Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Abstract

Among the exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgs in vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such as D-galactosamine (D-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS without D-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4 ؉ and CD8؉), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in the D-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with

Systemic Inflammatory Response Elicited by Superantigen Destabilizes T Regulatory Cells, Rendering Them Ineffective during Toxic Shock Syndrome

“…HLA-DR3 transgenic mice expressing HLA-DRA*0101 and HLA-DRB*0301 and IFN-γ deficient HLA-DR3 transgenic mice have already been described (31–33). These mice do not express any endogenous mouse MHC class II molecules.…”

“…In the current study, we therefore investigated whether increasing the numbers of endogenous Tregs directly in vivo using IL-2-anti-IL2 immune complexes (27, 28) or by adoptive transfer of ex vivo expanded Tregs (29, 30), could be protective in TSS using HLA-DR3 transgenic mouse model. Unlike conventional laboratory mice expressing endogenous mouse MHC class II molecules, HLA class II transgenic mice respond robustly to staphylococcal enterotoxin B (SEB) and suffer from an acute systemic inflammatory disease mimicking human TSS, without the use of any sensitizing or potentiating agents (31, 32). Hence, the HLA-DR3 transgenic mouse model was chosen.…”

Linezolid Is Superior to Vancomycin in Experimental Pneumonia Caused by Superantigen-Producing Staphylococcus aureus in HLA Class II Transgenic Mice

“…On the other hand, these agents might in fact be useful in humans. Since transgenic mice expressing HLA class II molecules respond robustly to SAg similarly to humans (barring certain species-level differences such as absence of emetic response in mice), they are more susceptible to S. aureus and Streptococcus pyogenes (which also produces SAg) infections than conventional mice (13,16,17). Therefore, we evaluated the activities of linezolid and vancomycin, particularly their abilities to inhibit SAg production, and compared their effectiveness in pneumonia induced by toxigenic S. aureus strains, using human leukocyte antigen (HLA) class II transgenic mice.…”

The Impact ofStaphylococcus aureus-Associated Molecular Patterns on Staphylococcal Superantigen-Induced Toxic Shock Syndrome and Pneumonia

“…Therefore, to accurately determine the modulatory role of staphylococcal PAMPs in vivo , we subsequently performed a series of in vivo studies using our robust HLA-DR3 and HLA-DQ8 transgenic mice, which closely mimic the human immune responses to SSAg [38]. …”