Autoimmunity in Rheumatic Diseases Is Induced by Microbial Infections via Crossreactivity or Molecular Mimicry

Rashid, Taha; Ebringer, Alan

doi:10.1155/2012/539282

Cited by 70 publications

(70 citation statements)

References 77 publications

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“…In the case of the GIT, a number of earlier studies focused on RA and other inflammatory arthropathies proposed a triggering role for Gram-negative intestinal bacterial pathogens. In this setting, immunogenic and pro-inflammatory bacterial products were proposed to access the systemic circulation and joints via translocation across a damaged gut epithelium [1][2][3][4][5][6][7]. Potential mechanisms of initiation and/or exacerbation of RA included: i) deposition of bacterial endotoxin in the joints [5,6]; and ii) production of antibodies and cytotoxic T lymphocytes reactive with cross-reactive epitopes present on both the putative causative bacterial pathogens and host synovial autoantigens [7].…”

Section: Introductionmentioning

confidence: 99%

“…In this setting, immunogenic and pro-inflammatory bacterial products were proposed to access the systemic circulation and joints via translocation across a damaged gut epithelium [1][2][3][4][5][6][7]. Potential mechanisms of initiation and/or exacerbation of RA included: i) deposition of bacterial endotoxin in the joints [5,6]; and ii) production of antibodies and cytotoxic T lymphocytes reactive with cross-reactive epitopes present on both the putative causative bacterial pathogens and host synovial autoantigens [7]. In keeping with these earlier studies, alterations in the GIT microbiome, resulting in replacement of beneficial commensals such as Bacteroides, Blautia, Lachnospiraceae and Group XIV Clostridia clades with the pro-inflammatory, Gram-negative, anaerobic rod, Prevotella copri have recently been linked to the pathogenesis of RA [8], possibly due to lifestyle factors such as diet and smoking [9].…”

Section: Introductionmentioning

confidence: 99%

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Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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Smoking is now well recognised not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. Recent studies have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smokingrelated RA. These involve release of the enzymes, peptidylarginine deiminases (PADs) 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. PADs, in turn, mediate the conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide/protein pathogenic autoantibodies (ACPA), an event which precedes the development of RA. This review is focused primarily on smoking-mediated harmful chronic inflammatory responses, both local and systemic, which promote the formation of ACPA, as well as the possible involvement of other types of outdoor and indoor pollution in the pathogenesis of RA. This is preceded by a brief overview of the evidence implicating smoking as a risk factor for development of ACPA-positive RA.Keywords: Anti-citrullinated peptide/protein antibodies; airway microbiota; atmospheric pollution; heavy metals; peptidylarginine deiminases; smoking cessation strategies. ImplicationsChronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of rheumatoid arthritis. These mechanistic insights not only reinforce the association between smoking and risk for rheumatoid arthritis, but also the necessity to increase the level of awareness in those at highest risk.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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“…Few reports have analyzed tolerance induction of endogenous T cells, and fewer still have analyzed the potential for the development of tolerance in endogenous memory T cells (9,10). Memory T cells may be more relevant to the development of some autoimmune diseases because preexisting cross-reactive memory cells may react with tissue-specific antigens through molecular mimicry (11,12). However, little is known regarding the mechanisms by which memory T cells may be tolerized.…”

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confidence: 99%

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

Jellison

Turner

Blair

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a selfspecific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.autoimmunity | AIRE | transgenic mouse

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“…Acinetobacter baylyi and Pseudomonas aeruginosa have been linked with the onset of multiple sclerosis 4 and Borrelia burgdorferi is linked with Lyme disease. [15] Whilst microbial triggers have also been postulated for lupus, the specific causative agents are yet to be identified. Similarly, members of the Enterobacteriaceae family are associated with Graves' disease and Kawasaki syndrome.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory activity of high antioxidant Australian native fruits against the bacterial triggers of selected autoimmune diseases

Maen¹,

Cock²

2014

Phcog Commn.

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Introduction: High antioxidant capacities have been linked to the treatment of rheumatic diseases and in the inhibition of microbial growth. Recent reports have identified several native Australian fruits with high antioxidant capacities. Despite this, several of these species are yet to be tested for the ability to inhibit the growth of the bacterial triggers of autoimmune inflammatory diseases. Methods: Solvent extracts prepared from selectedAustralian native fruits were analysed for antioxidant capacity by the DPPH free radical scavenging assay.Growth inhibitory activities against bacterial species associated with initiating rheumatoid arthritis and ankylosing spondylitiswere determined bydisc diffusion assay and quantified by MIC determination. Toxicity was determined by Artemia franciscana bioassay. Results: Methanolic extracts of all plant species displayed high antioxidant contents (equivalent to approximately 7-16 mg of vitamin C per gram of fruit extracted). Most aqueous extracts also contained relatively high antioxidant capacities. In contrast, the ethyl acetate, chloroform and hexane extracts for most species (except lemon aspen and bush tomato) had lower antioxidant contents (below 1.5 mg of vitamin C equivalents per gram of plant material extracted). Interestingly, the bacterial growth inhibitory activity of the extracts did not correlate with their antioxidant capacities. The fruit extracts with the highest antioxidant capacities (lemon aspen and desert lime methanolic extracts) had only low antibacterial activity, with MIC values generally >10,000 µg/ml against all bacterial species. In contrast, the Illawarra plum and desert lime ethyl acetate extracts, which had mid-range antioxidant capacities (1-6.5 mg ascorbic acid equivalents/g extracted), had potent bacterial growth inhibitory activity (200-400 µg/ml). The native tamarind ethyl acetate extract displayed low-moderate toxicity in the Artemia franciscana bioassay (LC50valuesbelow 1000 µg/mL).All other extracts were nontoxic. Conclusion: The lack of toxicity and inhibitory activity against microbial triggers of rheumatoid arthritis and ankylosing spondylitis by the fruit extracts indicates their potential in the treatment and prevention of these diseases.

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Autoimmunity in Rheumatic Diseases Is Induced by Microbial Infections via Crossreactivity or Molecular Mimicry

Cited by 70 publications

References 77 publications

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

Inhibitory activity of high antioxidant Australian native fruits against the bacterial triggers of selected autoimmune diseases

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