J. Kelly Smith^*

Emeritus Professor of Medicine, Department of Medical Education, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37604, USA

^*Corresponding Author: J. Kelly Smith, MD, FACP, Emeritus Professor of Medicine, Department of Medical Education, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, 37604, USA. e-mail address (smithj@etsu.edu) and phone number (423-439-8005).

Received: 11 June 2025; Accepted: 17 June 2025; Published: 20 June 2025.

Article Information

Citation: J. Kelly Smith. Rheumatoid Arthritis – The Immaculate Infection. Fortune Journal of Rheumatology 7 (2025): 24-25.

DOI: 10.26502/fjr.26880047

Abstract

Keywords

Rheumatoid arthritis, Autoimmunity, Molecular mimicry, Citrullination, Peptidylarginine deiminase (PAD), Porphyromonas gingivalis, Prevotella copri, Epstein-Barr virus, Gut microbiome, Infectious triggers.

Article Details

1. Introduction

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic synovial inflammation, autoantibody production, and joint destruction. Traditionally viewed as idiopathic and genetically influenced, evidence now implicates certain infections in the pathogenesis and propagation of RA. The concept of RA as an "immaculate infection" alludes to the possibility that subclinical or past microbial encounters may prime the immune system for sustained autoimmunity without an overt infectious illness [1].

2. Discussion

2.1 Infectious Triggers in RA

2.1.1 Periodontal Disease and Porphyromonas gingivalis: Among the most compelling associations is that between chronic periodontitis and RA. P. gingivalis, a keystone periodontal pathogen, expresses the enzyme peptidylarginine deiminase (PPAD), capable of citrullinating host proteins—a key step in generating anti-citrullinated protein antibodies (ACPAs) [2, 3]. This process may initiate an autoimmune cascade long before joint symptoms appear.

2.1.2 The Gut Microbiome and Prevotella copri: Alterations in gut microbiota have also been implicated. A landmark study found increased abundance of P. copri in the intestines of new-onset RA patients compared to healthy controls [4]. P. copri may promote systemic inflammation through Toll-like receptor signaling and promote Th17 polarization, both of which are known contributors to RA [5].

2.1.3 Epstein-Barr Virus (EBV): EBV, a ubiquitous herpesvirus, persists in B lymphocytes and can drive polyclonal B-cell activation. RA patients show elevated titers of anti-EBV antibodies, and EBV DNA has been detected in synovial tissues [6]. The virus may disrupt self-tolerance through molecular mimicry or epigenetic modifications [7].

2.1.4 Mycoplasma Species: Mycoplasma fermentans and M. pneumoniae have been detected in the synovial fluid of RA patients [8]. These pathogens can establish chronic, low-grade infections in joint tissues, potentially perpetuating immune activation.

2.2 Mechanistic Theories

2.2.1 Molecular Mimicry: Pathogens may harbor antigens that resemble host structures, leading to cross-reactive immune responses. For example, EBV nuclear antigen 1 (EBNA1) shares homology with RA-associated autoantigens [7].

2.2.2 Citrullination and Neoantigen Formation: PPAD from P. gingivalis and host PAD enzymes generate citrullinated proteins, which are targeted by ACPAs—a hallmark of RA [2, 3].

2.2.3 Microbial Dysbiosis: Loss of microbial diversity, particularly in the gut and oral cavity, may facilitate aberrant immune priming, mucosal inflammation, and barrier dysfunction, creating a systemic pro-inflammatory milieu [4, 5].

2.3 Therapeutic and Diagnostic Implications

If infectious agents contribute to RA pathogenesis, this opens novel avenues:

• • Antimicrobial Therapy: Targeting P. gingivalis or Mycoplasma may reduce inflammatory burden, though results remain inconclusive [9].
• • Microbiome Modulation: Prebiotics, probiotics, and dietary interventions to restore gut and oral microbial balance are under investigation [10].
• • Vaccination or Prophylaxis: In theory, vaccination against implicated pathogens might reduce RA risk in susceptible individuals [11].

Conclusion

The hypothesis that RA is precipitated by infection—albeit without traditional signs of illness—merits serious consideration. Pathogens such as P. gingivalis, P. copri, EBV, and Mycoplasma may act as triggers via citrullination, molecular mimicry, and mucosal dysbiosis. Understanding these mechanisms could lead to novel diagnostic biomarkers and therapeutic targets, reshaping the management of RA.

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