Expert Panel Workshop Consensus Statement on the Role of the Environment in the Development of Autoimmune Disease
2. Workshop Summaries
|We Are Confident of the Following||We Consider the Following Likely, but Requiring Confirmation||Broad Themes to Be Pursued in Future Investigations|
|Dysfunctions of B cell tolerance checkpoints are directly correlated with autoimmune disease in murine models;|
B cells modulate autoimmunity positively and negatively as secretors of antibodies and inflammatory cytokines, as antigen presenting cells to autoreactive T cells, and secretors of anti-inflammatory cytokines such as IL-10;
Follicular B cells (B2) are a major source of autoreactive pathogenic antibodies;
B cells secreting pathogenic autoantibodies can emerge when somatic hypermutation occurs outside of germinal centers;
Sex hormones like estrogen and prolactin can differentially activate autoreactive B cell populations from different subsets (e.g., B2).
|B1 cells and marginal zone B cells can modulate autoimmunity by exacerbating it through secretion of autoreactive antibodies and/or by down-modulating it through secretion of anti-inflammatory cytokines;|
B10 cells appear to exclusively secrete IL-10 may be functionally specialized to carry out a negative regulatory role in inflammation and autoimmunity.
|The roles of B1 and marginal zone B cells in autoimmunity;|
The role of the recently discovered B10 cell population in autoimmunity;
The survival/apoptotic pathways that when dysregulated lead to expansion and survival of autoreactive B cells (such as the BAFF/BlyS receptor system and CD40);
Tolerance checkpoint mechanisms regulating the formation of high affinity autoreactive B2 cells both in and outside the germinal center;
Environmental agents with the potential to disrupt B cell function.
|T-helper 17 (TH17) cells|
|Dysregulated Th17 cell activity can lead to pathology, as in chronic inflammatory diseases such as asthma or inflammatory bowel disease;|
Th17 cells are involved in multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn’s disease and psoriasis, where they seem to be involved in disease development and relapse.
|Smoking is an important risk factor for RA; and nicotine exerts effects via Th17 cells;|
Aryl-hydrocarbon Receptor (AhR) binding by aromatic hydrocarbons and non-halogenated polycyclic aromatic hydrocarbons favors differentiation of Th17 cells and can exacerbate autoimmunity.
|The involvement of environmental agents and exacerbation of autoimmune disease through Th17 cells;|
Therapeutic modulation of Th17 cells.
|The interaction between xenobiotics and Toll-like receptor (TLR) is a major mechanism involved in the interaction of environmental factors with autoimmunity development;|
Innate immune activation via TLR predisposes to toxic-induced inflammation;
Adjuvants activate both innate and adaptive immunity, inducing release of chemokines and inflammatory cytokines;
Immunization must be accompanied by a strong adjuvant, such as complete Freunds adjuvant, including the mycobacterium component. Incomplete Freund adjuvant results in production of antibodies, but without occurrence of autoimmune diseases.
|Altered innate immune responses and dysregulated TLR signaling are a key step in triggering autoimmune diseases, as in virus-induced animal models of type I diabetes;|
TLR activation in macrophages may predispose cells to toxin-induced inflammatory cytokine production;
Active infection or microbial products of infection can provide the adjuvant effect necessary for the induction of many autoimmune disorders.
|Allergenicity, functional mimicry of environmental contaminants and physical/chemical elements resembling TLR ligands;|
Dysregulation of the regulatory B cell (IL-10 producing, CD5+ B cells) through modulation of TLR signaling;
Molecular motifs of adjuvants and their physiological receptors that are associated with clinical manifestation of autoimmunity;
Genomic predisposition to innate immunity dysfunctions.
|T-regulatory (Treg) cells|
|Quantitative and qualitative Treg changes contribute to a breakdown in tolerance;|
The AhR ligand dioxin 2,4,7,8-tetrachlorodibenzo- p-dioxin (TCDD) induces immunosuppressive T cells expressing specific Treg markers;
AhR ligands also affect skewing of the T cell repertoire towards Treg cells indirectly via antigen presenting cells;
TCDD induces indoleamine 2,3-dioxygenase (IDO) transcription to skew the T cell repertoire towards FoxP3+ Tregs;
Activation of peroxisome proliferator-activated receptor gamma (PPARγ) promotes Treg induction from naïve cells.
|Most studies suggest that AhR activation in T cells or in antigen presenting cells may increase Treg production and therefore decrease autoimmunity, but the opposite outcome is also likely and possibly ligand-specific;|
Context-specific activation of the AhR by specific ligands may result in either increased or decreased Treg activity;
Sex hormones play an important role in Treg development and may underlie female predominance of autoimmune diseases.
|Specific chemical, infectious, or physical agents capable of modulating Tregs;|
Environmental modulators of AhR stimulation;
Mechanisms of sex-specific Treg changes.
|Modification of self-antigens|
|The majority of human proteins undergo post-tranlational modification (PTM) and these modifications or lack thereof may lead to tolerance breakdown;|
PTM may explain the tissue specificity of autoimmune diseases;
MS pathogenesis includes PTM that increase the complexity of myelin proteins through the autoimmune response or neurodegenerative processes;
In RA, citrullination is an apoptotic PTM that seems to be helpful in opening protein conformation and favoring cleavage processes;
In PBC, cholangiocytes do not covalently link glutathione to lysine-lipoyl groups during apoptosis leading to accumulation and exposure to potentially self-reactive antigens, accounting for bile duct specific pathology.
|Multiple self-protein modifications (phosphorylation, glycosylation, acetylation, deamidation) can lead to either T or B cell responses to self-antigens;|
Serum autoantibodies to modified self antigens may bind either modified or unmodified forms and thus be crucial to effector immune reaction in target tissues;
Mercury-induced cell death results in formation of a unique and more immunogenic 19 kDa cleavage fragment of fibrillarin.
|Mechanisms by which citrullination and glutathionylation lead to tolerance breakdown in susceptible individuals;|
The role of glucosylation in MS and other autoimmune diseases;
Experimental models to prove that autoantigens can be modified to increase their immunogenicity;
Technologies to reverse or induce PTM in animal models of autoimmunity.
|Modification of DNA methylation|
|DNA methylation profiles are associated with environmental factors including prenatal tobacco smoke, alcohol, and environmental pollutants;|
The importance of DNA methylation in regulating immune function is suggested by two rare congenital diseases, Silver-Russel and Beckwith-Wiedemann syndromes;
Changes in DNA methylation in specific peripheral immune cell types are associated with autoimmune diseases.
|Phenotypic differences are increased with age in twins in a trend coined as “epigenetic drift”, due to different environmental exposures, and may explain late-onset autoimmunity;|
Specific impairments in epigenetic regulation in immune cells may be responsible for immune-tolerance breakdown through hypo-methylation of genes or involvement of transcription repressors;
Recent genome-wide association studies demonstrate that genomics significantly predispose to systemic lupus erythematosus (SLE) onset, but experimental studies indicate that epigenetic mechanisms, especially impaired T and B cell DNA methylation, may be one of these factors.
|The functional effects
in vivo of DNA methylation changes under different environmental and genomic conditions;|
The development of new therapeutic molecules capable of preventing or counteracting DNA methylation changes in a cell-specific manner;
The DNA methylation changes in the target cells and not only in the rapidly accessible effector immune cells.
2.1.1. Effects on Innate Immunity
2.1.2. B Cell Activation
2.1.3. T-Helper 17 Cells
2.1.4. T Regulatory (Treg) Cells
2.1.5. Modification of Self-Antigens
2.1.6. Modifications of DNA Methylation
2.2. Animal Models
|We Are Confident of the Following||We Consider the Following Likely, but Requiring Confirmation||Broad Themes to Be Pursued in Future Investigations|
|Forms of inorganic mercury (HgCl2, vapor, amalgam) induce systemic autoimmune disease in rats (transient) and mice, and exacerbates systemic autoimmune disease in lupus-prone mice;|
Several mineral oil components and certain other hydrocarbons can induced an acute inflammatory arthritis in some rat strains;
The mineral oil component 2,6,10,14-tetramethylpentadecane (TMPD or pristane) induces lupus-like disease and inflammatory arthritis in several strains of mice;
For a limited number of pathogens there is a clear association with development of autoimmune diseases;
Excess iodine increases the incidence of autoimmune thyroiditis in genetically predisposed animal models.
|Gold causes (transient) nephropathy in rats. Gold and silver cause autoimmune responses, but not autoimmune disease, in mice; but the ability of silver and gold to exacerbate spontaneous autoimmune disease requires study;|
Silica exacerbates autoimmune disease but more studies are needed using more species/strains and a wider range of doses and exposure routes;
Trichloroethylene (TCE) exacerbates systemic autoimmunity although responses are often limited and transient. Studies of autoimmune liver disease are needed with additional species/strains and in developmental studies;
TCDD exposure during fetal or early neonatal development may promote autoimmunity;
Organochlorine pesticides may enhance lupus-like disease in a predisposed mouse strain;
Sunlight/ultraviolet (UV) light exposure exacerbates lupus in genetically prone mice.
|Studies should be “shaped by what is observed in humans, not by what is possible in mice” ;|
Studies should not be restricted to a “gold standard” animal model. Multiple models should be investigated to reflect human genetic heterogeneity;
When using spontaneous disease models it is important to consider whether environmental exposures directly impacts idiopathic autoimmunity, or reflects environmental factor-specific autoimmunity;
More studies on the effects of environmental factor exposure on expression of autoimmunity during different stages of life (gestational to adulthood) are needed.
2.3. Epidemiology/Human Studies
|We Are Confident of the Following||We Consider the Following Likely, but Requiring Confirmation||Broad Themes to Be Pursued in Future Investigations|
|Crystalline silica (quartz) contributes to development of several systemic autoimmune diseases, including RA, systemic sclerosis (SSc), SLE and anti-neutrophil cytoplasmic antibody|
Solvents contribute to development SSc.
Smoking contributes to development of anti-citrullinated protein antibody (ACPA)-positive and anti-rheumatoid factor.
(RF)-positive RA (with an interaction with the shared eptiope genetic susceptibility factor).
|Solvents contribute to development of MS.|
Smoking contributes to development of seronegative RA, MS, SLE, Hashimoto’s thyroiditis (HT), Graves’ disease (GD) and Crohn’s disease (CD).
Current smoking protects against development of ulcerative colitis (UC).
|There is insufficient evidence on the role of metals, including those associated with animal models of autoimmunity, e.g., mercury.
The identification of single causal agents within groups of exposures is needed (e.g., specific solvents or pesticides contributing to increased risk for the group).
Studies are needed on plasticizers (e.g., phthalates and bisphenol A), some of which may be endocrine or immune disruptors, and have been associated with other immune mediated diseases.
There is insufficient evidence on the role of cosmetics in autoimmune diseases.
|An inverse association exists between increased ultraviolet radiation exposure and risk of developing MS.||Ionizing radiation contributes to development of HT and GD.||There is insufficient evidence on a possible protective role of ultraviolet radiation on type 1 diabetes (T1D).|
Prospective data are needed on sun exposure as a risk factor for SLE (prior to early clinical symptoms) and dermatomyositis.
|Ingestion of gluten contributes to development of gluten-sensitive enteropathy (GSE).|
Ingestion of certain lots of l-Tryptophan contributes to development of eosinophilia myalgia syndrome.
Dietary intake of 1,2-di-oleyl ester (DEPAP)- and oleic anilide-contaminated rapeseed oil contributes to development of toxic oil syndrome.
|Epstein-Barr virus (EBV) infection contributes to MS development.
Early introduction of complex foods contributes to development of T1D and GSE.
Low dietary vitamin D intake and blood levels contribute to development of MS.
|Studies are needed on MS and vitamin D in racial/ethnic groups with darker skin (associated with UV-associated vitamin D deficiency), and examining dose-effects.|
Prospective data are needed on vitamin D and other autoimmune diseases.
Additional studies are needed on associations of food chemicals, dyes, or additives.
Prospective studies are needed on nitrates/nitrosamines and T1D.
2.3.1. Chemical Factors
2.3.2. Physical Factors
2.3.3. Biological Factors
2.4. Exposure Assessment in Human Studies
2.5. Transdisciplinary Breakout Panels
Topic 1—Do animal models recapitulate disease observed in humans following exposure?
Topic 2—Do exposures associated with autoimmune disease in vitro and in animal models have relevance to exposures in human populations?
Topic 4—To what extent does ability to quantify environmental exposures limit our ability to identify factors associated with human autoimmune disease?
Topic 5—How well do mechanistic studies in vivo or in vitro relate to clinical outcomes?
|Exposure-Disease Association in Humans||Evidence on in Vitro and in Vivo Mechanisms|
|Smoking and seropositive-RA||Post-translational modification—antigen citrullination and anti-cyclic citrullinated peptides (CCP) antibodies [80,82];|
|Nicotine and Th17 activation [86,87];|
|Upregulation of heat shock gene expression  *;|
|Disease relevant autoantibodies (RF, anti-HSP70)  *.|
|Silica and RA/SLE/SSc/ANCA-vasculitis||Aggravation of lupus in animal models ;|
|Adjuvant effect-apoptotic debris ;|
|Dysregulation of apoptosis  *;|
|Disease relevant autoantibodies (anti-dsDNA, anti-Ro/SSA, anti-La/SSB antibodies in silica associated SLE)  *;|
|Altered CD4+/CD4+ CD25+ T cell ratio  *.|
|Solvents and SSc||Accelerated autoimmunity in animal models |
|SSc disease relevant autoantibodies (anti-Scl-70) |
|Increased IFN-γ, reduced IL-4  *|
Topic 6—How well do in vitro mechanisms relate to in vivo mechanisms in animals or effects of human exposures?
3. Summary and Conclusions
3.1. Overall Advances in this Field
3.2. Conclusions and Recommendations
Conflicts of Interest
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© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Parks, C.G.; Miller, F.W.; Pollard, K.M.; Selmi, C.; Germolec, D.; Joyce, K.; Rose, N.R.; Humble, M.C. Expert Panel Workshop Consensus Statement on the Role of the Environment in the Development of Autoimmune Disease. Int. J. Mol. Sci. 2014, 15, 14269-14297. https://doi.org/10.3390/ijms150814269
Parks CG, Miller FW, Pollard KM, Selmi C, Germolec D, Joyce K, Rose NR, Humble MC. Expert Panel Workshop Consensus Statement on the Role of the Environment in the Development of Autoimmune Disease. International Journal of Molecular Sciences. 2014; 15(8):14269-14297. https://doi.org/10.3390/ijms150814269Chicago/Turabian Style
Parks, Christine G., Frederick W. Miller, Kenneth Michael Pollard, Carlo Selmi, Dori Germolec, Kelly Joyce, Noel R. Rose, and Michael C. Humble. 2014. "Expert Panel Workshop Consensus Statement on the Role of the Environment in the Development of Autoimmune Disease" International Journal of Molecular Sciences 15, no. 8: 14269-14297. https://doi.org/10.3390/ijms150814269