Staphylococcal Superantigens Research Articles

Metalloproteinase-7 contributes to joint destruction in Staphylococcus aureus induced arthritis

Septic arthritis induced by Staphylococcus aureus causes a rapid destruction of joint cartilage and periarticular bone. The mechanisms behind this phenomenon are not fully understood. Earlier studies have shown that cytokines and metalloproteinases are of importance in bone metabolism. Matrix metalloproteinase-7 (MMP-7) has pleiotropic function including facilitating migration of both macrophages and neutrophils. The aim of this study has been to investigate the significance of MMP-7 expression in septic arthritis. MMP-7 deficient mice and congeneic controls were intravenously inoculated with an arthritogenic dose of S. aureus LS-1. This study shows that MMP-7 deficient mice exposed to S. aureus developed significantly less severe arthritis both clinically and histologically. Despite this finding, bacterial growth in the deficient animals was significantly increased. In vitro responses to staphylococcal antigens and superantigens did not differ between MMP-7 +/+ and MMP-7 −/− mice with respect to cytokine production and if anything increased the production of certain chemokines. In addition MMP-7 −/− mice exhibited decreased numbers of peripheral blood mononuclear cells before and one day after bacterial inoculation, but increased numbers of peripheral granulocytes on day 1. In conclusion, MMP-7 contributes to the development of a destructive course of septic arthritis despite decreased bacterial load. In addition, expression of MMP-7 is of importance for the distribution of peripheral leukocytes.

Immunosuppression by T regulatory cells in cows infected with Staphylococcal superantigen

Our recent study has provided that the in vitro SEC-induced proliferation of bovine T cells is preceded by a period of a non-proliferative immunoregulation of T cells that may be associated with cytokine production regulated by type 1 or type 2 T cells. Inversion of CD4(+):CD8(+) T cell ratio and induction of CD8(+) T cells with immunoregulatory activity could increase the probability of intracellular survival of Staphylococcus aureus (S. aureus). The increase of activated CD8(+)(ACT2(+) BoCD8(+)) T cells in cows with mastitis caused by S. aureus may be associated with immune-regulatory function in the bovine mammary gland. The difference and similarity between bovine activated CD8(+) T cells (CD8(+)CD26(+)) and well-established human CD4(+)CD25(+) T regulatory (Tr) cells may help to reveal their unique immune regulatory system in the host infected with S. aureus.

5 Molecular Mechanisms that Staphylococcal Superantigens Contribute to the Persistence and Exacerbation of Allergic Skin Inflammation in Atopic Dermatitis(I. Molecular Pathogenesis of Allergic Diseases)

5 Molecular Mechanisms that Staphylococcal Superantigens Contribute to the Persistence and Exacerbation of Allergic Skin Inflammation in Atopic Dermatitis(I. Molecular Pathogenesis of Allergic Diseases)

Intrapleural Staphylococcal Superantigen Induces Resolution of Malignant Pleural Effusions and a Survival Benefit in Non-Small Cell Lung Cancer

Malignant pleural effusion (MPE) may occur in up to 50% of patients with non-small cell lung cancer (NSCLC). The majority of these patients have a poor performance status and a dismal prognosis, with survival duration ranging from 2 to 3 months. Since these patients are typically symptomatic from their MPE, prompt treatment is required. Patients with symptomatic MPE from NSCLC and poor performance scores (Eastern Cooperative Oncology Group [ECOG] score >/= 2, Karnofsky performance status [KPS] score < 50) are generally not offered systemic chemotherapy. Treatment is palliative and includes intrapleural catheter drainage or chemical pleurodesis with talc, doxycycline, or bleomycin. None of the latter modalities prolong survival. Our goal was to investigate the toxicity and therapeutic effect of a new therapeutic agent, Staphylococcus aureus superantigen (SSAg), a powerful T-cell stimulant administered intrapleurally to unselected, consecutive patients with MPE from NSCLC (stage IIIb with pleural effusion) and a poor performance status. By providing direct access of the SSAg to the bronchial and mediastinal lymphatics, we predicted that intrapleural administration of SSAg would induce resolution of MPE and prolong survival in this population with advanced NSCLC and a limited prognosis. Fourteen consecutive, unselected patients with MPE from NSCLC and a median pretreatment KPS score of 40 (range, 10 to 60) received pleural instillation of SSAg, 100 to 400 pg, once or twice weekly (mean, 3.7 +/- 1.3 treatments [+/- SD]) until the pleural effusions resolved. They were evaluated for drug toxicity, resolution, duration of MPE, and survival. Other than mild fever (maximum grade 2), toxicity of SSAg treatment was trivial and notably devoid of respiratory distress or hypotension. Eleven patients had a complete response (CR), and 3 patients had a partial response of their MPE. In 12 patients, the response endured for > 90 days, with a median time to recurrence of 5 months (range, 3 to 23 months). The median survival for the SSAg-treated group was 7.9 months (range, 2 to 36 months; 95% confidence interval [CI], 5.9 to 11.4 months), compared to a median survival of 2.5 months (range, 0.1 to 57 months; 95% CI, 1.3 to 3.4 months) for 18 consecutive, unselected patients with MPE from NSCLC (stage IIIb) treated with talc poudrage (p = 0.044). Survival duration of all 14 SSAg-treated cases and 13 talc-poudrage-treated patients with comparable pretreatment KPS (range, 10 to 60; median, 40 and 30, respectively), and distribution (p = 0.5) was 7.9 months (95% CI, 5.9 to 11.4 months) and 2.0 months (95% CI, 0.4 to 2.9 months), respectively (p = 0.0023). Nine of 14 patients treated with SSAg survived > 6 months, 4 patients survived > 9 months, and 3 patients survived > 350 days. One of the patients in the CR group has survived 36 months. None of the 13 talc-treated patients survived > 6 months. In 14 unselected, consecutive patients with MPE from NSCLC and poor pretreatment performance (median KPS of 40), the intrapleural administration of SSAg was efficacious in resolving the MPE without any clinically important adverse effects. SSAg-treated patients with a median KPS of 40 (range, 10 to 60) had a median survival that exceeded that with talc poudrage, and was comparable to current systemic chemotherapy used in patients with KPS >/= 70 status. SSAg treatment is simple to perform, minimally invasive, and does not require hospital time. It may be an attractive alternative to existing palliative modalities for stage IIIb patients with MPE and poor performance who are not candidates for systemic chemotherapy.

In Vitro and In Vivo Evaluation of Staphylococcal Superantigen Peptide Antagonists

Superantigen peptide antagonists failed to block T-cell activation and cytokine production as well as toxic shock induced by staphylococcal enterotoxin B (SEB) in HLA class II transgenic mice. They also failed to inhibit the binding of SEB to HLA class II molecules as well as activation of human T lymphocytes in vitro.

Staphylococcal enterotoxins condition cells of the innate immune system for Toll-like receptor 4 stimulation

In this report we examined overlap between superantigen (SAg) and Toll-like receptor 4 (TLR4) stimulation of the innate immune system. Before in vivo stimulation we found that mouse splenic DCs expressed unexpectedly low levels of surface TLR4 compared to macrophages. In response to LPS, TLR4 gene expression in fractionated spleen cells was downregulated. By comparison, surface TLR4 staining with the Sa15-21 mAb showed little downregulation, and the anti-TLR4 MTS510 mAb showed decreased staining, suggesting that LPS was bound to TLR4 at the time points examined. Interestingly, SAg stimulation induced decreased TLR4 staining as measured by the MTS510 mAb, even though the TLR4 gene was not downregulated. Nevertheless, LPS potently induced DCs to produce TNF and IL-12, but SAg did not, even though they efficiently activated DCs. Notwithstanding, in vivo stimulation with staphylococcal enterotoxin SAg conditioned the innate immune system to hyper-respond to various pathogen-associated molecular patterns (PAMPs). Specifically, pre-priming with SAg enhanced LPS-mediated DC synthesis of TNF and IL-12. Thus, SAgs may exert their pathogenesis on the host by conditioning DCs, in a T cell activation dependent manner to potentiate responses to PAMPs.

Presence of IgE Antibodies to Bacterial Superantigens and Increased IL-13-Producing T Cells in Myelitic Patients with Atopic Diathesis

Background: Superantigens are considered to exacerbate autoimmune inflammation through the expansion of autoreactive T cells; however, the immune response to bacterial superantigens has not been extensively studied in any type of myelitis. We recently reported the occurrence of a distinct type of myelitis in patients with atopic diathesis, which in a recent nationwide survey was reported to be widespread in Japan. The aim of this study was to investigate the presence of IgE antibodies to bacterial superantigens and the proportion of IL-13- or IL-5-producing CD4+ or CD8+ T cells in patients with myelitis and atopic diathesis. Methods: Twenty-four myelitic patients with and 12 myelitic patients without hyperIgEemia, 28 patients with multiple sclerosis (MS) and 34 healthy controls were enrolled in this study. IgE antibodies to staphylococcal enterotoxins A (SEA) and B (SEB) in sera were measured using a liquid-phase enzyme immunoassay, and the intracellular production of IL-5 and IL-13 in peripheral blood CD4+ and CD8+ T cells was measured by flow cytometry. Results: The myelitic patients with hyperIgEemia showed significantly higher positive rates of serum SEA/SEB-specific IgE antibodies (41.7 and 62.5%, respectively) than the healthy controls (5.9 and 8.8%), patients with MS (0 and 21.4%) and those with normoIgEemic myelitis (0 and 0%). Moreover, IL-13-producing CD4+ T cells and CD8+ T cells increased significantly in the myelitic patients with hyperIgEemia compared to the controls, while IL-5-producing CD4+ or CD8+ T cells did not. Conclusions: The IgE response to staphylococcal superantigens is heightened in myelitic patients with atopic diathesis, which might contribute to increases in IL-13-producing T cells and thus the development of myelitis.

Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications for therapy of toxic shock syndrome.

Administration of intravenous polyspecific immunoglobulin G (IVIG) has been proposed as adjunctive therapy for toxic shock syndrome caused by Streptococcus pyogenes or Staphylococcus aureus. We investigated whether superantigen-containing culture supernatants prepared from streptococcal isolates (n=21) and staphylococcal isolates (n=20) from cases of severe sepsis were inhibited to an equal extent by IVIG in proliferation experiments that used human peripheral blood mononuclear cells. All 3 IVIG preparations tested were highly efficient in neutralizing the superantigens, and most supernatants were completely inhibited at concentrations ranging from 0.05 to 2.5 mg IVIG/mL. An important finding was that culture supernatants from S. pyogenes isolates were consistently inhibited to a greater extent than those of S. aureus isolates (P<.01). The findings demonstrate that staphylococcal superantigens are not inhibited as efficiently as streptococcal superantigens by IVIG, and, hence, a higher dose of IVIG may be required for therapy of staphylococcal toxic shock syndrome in order to achieve protective titers and clinical efficacy.

HLA class II polymorphisms determine responses to bacterial superantigens.

The excessive immunological response triggered by microbial superantigens has been implicated in the etiology of a wide range of human diseases but has been most clearly defined for the staphylococcal and streptococcal toxic shock syndromes. Because MHC class II presentation of superantigens to T cells is not MHC-restricted, the possibility that HLA polymorphisms could influence superantigenicity, and thus clinical susceptibility to the toxicity of individual superantigens, has received little attention. In this study, we demonstrate that binding of streptococcal and staphylococcal superantigens to HLA class II is influenced by allelic differences in class II. For the superantigen streptococcal pyrogenic exotoxin A, class II binding is dependent on DQ alpha-chain polymorphisms such that HLA-DQA1*01 alpha-chains show greater binding than DQA1*03/05 alpha-chains. The functional implications of differential binding on T cell activation were investigated in various experimental systems using human T cells and murine Vbeta8.2 transgenic cells as responders. These studies showed quantitative and qualitative differences resulting from differential HLA-DQ binding. We observed changes in T cell proliferation and cytokine production, and in the Vbeta specific changes in T cell repertoire that have hitherto been regarded as a defining feature of an individual superantigen. Our observations reveal a mechanism for the different outcomes seen following infection by toxigenic bacteria.

Antibodies to highly conserved peptide sequence of staphylococcal and streptococcal superantigens in Kawasaki disease

Superantigen-mediated disease such as toxic shock syndrome is seen in patients who have a weak antibody response to the antigen toxic shock syndrome toxin 1 (TSST-1). We hypothesized that there may be deficiency in antibody production to staphylococcal and streptococcal toxins in Kawasaki disease (KD) children. A peptide was constructed from the homologous portion of the staphylococcal enterotoxins (SE) and streptococcal pyrogenic enterotoxins (SPE), and antibodies to the peptide were made. The anti-peptide antibody immunoblotted several of the SE toxins and SPE toxins. Presence of the peptide antibodies was investigated via ELISA in the sera of acute KD ( n = 30), convalescent KD ( n = 12), control adults ( n = 10), and children ( n = 19). The mean anti-peptide antibodies were indistinguishable between control children and KD before treatment with immunoglobulin ( P = 0.7) but rose significantly after therapy ( P < 0.01). The adults had significantly higher antibodies than the KD, both acute and late ( P < 0.0001) and the control children ( P < 0.0001). Thus, KD patients do not have a defective serological response against toxins such as SPE/SE/TSST-1. Normal children have significantly lower antitoxin antibody levels to the toxins compared to the adults.

Crystal and Solution Structures of a Superantigen from Yersinia pseudotuberculosis Reveal a Jelly-Roll Fold

Superantigens are a class of microbial proteins with the ability to excessively activate T cells by binding to the T cell receptor. The staphylococcal and streptococcal superantigens are closely related in structure and possess an N-terminal domain that resembles an OB fold and a C-terminal domain similar to a β-grasp fold. Yersinia pseudotuberculosis produces superantigens, YPMa, YPMb, and YPMc, which have no significant amino acid similarity to other proteins. We have determined the crystal and solution structures of YPMa, which show that the protein has a jelly-roll fold. The closest structural neighbors to YPMa are viral capsid proteins and members of the tumor necrosis factor superfamily. In the crystal structure, YPMa packs as a trimer, another feature shared with viral capsid proteins and TNF superfamily proteins. However, in solution YPMa behaves as a monomer, and any functional relevance of the trimer observed in the crystals is yet to be established.

Superantigens: Structure-function relationships

AbstractSuperantigens are a class of highly potent immuno-stimulatory molecules produced by Staphylococcus aureus and Streptococcus pyogenes. These toxins possess the unique ability to interact simultaneously with MHC class II molecules and T-cell receptors, forming a trimolecular complex that induces profound T-cell proliferation. The resultant massive cytokine release causes epithelial damage and leads to capillary leak and hypotension. The staphylococcal superantigens are designated staphylococcal enterotoxins A, B, C (and antigenic variants), D, E, and the recently discovered enterotoxins G to Q, and toxic shock syndrome toxin-1. The streptococcal superantigens include the pyrogenic exotoxins A (and antigenic variants), C, G – J, SMEZ, and SSA. Superantigens are implicated in several diseases including toxic shock syndrome, scarlet fever and food poisoning; and their function appears primarily to debilitate the host sufficiently to permit the causation of disease. Structural studies over the last 10 years have provided a great deal of information regarding the complex interactions of these molecules with their receptors. This, combined with the wealth of new information from genomics initiatives, have shown that, despite their common molecular architecture, superantigens are able to crosslink MHC class II molecules and T-cell receptors by a variety of subtly different ways through the use of various structural regions within each toxin.

Proliferation and production of interferon-gamma (IFN-gamma) and IL-4 in response to Staphylococcus aureus and staphylococcal superantigen in childhood atopic dermatitis.

We have examined the cell-mediated immunity (CMI) to Staphylococcus aureus (S. aureus) and Staphylococcal enterotoxin B (SEB) in peripheral blood mononuclear cells (PBMC) from children with atopic dermatitis (AD) and from non-atopic child controls by measurement of proliferative responses and production of the cytokines IFN-gamma and IL-4. PBMC from children with AD showed significantly higher proliferative responses to both S. aureus (P < 0.01) and SEB (P < 0.05). Despite this enhanced proliferation, production of IFN-gamma in response to S. aureus (P < 0.001) and SEB (P < 0.01) from these PBMC was significantly diminished. In contrast, PBMC from children with AD were significantly more likely to produce IL-4 in response to S. aureus (P < 0.01). These findings demonstrate in vitro heightened CMI to S. aureus in children with AD, and implicate S. aureus as a potent inflammatory stimulant. Impaired IFN-gamma production to S. aureus in vivo may result in failure to eradicate S. aureus from skin. The organism's persistence on skin would contribute to inflammation by causing continued T cell activation and release of pro-inflammatory mediators.

Superantigens from Staphylococcus aureus induce procoagulant activity and monocyte tissue factor expression in whole blood and mononuclear cells via IL-1β

Staphylococcus aureus is one of the most common bacteria in human sepsis, a condition in which the activation of blood coagulation plays a critical pathophysiological role. During severe sepsis and septic shock microthrombi and multiorgan dysfunction are observed as a result of bacterial interference with the host defense and coagulation systems. In the present study, staphylococcal superantigens were tested for their ability to induce procoagulant activity and tissue factor (TF) expression in human whole blood and in peripheral blood mononuclear cells. Determination of clotting time showed that enterotoxin A, B and toxic shock syndrome toxin 1 from S. aureus induce procoagulant activity in whole blood and in mononuclear cells. The procoagulant activity was dependent on the expression of TF in monocytes since antibodies to TF inhibited the effect of the toxins and TF was detected on the surface of monocytes by flow cytometry. In the supernatants from staphylococcal toxin-stimulated mononuclear cells, interleukin (IL)-1 beta was detected by ELISA. Furthermore, the increased procoagulant activity and TF expression in monocytes induced by the staphylococcal toxins were inhibited in the presence of IL-1 receptor antagonist, a natural inhibitor of IL-1 beta. The present study shows that superantigens from S. aureus activate the extrinsic coagulation pathway by inducing expression of TF in monocytes, and that the expression is mainly triggered by superantigen-induced IL-1 beta release.

Evidence for the Transmissibility of Atopy : Hypothesis

The etiology of atopy is unknown. Its family distribution suggests transmissibility. Populations moving from countries with a low incidence to those with a high incidence increase to the higher rate. African and New Guinea village groups developed asthma with return of individuals who have acquired atopy in the city. Protection (and possibly immunity) develops with early exposure to child care or to affected older siblings. T helper (Th) type 2 clones driving specific allergies remain active even without further allergen exposure. Other IgE responses remain normal. Once boosted to completeness, the patterns of skin test results remain quite stable, possibly by the localization of abnormality maintained by immunity. An example of a virus causing the immortality of Th2 cells is herpes simplex virus type 1. It infects mouse or human Th2 cells and, although it does not multiply, causes immortality by increasing FAS-mediated apoptosis of T cells directed against the infected cells. Human T-cell leukemia virus 1 and probably others use similar ploys. Abnormal levels of FAS receptors and resistance to FAS apoptosis in nasal polyp lymphocytes and abnormal Th2 clones of atopy are interesting in this regard. The localizing role of a staphylococcal superantigen in atopic dermatitis, and possibly in autoimmunity in nonatopic eczema and intrinsic asthma, encourage the consideration of roles for microorganisms in localization and etiology. The epidemiology and characteristics of atopic disease support the plausibility of a viral hypothesis.

The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling.

CD148 is a receptor-like protein tyrosine phosphatase up-regulated on T cells after T cell receptor (TCR) stimulation. To examine the physiologic role of CD148 in TCR signaling, we used an inducible CD148-expressing Jurkat T cell clone. Expression of CD148 inhibits NFAT (nuclear factor of activated T cells) activation induced by soluble anti-TCR antibody, but not by antigen-presenting cells (APCs) loaded with staphylococcal enterotoxin superantigen (SAg) or immobilized anti-TCR antibody. Immunofluorescence microscopy revealed that the extracellular domain of CD148 mediates its exclusion from the immunologic synapse, sequestering it from potential substrates. Targeting of the CD148 phosphatase domain to the immunologic synapse potently inhibited NFAT activation by all means of triggering through the TCR. These data lead us to propose a model where CD148 function is regulated in part by exclusion from substrates in the immunologic synapse. Upon T cell–APC disengagement, CD148 can then access and dephosphorylate substrates to down-regulate prolongation of signaling.

In vitro and in vivo T cell oligoclonality following chronic stimulation with staphylococcal superantigens

Microbial superantigens (SAg), including SEB and TSST-1, polyclonally activate T cells belonging to specific TCR BV families. A pathogenic role for SAg in various human diseases has been suggested, but enthusiasm for this view has been tempered by the T cell oligoclonality in these disorders. To assess whether T cell oligoclonality can emerge following protracted SAg stimulation, human PBMC were stimulated with SEB, TSST-1, or anti-CD3 mAb and maintained in culture with exogenous IL-2. Oligoclonality was appreciated by day 14 among CD4 + and CD8 + T cells. In addition, mice transgenic for human DR2 and DQ8 were injected weekly with SEB, and splenic CD4 + and CD8 + T cells were analyzed for oligoclonality. In mice that received one or three such injections, little-to-no oligoclonality was detected. In contrast, considerable oligoclonality was detected in mice that received eight weekly SEB injections. Many of these T cell oligoclones were identical to “spontaneously” arising oligoclones detected in SEB-naive mice. Thus, T cell oligoclonality can emerge following chronic SAg stimulation. In hosts who have lost tolerance to self Ag, chronic exposure to SAg may preferentially promote expansion of autoreactive T cells and facilitate development of clinical disease.

Inhibitory effect of catechin against the superantigen staphylococcal enterotoxin B (SEB).

Staphylococcal superantigens (SsAgs) have gained attention as one of the factors aggravating atopic dermatitis (AD) and several potential mechanisms of AD aggravation by SsAgs have been reported. Tea catechin has been found to have many unique antimicrobiological activities such as antibacterial, antiviral, antifungal and antitoxic effects. In the present study, we investigated the inhibitory effect of the green tea catechin extract, Polyphenon, and (-)-epigallocatechin gallate (EGCg) on staphylococcal enterotoxin B (SEB) and its mechanisms of action, and we also discuss the possibility of therapeutic benefits for AD patients of tea catechin. Polyphenon inhibited the lethal toxicity of SEB and the SEB-induced production of TNF-alpha, IFN-gamma and IL-4 following its intraperitoneal administration to BALB/c mice. Although Polyphenon is composed of several isomers among which EGCg is approximately 50% of the total, we considered that most of the inhibitory effect of Polyphenon in mice could be attributed to EGCg. EGCg was immediately bound to SEB molecules and neutralized SEB in a dose- and incubation time-dependent manner without molecular weight alteration of the SEB molecule. Furthermore, EGCg inhibited SEB-induced TNF-alpha and IFN- gamma production and IL-2, IFN-gamma, IL-10 and IL-12 p40 mRNA expression in human PBMCs from normal donors in a dose-dependent manner. Inhibition of SsAg-induced T-cell activation by catechin was observed in both in vivo and in vitro studies, suggesting that catechin may be useful in the treatment of AD.

Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients.

It has been suggested that increased monocyte responses might play a role in chronic allograft rejection. We investigated in vitro monokine responses in 112 patients with long-term stable kidney graft function (ST patients; n=80, non-mycophenolate mofetil [MMF]; n=32, MMF) and 25 patients with chronic renal transplant rejection (CR patients; non-MMF). Interleukin 10 and tumor necrosis factor (TNF)-alpha promoter gene polymorphisms were tested by polymerase chain reaction and sequence-specific primers; antigen-presenting capacity (AC) of monocytes was tested by incubation with staphylococcal superantigens (SEA, SEE, SED). Although non-MMF-based immunosuppression in ST patients did not result in compromised AC or lipopolysaccharide (LPS)-stimulated monokine responses compared with healthy controls, we found MMF therapy to be associated with significantly reduced TNF-R1 expression on monocytes (P<0.001), suppressed AC (P<0.02, SED), and suppressed LPS-stimulated IL-1 beta, IL-10, and TNF-alpha secretion (P<0.01). Coinciding with a significantly higher steroid dosage in CR patients, IL-6 receptor and TNF-R1 expression on monocytes were down-regulated (P< or =0.02) and AC was suppressed in CR compared with ST (non-MMF) patients (P<0.01, SED; P<0.05, SEE). However, LPS-stimulated monokine secretion was not decreased or even enhanced (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]; P<0.05). Enhanced in vitro IL-10 responses (>500 pg/mL) were found predominantly in non-MMF-treated patients with the IL-10 genotype GCC (GCC: 23/62 [37%], non-GCC: 2/27 [7%], P<0.005; GCC and non-MMF: 22/47 [47%], GCC and MMF: 1/15 [7%], P<0.005]. Steroids and azathioprine did not sufficiently suppress monokine responses, whereas MMF treatment might inhibit chronic graft rejection because of suppression of TNF-R1 expression and vigorous inhibition of monokine secretion. MMF treatment may especially be indicated in patients with the IL-10 "high-producer" genotype GCC.

Staphylococcal superantigens and T cell expansions in Wegener's granulomatosis.

In Wegener's granulomatosis (WG), a form of autoimmune systemic vasculitis, chronic carriage of Staphylococcus aureus constitutes a risk factor for the development of exacerbations. Circulating T cells in this disease are persistently activated, suggesting the presence of a chronic stimulus. A causal link between chronic carriage of S. aureus and chronic T cell activation in WG is conceivable, because S. aureus produces superantigens (SAg), which are potent T cell stimulators. Superantigenic stimulation of T cells results in expansion of T cell subsets expressing SAg-binding T cell receptor V-beta (Vbeta) chains. In the present study we hypothesized that in WG the presence of staphylococcal SAg is accompanied by expansion of SAg-reacting T cell subsets. We tested our hypothesis in a cross-sectional and a longitudinal study in which the association between seven staphylococcal SAg genes [typed by poplymerase chain reaction (PCR)], eight SAg-binding Vbeta chains and four SAg-non-binding Vbeta chains (assessed by flow-cytometry) was assessed. Both studies showed that T cell expansions were present at a significantly higher rate in WG patients than in healthy individuals, but were not associated with the presence of either S. aureus or its SAg. Moreover, T cell expansions were generally of small extent, and did not appear simultaneously in both CD4 and CD8 subsets. We conclude that in WG S. aureus effects its supposed pathogenic function by a mechanism other than superantigenic T cell activation.