New | Lyme arthritis: linking infection, inflammation and autoimmunity. #LymeDisease (a thread) 1/…
"In the USA, B. burgdorferi often disseminates in the blood during the first few weeks of infection in a process that requires the binding of Borrelia surface adhesins to host integrins on the vascular endothelium28–30. " 2/ Image
"As shown in mice, the spread of B. burgdorferi through the vasculature or lymphatics is dependent on the inter-actions of spirochaetal surface molecules and endothe-lial cell membrane proteins." 3/
"Bacterial–endothelial cell interactions result in the loosening of tight junctions and migration of spirochaetes into the synovial extra-cellular matrix via small vascular lesions." 4/
"Lyme disease spirochaetes are only transiently present in the blood and rapidly migrate to extravascular tis-sues via transendothelial migration." 5/
"With their unique planar wave motion, these bacteria are highly adapted to move through dense connective tissue, which requires the binding of plasminogen or its activators to the surface of the organism." 6/
"The spirochaetal adhesins decorin binding protein A (DbpA) and DbpB bind to host decorin, a proteoglycan that is bound to collagen, and spirochaetes can also bind directly to, invade and colo-nize native type I collagen lattices." 7/
"The binding of DbpA and DbpB to host decorin probably explains the alignment of spirochaetes with collagen fibrils in connective tissue in joints, heart or nerves." (⬅️ important!) 8/
"The antibody response to B. burgdorferi develops slowly, and during the first few weeks of infection an IgM response is seen in only a minority of patients." (⬅️ why standard 2-tier test will be false negative in early Lyme) 9/
"As B. burgdorferi disseminates and infects host tissues, an increasingly higher percentage of patients develop IgM and IgG responses to the spirochaete." (⬅️test begins to show positive after the infection has spread throughout the body) 10/
"To evade the host antibody response, spirochaetes seek protected niches and change the expression profile of their outer- surface proteins. In particular, the lipoprotein VlsE undergoes extensive antigenic variation." 11/
"In addition, B. burgdorferi evade innate immune responses by binding host complement regulator proteins to their surface, which inactivate complement and induce innate immune tolerance." (🤔 do these "niches" also allow B.b to hide from standard antibiotics?) 12/
"Dysregulation of innate immune responses during early disseminated infection might promote subsequent arthritis development." 13/
"Months after the initial infection, along with an expansion of the immune response to B. burgdorferi, untreated patients often develop marked joint swelling, frequently in one or both knees." 14/ (B.b can also spread to nervous system, brain, heart & other parts of the body)
"B. burgdorferi has rarely been cultured from the synovial fluid of patients with Lyme arthritis, but prior to antibiotic treatment, B. burgdorferi DNA (but not mRNA) can be found in the synovial fluid of ~70% of these patients." (B.b. is difficult to culture. Period) 15/
"This finding suggests that live spirochaetes might survive only in protected tissue niches within joints and are killed if they escape into synovial fluid." (🤔 might they also be surviving in other niches??) 16/
"The central feature of post-infectious Lyme arthritis is an excessive, dysregulated pro-inflammatory immune response during the infection phase that persists into the post-infectious period." 17/
This response is characterized by high amounts of IFNγ, IL-6, and inadequate amounts of the anti-inflammatory cytokine IL-10. 18/
"Several other types of immune regulation imbalance can result in high concentrations of IFNγ. In patients with post- infectious Lyme arthritis, a high percentage of CD4+CD25+ Tcells, which are ordinarily regulatory T (Treg) cells..." 19/
"By contrast, in patients with antibiotic- responsive Lyme arthritis, Treg cells secrete large amounts of anti- inflammatory IL-10 and negligible amounts of IFNγ."
"Although the pathogenic nature of Lyme autoanti-bodies has not yet been delineated, IgG4 Lyme disease autoantibody titres correlate with the magnitude of obliterative microvascular lesions and fibrosis in synovial tissue." 21/
"In a study in which HLA- DR- presented peptides were eluted from synovia of patients with post- infectious Lyme arthritis, four immunogenic peptides were identified that were derived from self- proteins, including endothelial cell growth factor..." 22/
"Thus, immune dysregulation in post- infectious Lyme arthritis leads to pro- inflammatory and tumour- like proliferative responses by synovial fibroblasts, rather than the wound healing and appropriate tissue repair responses..." 23/ Image
"In RA, evidence is emerging that bacteria- induced inflammation at mucosal sites in the periodontium, lung or bowel might trigger or enhance autoimmunity and joint disease in predisposed individuals." 24/
"For example, the periodontal pathogen Porphyromonas gingivalis is associated with RA, as is the gut commensal Prevotella copri." 25/ (⬅️ the infection connection.)
"In ankylosing spondylitis and Crohn’s disease- associated spondyloarthritis, strains of Escherichia coli or Prevotella spp. that adhere to the bowel mucosa have been implicated in the pathogenesis of joint disease." 26/
"Similarly, in psoriatic arthritis, skin flora might have a role in pathogenesis." 27/
"As with other arthritides, changes in host microflora could also affect the pathogenesis of Lyme arthritis. B. burgdorferi modulate the host microbiomes of their tick vectors to facilitate colonization and this process could also occur during tick- to- mammal transmission" 28/
Interesting read. I hope future steps include finding a direct detection method for #LymeDisease that would allow confirmation of cleared B.b. versus the assumption that post-treatment = post-infection. /end

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