Li-Chieh Wang

Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus.

CD4+ CD25+ regulatory T cells (Tregs) are critical in maintaining self‐tolerance and preventing organ‐specific autoimmunity. Their role in paediatric systemic lupus erythematosus (SLE), an autoimmune disease characterized by inappropriate regulation of hyperactivated B and T cells, has not been clearly defined. Using flow cytometry to determine cell populations and real‐time polymerase chain reaction to assay mRNA expression for FOXP3, CTLA‐4, and GITR, we characterized CD4+ CD25+ T cells in paediatric SLE patients and healthy subjects. The frequency of CD4+ CD25+ Tregs was significantly decreased in patients with active SLE compared with patients with inactive SLE and with controls (7·27% ± 2·50%, 9·59% ± 2·80% and 9·78% ± 2·11%, respectively; P = 0·027 and P < 0·001, respectively), and was inversely correlated with disease activity, as assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 scores (r = −0·59, P = 0·001) and serum anti‐double‐stranded DNA levels (r = −0·65, P < 0·001). Our preliminary investigations found elevated surface expression of GITR in CD4+ CD25+ T cells, elevated mRNA expression of CTLA‐4 in CD4+ T cells and higher amounts of mRNA expression for FOXP3 in CD4+ cells in patients with active SLE compared with patients with inactive disease and controls. We demonstrated reduced CD4+ CD25+ Treg levels were inversely correlated with disease activity, indicating a defective Treg population in paediatric SLE patients. The differences in the expression of FOXP3, CTLA‐4 and GITR imply the possible role of CD4+ Tregs in the pathogenesis of SLE.

The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma

Our purpose was to determine whether numbers of CD4+CD25+ T [T regulatory (Treg)] cells and mRNA expression of functional molecules of Treg are related to airway allergy and disease severity in 51 paediatric patients with allergic rhinitis or bronchial asthma and 47 healthy controls. Surface markers were evaluated with flow cytometry, and mRNA was determined with real‐time polymerase chain reaction. Children with allergic disease had fewer CD4+CD25+ T cells (8·49% ± 2·41% versus 9·58% ± 2·43%, P < 0·05) and CD4+CD25hi T cells (1·32% ± 0·68% versus 1·70% ± 0·68%, P < 0·01) than control subjects. Numbers of CD4+CD25+ and CD4+CD25hi T lymphocytes were higher in children with persistent allergic rhinitis and/or moderate–severe bronchial asthma than in those with respective milder disease. The number of Treg cells was correlated positively with total immunoglobulin E level. The mRNA expression of forkhead box P3 (FoxP3) was increased in moderate–severe versus mild asthma (2·93 ± 0·38 versus 1·60 ± 0·31, P < 0·01). Patients with moderate–severe bronchial asthma also had increased mRNA expression of interleukin (IL)‐10 compared with patients with mild asthma (15·24 ± 4·07 versus 3·77 ± 2·18, P < 0·01). The suppressive function of Treg cells from patients with more severe asthma was competent in vitro. On average, decreased numbers of Treg cells in children with allergic airway disease might represent a defect of the Treg population. With increased expression of FoxP3 and IL‐10 in Treg from patients with relatively severe allergic disease, adaptive and functional Treg might be generated in response to aggravated atopy and disease severity.

Neuropsychiatric manifestations in pediatric systemic lupus erythematosus: a 20-year study

The objective of this study was to investigate the manifestations, treatment and outcome of neuropsychiatric (NP) involvement in pediatric systemic lupus erythematosus (SLE) patients. The charts of 185 pediatric patients with SLE diagnosed between 1985 and 2005 in a tertiary referral hospital were retrospectively reviewed. NPSLE were defined using the American College of Rheumatology NPSLE case definitions. NPSLE developed in 34.6% (64/185) of the patients. The mean onset age was 15.2 years. Fourteen patients (21.9%) had NP manifestations on initial diagnosis of SLE. The median duration from the onset of SLE to NP manifestation was 11 months. The most frequent NP manifestations were seizure disorder (84.4%), ischemic stroke (28.1%) and psychosis (21.9%). However, the prevalence of manifestations of NPSLE might be underestimated by the retrospective design of our study. Higher mean C3/C4 levels, less percentage of anti-dsDNA antibodies elevation and higher percentage of elevated anticardiolipin antibodies were observed in NPSLE events than in non-NPSLE events (P 0.05). The mortality rate of NPSLE patients decreased from 52.2% in 1985–1994 cohort to 27.8% in 1995–2005 cohort. In the past 10 years, the leading cause of death in NPSLE patients was NPSLE itself. NPSLE is common in pediatric SLE patients. It has diverse manifestations and a high mortality.

The immunobiology of Henoch–Schönlein purpura☆

Henoch-Schönlein purpura (HSP) is a common but enigmatic systemic small vessel vasculitis that primarily affects children. Although the etiology of this disease is unknown, there are tantalizing clues on the natural history and immunopathogenesis. This article reviews these clues including aspects of disease-associated pathogens, immune regulation, with a focus on IgA, and finally the immunogenetic background of host. We also present a hypothetical model for the development of HSP and submit that this paradigm will be a generic one for similar vasculopathies.

Renal manifestations in Henoch–Schönlein purpura: a 10-year clinical study

Henoch–Schönlein purpura (HSP) is an IgA-mediated systemic small vessel vasculitis of childhood. It is characterized by the symptoms including nonthrombocytopenic purpura, abdominal pain, hematuria/proteinuria, and arthargia/arthritis. We conducted a retrospective study of 261 patients diagnosed with HSP from December 1991 to December 2001. Of the 261 patients, fifty-three (20.3%) developed renal manifestations after onset of the disease. Two patients developed nephrotic syndrome. Four patients had group A beta-hemolytic streptococcal pharyngitis and subsequent depressed serum C3 concentration typical of post streptococcal glomerulonephritis. During the study period, the renal survival rate after disease onset was 100%. The prognosis of renal involvement was better than reports from other series. In this study we also found factors associated with HSP nephritis; these included older age at onset, GI bleeding, and central nervous system involvement. The long-term morbidity of HSP is predominantly attributed to renal involvement. It is thus recommended that patients with HSP nephritis are followed for longer periods of time.

Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics

BACKGROUND The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization and infection by Staphylococcus aureus. Treatment with topical anti-inflammatory drugs alone can reduce S. aureus colonization. OBJECTIVES To compare the clinical severity of AD and the S. aureus colonization rate between AD patients treated with topical glucocorticoids and those treated with tacrolimus and to evaluate the effects of complementary topical antistaphylococcal antibiotic therapy and the development of fusidic acid-resistant S. aureus. METHODS Sixty AD patients were enrolled in a prospective, parallel, randomized study of an 8-week treatment with topical 0.05% fluticasone propionate or 0.03% tacrolimus, with or without complementary fusidic acid. Disease severity scoring of AD based on SCORing of Atopic Dermatitis (SCORAD), colonization rate and density of S. aureus on the skin, and antibiotic susceptibility of S. aureus isolates were evaluated. RESULTS The reduction in SCORAD scores correlated with the reduction of S. aureus numbers. Treatment with topical tacrolimus resulted in a comparable reduction in SCORAD scores to fluticasone but a slower eradication of S. aureus. Complementary fusidic acid had no additional benefit compared with fluticasone or tacrolimus alone. Two patients developed fusidic acid-resistant S. aureus after 8 weeks of fusidic acid treatment. CONCLUSION Tacrolimus is an appropriate alternative treatment for chronic AD. Topical anti-inflammatory therapy alone to improve the allergic skin inflammation of AD can reduce S. aureus colonization of the skin. Topical antibiotics should be reserved for short-term use in obvious secondary bacterial infection.

Clinical manifestations and outcomes of Henoch-Schönlein purpura: comparison between adults and children.

BACKGROUND Henoch-Schönlein purpura (HSP) primarily affects children, but age at onset is thought to be important in determining disease severity and outcome. This study compared the clinical and laboratory data from children and adults with HSP. METHODS This retrospective 5-year study enrolled 65 children and 22 adult HSP patients attending a medical center. RESULTS Gross hematuria and lower-extremity edema were significantly more frequent in adults (p < 0.05). All the children developed renal involvement within 2 weeks, while 67% of the adult patients developed hematuria by the fifth week of disease onset. Elevated white blood cell count and increased erythrocyte sedimentation rate were significantly more common in children (p < 0.05). Adults had a higher frequency of renal involvement (p < 0.05), though this was also present in 14 children (21.54%), 12 with isolated hematuria and proteinuria and two with nephrotic syndrome. All the children maintained normal renal function. Twelve adults had renal involvement (52.6%), six with progression to renal insufficiency. Patients with abdominal pain at disease onset had a significantly higher probability of developing nephrotic syndrome (p < 0.05). Logistic regression revealed that age >20 years, male, bloody stools, clinical course with relapse of purpuric rash, and persistent rash for >1 month were poor prognostic indicators for HSP nephritis (p < 0.05). CONCLUSIONS HSP nephritis in adults had a higher risk of progression to renal insufficiency. More aggressive treatment and extended follow-up with repeated urinalysis for at least 6 weeks were often necessary, especially in older patients.

Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma

Interleukin-1 (IL-1) is a proinflammatory cytokine and IL-1 receptor antagonist (IL-1ra) is a natural inhibitor that binds to IL-1 receptor type I without inducing signal transduction. It is suggested that IL-1 is required for allergen-specific T helper type 2 cell activation and the development of airway hyper-responsiveness (AHR), but the immunologic effect of exogenous IL-1ra in allergic asthma remains unclear. To examine the effect of IL-1ra on airway inflammation and immunoeffector cells in allergic asthma, recombinant adenovirus expressing human IL-1ra (Ad-hIL-1ra) was delivered intranasally into ovalbumin (OVA)-immunized mice. Single intranasal administration of Ad-hIL-1ra before airway antigen challenge in OVA-immunized mice significantly decreased the severity of AHR and reduced pulmonary infiltration of eosinophils and neutrophils. Suppression of IL-5 and eotaxin with concomitant enhancement of interferon gamma in bronchoalveolar lavage fluid was also noted in OVA-immunized mice by administration of Ad-hIL-1ra. In addition, histological studies showed that Ad-hIL-1ra was able to decrease OVA-induced peribronchial inflammation. Taken together, our results indicated that administration of Ad-hIL-1ra may have therapeutic potential for the immunomodulatory treatment of allergic asthma.

Atopic Dermatitis, Melatonin, and Sleep Disturbance

BACKGROUND AND OBJECTIVES: Sleep disturbance is common in patients with atopic dermatitis (AD). However, studies have largely been questionnaire-based, and the pathophysiology remains unclear. The aims of this study were to determine objective characteristics of sleep disturbance in children with AD and explore contributing factors and clinical predictors. METHODS: Sleep parameters were measured by actigraphy and polysomnography in 72 patients with AD and 32 controls ages 1 to 18 years. Urinary 6-sulfatoxymelatonin levels, serum cytokines, and total and allergen-specific immunoglobulin E (IgE) levels were also measured. RESULTS: The patients with AD had significantly reduced sleep efficiency, longer sleep onset latency, more sleep fragmentation, and less nonrapid eye movement sleep. Results from actigraphy correlated well with those from polysomnography. The AD disease severity was associated with sleep disturbance (r = 0.55−0.7), and a Scoring Atopic Dermatitis index of ≥48.7 predicted poor sleep efficiency with a sensitivity of 83.3% and a specificity of 75% (area under the curve = 0.81, P = .001). Lower nocturnal melatonin secretion was significantly associated with sleep disturbance in the patients with AD. Other correlates of sleep disturbance included pruritus, scratching movements, higher total serum IgE levels, and allergic sensitization to dust mite and staphylococcal enterotoxins. CONCLUSIONS: Poor sleep efficiency is common in children with AD and can be predicted by the Scoring Atopic Dermatitis index. Melatonin and IgE might play a role in the sleep disturbance. Further studies are required to explore the mechanisms and clinical implications, and actigraphy could serve as a useful evaluating tool.

Circulating IgA from acute stage of childhood Henoch‐Schönlein purpura can enhance endothelial interleukin (IL)‐8 production through MEK/ERK signalling pathway

Recently, sera from children with active Henoch‐Schönlein purpura (HSP) have been found to enhance interleukin (IL)‐8 production by human umbilical venous endothelial cells (HUVEC). To further determine the possible factor with the ability to enhance endothelial IL‐8 production in sera from acute stage of HSP, 10 children with HSP at the acute stage and 10 healthy controls were enrolled. IgA antiendothelial cell antibodies (AECA) were detected by cell‐based ELISA. Active sera with or without pretreatment with anti‐human IgA antibody, sera of controls, and immunoglobulin A (IgA) derived from sera were used to stimulate the HUVEC. The ability of these factors to enhance endothelial IL‐8 production was evaluated. Furthermore, signalling pathways were also assayed by different inhibitors, and confirmed by immunoblotting. Serum levels of IgA AECA in HPS patients at the acute stage were significantly higher than in controls (P < 0·001). The active sera could enhance endothelial IL‐8 production (P = 0·004, compared with control sera), and the ability of these sera was mostly abolished when pretreated with fixed anti‐human IgA antibody. The supernatant IL‐8 levels of endothelial cells stimulated by IgA derived from acute stage of HSP were statistically higher than controls (P < 0·001). PD98059, an inhibitor of ERK phosphorylation, significantly reduced IgA AECA‐stimulated endothelial IL‐8. IgA AECA also enhanced the phosphorylation of ERK1 with a time‐dependent manner. Together with these findings, it is concluded that IgA AECA derived from acute stage of HSP may bind to endothelial and enhance endothelial cells to produce IL‐8 via MEK/REK signalling pathway.