[Treatment of atopic dermatitis: practical approach]. / Traitement de la dermatite atopique: approche pratique.

Atopic dermatitis (AD) is a chronic disease frequent in childhood. The treatment is based on regular moisturizing of the skin, information to the parents on the chronic course with recurrent flares, topical anti-infectious therapy for superinfections and colonization of the skin by staphylococcus aureus, and topical steroids. The immuno-modulatory macrolides (tacrolimus and pimecrolimus) represent a new alternative to topical steroids. These molecules are well tolerated, but theirs effects on the long-term are unknown. A food allergy may be responsible for a AD flare in up to a third of the cases, but the presence of an allergy should be demonstrated before the prescription of an elimination diet. AD is often the first manifestation of atopy: the physician should be aware of the future occurence of respiratory symptoms.

"Adolescent-onset Still's disease": characteristics and outcome in comparison with adult-onset Still's disease.

OBJECTIVES: To determine if adolescent onset systemic juvenile idiopathic arthritis (JIA) and adult onset Still's disease (AOSD) represent the same clinical continuum of disease. METHODS: Retrospective review of available clinical data on all pediatric and adult patients diagnosed with Still's disease within the last 10 years at a university hospital. Assessment of functional outcomes at last visit by clinical evaluation and HAQ or c-HAQ. RESULTS: Nine patients were identified as adolescent onset systemic JIA and were compared with 10 patients with AOSD (onset > 18 years old). No statistically significant differences were found between the two groups in terms of clinical presentation at onset and outcome at follow up. CONCLUSION: Adolescent patients presenting with systemic JIA have a disease onset and course undistinguishable from that of AOSD patients, suggesting that they represent a continuum of a single disease entity.

Juvenile idiopathic arthritides evaluated prospectively in a single center according to the Durban criteria.

OBJECTIVE: Chronic arthritis in children represents a nonhomogeneous group of diseases with unknown etiology. To classify these patients in well defined diagnostic categories, a task force of the International League Against Rheumatism proposed a new classification with precise criteria. We analyzed the new criteria in children with chronic arthritis. METHODS: A cohort of children was prospectively and sequentially examined in a pediatric rheumatology clinic from April to June 1997. RESULTS: One hundred ninety-four children fulfilled the criteria of juvenile idiopathic arthritis and 80% of them (155 children) were classified in one of the 6 diagnostic categories. Seventeen children (9%) did not fit any other category and 22 (11%) could be classified in more than one category. The proportion of children fitting only one category was much lower for psoriatic arthritis and enthesitis related arthritis than for the other categories. CONCLUSION: Based on the results, we propose some modifications to the classification criteria. This new classification is an important tool for the diagnosis of chronic arthritis in children, but the criteria need further adjustments to improve the percentage of patients classified in one defined category.

[Atopic dermatitis: the first allergic step in children]. / Dermatite atopique: le premier pas allergique de l'enfant.

Atopic dermatitis is an early manifestation of atopy and is frequently present already during the first year of life. Atopic dermatitis is often associated with increased levels of serum IgE and with sensitization to food allergens. Some foods may be responsible for exacerbations of skin inflammation, but their pathogenic role need to be clinically assessed before an avoidance diet is prescribed. Staphylococcus aureus, which is known to colonize the skin of atopic dermatitis patients, may also exacerbate skin lesions and need to be treated with topical antibiotics. Children with atopic dermatitis are prone to allergies and are at risk to develop later respiratory allergic manifestations. In particular, if a sensitization to egg is present early in life, the risk for developing later an asthma due to house dust mites is increased. The care of children with atopic dermatitis should not be limited to the treatment of skin lesions, but should also involve preventive measures for respiratory allergies.

[The child, his mother and allergies]. / L'enfant, sa mère et l'allergie.

The prevalence of allergic diseases in childhood is regularly increasing, in particular asthma, which morbidity is important. Despite the persistence of a significative bronchial inflammation the severity of the disease may present with discrete symptoms. The recognition of asthma and its treatment is then insufficient and consequently potentially fatal asthma attacks may occur and there is a chronic remodeling of the airways. Allergenic sensitization occurs mainly during the first years of life and is related to the environment to which the child is exposed. The effect of early prevention was extensively studied in the past. A regimen with hydrolyzed cow's milk proteins during the first months of life decreases the incidence of milk allergy and atopic dermatitis, but does not seem to decrease the long term prevalence of allergies. Infectious agents are suspected to influence the type of cytokines produced by helper T cells and thus to promote or to prevent allergen sensitization. It has been shown recently that the influence of the environment during the first years of life is critical for the development of the IgE responses to allergens and as consequence for allergic manifestations. A better understanding of these mechanisms should allow to determine the reason(s) for the increase of allergic prevalence and improve the efficacy of preventive measures.

Staphylococcal toxins augment specific IgE responses by atopic patients exposed to allergen.

Microbial agents are known to play a significant role in aggravating allergic diseases. Recently described viral and bacterial superantigens represent one important strategy by which infectious agents can stimulate the immune response. In previous work, we reported that the staphylococcal toxin toxic shock toxin-1 (TSST-1), a prototypic superantigen, induces in vitro total IgE synthesis after cross-linking T and B cells. This study was carried out to establish a potential link between superantigens and the enhanced IgE response to specific allergens in allergic patients. Peripheral blood mononuclear cells from atopic patients were isolated during and outside the pollen allergen season and stimulated with TSST-1, a prototypic superantigen. Total IgE and interferon-gamma production were measured in supernatants of these cultures. Outside the pollen season, TSST-1 significantly increased total IgE production only in the presence of exogenous interleukin-4, whereas during the pollen season IgE production was significantly enhanced without the need of exogenous interleukin-4. This increase in the absence of exogenous interleukin-4 was associated with significantly lower interferon-gamma production by peripheral blood mononuclear cells stimulated by TSST-1 during the pollen season. Moreover, TSST-1 stimulation of peripheral blood mononuclear cells from inhalant allergic patients was followed by an increased production of allergen-specific IgE that was restricted to the allergen to which the patient was allergic and recently exposed. In addition, TSST-1 induced on B cells the expression of B7.2, a molecule that has recently been demonstrated to enhance T helper 2 responses and to be involved in IgE regulation. This study, by demonstrating that superantigens can augment allergen-specific IgE synthesis and B7.2 expression, provides a mechanism by which microbial superantigens may modulate allergic responses.

Enhanced expression of B7.2 (CD86) in patients with atopic dermatitis: a potential role in the modulation of IgE synthesis.

Recent studies have suggested that the accessory molecules B7.1 (CD80) and B7.2 (CD86) differ in their capacity to generate Th1 vs Th2 responses. Atopic dermatitis (AD) is a chronic allergic skin disease associated with increased IgE synthesis. To determine the potential role of B7.2 molecules in AD, the present study was conducted to compare the expression of B7.1 vs B7.2 on B cells from patients with AD vs normal subjects or patients with psoriasis. The expression of B7.2 on B cells of AD patients (53.67 +/- 3.10%) was significantly higher than normals (38.02 +/- 4.95%; p = 0.02) and psoriasis patients (40.19 +/- 2.70%; p = 0.006). In contrast, there was no significant difference in B7.1 expression among the three subject groups. Interestingly, total serum IgE from AD patients and normal subjects correlated significantly with B7.2 expression on B cells (r = 0.68; p = 0.004), suggesting a role for B7.2+ B cells in IgE synthesis. Indeed, purified B7.2+ B cells produced significantly more IgE than B7.2- B cells in vitro (p = 0.04). Anti-human B7.2, but not B7.1, mAb significantly (p < 0.05) decreased IgE production by PBMC stimulated with IL-4 and anti-CD40 mAb. Furthermore, B7.2+ B cells had a significantly higher level of IL-4R and CD23 expression than B7.1+ B cells. These data demonstrate the predominant expression of B7.2 in AD, but not psoriasis, and a novel role for this molecule in IgE synthesis.

Upregulation of B7.2, but not B7.1, on B cells from patients with allergic asthma.

BACKGROUND: Allergic asthma is associated with TH2-like cell responses and increased IgE production. Recent studies in mice have suggested that the costimulatory molecule B7.2 (CD86) may influence the development of TH2 cells. OBJECTIVE: We sought to determine the potential role of B7.2 in patients with asthma. METHODS: We performed an analysis of B cells from patients with allergic asthma and healthy control subjects for expression of B7.1 and B7.2 on B cells using five-parameter flow cytometry. RESULTS: We report that atopic patients with asthma who are exposed to allergens have significantly (p < 0.005) higher levels of B7.2 expression on B cells than atopic asthmatic subjects not exposed to allergen in vivo or nonatopic control subjects. In contrast, there were no differences in B7.1 (CD80) expression among the three study subject groups. When peripheral blood mononuclear cells from asthmatic patients or normal control subjects were stimulated with IL-4 or IL-13, the expression of B7.2, but not B7.1, was significantly increased (p < 0.005) on B cells. Interferon-gamma or IL-12 did not affect the expression of either molecule. The functional significance of B7.2 induction by IL-4 in allergic disease was suggested by the increased expression of this molecule on CD23+, but not CD23-, B cells. CONCLUSION: These results indicate that the same B cell involved in allergen presentation also expresses the costimulatory molecule B7.2 and support the hypothesis that this molecule is an important costimulatory molecule in allergic responses, the expression of which can be modulated by TH2-like cytokines.

Analysis of CD80 and CD86 expression on peripheral blood B lymphocytes reveals increased expression of CD86 in lupus patients.

We screened peripheral blood mononuclear cells from 13 SLE patients, all having quiescent disease at the time of analysis, 12 allergy patients, and 21 normal subjects for the expression of CD80 (B7-1) and CD86 (B7-2, B70) on small (resting) and large (activated) subsets of CD19+ B cells. The percentage of CD86+ cells was significantly higher in all B cell subsets in the SLE patients compared to either normal controls or allergy patients. No differences in the mean percentage CD86+ stained B cells (CD19+) were found when comparing the allergy patients and the normal controls. The percentage of CD80+ cells in the large activated B cell (CD19+) subset of the SLE patient population was significantly higher than in the comparable subset from the normal controls and the allergy patients. Comparison of the small resting B cell subset did not reveal a significant difference in CD80 expression between the normal controls, the allergy patients, and the SLE patients. Our findings suggest that the B7 family of molecules, and CD86 in particular, may reflect immunologic dysregulation in patients with autoimmune disease and may reflect a state facilitating heightened B cell activity and hypergammaglobulinemia that occur in active SLE.

Bacterial superantigens induce V beta-specific T cell receptor internalization.

Staphylococcal enterotoxins can cause toxic shock syndrome and autoimmune diseases. Circulating T cells from these diseases have a very wide range of expression in particular T cell receptor (TCR) beta chain variable regions (V beta). One possibility for this wide range of TCR V beta expression is that during acute infection with organisms secreting superantigens (SAg) these potent molecules might modulate TCR expression. To test this hypothesis, we investigated the potential effects of SAg on TCR V beta cell surface expression. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with staphylococcal SAg. Toxic shock syndrome toxin-1 (TSST-1) induced downregulation of V beta 2 expression, whereas staphylococcal enterotoxin (SE) B induced V beta 3-and V beta 12-specific downregulation. TSST-1 did not interfere with anti-V beta 2 mAb binding. Therefore, this downregulation was not due to steric hindrance of Ab binding by TSST-1. TSST-1 induced V beta 2 downregulation was time-, dose- and temperature-dependent. CD3 expression decreased in parallel with reduction of V beta expression. CD4 and CD8 expression were only slightly decreased. CD2, CD25 and HLA-DR expression were upregulated following TSST-1 stimulation of T cell lines. To investigate the fate of TCR after toxin stimulation, V beta 8+ Jurkat T cells were incubated with SEE which is known to stimulate V beta 8+ T cells, and analysed with fluoresence microscopy, and immunoprecipitation and Western blotting. After SEE stimulation, there was an increase in V beta 8 molecules found in the cytoplasm which correlated with loss of cell surface V beta 8 molecules, suggesting internalization of cell surface V beta 8 molecules was induced by SEE stimulation. Shedding of V beta 8 molecules into the culture supernatant was not detected. These data demonstrate that SAg mediated downregulation of TCR expression occurs primarily as the result of TCR internalization. This downregulation phenomenon may have physiological and pathological consequences in patients infected with Staphylococcus aureus.

Differential effects of staphylococcal toxic shock syndrome toxin-1 on B cell apoptosis.

Superantigens, such as toxic shock syndrome toxin 1 (TSST-1), have been implicated in the pathogenesis of several autoimmune and allergic diseases associated with polyclonal B cell activation. In this report, we studied the in vitro effects of TSST-1 on B cell activation. We show herein that TSST-1 produced antagonistic effects on Ig synthesis by peripheral blood mononuclear cells (PBMC) from normal subjects, depending on the concentration used; Ig production was inhibited at 1000 pg/ml (P < 0.01) and enhanced at 1 and 0.01 pg/ml (P < 0.01) of toxin. Cultures of PBMC were then examined for morphologic features and DNA fragmentation characteristic for apoptosis. B cells exhibited a significantly higher (P < 0.01) incidence of apoptosis after stimulation with 1000 pg/ml of TSST-1 compared with 1 or 0.01 pg/ml of toxin or medium alone. Abundant expression of Fas, a cell surface protein that mediates apoptosis, was detected on B cells after stimulation with 1000 pg/ml of TSST-1 and was significantly higher on B cells undergoing apoptosis than on live cells (P = 0.01). Additionally, increased Fas expression and B cell death occurred at concentrations of TSST-1 inducing the production of high amounts of gamma interferon (IFN-gamma), and both events could be blocked by neutralizing anti-IFN-gamma antibody. These findings suggest that high concentrations of TSST-1 can induce IFN-gamma-dependent B cell apoptosis, whereas at low concentrations it stimulates Ig synthesis by PBMC from normal subjects. These findings support the concept that staphylococcal toxins have a role in B cell hyperactivity in autoimmunity and allergy.

Upregulation of IgE synthesis by staphylococcal toxic shock syndrome toxin-1 in peripheral blood mononuclear cells from patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic skin disease associated with increased IgE synthesis and colonization with Staphylococcus aureus secreting exotoxins, such as Toxic Shock Syndrome Toxin-1 (TSST-1). OBJECTIVES: In this study, we were interested in determining the in vitro effects of TSST-1 on IgE synthesis in peripheral blood mononuclear cells from patients with AD. METHODS: We stimulated peripheral blood mononuclear cells (PBMC) from AD patients with a wide range of TSST-1 concentrations and measured IgE synthesis by enzyme-linked immunosorbent assay (ELISA) after 14 days. RESULTS: We show herein that TSST-1 produced antagonistic effects on IgE synthesis by PBMC from AD patients, depending on the concentration used: IgE synthesis was inhibited at 1000 pg/mL (P < 0.05) and enhanced at 0.01 pg/mL (P < 0.01) of toxin. TSST-1 was found to induce the production of much higher amounts of interferon-gamma (IFN gamma) at 1000 pg/mL than at 0.01 pg/mL of toxin (P = 0.0001). More importantly, immunoglobulin E (IgE) synthesis was enhanced by TSST-1 at 1 pg/mL in the presence of antibodies blocking IFN gamma activity. The other immunoglobulin (Ig) isotypes were also increased after TSST-1 stimulation suggesting that the enhanced IgE synthesis was secondary to a polyclonal B cell activation rather than an isotype switch. TSST-1-stimulated IgE synthesis was T cell-dependent because purified tonsil B cells were only able to synthesize increased amounts of IgE when small numbers of T cells were added to the cultures. Anti-HLA-DR and anti-LFA-1 monoclonal antibodies (MoAb) inhibited TSST-1-enhanced IgE synthesis, suggesting that the bridging of the T cell receptor (TCR) and major histocompatibility complex (MHC) class II on B cells was necessary for activation of B cell differentiation. CONCLUSION: These data indicate that staphylococcal superantigens are able, at concentrations inducing low amounts of IFN gamma, to stimulate IgE synthesis by PBMC from AD patients, and suggest that staphylococcal toxins may contribute to elevated IgE synthesis in AD.

Modulatory effects of staphylococcal superantigen TSST-1 on IgE synthesis in atopic dermatitis.

Atopic dermatitis (AD) is a chronic skin disorder associated with elevated serum IgE and colonization of the skin by Staphylococi which secrete toxins with superantigenic activity. The present study examined the immunomodulatory effects of toxic shock syndrome toxin (TSST)-1, a prototypic superantigen, on IgE synthesis by interleukin (IL)-4-stimulated peripheral blood mononuclear cells (PBMC) from five patients with AD and five normal subjects. TSST-1 inhibited IL-4-induced IgE synthesis by AD and normal PBMC (P < 0.05). In contrast, IgG synthesis was not similarly affected (P > 0.30). Inhibition of IL-4-induced IgE production was associated with induction of interferon (IFN)-gamma synthesis by TSST-1 (P < 0.02). Normal PBMC synthesized significantly more (P < 0.005) IFN-gamma than AD PBMC. A neutralizing antibody to IFN-gamma reversed TSST-1-induced suppression of IgE synthesis by the normal PBMC (P < 0.03), but not the AD PBMC. In AD, but not normal, PBMC anti-IFN-alpha antibody reversed the suppression of IgE synthesis induced by TSST-1. These results demonstrate that TSST-1 uses different mechanisms for modulation of IgE synthesis in AD versus normal PBMC. Furthermore, the reversal of TSST-1-induced suppression of IgE synthesis in AD PBMC by anti-IFN-alpha, but not anti-IFN-gamma, is consistent with the concept that AD is associated with defective Th1 cell function and enhanced monocyte activity.

Down-regulating effects of IL-4 and IL-10 on the IFN-gamma response in atopic dermatitis.

Atopic dermatitis (AD) is a chronic allergic disease associated with toxin (superantigen)-producing Staphylococcus aureus skin infections, impaired delayed hypersensitivity responses, and the expansion of IL-4-secreting Th2 cells, as well as diminished IFN-gamma synthesis. IL-12 is known to induce IFN-gamma synthesis and to augment Th1 responses. In this study, therefore, we examined the potential role of IL-12 in the immunopathogenesis of AD. We show that, after stimulation with staphylococcal toxic shock syndrome toxin-1 (TSST-1) or IL-12, PBMC from patients with AD are deficient in their ability to produce IFN-gamma. PBMC from AD patients, however, produced normal quantities of IL-12 and expressed normal levels of IL-12R. Induction of IFN-gamma by TSST-1 was decreased by neutralizing anti-IL-12 Ab in normal donors, but not in AD patients. The latter observation is consistent with a defective response to IL-12 in AD PBMC. Because AD is associated with increased production of IL-4 and IL-10, we examined the effect of IL-4 on IL-12- or TSST-1-induced IFN-gamma production in normal donors. IL-4 inhibited IL-12-induced IFN-gamma production. Furthermore, Ab neutralization of IL-4 caused increased production of IFN-gamma in AD PBMC. However, neutralization of IL-10 activity caused an even greater augmentation of IFN-gamma production. Our data suggest that despite normal levels of IL-12 production and IL-12R expression, PBMC from AD patients are unable to generate normal IL-12-induced IFN-gamma responses. This defective response may be due to the excess production of IL-4 and IL-10 in this common allergic condition.