Researchers from the University of Colorado Anschutz Medical Campus have shown that patients with early-onset rheumatoid arthritis (RA) show high levels of the immune system’s pathogen-attacking protein granzyme and remnants of the bacteria that causes gum disease, Porphyromonas gingivalis, in their joints. The findings, published recently in the journal Immune Network, have the potential to lead to earlier diagnosis and treatment of RA.
The research analyzed joint tissue from early RA patients and found elevated levels of proteins in the granzyme-perforin (GZM-PRF-1) pathway, a system used by the immune system’s killer cells to eliminate pathogens. The proteins granzymes A, B, H, K, and M, along with perforin-1 and serglycin were found in high levels, particularly in tissues showing a lymphoid pattern of inflammation.
The findings suggest that the granzyme-perforin system may represent a local immune mechanism active in early RA that could be targeting residual bacterial material in the joint. If further validated, the pathway may serve both as a biomarker for disease progression and a novel target for early intervention.
This research builds on prior work showing granzymes are present in RA-affected tissue and fluid, but it is the first to comprehensively analyze the expression of all five granzymes, perforin-1, and serglycin in both synovial tissue and blood, in relation to RA pathotypes. Previous studies had linked elevated GZM B levels to disease severity, and some had associated genetic variants in GZM B with joint damage.
They team also found that the abundance of these immune proteins in joint tissue strongly correlated with RA disease activity scores, but this correlation was absent in blood, suggesting a localized immune process.
In addition, the study identified remnants of P. gingivalis, but not live bacteria—only traces of bacterially-derived material—in the joint tissue, particularly in regions with high granzyme activity.
The findings suggest that the granzyme-perforin system may represent a local immune mechanism active in early RA that could be targeting residual bacterial material in the joint. If further validated, the pathway may serve both as a biomarker for disease progression and a novel target for early intervention.
“We found tiny traces of it in the joint tissue, especially in areas where those immune proteins were highly active—supporting the idea that a past infection might help trigger RA,” said the study’s senior author Nirmal K. Banda, PhD, professor in the division of rheumatology at the Barbara Davis Center for Diabetes at CU Anschutz.
While a connection between gum disease and RA has been proposed for years, this is the first study to detect P. gingivalis antigens directly within early RA synovial tissue. The researchers propose that a low-grade or cleared infection may have triggered localized immune activation, potentially through the granzyme-perforin system.
“We asked the question whether high expression of GZM-PRF-1 pathway-related genes in the synovium of eRA patients is due to any kind of bacterial infection in the eRA synovium?” the researchers wrote. “We found the presence of a very low level of speckles of P. gingivalis Ag deposits in the eRA synovium.”
Using bulk RNA sequencing data from two clinical trials, the team found that the monoclonal antibodies rituximab (a B cell-targeting drug) and tocilizumab (an IL-6 receptor inhibitor) both reduced expression of the granzyme-related genes in joint tissue, providing additional evidence of this pathway’s role in RA-associated inflammation.
Gene expression patterns were consistent across both seropositive and seronegative RA patients, implying the GZM-PRF-1 pathway may operate independently of classical autoantibody profiles like anti-citrullinated protein antibodies (ACPA) or rheumatoid factor (RF).
“This would suggest that removal of B cells leads to coordinating removal of other cell types such as CTL and macrophages which contribute to expression of GZM system genes,” the researchers wrote, highlighting the potential of GZM-related proteins as biomarkers for inflammation and potentially new therapeutic targets for RA treatment development.
