Rheumatoid arthritis (RA) is a highly prevalent autoimmune disease in which chronic inflammation leads to joint erosions and ultimately joint destruction. RA is thought to be a T-cell–mediated disease, based on its strong genetic association with susceptible HLA class II alleles.1 Traditionally, RA has been divided into seropositive and seronegative disease according to the presence or absence of 2 distinct classes of autoantibodies: rheumatoid factor (RF; antibodies that bind to the Fc region of IgG antibodies) and anticitrullinated protein antibodies (ACPA; antibodies that bind to an array of peptides and proteins that have been posttranslationally modified by peptidyl arginine deiminase [PAD] enzymes). The vast majority of individuals with RA (> 70%) are seropositive, and the presence of ACPA in particular is a strong clinical predictor of radiologic progression as measured by erosions.2,3 Further, RA-susceptible HLA class II alleles have been shown to have a unique preference for presenting citrullinated peptides, and multiple studies demonstrate that the presence of T cells specific for citrullinated antigens is associated with RA.4-6 These associations intimately link protein citrullination with the etiology of RA. Several plausible mechanisms have been proposed to explain the early events that initiate the development of RA. Among these, the mucosal origins hypothesis suggests that inflammation at mucosal surfaces and dysbiosis promotes local IgA ACPA and RF production, followed by systemic autoimmunity, synovitis, and finally classifiable disease.7 However, the mechanisms by which a localized insult leads to systemic autoimmunity have not been fully elucidated.
One possible mechanism that has been postulated for the initiation of adaptive immune responses against citrullinated proteins is through the release of neutrophil extracellular traps (NETs) in response to mucosal insult. This leads to the citrullination of self-peptides by PADs and the formation of first, localized mucosal autoimmunity, and then systemic autoimmunity that becomes entrenched in the synovium of affected joints (Figure, upper text). NET formation (NETosis) is increased in individuals with RA and correlates with ACPA levels both in established RA and in subjects at risk for development of RA.8-10 Importantly, NETosis releases PADs—the enzymes responsible for catalyzing protein citrullination.11 NETs have been shown to contain citrullinated vimentin and citrullinated histone 4, both of which are established autoantigen targets.8 Further, it has been demonstrated that fibroblast-like synoviocytes internalize NETs, leading to production of inflammatory cytokines and presentation of NET-derived citrullinated peptides on MHC class II molecules to CD4 T cells.12 This positions neutrophilic NETs as a nexus for generalized inflammation and the induction of antigen-specific adaptive immunity in the synovium.
Mucosal initiation of autoimmunity in RA. (Upper text) During the initiation of RA, a canonical mechanism has been postulated, in which oral or lung insults lead to neutrophil recruitment. Subsequent NETosis and the release of PAD4 enzyme leads to the citrullination of various self-peptides. In the presence of danger signals, the resulting citrullinated determinants elicit ACPA-specific B cells, which can differentiate into IgA-producing plasmablasts and localized and T-cell autoimmunity. This is followed by additional rounds of B- and T-cell immune crosstalk, promoting spread to a systemic immune response that includes sustained production of ACPA by IgG plasmablasts, spread of B- and T-cell reactivity to encompass a wider array of determinants, and development of localized arthritis in affected joints. (Lower text) Acharya et al22 report new data that augment this model, emphasizing the importance of mucosal breach in the oral cavity, direct recognition of citrullinated pathogens, and the subsequent reprogramming of macrophages as important contributors to both the loss of mucosal tolerance and the triggering of systemic autoimmunity. Figure created with elements from BioRender.com. ACPA: anticitrullinated protein antibodies; Cit: citrullinated; NETosis: neutrophil extracellular trap formation; PAD: peptidyl arginine deiminase.
Epidemiologic data implicate specific insults as possible triggers for RA. For example, multiple lung insults, including smoking and occupational exposure to silica or mineral dust have been associated with increased risk of disease.13 Smoking has been shown to upregulate PAD expression/activation in the airways leading to an increase in the abundance of citrullinated neoantigens, creating a plausible link between lung insult and systemic autoimmunity.14 Periodontal disease is strongly associated with risk of RA in that severe gum disease is common in RA and can accelerate joint destruction, whereas treating periodontal issues may reduce RA disease activity.15 Multiple mechanisms have been proposed for this observed association. One possible factor is induction of an inflammatory microenvironment through chronic exposure to oral microbes and the corresponding high levels of Toll-like receptor engagement.16 Indeed, general dysbiosis in the oral microbiome of at-risk individuals and individuals with RA has been observed, and periodontal disease has been linked with increased levels of inflammatory cytokines.17 Studies have also implicated individual oral organisms, including Porphyromonas gingivalis and Streptococcus species.18-20 The concepts of general oral inflammation and individual causal organisms suggest 2 distinct pathways that promote protein citrullination: (1) PAD release by periodontal neutrophils and NETs, and (2) citrullination mediated by the PAD enzyme expressed by P. gingivalis.21 Proteins citrullinated through either pathway can readily enter circulating blood, possibly leading to systemic autoimmunity. However, important questions remain about the mechanisms through which host immunity and the pathogenic insults that occur during periodontal disease promote RA.
In this issue, Acharya et al22 report a new investigation of the mechanisms by which oral bacterial infections in damaged periodontal tissue promote joint inflammation and destruction in individuals with RA. To model this biology, the authors cultured multiple commensal oral bacteria species with human neutrophils, resulting in NETosis. As expected, the resulting NETs contained active PAD enzyme, which mediated the citrullination of both host and bacterial proteins. Through this work, Acharya et al22 make a few important observations: (1) citrullinated bacteria, as compared to native bacteria, exhibited an increased capacity to drive B-cell differentiation into plasmablasts; (2) ACPA can bind to citrullinated-forming immune complexes that are capable of activating macrophages and neutrophils; and (3) coculture with oral bacterial NETs or citrullinated bacteria immune complexes reduced the proportion of antiinflammatory macrophages and augmented tumor necrosis factor and interleukin 6 secretion by macrophages. These observations add to the canonical model, emphasizing the importance of mucosal breach and direct recognition of citrullinated pathogens as key events that promote loss of mucosal tolerance and contribute to systemic autoimmunity (Figure, lower text).
As discussed above, there is a clear epidemiological link between periodontal disease and RA that had previously been attributed to self-protein citrullination as a mechanism of neoepitope formation and loss of self-tolerance.17 The findings of this new study22 add an important new layer to this disease axis by implicating host citrullination of microbial proteins and the subsequent formation and effects of ACPA/bacterial immune complexes as key factors in the loss of tolerance, initially at the oral mucosa and with subsequent systemic consequences. As such, this work provides important new insights about mechanisms through which citrullinated oral bacteria contribute to synovial tissue destruction. This new mechanistic understanding of the link between oral bacterial insult, neutrophil activity, and innate and adaptive immune activation illuminates the etiology of RA and suggests new concepts that could inform new strategies for therapy. However, the work raises additional questions that should be addressed through further research. Citrullination of oral bacteria could be considered a desirable process, through which the bacteria are rendered more immunogenic and can be eliminated. The authors note that one species, Streptococcus parasanguinis, consistently elicited greater PAD secretion. The idea that certain species are more prone to eliciting ACPA in a manner that is “too much of a good thing” is worthy of further exploration. Acharya et al22 intentionally selected oral bacteria that lack bacterial PAD expression to avoid this confounding effect. Although understandable, this leaves unanswered questions about the degree to which bacterial PAD citrullination might potentiate the observed effects or other complementary effects. Finally, whereas the observed effects on B-cell maturation into plasmablasts, ACPA formation, and macrophage polarization are robust, the current study failed to explore the concept of molecular mimicry. Direct mimicry between citrullinated bacterial proteins and self-proteins or peptides remains controversial, but the concept provides an attractive explanation of how effects that begin as localized interactions at mucosal surfaces could spread into the systemic effects that lead to classifiable RA.
Footnotes
See Periodontal disease and RA, page 868
FUNDING
The author declares no funding or support for this work.
COMPETING INTERESTS
The author declares no conflicts of interest relevant to this article.
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