Background

The adaptive response is very focused and efficient in getting rid of invasive pathogens. However, it is essential for the immune system to discriminate between self and foreign chemicals in order to prevent harming the body's own components.

Genetics, contextual effects, and antigen-presenting cells are some of the variables that aid adaptive immune cells in learning to recognize foreign substances. This mechanism is significantly regulated by cytokines. The cells develop into a variety of subpopulations, such as Th1, Th2, Th17, Th19, and Th22, upon antigen engagement, guided by the cocktail of cytokines they come into contact with. Th cells have an impact on how other immune cells react once they have developed.

Allergic reactions, also known as type I hypersensitivity, involve an immune response triggered by the presence of an antigen. This reaction, which aims to neutralize the danger, is predominantly mediated by Th2 cells.

Venom immunotherapy (VIT) is a possible treatment strategy for the management of venom allergies. It aims to modify the immune response to venom allergens and enhance its precision. Previous studies have demonstrated that VIT induces a shift in T helper cell responses from Th2 to Th1, characterized by the production of IL-2 and interferon-gamma by CD4+ and CD8+ cells, as observed in the supernatants of stimulated PBMCs obtained from desensitized patients.

Research Question and Methods

In order to explore long-term pathways following VIT treatment and verify potential new outcomes, the serum concentrations of 30 cytokines were assessed in a cohort of 61 patients (18 control, 43 study group) exhibiting hypersensitivity to wasp venom. Cytokine levels were measured at 0, 2, 6, and 24 weeks after the initiation phase of VIT in the study group.

Results

Following VIT, the present study found no appreciable changes in the levels of IL-2 and IFN-γ in the peripheral blood. However, the concentration of IL-12, a cytokine capable of promoting the differentiation of Th0 cells into Th1 cells, significantly increased, which was a surprising observation. This observation confirms that the Th1 pathway is involved in the desensitization process caused by VIT.

Additionally, the study documented a time-dependent increase in the serum concentration of the chemokines CCL4 and CCL5, which are produced by various inflammatory cells. Notably, CCL4 and CCL5 contribute to the recruitment of Th1 cells. It is worth noting that CCL5 levels did not significantly increase in the serum after the first day of VIT with wasp venom but did increase after VIT with bee venom. Both CCL5 and CCL4 activate CCR5, which is a receptor expressed on T follicular helper cells (CXCR5+ FoxP3+ cells). These cells play a role in B-cell maturation and the switching of immunoglobulin classes and are also capable of suppressing T- and B-cell responses20. The increase in IL-12, CCL5, and CCL4 in the serum after VIT suggests that the Th1 pathway is involved in long-term changes, including a switch in the production of B-cell wasp-specific antibodies from IgE to IgG.

Additionally, the study revealed a significant rise in the levels of IL-9 and TGF-β after VIT. These cytokines may contribute to the generation of inducible regulatory T (Treg) cells, suggesting their potential significance in the immune response to venom allergens and the VIT-associated desensitization process.

In conclusion, the cytokine network has the ability to modulate the immune response patterns following antigen exposure. These alterations are associated with modifications in T helper cells, which play a pivotal role in regulating immune responses. During the long-term response to venom immunotherapy, two main pathways, namely Th1 and Th9, are involved in the modulation of B-cell responses. Among these pathways, IL-9 and TGF-β signaling involvement is particularly significant.

Nevertheless, further investigations are required to comprehensively comprehend the underlying mechanisms driving the VIT process.

Article Source: https://www.nature.com/articles/s41598-023-37593-0