Definition of the mitogenic factor (MF) as a novel streptococcal superantigen that is different from streptococcal pyrogenic exotoxins A, B, and C

Toyosaki, Tomoko; Yoshioka, Takeshi; Tsuruta, Yuji; Yutsudo, Takashi; Iwasaki, Makoto; Suzuki, Ryuji

doi:10.1002/eji.1830261122

Cited by 27 publications

(33 citation statements)

References 38 publications

(15 reference statements)

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“…We conclude that the tiny amounts of SMEZ present in culture supernatants from H293, calculated by bioassay to be ϳ5 pg/ml, are largely responsible for the mitogenic activity of this strain. Native preparations of a wide range of streptococcal proteins, including M protein, SPEA, SPEB, and MF were previously reported to selectively stimulate human T cells bearing TCR V␤8 (11)(12)(13)(14)(15). More recently a previously unknown streptococcal superantigen, SPEX (identical to SMEZ) was shown to underlie the potent stimulation of human V␤8 ϩ T cells attributed to SPEB and MF (16,17).…”

Section: Discussionmentioning

confidence: 99%

The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent ofStreptococcus pyogenes

Unnikrishnan

Altmann

Proft

et al. 2002

The Journal of Immunology

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The gene encoding streptococcal mitogenic exotoxin Z (SMEZ) was disrupted in Streptococcus pyogenes. Despite the presence of other superantigen genes, mitogenic responses in human and murine HLA-DQ transgenic cells were abrogated when cells were stimulated with supernatant from the smez− mutant compared with the parent strain. Remarkably, disruption of smez led to a complete inability to elicit cytokine production (TNF-α, lymphotoxin-α, IFN-γ, IL-1 and -8) from human cells, when cocultured with streptococcal supernatants. The potent effects of SMEZ were apparent even though transcription and expression of SMEZ were barely detectable. Human Vβ8+ T cell proliferation in response to S. pyogenes was SMEZ-dependent. Cells from HLA-DQ8 transgenic mice were 3 logs more sensitive to SMEZ-13 than cells from HLA-DR1 transgenic or wild-type mice. In the mouse, SMEZ targeted the human Vβ8+ TCR homologue, murine Vβ11, at the expense of other TCR T cell subsets. Expression of SMEZ did not affect bacterial clearance or survival from peritoneal streptococcal infection in HLA-DQ8 mice, though effects of SMEZ on pharyngeal infection are unknown. Infection did lead to a rise in Vβ11+ T cells in the spleen which was partly reversed by disruption of the smez gene. Most strikingly, a clear rise in murine Vβ4+ cells was seen in mice infected with the smez− mutant S. pyogenes strain, indicating a potential role for SMEZ as a repressor of cognate anti-streptococcal responses.

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Section: Discussionmentioning

confidence: 99%

The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent ofStreptococcus pyogenes

Unnikrishnan

Altmann

Proft

et al. 2002

The Journal of Immunology

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“…We previously reported that PBMC of healthy donors was stimulated by mitogenic factors rSPE-A and rSPE-C (16) and that rSPE-C selectively stimulated TCRBV2-or TCRBV6S5-bearing T-cells when the donor had HLA-DRB1*0901 (16). In …”

Section: Stimulation Of Selected Tcrbv-bearing T-cells By Rspe-amentioning

confidence: 99%

“…We previously reported selective expansion of TCRBV2 and TCRBV6S5 after in vitro stimulation of T-cells with recombinant streptococcal pyrogenic exotoxin-C (SPE-C) (16). We also reported polyclonal expansion of TCRBV2 and TCRBV6S5-bearing T-cells in patients in the acute phase of KD but not in those in the convalescent phase of KD or in age-matched controls (17).…”

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confidence: 93%

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Relation of Streptococcal Pyrogenic Exotoxin C as a Causative Superantigen for Kawasaki Disease

et al. 2003

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We previously reported that the frequency of TCRBV2 and TCRBV6S5-bearing T-cells was high in patients in the acute phase of Kawasaki disease (KD) and that streptococcal pyrogenic exotoxin C (SPE-C) was a potent stimulator of these TCRBV-bearing T-cells. To further elucidate the pathogenesis of KD, we examined the T-cell receptor (TCR) repertoire, human leukocyte antigen (HLA)-DRB1 genotype, and antibody responses to recombinant(r) SPE-C in patients with KD. We also performed in vitro stimulation with rSPE-A and rSPE-C of peripheral blood mononuclear cells from healthy donors and characterized the reacting T-cells. The percentage of T-cells bearing TCRBV2 and TCRBV6S5 was high in patients in the acute stage of KD. rSPE-C stimulation of PBMC from healthy donors induced expansion of TCRBV2 and TCRBV6S5-bearing T-cells. Furthermore, serum levels of anti-SPEC antibodies, which did not display antimitogenic activity, were higher in patients with acute KD than in age-matched controls. The frequencies of the DRB1*04051, 0406, and 0901 were high, whereas that of the DRB1*1101 was low among patients with KD as compared with the healthy adults. Kawasaki disease (KD) is an acute illness of early childhood. It is characterized by fever lasting Ͼ5 d, edema and redness of hands and feet, erythematous skin rash, bilateral conjunctival congestion, redness of oropharyngeal mucosa, strawberry tongue, red and fissuring lips, and nonsuppurative cervical lymphoadenopathy. The clinical features of the acute phase of KD were first described as a new mucocutaneous lymphocytotic syndrome by Kawasaki in 1967 (1). Although the symptoms of KD are usually self-limited, coronary artery abnormalities develop in 15% to 25% of patients. In Japan and the United States, KD has become one of the most common causes of acquired heart disease in children. It has been demonstrated that i.v. administration of gamma globulin during the acute phase of KD can significantly decrease the prevalence of coronary artery lesions.In general, normal antigens to MHC class II and the complementarity-determining region 3 of TCR V␤ receptor recognize the specificity of antigens and lead to clonal expansion of T-cells. However, superantigens (SAs) produced by bacteria simultaneously bind to MHC class II and T-cell receptor (TCR) molecules via a certain TCR V␤ domain that is outside the normal antigen binding site; thus, a given SA can stimulate all T-cells that bear the appropriate TCR V␤ receptor in a polyclonal manner. These SAs also stimulate high systemic levels of proinflammatory cytokines that cause hypertension, fever, and shock.Investigators have reported that there is marked activation of T-cells (2) and monocyte/macrophages (3-6) and increased production of cytokines (6) at the acute phase of KD. These immunopathological features are similar to those of diseases caused by bacterial toxins acting as SAs. Immunologic and clinical studies have revealed that there is a remarkable similarity among KD, toxin-mediated staphylococcal and streptococcal toxic shock syn...

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“…SPEs have many biological activities such as pyrogenicity, mitogenicity, enhancement of susceptibility to endotoxin shock and suppression of immunoglobulin M production (3). Besides three serologically distinct SPEs, (SPEA, SPEB and SPEC), SSA (13) and MF (14,18) have been reported as a group of superantigens, and the nucleotide sequences of the genes that encode them have been determined (7,8,10,15,19). Superantigens from Streptococcus pyogenes, toxic shock syndrome toxin 1 (enterotoxins A to E) and exofoliative toxins A and B from Staphylococcus aureus comprise a family of superantigens that stimulate T cells by crosslinking different parts of the T-cell receptor with major histocompatibility class II molecules in accessory cells (4-6, 9, 12, 20).…”

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confidence: 99%

Serologic Evidence That Streptococcal Superantigens Are Not Involved in the Pathogenesis of Kawasaki Disease

Morita

Imada

Igarashi

et al. 1997

Microbiology and Immunology

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Kawasaki disease (KD) is an acute multisystem vasculitis of unknown etiology and is associated with marked activation of T cells and monocyte macrophages, leading to the assumption that superantigens are involved in its pathogenesis. To determine if an association exists between streptococcal superantigens and KD, we examined serum antibody responses to superantigens in sera from 50 paired acute and convalescent KD patients using purified recombinant streptococcal superantigens, such as SPEA, SPEC, SSA and MF. We found a very low frequency of detection of anti-superantigen antibodies by ELISA and no marked IgG seroconversion to each superantigen, indicating the absence of a serological relationship between toxin-producing streptococcal infection and the onset of KD.

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Definition of the mitogenic factor (MF) as a novel streptococcal superantigen that is different from streptococcal pyrogenic exotoxins A, B, and C

Cited by 27 publications

References 38 publications

The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent ofStreptococcus pyogenes

The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent ofStreptococcus pyogenes

Relation of Streptococcal Pyrogenic Exotoxin C as a Causative Superantigen for Kawasaki Disease

Serologic Evidence That Streptococcal Superantigens Are Not Involved in the Pathogenesis of Kawasaki Disease

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