Utilizing the largest published GWAS of peripheral immune cell phenotypes to date, we evaluated the causal relationship between peripheral immune cell traits and AD risk by two-sample MR analysis. To data this is the most comprehensive MR study exploring a potential protective causal relationship between peripheral immune cell traits and AD. Mendelian randomization analysis uses genetic variants strongly associated with exposure as instrumental variables to infer causal relationships between exposure and outcome while avoiding bias from various confounding factors and reverse causal associations. In the present study, we identified a total of six peripheral immune phenotypes significantly associated with a low risk of AD, including four Treg-associated immune phenotypes (CD25 + + CD45RA- CD4 not regulatory T cells in T cells or CD4 + T cells, Secreting or Activated & secreting CD4 regulatory T cells in CD4 regulatory T cells), one monocyte-associated phenotype (HLA DR + + monocyte % monocyte ), and one belonging to a dendritic cell subpopulation (HLA DR on myeloid Dendritic Cell). Notably, all four protective immune features were associated with Tregs, suggesting that Tregs may potentially perform a potential protective role in AD progression.
The first type of protective feature is the Treg-related immunophenotype (CD25 + + CD45RA-CD4 not regulatory T cells % T cells or CD4 + T cells, Secreting or Activated & secreting CD4 regulatory T cells % CD4 regulatory T cells). Distinct subpopulations of Treg cells have divergent immune functions and play different roles in disease. Tregs can be divided into activated (CD25+++ CD45RA-), resting (CD25 + + CD45RA +), and secreting (CD25 + + CD45RA -) types according to the cell surface markers.22 Resting Tregs are Tregs in their naive form before antigen presentation, whereas activated Tregs are generated largely from resting Tregs after exposure to self-antigens. In the present study, there were noticeable dissimilarities in Treg cell function among the three subtypes. Resting Tregs and activated Tregs have an immunosuppressive function, while secreting Tregs have almost no immunosuppressive function and can secrete a large number of cytokines such as interleukin (IL) -2, IL-10, interferon (IFN)-\(\gamma\).
In this study, secreting Tregs likely exerted immunosuppressive effects through secreted cytokines, such as IL-2. In the peripheral immune system, the predominant roles of IL-2, which is responsible for activating immune cells, are activating Treg cells, controlling inflammation, and alleviating the pathological course of AD. Biological evidence from an experimental AD mouse model has explained that IL-2 triggers the activation of Tregs and astrocytes in APP/PS1 mice and increases the recruitment of astrocytes around amyloid plaques, reducing Aβ and slowing the development of AD.23 This may underlie the protective effects on AD of the high proportion of Secreting or Activated & secreting CD4 regulatory T cells in CD4 regulatory T cells observed in this study.
Other research has also demonstrated that Treg cells can exert their strong anti-inflammatory effects and delay AD progression by activating M2-type microglia. This supports our findings that Treg cells potentially protect against AD.24 A study based on an animal model of AD reported that the transient depletion of Tregs at the early stage accelerated the development of cognitive dysfunction in APP/PS1 mice. This early cognitive decline was associated with reduced recruitment of activated microglia to Aβ deposition by Tregs.25 This suggests that Tregs play a beneficial role in the development of AD disease, which was further supported by our study confirming that Tregs can reduce AD risk. The results of this study further implicate Tregs in immunotherapy as etiologically effective, although additional clinical trials are necessary to verify the specific therapeutic effects.
The second category of protective factors analyzed in this study is the high proportion of HLA DR + + monocyte in monocyte. HLA DR is a major human histocompatibility complex antigen, and its peripheral expression is generally considered to be an important indicator of immune competence. As the most critical antigen-presenting cell in the body, HLA-DR expressed via monocyte is the key effector molecule playing a role in presenting antigens, and its expression level represents the antigen-presenting ability of monocytes. The definitive mechanism underlying our findings remains obscure. Nevertheless, there is a multitude of research providing support for the conclusion that a higher proportion of HLA DR + + monocyte in monocyte is a protective factor against AD. A recent study reported that in an APP/PS1/Cx3cr1AD mouse model, patrolling monocytes could climb up the lumen wall of Aβ-positive veins and target Aβ clearance from the venous lumen, as observed by in-vivo two-photon microscopy.26 The selective removal of these monocytes resulted in a significant increase in Aβ load in the brain of the APP/PS1 mice. A recent MR study found an inverse association between monocyte count and AD risk, and our MR analysis obtained consistent results.27
The third category of protective factors is myeloid dendritic cells with the high expression of HLA DR. Dendritic cells (DCs) can be divided into plasma cell-derived (CD123+) and myeloid-derived (CD11c+) according to their origin.28 DCs are professional antigen-presenting cells that can activate naive T cells for proliferation and play an invaluable role in the induction of immune response.29 Ciaramella et al.30 showed that in the peripheral blood of AD patients, the number of mDCs was specifically reduced compared to healthy controls while the plasma cell-derived DC (pDC) subpopulation remained unchanged, suggesting a potentially important role of blood mDCs in regulating brain immune responses in AD. Our findings of a negative association between peripheral mDCs with the high expression of HLA DR and AD risk likely reinforce the innovative idea that blood mDC represents a potential participant in AD from an epidemiological perspective.