Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability

Abstract

We review the evidence that infectious agents, including those that become dormant within the host, have a major role to play in much of the etiology of rheumatoid arthritis and the inflammation that is its hallmark. This occurs in particular because they can produce cross-reactive (auto-)antigens, as well as potent inflammagens such as lipopolysaccharide that can themselves catalyze further inflammagenesis, including via β-amyloid formation. A series of observables coexist in many chronic, inflammatory diseases as well as rheumatoid arthritis. They include iron dysregulation, hypercoagulability, anomalous morphologies of host erythrocytes, and microparticle formation. Iron dysregulation may be responsible for the periodic regrowth and resuscitation of the dormant bacteria, with concomitant inflammagen production. The present systems biology analysis benefits from the philosophical idea of “coherence,” that reflects the principle that if a series of ostensibly unrelated findings are brought together into a self-consistent narrative, that narrative is thereby strengthened. As such, we provide a coherent and testable narrative for the major involvement of (often dormant) bacteria in rheumatoid arthritis.Impact statementRheumatoid arthritis (RA) is accompanied by long-term inflammation that is mediated by cytokines and cross-reactive (auto-)antigens. Here we suggest one explanation is the presence of a (dormant) microbiome in RA that sheds the highly potent inflammagen, lipopolysaccharide lipopolysaccharides (LPS) to catalyze inflammagenesis, including via β-amyloid formation. We discuss various co-existing features in RA, including iron dysregulation, hypercoagulability, anomalous morphologies of host erythrocytes, and microparticle formation. We review literature and provide coherent evidence that an aberrant blood microbiome in RA has a major involvement in the development, progression, and therefore over-all etiology of the disease.

Pathogenesis of Proteus mirabilis Infection

“…A correlation between P. mirabilis and RA has been observed in multiple patient studies (83); however, the urease/hemolysin hypothesis has not yet been directly tested. Importantly, other microbes have also been linked to RA, and it is possible that there are multiple infectious triggers for RA in vulnerable populations (84). …”

A Dormant Microbial Component in the Development of Preeclampsia

“…For rheumatoid arthritis (142, 458–460) and diseases of pregnancy, UTI (see below and Table TT) also provides a major source.…”

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

“…These results are of particular importance when it is noted that bacterial involvement might play a role in both the development and progression of PD, and specifically, circulating bacterial inflammagens such as LPS have been implicated (Tufekci et al, 2011;De Chiara et al, 2012;Potgieter et al, 2015;Friedland and Chapman, 2017). We have also suggested that LPS may both maintain systemic inflammation, as well as the disease aetiology itself in PD (but also in other inflammatory diseases like type 2 diabetes, pre-eclampsia, sepsis, rheumatoid arthritis and Alzheimer's disease, where LPS presence has been implicated in the aetiology of the condition) (Kell and Kenny, 2016;Pretorius et al, 2016a;Pretorius et al, 2016b;Pretorius et al, 2017a;Pretorius et al, 2017b;Pretorius et al, 2017c;Kell and Pretorius, 2018b). Indeed in 2018, we showed that LPS from E. coli could be identified with fluorescent LPS E. coli antibodies in clots of PD, type 2 diabetes and AD (de Waal et al, 2018).…”

“…What is not immediately clear is the actual origin of the inflammation and how and why it is chronic. For this and other diseases (Potgieter et al, 2015;Kell and Kenny, 2016;Pretorius et al, 2016a;Pretorius et al, 2017a;de Waal et al, 2018;Kell and Pretorius, 2018a;Kell and Pretorius, 2018b) we have brought together evidence that a chief cause may be (dormant) microbes that upon stimulation, especially with unliganded iron (Kell, 2009), can briefly replicate and shed potent (and well known) inflammagens such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA) Kell and Pretorius, 2018a). These are well-known ligands for receptors such as Toll-like receptor 4 (TLR4) and can thus stimulate inflammation, as observed through a variety of inflammatory cytokines (Olumuyiwa-Akeredolu et al, 2019).…”