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

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Abstract

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.

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Abbreviations

ACPA:

Anti-citrullinated peptide antibodies

AMPA:

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

anti-CarP:

Anti-carbamilated peptide antibodies

ATS-CVD:

Atherosclerosis-associated cardiovascular disorders

IL:

Interleukin

HLA:

Human leucocyte antigen

IFN:

Interferon

RA:

Rheumatoid arthritis

SE:

Shared epitope

RANKL:

A receptor activator of nuclear factor kappa-B ligand

NETs:

Neutrophil extracellular traps

OPG:

Osteoprotegerin

PTM:

Post-translational modifications of proteins

RF:

Rheumatoid factor

TMAO:

Trimethylamine N-oxide

Th:

T helper cell

TNF:

Tumor necrosis factor

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Funding

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

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Authors and Affiliations

  1. Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Alexander Kalinkovich & Gregory Livshits

  2. Department of Internal Medicine, Kazakh National Medical University, Almaty, Kazakhstan

    Gulzan Gabdulina

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  1. Alexander Kalinkovich
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  2. Gulzan Gabdulina
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  3. Gregory Livshits
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Correspondence to Gregory Livshits.

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Take-home messages

• The at-risk RA stage is characterized by the creation of a link between autoimmunity, low-grade inflammation, and dysbiosis proposed to determine the development of bone damage and atherosclerosis-associated cardiovascular morbidity and govern the transition to the classified RA stage.

• However, causal relationships in this link remain unrevealed and need to be firmly established in longitudinal studies where the transition from preclinical to clinical RA can be evaluated.

• Specific mechanisms by which autoimmunity is triggered in at-risk individuals by dysbiosis at the oral, lung, and/or gut mucosal sites such as molecular mimicry, ability to produce post-translational modified proteins, and creation of pro-inflammatory immune profile, all resulted in the production of various autoantibodies remain to be elucidated.

• Deciphering the mechanisms underlying the transition from the preclinical to the clinical RA stage may pay the way to new prophylactic interventions preventing the development of RA.

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Kalinkovich, A., Gabdulina, G. & Livshits, G. Autoimmunity, inflammation, and dysbiosis mutually govern the transition from the preclinical to the clinical stage of rheumatoid arthritis. Immunol Res 66, 696–709 (2018). https://doi.org/10.1007/s12026-018-9048-x

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