Based on open, openly accessible genetic data, our study evaluated the causal relationship between 731 types of immune cells and PTSD. To our knowledge, this novel study aimed to provide more insight into the pathogenesis of PTSD in the fields of immunology and genetics. After strict screening and analysis, we identified 10 immunological characteristics that had a causal relationship with PTSD.
In our study, we found a close association between CD33-related immune cell subtypes and PTSD risk factors. CD33 is a receptor belonging to the sialic acid-binding immunoglobulin-like lectin (Ig) family that is primarily expressed by myeloid cells and microglia and participates in the adhesion of human primitive immune cells and the mediation of cell‒cell interactions (25). Increasing evidence has shown that CD33-related cells are linked to Alzheimer's disease (AD). Studies have shown that the expression of CD33 in the brains of AD patients is associated with a protective allele of a SNP (26, 27), which is related to a reduction in insoluble amyloid-beta 42 (Aβ42) levels. Coincidentally, in autoimmune conditions, such as celiac disease (CeD), researchers identified a novel bioprofile characterized by elevated CD64 and reduced CD33 levels (28). However, there is no information about the links between PTSD and CD33-related immune cells. More regrettably, even though we were the first to discover this mechanism, we were unable to explore the specific mechanism of CD33-related immune cells and PTSD, but at least we provided a direction for subsequent researchers to obtain some insight.
In addition to the CD33-related immune cells we mentioned, we were surprised to find that CD45RA+ CD8+ T cells are a protective mechanism against PTSD. CD45, also called the leukocyte common antigen, is a cell surface glycoprotein with tyrosine phosphatase activity that is expressed on nearly all hematopoietic cells in various isoforms related to their stage of development and activation (29). One of the isoforms is CD45RA, which identifies naive T cells (30). However, although many researchers have studied T cells or CD45, there is still not enough information on CD45RA+ CD8+ T cells or CD45RA. We look forward to future conclusions that will enable us to better understand the possible protection mechanisms of PTSD.
Effector memory CD4-CD8- T cells. In a study on psoriasis, researchers have shown that electrostimulation (ES) occurs through the downregulation of the psoriasis channel Kv1.3 on T cells and the reduction of cd4/cd8 effector memory (t++em) and CD8 skin resident memory T (t+rm) cells. However, ES failed to further suppress T-cell memory in Kv1.3-deficient cells (31). This also provides us with some insight into the treatment of PTSD. Some researchers have also attempted to assess the acute effects of a single session of whole-body electromyostimulation (WB-EMS) on the physical performance and serum levels of neurotrophic factors in Parkinson's disease (PD) patients (32). Will the same mechanism occur in PTSD patients? We cannot tell that answer for now. One day in the future, after we gain enough information, we will have more treatment or prevention methods available.
CD39+ CD8+ T cells. CD39 is an ectonucleotidase expressed by B cells, innate cells, regulatory T cells, and activated CD4 + and CD8 + T cells, which can result in the local production of adenosine, leading to an immunosuppressive environment (33-36). One study demonstrated the coexpression of CD39 with a marker of resident memory CD8 + T cells, indicating that CD39 plays a protective role in cancer survival in these cells (37,38), rather than being a risk factor for PTSD patients in our study. However, the exact mechanism involved in CD39 + CD8 + T cells in PTSD patients is still unknown.
There are many studies on the effect of CD34 on haematopoietic stem cells. The ex vivo expansion of high-quality hematopoietic stem cells is considered a paramount issue in cell and gene therapy for hematological diseases (39). In a study of diabetes, researchers found that angiotensin (Ang)-(1-7) stimulates the vasoprotective functions of diabetic (DB) CD34 hematopoietic stem/progenitor cells partly by decreasing reactive oxygen species (ROS), increasing nitric oxide (NO) levels and decreasing TGFβ1 secretion (40). The effect of CD34 on haematopoietic stem cells is also a topic of interest in tumour research, as some haematopoietic cancers are known to be related to CD34. However, few studies on mental disorders or diseases have reported the effect of CD34 on haematopoietic stem cells. Moreover, we cannot explore further mechanisms through our results.
Our study is exploratory, and we conducted a bulk two-sample MR analysis based on published large GWAS datasets; thus, this study has high statistical efficiency. Our research aimed to explore more information about PTSD from the perspective of immune cells to help us better understand PTSD and explore clues or evidence, including risk factors or possible protective mechanisms. After strict screening and analysis, our study did not show horizontal pleiotropy or heterogeneity, and our results are robust. However, the study has several limitations. First, we analysed only European data, which limits the applicability of the results to non-European populations. Second, we cannot learn the specific information of the subjects; that is, we cannot classify the patients, including from the perspective of different disease inducements and different occupational groups. Third, our MR is only linear. We hope to learn more about them in the future in different ways.