A Potential Link between Environmental Triggers and Autoimmunity

Abstract

Autoimmune diseases have registered an alarming rise worldwide in recent years. Accumulated evidence indicates that the immune system's ability to distinguish self from nonself is negatively impacted by genetic factors and environmental triggers. Genetics is certainly a factor, but since it normally takes a very long time for the human genetic pattern to change enough to register on a worldwide scale, increasingly the attention of studies has been focused on the environmental factors of a rapidly changing and evolving civilization. New technology, new industries, new inventions, new chemicals and drugs, and new foods and diets are constantly and rapidly being introduced in this fast-paced ever-changing world. Toxicants, infections, epitope spreading, dysfunctions of immune homeostasis, and dietary components can all have an impact on the body's delicate immune recognition system. Although the precise etiology and pathogenesis of many autoimmune diseases are still unknown, it would appear from the collated studies that there are common mechanisms in the immunopathogenesis of multiple autoimmune reactivities. Of particular interest is the citrullination of host proteins and their conversion to autoantigens by the aforementioned environmental triggers. The identification of these specific triggers of autoimmune reactivity is essential then for the development of new therapies for autoimmune diseases.

Figure 1

The balance of immunity. A combination of host genetic factors and exposure to environmental triggers promote the development of autoimmune disease. A balance must be maintained between the regulatory T cells and the pathogenic T effector cells.

Figure 2

Differentiation of naïve T cells into pathogenic effector T cells. APCs can be activated by numerous factors, resulting in the release of cytokines that promote the differentiation of naïve T cells into various subsets of pathogenic effector T cells that drive inflammation, tissue injury, and autoantibody production. Segmented filamentous bacteria (SFB) can also promote the development of Th17 cells and autoimmune responses in vivo. Proinflammatory cytokines derived from both innate and adaptive immune cells attenuate T_REG cell-mediated suppression of effector T cells.

Figure 3

Putative mechanism of chemical-induced autoimmunity.

Figure 4

Potential molecular mechanisms implicated in chemical-induced autoimmune reactivities.

Figure 5

Mechanisms of infection-induced autoimmunity through molecular mimicry. Bacterial induction of self-tissue antigen release and simultaneous presentation of bacterial and self-tissue antigens to T cells; activated T cells can produce antibodies against both bacterial and self-tissue antigens.

Figure 6

Bacterial infection induces release of tissue antigen and presentation of bacterial and self-tissue antigens resulting in the induction of autoreactive T cells. T cells and inflammatory mediators cause the release of more self-antigens which differ from the original antigens. T-cell responses can then spread to involve T cells specific to other self-antigens. This T-cell response against different epitopes results in antibody production against multiple tissue antigens.

Figure 7

Microbial infection stimulates toll-like receptors (TLRs) and other pattern recognition receptors on antigen-presenting cells (APCs), leading to the production of proinflammatory mediators, which in turn can lead to tissue damage. The release of both tissue antigens and bacterial antigens results in bacterial-specific T cells and autoreactive T cells in the process called bystander activation, which contributes to autoimmunity.

Figure 8

Superantigens and autoimmunity. Infection can lead to the release of superantigens, which can cross-link between MHCII and TCR, causing broader bystander activation, some of which may be specific for self-antigens, leading to attack on self-tissues.

Figure 9

Infections, B cells, and autoimmunity. Prolonged infection with a virus, such as EBV, can lead to constant activation and proliferation of B cells, resulting in the production of monoclonal and polyclonal antibodies as well as immune complexes, causing autoimmune disease.

Figure 10

Salt affects the differentiation of naïve CD4⁺ cells. Increased concentrations of salt resulted in the differentiation of naïve CD4⁺ T cells into a greater number of T_H17 cells.

Figure 11

Mechanism by which a high-salt diet enhances the differentiation of naïve CD4⁺ cells to pathogenic T_H17 cells that may exacerbate experimental autoimmune encephalitis. High salt concentration, change in osmolarity, the influence of IL-23 and IL-23 receptor signaling, and the activation of various enzymes drive the expression of T_H17-associated cytokines and the formation of pathogenic T_H17 phenotype.

Figure 12

High-salt diet increases risk of autoimmune disease. In two groups of mice, both of which were immunized with MOG to induce EAE, the mice that had been given a high-salt diet (HSD) showed enhanced differentiation of naïve T cells into pathogenic T_H17 cells and a subsequent increased, more profligate development of EAE.

Figure 13

The central role of catalytic enzymes in celiac disease and rheumatoid arthritis. Key enzymes that catalyze the modification of glutamine to glutamic acid or arginine to citrulline as new epitopes have a central role in CD and RA.

Figure 14

Potentiation by oral pathogens. Oral pathogens such as P. gingivalis can potentiate the deamination of arginine or formation of citrullinated proteins and peptides in joint and other tissues.

Figure 15

Proposed model for the pathogenesis of multiple autoimmune reactivities by infection. Bacterial generation of autoantigens, local inflammation generating autoantigens by PAD, antibody production against one autoantigen, epitope spreading, antibody production against multiple antigens, systemic inflammation, and multiple autoimmune reactivities.