HLA‐DR polymorphisms influence in vivo responses to staphylococcal toxic shock syndrome toxin‐1 in a transgenic mouse model

Abstract

Toxic shock syndrome toxin-1 (TSST-1) is a potent superantigen produced by Staphylococcus aureus. In addition to menstrual and nonmenstrual toxic shock syndromes, TSST-1 is also implicated in the immunopathogenesis of pneumonia, infective endocarditis, neonatal exanthematous disease, and atopic dermatitis among others. Superantigens first bind to major histocompatibility complex (MHC) class II molecules and then activate a large proportion of T cells by cross-linking their T cell receptor. As binding to MHC class II molecules is a critical step in the robust activation of the immune system by TSST-1 and other superantigens, polymorphic variations between different HLA-DR alleles could potentially influence the magnitude of immune activation and immunopathology caused by TSST-1. As TSST-1 is highly toxic to humans and given that multiple variations of alleles of HLA-DR and HLA-DQ are expressed in each individual, it is difficult to determine how HLA-DR polymorphisms quantitatively and qualitatively impact immune activation caused by TSST-1 in humans. However, such investigations can be conducted on transgenic mice lacking all endogenous MHC class II molecules and expressing specific HLA class II alleles. Therefore, transgenic mice expressing different HLA-DRB1 alleles (HLA-DRB1*15:01, HLA-DRB1*15:02, HLA-DRB1*03:01, HLA-DRB1*04:01), and sharing HLA-A1*01:01 chain, were systemically challenged with purified TSST-1 and multiple immune parameters were assessed. Among the HLA-DR alleles, mice expressing HLA-DRB1*15:01 allele elicited a significantly higher serum cytokine/chemokine response; greater splenic T cell expansion and most severe organ pathology. Our study highlights the potential utility of human leukocyte antigen (HLA) transgenic mice in understanding the impact of HLA polymorphisms on the outcomes of diseases caused by TSST-1 and other superantigens.

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

“…One hypothesis is that to be able to bind highly variable molecules such as the TCR, SAgs too need to be diverse in order to reliably stimulate T cells. This may also be paralleled, in part, by the ability of SAgs to display binding preferences for different MHC class II molecules [ 59 , 60 , 61 ]. Another possibility is that the different toxin sequences allow for antigenic variation and exploit this to retain the ability to activate T lymphocytes even when neutralising antibodies are present to other SAgs.…”

Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease

“…Additionally, class II HLA molecules have a role in innate immunity and in the regulation of macrophages, including antigen-presenting cells. For example, super-antigen-engaged antigen-presenting cells induce proinflammatory cytokines [ 37 ].…”

Concomitant Disruption of CD4 and CD8 Genes Facilitates the Development of Double Negative αβ TCR+ Peripheral T Cells That Respond Robustly to Staphylococcal Superantigen

“…Tissues collected in buffered formalin were paraffin embedded, cut, and stained with H&E per standard procedure for histopathologic analysis. To numerically quantify the extent of inflammation, H&E stained sections were objectively evaluated in a blinded fashion as described previously (39). A score of 0 to 3 were given to each slide based on the extent of tissue involvement.…”