, peach imitation, liqueur flavorings, and various “floral” and “muscatel” flavors. The concentration of 2-octynoic acid methyl ester in those products is normally low (0.1–2 ppm), but in chewing gum it may reach 10–20 ppm. Although PDC-E2 is the major autoantigen in PBC, the lipoyl domain of the other members of the 2-oxoacid dehydrogenase complexes are also targets of AMA, including the E2 subunit of the branched chain 2-oxoacid dehydrogenase complex, the E2 subunit of the 2-oxoglutarate dehydrogenase complex and the E3BP subunit of PDC. In mammals, attachment of LA to the lipoyl domain is achieved by the lipoate-protein ligase in a two-step reaction. Lipoic acid is activated by ATP (or GTP) and the lipoyl residue from the resulting lipoyl-AMP (or GMP) intermediate is transferred to the lysine residue on the lipoyl domain. It is noteworthy that the lysine residue of the PDC can accept a variety of carboxylic acids aberrantly even without the dithiolane ring. Since humans are exposed to a large number of xenobiotics and such exposure commonly occurs in the liver, many of these compounds have the potential to modify a lysine residue of PDC and trigger cross-reactive immune responses.
Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid, 2005
Environment and primary biliary cirrhosis: Electrophilic drugs and the induction of AMA, 2013
b) Phtalates in systemic lupus erythematosus
Phthalic acid
Phthalic acid and phthalate esters, such as 1,2-diethylhexyl phthalate (DEHP), are used in the production of a variety of household and consumer goods; including plastic polymers used in food-packaging materials, biomedical devices, children’s toys, lubricating oils, and carriers for perfumes in cosmetics. Phthalate compounds are present in water, soil, food and even in the human body. Ortho-Phthalic acid, the predominant metabolite of DEHP leaches out of polyvinyl chloride (PVC) plastics and appears in the urine of uremic patients receiving continuous ambulatory peritoneal dialysis. Son-Yon et al published several reports showing that immunization of mice with several types of phthalate conjugated to a protein carrier induces production of high affinity IgG antibodies displaying intense cross-reactivity toward single and double-stranded DNA in both BALB/c and lupus-prone NZB/NZW F1 mice. These antibodies caused a lupus-like picture and progressive renal failure only in NZB/NZW F1 mice, but not in BALB/c mice. Intriguingly, this difference correlated with development, only in BALB/c mice, of CD8+ cytotoxic T cells capable to suppress the autoimmune response by killing the phthalate-induced autoreactive B cells in an antigen-specific manner before they could cause the disease. Moreover, the two strains displayed different responses in terms of autoantibody class-switching and T helper cytokine responses. Phthalates can thus be regarded as autoantigens with ability to engender lupus-like autoimmune disorders in genetically prone strains of mice (Autoreactive responses to environmental factors: 3. Mouse strain-specific differences in induction and regulation of anti-DNA antibody responses due to phthalate-isomers, 2005.)
By translating these data to humans, it may be suggested that exposure to phthalates (for instance use of lipstick) and possibly other xenobiotics may favor development of SLE in genetically prone subjects displaying an unfavorable immune response due to peculiarities in key processes such as antigen processing and presentation, or the T helper effector response, or the peripheral tolerance machinery. Other works suggested that additional predisposing genetic factors may relay on the metabolism and detoxification systems of xenobiotics. In fact, epidemiological, genetic, and biochemical data suggest possible roles of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin).
A possible role of xenobiotics in SLE development is supported by the observation that, in 1981, the ingestion of contaminated rape oil seed resulted in the toxic oil syndrome with cases of SLE-like disease, scleroderma-like disease and a number of general clinical manifestations that persisted in 10% of the subjects.
Toxic oil syndrome: a syndrome with features overlapping those of various forms of scleroderma, 1986
The chemical defensive system in the pathobiology of idiopathic environment-associated diseases, 2009
4. Conclusions
Xenobiotics may represent additional etiologic factors for autoimmune diseases flanking other stronger environmental factors such as infections. A possible mechanism of action has been described in the previous section and consists in their capacity to act as haptens binding to self-proteins and creating novel antigens cross-reacting with the native ones. However, two other mechanisms have been suggested. First, chemical modifications of native cellular proteins may change processing in antigen-presenting cells and lead to the presentation of cryptic, potentially immunogenic peptides. Second, a direct toxic effect of xenobiotics may cause cell death by apoptosis inducing the generation of immunogenic auto-epitopes (indeed, apoptotic cells have been considered key immunogens in SLE).
Probably, the genetic background might influence the susceptibility to these effects by modulating the detoxifying systems, the apoptotic response, and the immune response. Identification of these susceptible genetic backgrounds would be an evaluable tool to detect subjects that should limit risky exposures. In the case of lipstick, this tool would help to determine the personal “therapeutic window” between beauty and disease.
