In a groundbreaking study utilizing extensive genetic datasets, we investigated potential causal links between 731 immune cell traits and RA. To the best of our knowledge, this represents the first comprehensive MR analysis aimed at deciphering the intricate causal relationships between a wide array of immune cell traits and RA. we identified that nine immune cell traits appear to exert causal influences on the development and progression of RA (FDR<0.20). Conversely, we also discovered that RA demonstrated significant causal effects on the 12 immune cell traits (FDR<0.05).
Recently, a pivotal study undertook an exhaustive cellular analysis of the synovium in patients with RA, yielding profound insights into the diverse roles played by immune cells in this condition. The research highlighted that various immune cells within the RA synovium, including T cells, B cells, NK cells, and myeloid cells, exhibit a range of subtypes and activation states. This diversity underscores the complexity and dynamic nature of RA pathology [32]. While assessing the status of immune cells in synovial tissue offers a more precise picture of joint inflammation in RA, the practicality of this approach is limited by the challenges in sample collection. In contrast, the analysis of immune cells in peripheral blood, being more accessible and indicative of systemic inflammation, presents a more promising avenue for future research and clinical applications.
CD8+ T cells play a crucial role in the pathogenesis of RA, comprising various subpopulations whose specific connections to RA disease activity remain to be fully understood [33]. CD28, a vital co-stimulatory molecule for T-cell activation, can be lost during activation in some T cells, indicating a shift towards CD28 independence. These particular CD8+ T cell subtypes, devoid of CD28 expression, are typically well-experienced and highly differentiated. They are believed to contribute to the aggravation of RA, either through the secretion of pro-inflammatory cytokines or by directly inflicting damage on joint tissues [34]. Notably, these cells show increased expression in diseases characterized by chronic antigen exposure, such as autoimmune disorders [35]. Studies have revealed a positive correlation between CD28-CD8+ T cells and elevated levels of erythrocyte sedimentation, C-reactive protein (CRP), and rheumatoid factor (RF) in RA patients [36],suggesting a crucial link between the presence of CD28-CD8+ T cells and the progression of RA. Our forward MR results suggested that CD28-CD8+ T cells were positively correlated with the development of RA, however, our reverse MR results suggested that RA suppressed the expression of CD28-CD8+ T cells, which may be a negative feedback regulatory mechanism in the organism.CD45RA serves as a distinguishing feature among various differentiation stages of T cells. Neonatal "naïve" T cells typically exhibit CD45RA expression. As these cells undergo activation and maturation, they transition into "memory" T cells characterized by CD45RO expression, while concurrently losing CD45RA expression. Consequently, the presence of CD45RA- indicates the maturation of T cells into a more memory-oriented state [37].Our research suggests an association between CD45RA− CD28− CD8+ T cell %T cell and the onset of RA, And we also found that there is a common genetic variant rs130071 between the two, and further studies revealed that rs130071 is closely related to the expression of the gene CCHCR1.Based on this, we performed drug target MR analysis and found that CCHCR1 may inhibit RA by mediating CD45RA- CD28-CD8+ T cell %T cell expression.However,there is currently no supporting evidence from foundational studies to confirm this finding. Further validation is needed in future investigations.
Central memory CD8+ T cells are memory T cells produced after the body's first encounter with a specific antigen. Compared to effector memory T cells, central memory T cells reside more frequently in lymph nodes and are rapidly expanded and activated upon re-exposure to the same antigen, providing long-term immune protection.CD3 and the T-cell receptor (TCR) form the TCR/CD3 complex, which plays a key role in T-cell stimulatory signalling and T-cell activation [38].CD3 on Central Memory CD8+ T cells may help control the inflammatory response and reduce the symptoms of RA by secreting specific cytokines or regulating the function of other immune cells. Further research is needed in the future.HVEM is a surface protein that belongs to the tumour necrosis factor receptor family. It is expressed on a variety of immune cells, including T cells.HVEM is involved in the regulation of T cell activation and function through binding to its ligands, such as LIGHT and BTLA. In peripheral blood D8+ T cells in RA patients express HVEM less than in healthy individuals [39]. And the expression of HVEM on Central Memory CD8+ T cells in peripheral blood of patients and its mechanism of action have not been reported.
Similar to CD8+ T cells, CD4+ T cells have different subtypes and play different roles in the development of RA. In the immune system, regulatory T cells (Treg cells) are essential for maintaining immune homeostasis and preventing over-activation of the autoimmune response [40].CD39 is a nucleotidase that regulates the level of extracellular ATP and thus influences the activity of immune cells.CD39+ Treg cells are thought to play an important role in suppressing the over-immune response, helping to prevent autoimmune disease [41].Our MR results also seem to support this theory.As previously described, HVEM is involved in the regulation of T cell activation and function through binding to its ligands. In patients with rheumatoid arthritis, there is a significant negative correlation between the level of rheumatoid factor and the percentage of HVEM-CD4+ T lymphocytes [39].HLA-DR is a major histocompatibility complex (MHC) class II molecule, known in humans as part of the human leukocyte antigen (HLA) system [42].HLA-DR molecules are primarily expressed on the surface of antigen-presenting cells, but in some cases can also be expressed on other cell types, including T cells. HLA-DR expression on T cells is often a marker of immune activation and inflammatory states, indicating that these cells have been activated and are involved in the immune response [43].HLA-DR expression increase may reflect the immune system's active surveillance and identification of potential pathogens or abnormal cells. This heightened expression enhances the immune system's ability to more effectively recognize and ignore normal, healthy tissues, potentially reducing the attack on self-tissues. This mechanism may, to some extent, alleviate or suppress the onset of RA.Although we found that CD4 on HLA DR+ CD4+ T cells is negatively correlated with the occurrence of RA, and discovered a common genetic variation rs4371876 between them, unfortunately, we have not identified any related targets.
Dendritic cells play a crucial role in the immune response by activating T cells through antigen presentation. Research has shown that in patients with rheumatoid arthritis, there is a significant decrease in the number of myeloid dendritic cells (mDCs) in the peripheral blood. Furthermore, these mDCs exhibit a reduction in the expression level of CD62L, a key adhesion molecule. The study indicates that the downregulation of adhesion molecules like CD62L plays a critical role in the mobilization of CD34+ progenitor cells from the bone marrow to the peripheral blood. Additionally, the presence of a dendritic cell population in the peripheral blood with low CD62L expression may suggest a change in their circulatory patterns, or indicate an adjustment in the release mechanisms of dendritic cell precursors from the bone marrow [44-46].The mechanism of CD62L-mDCs in RA is currently unclear, and our MR results suggest that this cell may contribute to the development of RA. Further studies are needed in the future.
CD14 is a co-receptor involved in recognizing bacterial lipopolysaccharides (LPS) and other pathogen-associated molecular patterns (PAMPs), crucial for activating monocytes and initiating immune responses. CD16, as an Fc receptor, participates in immune responses through antibody-dependent cell-mediated cytotoxicity (ADCC), specifically identifying and eliminating antibody-tagged target cells. Previous studies have found an increased expression of CD14+CD16+ monocytes in the peripheral blood of rheumatoid arthritis (RA) patients, serving as a primary source of osteoclasts. Furthermore, Tyro3TK expression is significantly upregulated on CD14CD16 monocytes in RA patients, showing a positive correlation with disease manifestations such as IgM levels, joint tenderness counts, and disease activity scores [47-49].Our MR results seem to be the opposite: CD14+CD16+ monocytes seem to reduce the risk of RA. The regulation of the immune system is very complex, especially in autoimmune diseases such as RA. although CD14+CD16+ monocytes play a pro-inflammatory role in the pathological process of RA, they may also be involved in immune regulation and inflammation control, thus exhibiting anti-inflammatory or protective effects in some cases. Of course this is only speculation and further research is needed in the future.
In conclusion,in the pathogenesis of RA , various immune cell subtypes each play a unique role. To date, although some subtypes have been studied in relative depth, the understanding of most subtypes is still in an active exploratory phase. In particular, it should be emphasised that the regulatory mechanisms of the immune system are extremely complex, leading to the possibility that the same cell subtype may exhibit very different or even opposite roles at different stages of RA. In addition, with the continuous development of experimental techniques, we may identify more subdivided subtypes, and these newly discovered subtypes may play different roles in the course of RA. The present Mendelian randomization analysis provides an initial direction for exploring the relationship between immune cell characteristics and RA, a finding that requires further validation and in-depth study by experimental methods in the future.
However, this study has several notable limitations. First, the GWAS only included individuals of European descent, limiting the applicability of our results to other ethnicities and regions. Second, our Forward MR analysis employed a P-value cut-off of less than 5 × 10-6, due to a lack of sufficient SNPs at the more stringent threshold of 5 × 10-8, which is generally considered more appropriate [50]. Lastly, the influence of specific factors such as age and gender on our findings has yet to be fully explored. Future research may require a greater number of SNPs or larger sample sizes to address these issues more comprehensively.