Contribution of bacterial pathogens to evoking serological disease markers and aggravating disease activity in rheumatoid arthritis

Abstract

Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes.Trial registration: UMIN CTR UMIN000012200

Antibodies Isolated from Rheumatoid Arthritis Patients against Lysine-Containing Proteus mirabilis O3 (S1959) Lipopolysaccharide May React with Collagen Type I

“…An example which may be used is the above observation that, in patients treated MTX, reaction with Lys-GalA and O3 LPS was lower. Results obtained with the correlation of MTX treatment and sera reactivity do not confirm earlier studies that show that MTX treatment patients had increased reaction with LPS of environment bacteria [ 5 ].…”

“…It is believed that RA development is dependent on genetic factors, HLA polymorphisms, and environmental factors such as smoking and infectious agents [ 4 ]. It is assumed that autoimmunity caused by infective agents is induced by molecular mimicry, cross-reactions, or the formation of immunological complexes [ 5 ]. One of the most common bacteria linked with the etiopathogenesis and development of RA is Proteus mirabilis .…”

New Studies of Pathogenesis of Rheumatoid Arthritis with Collagen-Induced and Collagen Antibody-Induced Arthritis Models: New Insight Involving Bacteria Flora

“…Bacteria number changes in the intestinal flora including these bacteria might be closely related to the effectiveness of MTX and remission of RA. Our report indicated that the IgA and IgG levels against P. gingivalis significantly increased in sera from RA patients treated with MTX for a long period, suggesting MTX may change the intestinal bacterial balance including P. gingivalis [20,100,105]. As previously described, immune suppressed mice become highly susceptible against LPS toxicity and develop severe and destructive arthritis with a single IP injection of LPS.…”

“…RA patients harboring the HLA-DR4 gene with severe arthritic inflammation have low levels of anti-type II collagen autoantibodies, in contrast to CIA-susceptible DBA/1 mice. Therefore, RA can be characterized into two types, both of which are related to environmental factors, but differ regarding how antibodies induce pathology [ 19 , 20 ].…”

“…Other common factors may include changes in substances produced by intestinal bacteria and destruction of mucosal barriers and gastrointestinal defense mechanisms. In addition, it is also important to assess the contribution of antibody reactions, which play important roles in immune defense [ 19 , 20 ].…”