Table 1.

Panel findings on mechanisms involved in the role of environmental factors and development of autoimmune disease.

We Are Confident of the Following	We Consider the Following Likely, but Requiring Confirmation	Broad Themes to Be Pursued in Future Investigations
B cells
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.
Innate Immunity
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.