Cutaneous colonization with staphylococci influences the disease activity of Sézary syndrome: a potential role for bacterial superantigens

Abstract

It has previously been shown that circulating Sezary cells respond in vitro to superantigenic staphylococcal exotoxins in a manner that is restricted by their Ylj usage. This study was conducted to examine whether cutaneous colonization with Staphylococcus aureus influences the activity ofthe skin lesions of Sezary syndrome, and whether S. aureus isolated from patients with Sezary syndrome stimulates circulating Sezary cells in vitro. Two patients with Sezary syndrome, whose skin was colonized with S. aureus. were treated with antibacterial agents, and the relation between the severity ofthe skin disease and the degree oi S. aureus colonization was assessed. In addition, the patients' peripheral blood mononuclear cells were cultured in the presence of mitomycin C-treated S. aureus or superantigenic staphylococcal toxins. The antibacterial treatment improved the skin disease, and eliminated S. aureus in both patients. In one patient, 98% of the peripheral blood mononuclear cells bore VQ2V/31 7 of the T-cell receptor, indicative of the presence of an extremely high percentage of circulating Sezary cells. The peripheral blood lymphocytes from this patient responded well in vitro to superantigenic staphylococcal enterotoxin (SE), but not to SEA or toxic shock syndrome toxin-1. or to mitomycin-treated S. aureus isolated from the same patient. Cutaneous colonization by S. aureus influences the disease activity of CTCL. possibly by activation of Sezary cells by bacterial superantigenic exoproteins.

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

“…13 As mentioned earlier, SEs have long been suspected to drive chronic activation of malignant T cells. 40,50,[68][69][70]74 Originally, it was thought that toxins triggered proliferation and expansion of malignant T cells through direct binding and activation of malignant T-cell clones expressing the appropriate TCR-Vb, even though little data were available to support this hypothesis; others, however, contradicted this view (reviewed in Willerslev-Olsen et al 38 ). Our findings presented in this study have significant implications for the understanding of the interplay between bacterial toxins and malignant T cells.…”

“…This finding is important because, for decades, SEs have been suspected to play a tumor-promoting role in CTCL. 39,40,45,50,[68][69][70] We now propose that SEA-mediated cross talk between malignant and nonmalignant T cells triggers oncogenic STAT3 activation in vivo. Our findings provide a plausible explanation for clinical observations indicating that SE-producing staphylococci promote tumor growth and aggravate the disease and, conversely, that antibiotic therapy may halt disease progression and even induce tumor regression in some CTCL patients.…”

“…Our findings provide a plausible explanation for clinical observations indicating that SE-producing staphylococci promote tumor growth and aggravate the disease and, conversely, that antibiotic therapy may halt disease progression and even induce tumor regression in some CTCL patients. 40,45,50 Despite the well-established role of STAT3 in CTCL pathogenesis, it has not been clear what drives malignant STAT3 activation in vivo. Recently, activating mutations have been described in a subset (12.5%) of CTCL patients, 28,29 but it remains unknown what drives aberrant STAT3 activation in the majority of patients.…”

“…49 The importance of SEs is emphasized by reports indicating that antibiotic therapy of staphylococcal infections in CTCL is associated with clinical improvement and, in some cases, remission of the lymphoma. 40,45,50 However, the mechanisms involved in disease aggravation and progression mediated by S aureus and SEs are poorly understood.…”

Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

“…[38][39][40] Intriguingly, eradication of SA by antibiotics is associated with significant clinical improvement in colonized patients, including a reduced involved body-surface area as well as decreased redness and pruritus of the skin. 38,39,41 It has further been reported that staphylococcal sepsis in SS patients is accompanied by increased disease activity often in absence of fever. 38,42 Therefore, it has been suspected for decades that SA fosters the disease activity in CTCL, but the underlying mechanisms remain poorly characterized, and it is not common practice to initiate antibiotic treatment of colonized patients.…”