System lupus erythematosus and the environment

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by myriad of clinical manifestations, degrees of severity, and alternating phases of remission and flares, that may be defined as a syndrome rather than a single autoimmune disease. The pathogenesis of SLE encompasses complex interactions between genetic susceptibility, immune dysregulation, hormonal, and environmental factors, namely, the mosaic of autoimmunity. The inheritance of genes alone is insufficient to explain the development of SLE, even if multiple genetic and epigenetic alterations are taken into consideration. Thus environmental triggers have long been associated with SLE pathogenesis as well as its various phenotypes.

The SLE exposome (i.e., environmental influences) include “classical” triggers and ones reported in recent years. SLE exposome include ultraviolet (UV) light, certain infections, solvents and cosmetics, residential and agricultural pesticides, heavy metals, crystalline silica, and cigarette smoke. Drugs, particularly oral contraceptives and postmenopausal hormone replacement, as well as vaccinations have been hypothesized to be related to SLE risk. Of note, an inverse association was documented between SLE and alcohol use. Recently, SLE was related to air pollution, like living environment, urban-rural differences, seasonality, microbiome, stress, and physical activity.

In this context, perhaps one of the most imperative in recent understanding is that environmental exposures do not only have a synergetic effect within the mosaic of autoimmunity, but actually directly interact with the different factors such as genetics throughout lifespan.

Experimental data strongly suggests that environmental influence alter genetic material mainly via epigenetic changes. The latter are dynamic, allowing cells and tissues to differentiate and adjust. It is known that the harmful effects of smoking and hormonal therapy are associated with specific genetic polymorphisms, both of which enhance the complex interplay between gene-environment and SLE.

Loss of tolerance is fundamental to the development of autoimmunity in general. Immune tolerance consists of a central tolerance occurring in the thymus and bone marrow for T-cells and B-cells, respectively, and peripheral tolerance of mature cells that take place in tissues and lymph node. Peripheral tolerance is the main mechanism by which immune responses to environmental factors are controlled. On the other hand, the exposome affects the innate and adaptive immune responses in SLE, such as activation of Toll-like receptor (TLR) by xenobiotics, adjuvants, or the modifications of self-antigens following infection. Likewise, environmental factors may induce activation of Th-17 cells, downregulation of T regulatory cells, activation of B cells, and the production of autoantibodies. The followings are the hallmark of SLE and typically appear prior to clinical manifestations of the disease. Hence, SLE-related autoantibody production (e.g., antidsDNA, or antiRo/SSA) may be induced by infectious agents, vaccines, or drugs.

In this chapter we review the data regarding the subtle interactions between environmental factors, host immunity, and SLE diseases. Some may be avoided (e.g., smoking), thereby decreasing the risk of developing SLE.

Infectious agents, dysbiosis the microbiome, and SLE

Infectious agents play a bidirectional role in driving the autoimmune process via mechanisms leading to immune dysregulation or enhanced immune control. The mechanisms include molecular mimicry between infectious epitopes and self-antigens, loss of tolerance (central or peripheral), epitope spreading, in which one epitope evolve into cryptic or neo-epitopes; bystander activation as a result of cytokine production, T-cell activation, viral persistence, and B-cell polyclonal activation.

Notably, a large Danish registry shed light on the association between history of hospitalization for infections and the diagnosis of SLE. Some infectious agents were linked to clinical manifestations of autoimmune disease, for instance, bacteria such as Mycobacteria pneumoniae, and Klebsiella were allied with induction of antidsDNA antibodies, both in animal models and in humans. Viruses like Epstein-Barr virus (EBV), cytomegalovirus, parvovirus B19, rubella, mumps, retroviruses, and transfusion-transmitted viruses were associated with triggering of SLE. EBV perhaps, being the most notorious and dually linked to SLE. EBV seropositivity is higher in adults and children with SLE than with age-matched controls, suggesting a suboptimal antiviral response of the host. EBV-specific antigens are associated with the production of SLE-related autoantibodies and clinical manifestations. In a meta-analysis of 25 case-control studies, a statistically significant high seroprevalence of antiviral capsid antigen IgG [OR 2.08; 95% confidence interval (CI) 1.15 to 3.76; P = .007] and antibodies to EBV early antigen diffusion, a marker of viral replication were documented in SLE patients compared to controls (OR 4.5; 95% CI 3.00 to 11.06; P < .00001) In animal models injection of EBV nuclear antigen-1 (EBNA-1) was found to induce the production of SLE-specific antibodies directed at Sm, Ro, and ds-DNA antigens. Moreover, exposure to EBV in humans is commonly accompanied by high titers of antiSSA/Ro antibodies and a mild clinical phenotype of SLE involving the skin and joints. This concept of infectious agents determining the clinical presentation of disease has been advocated also for other agents, such as rubella leading to SLE central nervous system manifestations.

Human papilloma virus (HPV) was also linked with SLE. In a recent study from Taiwan a significantly higher risk of SLE was reported among HPV-infected patients, more prevalent among men aged 16-45 years diagnosed with SLE. Other publications have implied an association between HPV and SLE at the epidemiological level, as well as the development of autoimmune phenomena postHPV vaccination. Raising the hypothesis that exposure to HPV antigens may be a trigger for SLE development in prone individuals. A possible mechanism for such a process is molecular homology or shared peptides between HPV and human proteins, leading to an immune crossreaction that may result in autoimmune disease.

Alternatively, some infectious agents may exert opposite or “protective” effects. This notion was first proposed in the hygiene hypothesis, which aimed to explain the inverse association between some endemic infections and allergic or autoimmune diseases. In this line of thought, infections with plasmodium or parasites correlate with a lower prevalence of SLE in humans and animal models.

Finally, the effect of the microbiome and specifically the gut microbiome was related to autoimmunity and SLE. Several hypotheses shed light on mechanisms at the cellular and molecular level by which the microbiome affects autoimmune diseases. At the molecular level, posttranslational modification and crossreactivity are two central mechanisms of how the microbiota may promote autoimmune dysregulation. Additionally, translocation of gut bacteria across a dysfunctional gut barrier and the effect of commonly used drugs such as nonsteroidal antiinflammatory (NSAIDS) or proton pump inhibitors (PPIs) also contribute to the complex interaction between the host and the microbiome, which can promote autoimmunity. One measurable parameter to these interactions is the abundance of several genera (e.g., Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium and Flavonifractor, Lachnospiraceae), and lack of others in SLE patients (e.g., Dialister and Pseudobutyrivibrio, Lactobacillaceae, Rikenellaceae, Odoribacteraceae, Christensenellaceae and Peptococcaceae).

Hence, these recent studies reinforce that concept modulation of infectious agents, infectious disease, and the host microbiome promote the progression of autoimmunity, predominantly SLE.

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