Abstract
Infections are considered important environmental triggers of autoimmunity and can contribute to autoimmune disease onset and severity. Nucleic acids and the complexes that they form with proteins—including chromatin and ribonucleoproteins—are the main autoantigens in the autoimmune disease systemic lupus erythematosus (SLE). How these nuclear molecules become available to the immune system for recognition, presentation, and targeting is an area of research where complexities remain to be disentangled. In this review, we discuss how bacterial infections participate in the exposure of nuclear autoantigens to the immune system in SLE. Infections can instigate pro-inflammatory cell death programs including pyroptosis and NETosis, induce extracellular release of host nuclear autoantigens, and promote their recognition in an immunogenic context by activating the innate and adaptive immune systems. Moreover, bacterial infections can release bacterial DNA associated with other bacterial molecules, complexes that can elicit autoimmunity by acting as innate stimuli of pattern recognition receptors and activating autoreactive B cells through molecular mimicry. Recent studies have highlighted SLE disease activity-associated alterations of the gut commensals and the expansion of pathobionts that can contribute to chronic exposure to extracellular nuclear autoantigens. A novel field in the study of autoimmunity is the contribution of bacterial biofilms to the pathogenesis of autoimmunity. Biofilms are multicellular communities of bacteria that promote colonization during chronic infections. We review the very recent literature highlighting a role for bacterial biofilms, and their major components, amyloid/DNA complexes, in the generation of anti-nuclear autoantibodies and their ability to stimulate the autoreactive immune response. The best studied bacterial amyloid is curli, produced by enteric bacteria that commonly cause infections in SLE patients, including Escherichia coli and Salmonella spps. Evidence suggests that curli/DNA complexes can trigger autoimmunity by acting as danger signals, molecular mimickers, and microbial chaperones of nucleic acids.
Highlights
Nucleic acids and the proteins that bind to nucleic acids are the main autoantigens in the autoimmune disease systemic lupus erythematosus (SLE) [1]
The frequency of infection before lupus onset has not been thoroughly documented in the literature, some case reports suggest that it is increased, especially in pediatric lupus [77, 78], suggesting that infections accelerate SLE onset in predisposed individuals
The opposite was true when the caspase-activated DNase (CAD) impairment was in spontaneous genetically driven lupus models, since the absence of CAD resulted in higher levels of autoAbs in triple congenic B6.Sle1,2,3 spontaneous lupus mice [112]. These results suggest that in induced autoimmunity, chromatin fragmentation is essential for the presentation of nuclear autoantigens, while in mice genetically predisposed to autoimmunity the absence of nuclear modifications occurring during apoptosis promotes B cell autoreactivity, possibly by preventing the induction of self-tolerance toward DNA [112]
Summary
Nucleic acids and the proteins that bind to nucleic acids are the main autoantigens (autoAgs) in the autoimmune disease systemic lupus erythematosus (SLE) [1]. We present findings from recent literature highlighting a role for bacterial infections and bacterial biofilms in the extracellular exposure of nuclear autoAgs, and their ability to stimulate the autoreactive immune responses in SLE (Figure 1).
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