Slipping through the Cracks: Linking Low Immune Function and Intestinal Bacterial Imbalance to the Etiology of Rheumatoid Arthritis

Autoimmune diseases (ADs) are considered to be caused by the host immune system which attacks and destroys its own tissue by mistake. A widely accepted hypothesis to explain the pathogenic mechanism of ADs is “molecular mimicry,” which states that antibodies against an infectious agent cross-react with a self-antigen sharing an identical or similar antigenic epitope. However, this hypothesis was most likely established based on misleading antibody assay data largely influenced by intense false positive reactions involved in immunoassay systems. Thus reinvestigation of this hypothesis using an appropriate blocking agent capable of eliminating all types of nonspecific reactions and proper assay design is strongly encouraged. In this review, we discuss the possibility that low immune function may be the fundamental, common defect in ADs, which increases the susceptibility to potential disease causative pathogens located in the gastrointestinal tract (GI), such as bacteria and their components or dietary components. In addition to these exogenous agents, aberrations in the host’s physical condition may disrupt the host defense system, which is tightly orchestrated by “immune function,” “mucosal barrier function,” and “intestinal bacterial balance.” These disturbances may initiate a downward spiral, which can lead to chronic health problems that will evolve to an autoimmune disorder

Linkage of RF with IgG and IgA antibody responses to bacterial pathogens in RA patients.

<p>IgG and IgA antibody levels against individual pathogens and their IgA/IgG antibody ratio were analyzed for possible correlation with RF levels in 54 patients with RRP (a) and 101 patients with non-RRP (b) by Spearman’s rank correlation coefficient analysis. NOTE: Pink: significant correlation at p<0.05, Blue: trending toward correlation at 0.05≤p<0.15, No color: no correlation.</p

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

<div><p>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, <i>Escherichia coli</i>-lipopolysaccharide (<i>E</i>. <i>coli</i>-LPS), <i>Porphyromonas gingivalis</i>-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from <i>Streptococcus pyogenes</i>, 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-<i>E</i>. <i>coli</i>-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.</p><p><b>Trial registration</b>: UMIN CTR <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014218" target="_blank">UMIN000012200</a></p></div

Relationship of RF with antibody response functions and clinical maker levels in patients with RRP and non-RRP.

<p>RF levels were compared with IgG and IgA index values, severity of arthritis, disease marker levels, serum cytokine levels, and hematological values in 54 patients with RRP and 101 patients with non-RRP, using Spearman’s rank correlation coefficient analysis. NOTE: Plot: Visual display for positive and negative “ρ” value of Spearmen correlation coefficient. Cells highlighted with yellow indicate significant correlation at p<0.05. Index 1: sum of anti-<i>E</i>. <i>coli</i>-LPS + anti-Pg-LPS, Index 2: sum of anti-<i>E</i>. <i>coli</i>-LPS + anti-PG-PS, Index 3: sum of anti<i>-E</i>. <i>coli</i>-LPS + anti-Pg-LPS + anti-PG-PS.</p

Linkage of RF with IgG and IgA antibody responses to bacterial pathogens in RA patients.

<p>IgG and IgA antibody levels against individual pathogens and their IgA/IgG antibody ratio were analyzed for possible correlation with RF levels in 54 patients with RRP (a) and 101 patients with non-RRP (b) by Spearman’s rank correlation coefficient analysis. NOTE: Pink: significant correlation at p<0.05, Blue: trending toward correlation at 0.05≤p<0.15, No color: no correlation.</p

Relationship of ESR with antibody response functions and clinical marker levels in patients with RRP and non-RRP.

<p>ESR values were compared with IgG and IgA index values, severity of arthritis, disease marker levels, serum cytokine levels, and hematological values in 54 patients with RRP and 101 patients with non-RRP, using Spearman’s rank correlation coefficient analysis. NOTE: Plot: Visual display for positive and negative “ρ” value of Spearmen correlation coefficient. Cells highlighted with yellow indicate significant correlation at p<0.05. Index 1: sum of anti-<i>E</i>. <i>coli</i>-LPS + anti-Pg-LPS, Index 2: sum of anti-<i>E</i>. <i>coli</i>-LPS + anti-PG-PS, Index 3: sum of anti<i>-E</i>. <i>coli</i>-LPS + anti-Pg-LPS + anti-PG-PS.</p

Linkage of CRP with IgG and IgA antibody responses to bacterial pathogens in RA patients.

<p>IgG and IgA antibody levels against individual pathogens and their IgA/IgG antibody ratio were compared with CRP levels in 54 patients with RRP (a) and 101 patients with non-RRP (b) by Spearman’s rank correlation coefficient analysis. NOTE: Pink: significant correlation at p<0.05, Blue: trending toward correlation at 0.05≤p<0.15, No color: no correlation.</p

Comparison of antibody responses to potential pathogenic environmental agents between RA and NL controls.

<p>IgG and IgA antibody levels against <i>E</i>. <i>coli</i>-LPS, Pg-LPS and PG-PS were determined in sera from 38 NL controls, 54 patients with RRP and 101 patients with non-RRP (a). IgG and IgA antibody levels of individual patients were divided by the average values of NL controls, and shown as IgG and IgA index values (b). Data are shown as median and interquartile range (IQR). <i>E</i>. <i>coli</i>: <i>Escherichia coli</i>, Pg: <i>Porphyromonas gingivalis</i>, LPS: lipopolysaccharide, PG-PS: peptidoglycan polysaccharide from <i>Streptococcus pyogenes</i>, RRP: rapid radiographic progression, NOTE: Index 1: sum of anti-<i>E</i>. <i>coli</i>-LPS + anti-Pg-LPS, Index 2: sum of anti-<i>E</i>. <i>coli</i>-LPS + anti-PG-PS, Index 3: sum of anti<i>-E</i>. <i>coli</i>-LPS + anti-Pg-LPS + anti-PG-PS.</p