Impaired humoral and T helper cell responses to toxic shock syndrome toxin-1 (TSST-1) in granulomatosis with polyangiitis

Objectives Nasal carriage of toxic shock syndrome toxin-1 (TSST-1)-positive Staphylococcus aureus (SA) is associated with a high relapse rate in granulomatosis with polyangiitis (GPA), suggesting TSST-1’s role in disease progression. This study investigated the immune response to S. aureus-derived TSST-1 and characterized TSST-1-specific Th cells in GPA-patients. Methods Plasma anti-TSST-1 IgG levels were measured in 45 remission GPA-patients and 25 healthy controls (HCs) using ELISA. Circulating TSST-1-reactive CD4+T helper (Vβ2+Th) cells were analyzed and subclassified in 62 remission GPA-patients and 22 HCs by flow cytometry. Additionally, PBMCs were stimulated in vitro with TSST-1 for 14 days to evaluate its effect on PR3-ANCA production and CD4+Th cell cytokine production (IFNγ, IL-4, IL-17, IL-21) measured by Phadia-ImmunoCAP®250 and flow cytometry, respectively. Results GPA-patients with nasal SA carriage (SA+) had lower plasma anti-TSST-1 IgG levels and reduced numbers of circulating Vβ2+Th cells compared with HCs.An increased frequency of Vβ2+Th cells expressing the phenotype of peripheral helper T cells (TPh; PD-1HighCXCR5Neg) was observed in SA+ GPA-patients compared with HCs. TSST-1 stimulation enhanced IL-21 production in Th cells from SA+ patients and induced PR3-ANCA production in vitro in a subset of GPA-patients. Notably, numbers of circulating Vβ2+Th cells correlated positively with increased relapse-free survival in SA+ GPA-patients. Conclusion Impaired humoral immunity against Vβ2-restricted superantigens in SA+ GPA patients, may lead to insufficient clearance of TSST-1. TSST-1-driven IL-21 production could enhance ANCA production and promote disease progression. Reduced Vβ2+Th cells may increase relapse risk, emphasizing their potential value as a tool for monitoring disease progression.