Blocking Superantigen-Mediated Diseases: Challenges and Future Trends

Abstract

Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vβ and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases.

Figure 1

Phylogenetic tree of known bacterial SAgs: the unrooted tree was constructed using the amino acid sequence alignment method of unweighted pair group using arithmetic averages (UPGMA) in Mega11. It is divided into five major groups, representing distinct classes of SAgs.

Figure 2

Mechanism by which antigens activate the immune system: endogenous antigens are processed by proteasome into antigenic peptides, which recruit MHC I to the endoplasmic reticulum and bind to it to form the antigenic peptide-MHC I complex. The complex is processed on the Golgi apparatus/endoplasmic reticulum and secreted to the cell membrane surface, and the antigen is presented to CD8 T cells. After processing by lysosomes into antigenic peptides, exogenous antigens recruit MHC II on the endoplasmic reticulum and bind to it to form an antigenic peptide-MHC II complex. After processing by the Golgi apparatus/endoplasmic reticulum, the antigen is secreted to the surface of the cell membrane and presented to CD4 T cells.

Figure 3

Crystal structure of SEA in complex with human MHC class II. Data from RCSB (https://www.rcsb.org, entry ID: 1LO5).

Figure 4

MHC Ⅱ binding sites and SAgs stimulating specific T cells with TCR Vβ.

Figure 5

A DNA nanorobot springs open like a clamshell to reveal its payload, antibody drugs (purple). The DNA shell is held together by 2 DNA locks (red) that open when they meet molecular keys (green) found on the surface of a cell. The top left shows a side view of the DNA shell in its closed state.