After a comprehensive study of 731 immune cells and OA, we identified 166 immune cells associated with hip OA. After Bonferroni correction and multiple sensitivity analyses, eight immune cells with significant causal associations with six OA phenotypes were identified. In addition, this study involved eight important immune cells with six OA phenotypes. To our knowledge, this is the first MR study to comprehensively assess the pathogenic and protective role of immune cells in OA. Our study opens new possibilities for more targeted therapies and sheds light on the role of the immune system in OA.
OA is tightly linked to the immune system in both its onset and progression, according to several studies. One of the main characteristics of OA is T-cell infiltration into the joints. Few tissue-resident T lymphocytes are present in the synovium or synovial fluid at any given moment in healthy joints (15). Compared to normal synovium, which has a CD4 +/CD8 + T cell ratio of 2:1, OA synovial tissue has been discovered to have a comparatively high concentration of CD4 + T cells(16). Additionally, the synovial aggregates of OA express CD80, an inducible co-stimulatory ligand involved in T-cell stimulation(17). These results imply that T cells might play a role in OA pathogenesis. Based on their distribution, surface markers, and functional characteristics, B cells can be divided into two subgroups: B1 and B2. In a mouse model, B1 cells generate naturally occurring antibodies called IgM, which have anti-inflammatory properties, while B2 cells generate IgG, which are pathogenic cells linked to inflammation related to obesity (18). Second, the plasma cells produced by the activated B cells boost the production of antibodies(19). Numerous investigations have shown that autoantibodies against proteins derived from cartilage, including osteopontin, cartilage intermediate layer protein, YKL-39, fibulin, and collagen, are present in individuals with OA(20). In all diseases, but notably in OA, where inflammation plays a major role, the generation of antibodies is crucial. In addition to T and B cells, monocytes, DCs, and myeloid cells also play a role in the formation and development of OA.
Our study identified eight immune cells that were causally associated with the six OA phenotypes. With increasing research on T cell subsets, a group of cells capable of actively maintaining immune homeostasis and peripheral immune tolerance has been identified and defined as Tregs(21). CD4 + CD25 + Tregs are negative immunoregulatory cells that play key roles in inhibiting the progression of autoimmune diseases, controlling potentially harmful inflammatory responses, and maintaining autoimmune homeostasis(22, 23). Consequently, more CD25-expressing Tregs or higher CD25 expression levels can improve Treg function, which is essential for preventing the development of immunological inflammation. In our investigation, there was a substantial correlation between hip OA and CD25 expression in CD45RA + CD4 non-Tregs. The reason for this subpopulation could be higher levels of CD25 expression. These cells attach to interleukin (IL)-2 competitively and, when stimulated, quickly begin to inhibit the immune system(24). Studies have shown that IL2RA and RBM17 (gene) act on CD25 on CD45RA + CD4, but not on Tregs, and can be used to treat alopecia areata, primary sclerosing cholangitis, multiple sclerosis, and psoriasis by modulating the CD25 primary drug target(11). This could be a potential therapeutic target for OA.
CD247 is a protein on the surface of T cells and NKs, and when the T cell receptor (TCR) binds to the antigen, CD247 interacts with other CD3 chains (e.g., CD3γ, CD3δ, CD3ε, and CD3ζ) as well as the TCR α and β chains to form the TCR-CD3 complex(25). This complex activates T cells through intracellular signaling pathways, leading to an immune response against antigens(26). This enables T cells to mount effective immune responses against infections, tumor cells, and other abnormal cells(27). CD39 is a transmembrane protein with two transmembrane and one extracellular structural domains. Functionally, CD39 binds to extracellular adenosine triphosphate ATP (eATP) and hydrolyzes it to adenosine monophosphate (AMP), whereas another extracellular nuclease, CD73, hydrolyzes AMP to adenosine (ADO)(28). In the ATP-ADO pathway, CD39 is the rate-limiting enzyme for eATP hydrolysis. In addition, CD39 hydrolyzes ADP at a lower efficiency(29). In the tumor microenvironment, eATP exerts immune activation in multiple cell types through purinergic receptors, whereas ADO suppresses immune responses in the same cells through multiple mechanisms mediated by ADO receptors(30). This finding implies that an increase in CD39 levels causes immunosuppression. It has been shown that CD247 (gene) acting on CD3 on CD39 + CD4 + cells can be used to treat systemic sclerosis and allergic diseases (asthma, hay fever, or eczema) through the modulation of the CD3 Primary drug target(11). In our study, CD3 expression on CD39 + CD4 + resting Tregs was significantly associated with hand joint OA. It can also be regulated by the CD3 Primary drug target. This may represent a new approach for the treatment of OA.
CD11c + myeloid cells modulate immunity by releasing exosomal miR-146a via RAB27A and RAB27B, thereby reducing intestinal inflammation in colitis(31). microRNA (miR)-146a was the first miRNA found to negatively modulate immune-inflammatory responses through inflammatory factors in the immune system, and its normal expression in the body facilitates the control of inflammation. The Notch signaling system has been linked to cartilage homeostasis and the development of osteoarthritis (OA), and Notch1 receptors are strongly expressed in articular chondrocytes on the surface of mouse and human articular cartilage(32, 33). Studies on the Notch1 receptor have revealed that miR-146a prevents articular cartilage degeneration and protects articular cartilage by inhibiting Notch1/IL-6 signaling during aging or trauma. It was also found that cartilage degeneration in miR-146a knockout individuals was mediated by Notch1, and that miR-146a overexpression prevented aging and trauma-related OA(34, 35). MiR-146a was found to prevent the onset of OA by inhibiting Notch signaling. This was demonstrated by the attenuation of IL-1β-induced joint destruction and reduction of joint degeneration in miR-146a-deficient mice when miR-146a was overexpressed in cartilage tissues or when Notch1 inhibitors were administered intra-articularly(33, 34, 36).
T cells, platelet transport, and the innate immune system all depend on CD62L (L-selectin). Selectins are involved in constitutive lymphocyte homing and chronic and acute inflammatory processes. Deficiency of selectins or their ligands leads to the development of recurrent bacterial infections and persistent diseases. Selectin binding plays a key role in many normal physiological processes, mediating leukocyte adhesion to endothelial cells, followed by leukocyte extravasation to sites of inflammation or injury to eliminate infection and healing wounds.CD62L is a key regulator of leukocyte rolling after surgical trauma and is required for neutrophil recruitment after inflammation(37). Our study showed that CD11c on CD62L + myeloid DCs reduced the risk of hip OA, which may be related to the roles of CD11c and CD62L. It has been shown that IgA nephropathy and systemic lupus erythematosus can be treated by CD11c on the myeloid DC pathway of the CD11c primary drug target(11).
Our MR analyses have numerous advantages. First, we use a large sample size, which allows us to avoid confounding and reverse causality to a greater extent and allows us to avoid the limitations of traditional observational studies (which are lengthy and costly). Second, our results were subjected to several statistical analyses and are highly credible.
However, there were limitations to our study. First, our results were obtained by studying a small number of people and are not necessarily generalizable to the entire human population. Second, our study lacked stratification based on age and disease severity.
In conclusion, we performed two-sample MR analyses and obtained strong correlations between eight immune cells and six OA phenotypes. Additionally, the potential immune action mechanisms were examined, yielding fresh perspectives on the management and prophylaxis of OA. To clarify the connection between the immune system and OA, more research is necessary.