Immunologic Research

, Volume 66, Issue 6, pp 696–709 | Cite as

Autoimmunity, inflammation, and dysbiosis mutually govern the transition from the preclinical to the clinical stage of rheumatoid arthritis

  • Alexander Kalinkovich
  • Gulzan Gabdulina
  • Gregory LivshitsEmail author


Currently, it is well recognized that in the natural history of rheumatoid arthritis (RA), an at-risk phase, characterized by the development of autoimmunity, precedes the onset of clinical symptoms in a large proportion of patients. For individuals who later develop seropositive RA, this manifests as autoantibodies directed against proteins that have undergone specific post-translational modifications (PTM). These anti-PTM autoantibodies (APMA) are an important biomarker and risk factor for future RA. However, the triggers of autoimmunity remain unknown. This review summarizes data supporting the view that the transition from the at-risk stage to clinical RA is governed by a link between autoimmunity, inflammation, and dysbiosis. In particular, dysbiosis was shown to enhance the generation of PMT-peptides, create an antigenic mimicry with self-antigens, and establish the pro-inflammatory immune profile, all of which lead to the initiation of APMA production. Moreover, we present data supporting a major role of the autoimmunity-inflammation-dysbiosis axis in the development of bone damage and atherosclerosis-associated cardiovascular morbidity in at-risk RA individuals, and we describe potential mechanisms underlying these events. We believe that clarification of the mechanisms triggering the transition from a preclinical to clinical RA stage will pay the way to new prophylactic interventions that will prevent development of classified RA.

Graphical abstract


Rheumatoid arthritis Autoimmunity Inflammation Dysbiosis Bone damage Atherosclerosis 



Anti-citrullinated peptide antibodies


Anti-modified peptide antibodies (AMPA) against different PTM peptides


Anti-carbamilated peptide antibodies


Atherosclerosis-associated cardiovascular disorders




Human leucocyte antigen




Rheumatoid arthritis


Shared epitope


A receptor activator of nuclear factor kappa-B ligand


Neutrophil extracellular traps




Post-translational modifications of proteins


Rheumatoid factor


Trimethylamine N-oxide


T helper cell


Tumor necrosis factor


Funding information

This study was supported by the Israel Science Foundation (grant no. 1018/13) to GL.

Compliance with ethical standards

The manuscript has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors, and if accepted, it will not be published elsewhere including electronically in the same form, in English or in any other language, without the written consent of the copyright-holder.

Conflict of interest

The authors declare that that they have no competing interests.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Alexander Kalinkovich
    • 1
  • Gulzan Gabdulina
    • 2
  • Gregory Livshits
    • 1
    Email author
  1. 1.Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael
  2. 2.Department of Internal MedicineKazakh National Medical UniversityAlmatyKazakhstan

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