Rheumatoid Arthritis (RA): Immune Aging as a Novel Mechanism Driving Autoimmune Disease

Rheumatoid Arthritis (RA) is a classic autoimmune disease, commonly affecting middle-aged and elderly populations. For a long time, immune system aging was considered a consequence of RA's chronic inflammation. However, a groundbreaking study from the University of Birmingham, published in eBioMedicine, proposes a paradigm shift: immune aging may precede RA onset and act as a driver of the disease. This finding opens new possibilities for early intervention in RA.

The research team began by examining the T-cell lineage, comparing immune states across different disease stages. They found that even in the pre-RA phases of joint pain and undifferentiated arthritis, patients already showed signs of immune aging: a reduced proportion of naïve CD4 T cells and fewer recent thymic emigrants. This "premature exhaustion" suggests the immune system loses its renewal capacity early in the disease process. As the disease progresses to confirmed RA, more terminally differentiated and senescent T cells (CD28- CD57+) appear, accompanied by a significant expansion of inflammatory Th17 cells. This indicates that RA's immune imbalance builds on early aging, later exacerbated by inflammatory T cells.

Figure 1. CD4+ T-cell subsets contributing to rheumatoid arthritis progression across disease stages

Building on this, the researchers developed the Immune Age Index (IMM-AGE) to comprehensively assess immune system aging. Results showed that individuals with undifferentiated arthritis or early RA had significantly higher IMM-AGE scores than age-matched healthy controls. This accelerated immune aging strongly correlated with elevated serum inflammatory markers, including IL-6, TNFα, and CRP. Longitudinal follow-ups revealed that those with higher IMM-AGE scores were more likely to progress to rheumatoid arthritis. Thus, IMM-AGE serves not only as a measure of aging but also as a potential early predictive tool for identifying high-risk individuals.

Figure 2. Multiple linear regression of IMM-AGE scores with demographic and clinical parameters in joint pain patients

In addition to T cells, B-cell aging characteristics were also evident in the preclinical stages of the disease. In patients with undifferentiated arthritis, researchers observed an increased proportion of IgD-CD27-age-associated B cells (ABCs), which are typically linked to immune aging and autoantibody production. As the disease progressed, these B-cell abnormalities accumulated, accompanied by an increase in plasmablasts, suggesting that RA's autoantibody response may be rooted in early B-cell aging.

Figure 3. B-cell subsets contributing to rheumatoid arthritis progression across disease stages

Further functional experiments revealed that early-stage patients' T cells exhibited defects in proliferation and DNA repair, consistent with immune aging characteristics. These T cells also displayed enhanced pro-inflammatory capacity, secreting higher levels of IL-17 and other factors, driving sustained inflammatory responses. This suggests that immune aging not only involves changes in cell proportions and phenotypes but also directly causes functional impairments, making the immune system more prone to inflammation.

Figure 4. Serum cytokine levels

To elucidate the molecular pathways enhancing immune aging in rheumatoid arthritis (RA), the study analyzed 770 genes in PBMCs from age- and sex-matched Caucasian participants with no smoking history and normal BMI, using Nanostring nCounter technology. Key findings include RA patients showing downregulation of anti-inflammatory genes and upregulation of inflammatory mediators/cytokines (no such anti-inflammatory changes in early disease); upregulation of autoimmune-related genes; downregulation of autophagy-related genes, with early-stage autophagy potentially promoting disease progression by enhancing apoptosis resistance and impairing antigen clearance; and changes in metabolic reprogramming markers, leading to T-cell senescence and promoting arthritogenic properties.

Figure 5. Transcriptomic features across rheumatoid arthritis disease stages

Finally, combining longitudinal follow-up and mechanistic analysis, the researchers linked these immune aging features: before RA diagnosis, loss of naïve T cells, elevated IMM-AGE scores, and ABC accumulation set the stage for disease; as senescent T cells and inflammatory Th17 cells expand post-RA diagnosis, clinical symptoms emerge. Mechanistically, impaired autophagy and senescent cell accumulation may be key bridges between immune aging and RA onset. This comprehensive timeline suggests that RA follows an "aging first, inflammation later" trajectory, with immune aging likely driving the disease's onset.

Figure 6. Accelerated immune aging in joint pain and undifferentiated arthritis patients subsequently progressing to rheumatoid arthritis

In summary, rheumatoid arthritis does not exhibit immune aging only after disease establishment; signs of premature immune system aging are detectable in preclinical stages like joint pain and undifferentiated arthritis. Patients show a significant reduction in naïve T cells and recent thymic emigrants, replaced by increased memory and senescent T cells; concurrently, B cells exhibit a higher proportion of age-associated B cells and plasmablast expansion, indicating the foundation for autoantibody responses is already established. The immune age score further reveals that this accelerated aging correlates closely with elevated inflammatory markers and can predict disease progression. Overall, the study proposes that immune aging is a driver of RA rather than a consequence, offering new directions for early disease identification and interventions targeting aging pathways.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease driven by abnormal immune system activation, with its core mechanism involving sustained aberrant interactions between adaptive and innate immunity. In the early stages, genetic predispositions (e.g., HLA-DRB1 "shared epitope") and environmental factors (e.g., smoking, microbial exposure) jointly trigger immune tolerance breakdown, leading to the production of autoantibodies like anti-citrullinated protein antibodies (ACPA). This is a disease driven by immune aging, lymphocyte dysfunction, and an amplified inflammatory cytokine network.

abinScience, founded in Strasbourg, France, leverages the region's exceptional research and innovation ecosystem to focus on developing and producing high-quality life science reagents. Guided by the vision of "Empowering Bioscience Discovery," abinScience prioritizes autoimmune disease research as a key focus, continuously expanding its core product lines for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and myasthenia gravis (MG). The company is dedicated to providing researchers worldwide with efficient, reliable experimental solutions to explore immune mechanisms, discover novel therapeutic targets, and advance cutting-edge life science research.

Below is a list of RA-related products offered by abinScience: