How Rheumatoid Arthritis Can Result from Provocation of the Immune System by Microorganisms and Viruses

Abstract

The pathogenesis of rheumatoid arthritis (RA), similar to development of a majority of inflammatory and autoimmune disorders, is largely due to an inappropriate or inadequate immune response to environmental challenges. Among these challenges, infectious agents are the undisputed leaders. Since the 1870s, an impressive list of microorganisms suspected of provoking RA has formed, and the list is still growing. Although a definite causative link between a specific infectious agent and the disease has not been established, several arguments support such a possibility. First, in the absence of a defined pathogen, the spectrum of triggering agents may include polymicrobial communities or the cumulative effect of several bacterial/viral factors. Second, the range of infectious episodes (i.e., clinical manifestations caused by pathogens) may vary in the process of RA development from preclinical to late-stage disease. Third, infectious agents might not trigger RA in all cases, but trigger it in a certain subset of the cases, or the disease onset may arise from an unfortunate combination of infections along with, for example, psychological stress and/or chronic joint tissue microtrauma. Fourth, genetic differences may have a role in the disease onset. In this review, two aspects of the problem of "microorganisms and RA" are debated. First, is there an acquired immune deficiency and, in turn, susceptibility to infections in RA patients due to the too frequent and too lengthy infections, which at last break the tolerance of self antigens? Or, second, is there a congenital deficiency in tolerance and inflammation control, which may occur even with ordinary infection frequency and duration?

Keywords: Infection; immune system provocation; microorganisms; rheumatoid arthritis; viruses.

FIGURE 1

In case of infection, the cellular and molecular players of rheumatoid arthritis (RA) are affected. Infections are able to promote citrullinisation (1) and antigen presentation (2) through HLA-DR overexpression in antigen presenting cells (APC); to interfere with T helper (Th) polarization (3) and cytokine production (4); to reduce lymphocytotoxic activity (5) as well as antibody production (6) and antigen presentation by B cells (7). Abbreviations: Mono, Monocyte; Mp – macrophage; TCR, T cell receptor; PAD4, peptidyl arginine deaminase 4; ACPA, anti-citrullinated protein antibodies; IL, interleukine; IFNγ, interferon gamma; TNFα, tumor necrosis factor alpha; IC, immune complex; RF, rheumatoid factor.

FIGURE 2

Activation of the NF-κB and JAK-STAT signaling pathways are crucial for proper antiviral response. However, in case of infection, bacteria/viruses have a number of opportunities to inhibit both pathways: trigger NF-κB translocation from cytoplasm into the nuclei (1) through plasma membrane (2, bacteria) or endosomal (3, viruses) TLR activation; by activing various STAT family members that being important for the virus replication (4), by controlling STAT activation/translocation to the nucleus (5); and last but not least by reducing the activity of the suppressor of cytokine signaling-3 (SOCS3), a host negative regulator of the JAK/STAT pathway (6). Abbreviations: TLR, Toll like receptor; TIR, Toll/IL-1R; MyD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor kappa B; IkB – inhibitor of the NF-κB kinase; P – phosphate residue (activated form); Cytokine R, a cytokine receptor with β1 and β2 subunits; JAK, Janus tyrosine kinase familly; STAT, signal transducer and activator of transcription family; SOCS3, suppressor of cytokine signaling 3.

FIGURE 3

Dangerous liaisons between infections and RA. In case of viral infections such as observed with Herpesviridae, the immune system limits viral infection by producing proinflammatory cytokines (e.g., interferon, IFN), anti-viral antibodies and through the activation of cytotoxic cells such as CD8+ T cells and innate natural killer cells (iNK). In case of RA, a defective antiviral activity is observed together with factors promoting Herpesviridae propagation (e.g., herpes virus entry mediator, HVEM, and epidermal growth factor receptor, EGFR, overexpression; downregulation of the opsonic factor MBL, mannose binding lectin). At the opposite, infections promote autoimmunity by inducing protein citrulinisation, by promoting HLA-DR overexpression, and by interfering with the pathways involved in the production of cytokines and chemokines, Jak/STAT and NF-κB (see Figure 2).