Triggers of Autoimmunity: The Role of Bacterial Infections in the Extracellular Exposure of Lupus Nuclear Autoantigens

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.

Keywords: autoantibodies; autoantigens; bacterial infections; extracellular DNA; lupus (SLE).

Figure 1

Model of the contribution of bacterial infections and bacterial biofilms to the pathogenesis of autoimmunity. Infections can be a source of extracellular nuclear antigens because they expose nucleic acids derived from bacteria and especially from bacterial biofilms, which are very rich in bacterial DNA and amyloids carrying extracellular DNA. Amyloid curli/DNA complexes can trigger autoimmunity by acting as danger signals to activate innate immunity and as molecular mimickers to activate autoreactive B cells. Moreover, infections can release host nucleic acids because of the different types of cell death that can occur during infection, notably pyroptosis and the extrusion of neutrophil extracellular traps (NETs). Defective clearance of apoptotic cells and subsequent post-apoptotic necrosis may also be a source of extracellular nucleic acids.