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ABSTRACTThe pathogenesis of acute rheumatic fever (ARF) is poorly understood. We identified two contiguous bacteriophage genes, designated speLand speM, encoding novel inferred superantigens in the genome sequence of an ARF strain of serotype M18 group A streptococcus (GAS). speLand speMwere located at the same genomic site in 33 serotype M18 isolates, and no nucleotide sequence diversity was observed in the 33 strains analyzed. Furthermore, the genes were absent in 13 non-M18 strains tested. These data indicate a recent acquisition event by a distinct clone of serotype M18 GAS. speLand speMwere transcribed in vitro and upregulated in the exponential phase of growth. Purified SpeL and SpeM were pyrogenic and mitogenic for rabbit splenocytes and human peripheral blood mononuclear cells in picogram amounts. SpeL preferentially expanded human T cells expressing T-cell receptors Vβ1, Vβ5.1, and Vβ23, and SpeM had specificity for Vβ1 and Vβ23 subsets, indicating that both proteins had superantigen activity. SpeL was lethal in two animal models of streptococcal toxic shock, and SpeM was lethal in one model. Serologic studies indicated that ARF patients were exposed to serotype M18 GAS, SpeL, and SpeM. The data demonstrate that SpeL and SpeM are pyrogenic toxin superantigens and suggest that they may participate in the host-pathogen interactions in some ARF patients.

Background:Staphylococcus aureuscolonizes the skin lesions of more than 90% of patients with atopic dermatitis (AD). The mechanism for increased S aureuscolonization in AD is unknown. However, the initial event in colonization requires adherence of S aureusto the skin. Objective:The purpose of this study was to examine the roles of various bacterial adhesins on S aureusbinding to AD skin. Methods:In an attempt to delineate the mechanism behind this adherence process, an in vitro bacterial binding assay was developed to quantitate the adherence of various S aureusstrains to AD, psoriatic, and normal skin sections. S aureusstrains used in this study were obtained either from cultures of AD skin lesions or from genetically manipulated strains of S aureusthat lacked specific microbial surface components recognizing adhesive matrix molecules (MSCRAMMs)—namely, fibronectin-binding protein (Fnbp), fibrinogen-binding protein (Clf), collagen-binding protein (Cna), and their parent strains. In addition, S aureusstrains from patients with AD were pretreated with fibronectin or fibrinogen to block MSCRAMM receptors and interfere with binding. Results:Under all experimental conditions, binding of S aureuswas localized primarily to the stratum corneum. Immunocytochemical staining of AD skin sections showed a redistribution of fibronectin to the cornified layer, an observation not seen in normal skin. S aureusbinding to uninvolved AD skin was significantly greater than the binding to uninvolved psoriatic skin (P< .0001) and normal skin (P< .0005). The Fnbp-negative S aureusshowed a significant reduction in binding to the AD skin (P< .0001) but not to the psoriatic and normal skin. In the AD skin, a significant reduction in the binding of S aureuswas also observed in the Clf-negative strain (P< .0001) but not in the Cna-negative S aureus. Preincubation of S aureuswith either fibronectin or fibrinogen also inhibited bacterial binding to AD skin (P< .0001). Conclusion:These data suggest that fibronectin and fibrinogen—but not collagen—play a major role in the enhanced binding of S aureusto the skin of patients with AD. (J Allergy Clin Immunol 2001;108:269-74.)

BACKGROUND: Erythema multiforme and toxic epidermal necrolysis can occur as serious and even life-threatening adverse drug reactions. The underlying mechanisms are unknown, but evidence suggests that affected individuals may have impaired capacity to detoxify reactive intermediate drug metabolites. Such intermediates may be directly toxic or may react with host tissues to form antigens, evoking an immune response. We describe our investigation of a patient with carbamazepine-induced erythema multiforme and toxic epidermal necrolysis. The inflammatory infiltrate was examined immunocytochemically in lesional skin specimens from the patient, in the patient's patch test response to carbamazepine, and in lesional skin specimens from five other patients with drug-induced erythema multiforme. The patient's lymphocytes were examined both for susceptibility to cytotoxic damage by liver microsome—induced carbamazepine metabolites and for proliferative responses to native carbamazepine, which might indicate cell-mediated immune sensitization. OBSERVATIONS: Lesions of toxic epidermal necrolysis were more florid, but findings were essentially similar in all the skin samples examined. In the dermis there were CD14+ macrophages, CD1a+ Langerhans cells, and CD3+, CD45RO+ T cells. The CD4-CD8 T-cell ratio was 2:1, and 10% of the T cells were CD25+, suggesting activation by recent encounter with antigen. The epidermis contained CD14+ macrophages and T cells, but the CD8+ cells out-numbered the CD4+ cells. Up to 25% of the T cells were CD25+. Lymphocyte proliferation was not induced by native carbamazepine, but the patient's lymphocytes were significantly more susceptible to cytotoxic killing by liver microsome—induced carbamazepine intermediates. CONCLUSIONS: The inflammatory reaction in skin affected by erythema multiforme and toxic epidermal necrolysis was rich in CD8+ T cells, suggesting an immune cytotoxic reaction. The patient appeared to have a reduced capacity to detoxify reactive intermediates. This, together with the lack of lymphocyte response to native drug but a positive patch test response, suggests that the immune response may be directed at drug-modified epidermal cells.(Arch Dermatol. 1994;130:598-604)