Comment on “
            <i>Aggregatibacter actinomycetemcomitans</i>
            –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis”

Volkov, Mikhail; Dekkers, Jacqueline; Loos, Bruno G.; Bizzarro, Sergio; Huizinga, T.W.J.; Praetorius, Helle A.; Toes, René E. M.; Woude, Diane van der

doi:10.1126/scitranslmed.aan8349

Cited by 27 publications

(32 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, compared with other populations, we confirmed a high frequency of anti-LtxA IgG positivity in controls and PH individuals from Sweden. In a recent study of healthy controls without known periodontal status from Leiden, Volkov et al [ 8 ] reported a prevalence of 22% of anti-LtxA IgG positivity as compared to 38% of Swedish controls (also with unknown periodontal status). In PH subjects from the United States [ 5 ], we previously reported a prevalence of 11% for anti-LtxA IgG positivity, while the prevalence was more than double in PH individuals from Sweden (25%).…”

Section: Discussionmentioning

confidence: 99%

“…During this process, membranolytic damage by LtxA induces prominent intracellular calcium flux and osmotic lysis, leading to hyperactivation of citrullinating enzymes and hypercitrullination of a broad range of substrates [ 5 , 7 ]. IgG antibodies to LtxA used as markers of previous Aa exposure are significantly associated with established and early RA when compared to periodontally healthy (PH) subjects and healthy controls regardless of their periodontal status, respectively [ 5 , 8 , 9 ]. Together, these studies provide mechanistic and clinical evidence implicating Aa in the pathogenesis of RA.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exposure to Aggregatibacter actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis

Gómez-Bañuelos

Johansson

Konig

et al. 2020

JCM

View full text Add to dashboard Cite

Periodontal disease has been implicated in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease characterized by immune-mediated synovial damage, and antibodies to citrullinated antigens. Here, we investigate the association between exposure to the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) and the development of RA. IgM, IgG and IgA antibodies to Aa leukotoxin A (LtxA) were detected by ELISA in plasma from a cohort of Swedish adults at different stages of RA development, from before onset of symptoms to established disease. Patients with early and established RA had increased levels of anti-LtxA IgM compared with matched non-RA controls and periodontally healthy individuals. Logistic regression revealed that anti-LtxA IgM levels were associated with RA during early disease (OR 1.012, 95%CI 1.007, 1.017), which was maintained after adjustment for smoking, anti-CCP antibodies, rheumatoid factor, HLA-DRB1 shared epitope alleles and sex. We found no association between anti-LtxA IgG/IgA antibodies and RA at any stage of disease development. The data support a temporal association between anti-LtxA IgM antibodies and the development of RA, suggesting that a subset of RA patients may have been exposed to Aa around the time of transition from being asymptomatic to become a patient with RA.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exposure to Aggregatibacter actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis

Gómez-Bañuelos

Johansson

Konig

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…The same study also suggested that in RA patients, the relationship between HLA‐SE alleles and the presence of ACPA is limited to the individuals exposed to Aa . However, this latter observation was not reproduced when tested in another cohort …”

Section: Hypotheses Elucidating Mechanisms Of Autoimmunity In Ramentioning

confidence: 99%

“…However, this latter observation was not reproduced when tested in another cohort. 140 For a long time, the gut has been hypothesized to be related to RA pathogenesis, but it remains a highly challenging topic to study. In mice, the K/BxN model of autoimmune arthritis appears to be greatly influenced by the gut microbiota via T follicular helper cells.…”

Section: Microbiome and Citrullinated Antigensmentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

Self Cite

111

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. In the last few decades, new insights into RA‐specific autoantibodies and B cells have greatly expanded our understanding of the disease. The best‐known autoantibodies in RA—rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA)—are present long before disease onset, and both responses show signs of maturation around the time of the first manifestation of arthritis. A very intriguing characteristic of ACPA is their remarkably high abundance of variable domain glycans. Since these glycans may convey an important selection advantage of citrulline‐reactive B cells, they may be the key to understanding the evolution of the autoimmune response. Recently discovered autoantibodies targeting other posttranslational modifications, such as anti‐carbamylated and anti‐acetylated protein antibodies, appear to be closely related to ACPA, which makes it possible to unite them under the term of anti‐modified protein antibodies (AMPA). Despite the many insights gained about these autoantibodies, it is unclear whether they are pathogenic or play a causal role in disease development. Autoreactive B cells from which the autoantibodies originate have also received attention as perhaps more likely disease culprits. The development of autoreactive B cells in RA largely depends on the interaction with T cells in which HLA “shared epitope” and HLA DERAA may play an important role. Recent technological advances made it possible to identify and characterize citrulline‐reactive B cells and acquire ACPA monoclonal antibodies, which are providing valuable insights and help to understand the nature of the autoimmune response underlying RA. In this review, we summarize what is currently known about the role of autoantibodies and autoreactive B cells in RA and we discuss the most prominent hypotheses aiming to explain the origins and the evolution of autoimmunity in RA.

show abstract

“…In a cohort of established RA, almost half of the patients had evidence of exposure to leukotoxic strains of Aa , as measured by the presence of antibodies to LtxA. Similarly, a high prevalence of Aa exposure was recently confirmed in a Dutch cohort of patients with early RA . Whether infection with leukotoxic strains of Aa pre‐dates the onset of clinical RA has not yet been determined.…”

Section: Phase 2: Preclinical Ramentioning

confidence: 99%

Individuals at risk of seropositive rheumatoid arthritis: the evolving story

Rantapää-Dahlqvist

Andrade

2019

J Intern Med

View full text Add to dashboard Cite

The aetiology of the autoimmune disease rheumatoid arthritis (RA) involves a complex interplay between genetic and environmental factors that initiate many years before the onset of clinical symptoms. These interactions likely include both protective and susceptibility factors which together determine the risk of developing RA. More than 100 susceptibility loci have been linked to RA. The strongest association is with HLA‐DRB1 alleles encoding antigen presenting molecules containing a unique sequence in the peptide‐binding grove called the ‘shared epitope’. Female sex, infections during childhood, lifestyle habits (e.g. smoking and diet) and distinct microbial agents, amongst many others, are interacting risk factors thought to contribute to RA pathogenesis by dysregulating the immune system in individuals with genetic susceptibility. Interestingly, patients with RA develop autoantibodies many years before the clinical onset of disease, providing strong evidence that the lack of tolerance to arthritogenic antigens is amongst the earliest events in the initiation of seropositive RA. Here, we will discuss the clinical and mechanistic evidence surrounding the role of different environmental and genetic factors in the phases leading to the production of autoantibodies and the initiation of symptomatic RA. Understanding this complexity is critical in order to develop tools to identify drivers of disease initiation and propagation and to develop preventive therapeutics.

show abstract

Comment on “ Aggregatibacter actinomycetemcomitans –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis”

Abstract: The link between rheumatoid arthritis and exposure to a bacterial toxin was not found in a population of rheumatoid arthritis patients from Netherlands.

Cited by 27 publications

References 6 publications

Exposure to Aggregatibacter actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis

Exposure to Aggregatibacter actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Individuals at risk of seropositive rheumatoid arthritis: the evolving story

Contact Info

Product

Resources

About