The Autoimmune Ecology

Abstract

Autoimmune diseases (ADs) represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology), which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation). As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology). In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics) to favor or protect against autoimmunity and its outcomes. Herein, we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status (SES), gender and sex hormones, vitamin D, organic solvents, and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied.

Keywords: autoimmune disease; ecology; environment; personalized medicine; polyautoimmunity.

Figure 1

Interaction of living and non-living components in the conformation of the biosystem. A system consist of regularly and interdependent components forming a unified whole. Systems containing living (i.e., biotic) and non-living (i.e., abiotic) components constitute biosystems, and range from genetic systems to ecosystems, all of them influencing their function and homeostasis. This multifactorial biosystem has a major effect in health, resulting into the concept of “the ecology of medical care.” Adapted from Ref. (4).

Figure 2

Environmental exposures associated with the development of autoimmune diseases (ADs). ADs are the result of the interaction between hereditary (i.e., genetic and epigenetic) and environmental factors over time. Autoimmune ecology is defined as the environmental exposures (i.e., cigarette smoking, coffee and alcohol intake, socioeconomic status, chemical agents, vaccines, incidental exposures, infectious agents, and microbiota) influencing the development of ADs and their outcome.

Figure 3

Pathogens-induced TLR signaling cascade in innate immune cells may exacerbate autoimmune diseases. Lipopolysaccharide (LPS) binds to TLR4 and peptidoglycans bind to TLR2, which initiates signaling by recruiting the adaptor proteins myeloid differentiation primary response protein 88 (MYD88), the TIR domain-containing adaptor protein (TIRAP), TIR domain-containing adaptor protein inducing IFN-β (TRIF), and TRIF-related adaptor molecule (TRAM). MYD88 associates with IL-1R-associated kinase 1 (IRAK1) and IRAK4 and recruits TNFR-associated factor 6 (TRAF6). This complex recruits TGFβ-activated kinase 1 (TAK1), leading to phosphorylation of NF-κB inhibitor (IκB), activation of nuclear factor-κB (NF-κB), and consequent transcription of a range of genes coding for proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), pro-IL-1β, and pro-IL-18. In addition, TLR agonists activate the interferon regulatory factor (IRF) pathways, leading to the production of IL-12p35 and type I IFNs. TLR-induced activation of TAK1 also results in phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 and extracellular signal-regulated kinase (ERK). Phosphorylation of ERK promotes the transcription of the gene encoding IL-23p19 and subsequent IL-23 synthesis. Phosphorylation of p38 activates cAMP response element-binding protein (CREB), leading to IL-10 production. IL-1β activates its own receptor, which also signals via the same TLR pathway components to produce IL-1β. Adapted from Ref. (35).

Figure 4

Mechanisms by which adjuvants trigger autoimmunity. Adjuvants (mainly alum) may function as delivery systems by generating depots that trap antigens at the injection site, providing slow release in order to continue the stimulation of the immune system, thus enhancing the antigen persistence and increasing recruitment and activation of dendritic cells (DC) (depot’s effect). Other adjuvants, essentially ligands for pattern recognition receptors (PRR), act by inducing the innate immunity by targeting the DC via toll-like receptors (TLRs). Adjuvants can direct support antigen presentation by the major histocompatibility complexes (MHC), inducing the differentiation of a naïve T cell in T helper 1 cells (Th1), T helper 2 cells (Th2), T regulatory cells (Treg), and T helper 17 cells (Th17). Adapted from Ref. (45).

Figure 5

Self nucleic acids recognition by TLRs in autoimmunity. Autoantibodies and autoreactive B-cell receptor BCRs, such as rheumatoid factor (RF) and anti-small nuclear ribonucleoprotein (snRNP) or anti-DNA antibodies mediate the access of self-nucleic acids to endolysosomal toll-like receptors (TLRs), leading to the production of type I interferon (IFN) from dendritic cells (DCs) and autoantibodies of corresponding specificities from B cells. The major snRNP antigen for anti-snRNP autoantibodies contains small nuclear RNA (snRNA), whereas the antigenic targets of anti-DNA autoantibodies are apoptotic or necrotic material containing DNA; accordingly, anti-RNP B cells are activated by TLR7 ligands, whereas anti-DNA or RF-producing B cells are activated by either TLR9 or TLR7 ligands. Adapted from Ref. (62).

Figure 6

Epigenetic autoimmune ecology pathways. Different environmental factors, such as cigarette smoke, chemicals, UV light, and viral infections cause oxidative stress, which lead to activation of the mammalian target of rapamycin (mTOR) pathway that can directly inhibit DNA methyltransferase 1 (DNMT1). Oxidative stress contributes in CD4⁺ T cells to site-specific decrease in phosphorylation of protein kinase C (PKC)δ T⁵⁰⁵, leading to functional loss of PKC and parallel reduction of extracellular signal-regulated kinase (ERK) phosphorylation. As a result of ERK activity, expression of DNMT1 is reduced, DNA hypomethylation occurs and CD4⁺ T cells become autoreactive. Adapted from Ref. (101).

Figure 7

Factors influencing gut microbiota. A balancing microbiota in symbiosis influences the equilibrium between T regulatory cells (Treg) and effector T cells (Th1, Th17). As a consequence, the gut can respond to an infection but this also leads to the permanence of microbiota and favors the host. By contrast, if the environment induces the rupture of the equilibrium, it induces a state of dysbiosis. Hence, the percentage of anti- inflammtory microorganisms (e.g., Bacteroidetes and Lactobacillus) may be lower than proinflammatory microorganisms (e.g., Firmicutes). Eventually, this may lead to an inflammatory profile that favors the development of autoimmunity. Adapted from Ref. (129, 130).

Figure 8

Socioeconomic status (SES) and autoimmune diseases (ADs). Some of the main findings associated with autoimmune diseases related to high or low socioeconomic position are shown.

Figure 9

Association between hormonal replacement therapy (HRT) exposure and risk of developing SLE. Forest plot of studies meta-analyzed. Final common effect size based on a random model. CI: confidence interval; SLE: systemic lupus erythematosus; HRT: hormonal replacement therapy. Adapted with authors’ permission from Ref. (217).

Figure 10

Predictive factors associated with AITD PolyA in SLE. Sjögren syndrome and ever smoking are the main factors associated with the development of AITD in SLE. AITD, autoimmune thyroid disease; PolyA, Polyautoimmunity; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome. Adapted from Ref. (237).

Figure 11

Cigarrete smoking and autoimmunity. In predisposed individuals carrying certain autoimmune alleles at HLA-DRB1, PTPN22, and PADI4 genes, cigarette smoke triggers citrullination by activating PAD enzyme, a mechanism that is estrogen dependent. Citrullinated proteins act as auto-antigens and induce the formation of anticitrullinated protein autoantibodies (ACPAs) by autoreactive B cells. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), released during cigarette smoking, acts as the best-known ligand for aromatic hydrocarbon receptor (AhR). AhR activation induces boosts T helper 17 (Th17) cells. Nicotine stimulates the α7-nicotine acetylcholine receptors (α7nAChRs), and increases TNFα, IL-6, IL-8, and IL-1 synthesis. The effect on T regulatory (Treg) function is controversial. All of these molecular pathways are responsible for the clinical manifestations listed on the right. PAD, peptidylarginine deiminase; SE, shared epitope; DC, dendritic cell; MS, multiple sclerosis; PBC, primary biliary cirrhosis; AITD, autoimmune thyroid disease; RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drug; CVD, cardiovascular disease; ADs, autoimmune diseases; PolyA, polyautoimmunity; SLE, systemic lupus erythematosus; SS, Sjögren syndrome; aPL-abs, antiphospholipid antibodies.