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Review
. 2017 Feb;242(4):355-373.
doi: 10.1177/1535370216681549. Epub 2016 Nov 26.

Major Involvement of Bacterial Components in Rheumatoid Arthritis and Its Accompanying Oxidative Stress, Systemic Inflammation and Hypercoagulability

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Free PMC article
Review

Major Involvement of Bacterial Components in Rheumatoid Arthritis and Its Accompanying Oxidative Stress, Systemic Inflammation and Hypercoagulability

Etheresia Pretorius et al. Exp Biol Med (Maywood). .
Free PMC article

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.

Keywords: Proteus; Rheumatoid arthritis; atopobiosis; comorbidities; dormancy; infectious agents; inflammation; iron dysregulation; lipopolysaccharides.

Figures

Figure 1
Figure 1
Genetically susceptible individuals exposed to environmental factors (1) that act as triggers (2) cause an immunological reaction followed by an autoimmune response (3) that may lead to rheumatoid arthritis (RA) (4). We discuss Ebringer’s theory (5), suggesting the cause of the trigger being microbes (6) and the role of LPS (7) that may result in an imbalance between pro- and anti-inflammatory cytokines, followed by systemic inflammation and the effect on the cardiovascular and hematological health of the RA patient (8). (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
A bacterial system contains distinct subpopulations (1), that we classify as culturable, dormant and non-culturable (2). Specific attention is given to persister cells (3), and the inter-relationship (4) between the subpopulations and phenotypic switching between culturability and dormancy (5). Throughout we follow a systems biology approach to suggest resuscitation due to various triggers like iron and noradrenaline (6). (A color version of this figure is available in the online journal.)
Figure 3
Figure 3
Fibrin fiber formation in the presence of thrombin (a) healthy fibrin and (b) rheumatoid arthritis fibrin with matted fibrin. Scale: 1 µm
Figure 4
Figure 4
(a) A healthy platelet with prominent cell body and pseudopodia formation and smooth membrane; (b) two spreaded and activated platelets with microparticle formation (irregularly shaped structures closely associated with membranes (white arrows)) in rheumatoid arthritis; red arrows showing much rounder structures – possibly ultrabacteria; (c) a higher magnification of an RA platelet with microparticles budding off spreaded platelet. The scale bars are (a): 200 nm; (b): 1 µm and (c): 200 nm. (A color version of this figure is available in the online journal.)
Figure 5
Figure 5
(a) and (b) A representative healthy RBC (b is higher magnification showing the membrane); (c and d) A representative rheumatoid arthritis RBC with folding (c) and visible membrane microparticle formation. Scale bars for (a) and (c): 1 µm; scale bars for (b) and (d): 100 nm
Figure 6
Figure 6
RBC membrane roughness analysis as seen with atomic force microscopy (AFM) of a representative micrograph from a healthy RBC (a) and a rheumatoid arthritis RBC (b). (A color version of this figure is available in the online journal.)
Figure 7
Figure 7
The LPS-mediated cellular production of inflammatory cytokines. Canonical pathway of LPS-mediated release and nuclear translocation of NF-κB (based on O'Neill et al.) taken from Kell and Pretorius. (A color version of this figure is available in the online journal.)
Figure 8
Figure 8
The intracellular LPS-mediated activation of caspase-1 leading to IL-1β production (after Latz et al.) taken from Kell and Pretorius. (A color version of this figure is available in the online journal.)

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