Jyh-Hong Lee

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.

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.

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.

Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus

OBJECTIVE Identification of the genes responsible for systemic lupus erythematosus (SLE). METHODS All the exons and putative promoter regions of 53 candidate genes (TNFRSF6/Fas, TNFSF6/FasL, Fli1, TNFSF10/TRAIL, TNFSF12/TWEAK, Bcl-2, PTEN, FADD, TRADD, CDKN1A, TNFRSF1A/TNFR1, TNFRSF4/OX40, TNFSF4/OX40L, TNFSF5/CD40L, TNFSF13B/BAFF, ICOS, CTLA4, CD28, FYN, G2A, CR2, PTPRC/CD45, CD22, CD19, Lyn, PDCD1, PTPN6, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3, CD3Z, DNASE1, APCS, MERTK, C3, C1QA, C1QB, C1QG, C2, MBL2, IGHM, IL-2, IL-4, IL-10, IFNG, TNFA, MAN2A1, TNFRSF11A/RANK, TNFRSF11B/OPG, TNFSF11/OPGL) were screened for single nucleotide polymorphisms (SNPs) and their association with SLE was assessed by case-control studies. A total of 509 cases and 964 controls of Japanese descent were enrolled. RESULTS A total of 316 SNPs was identified. When analysed in the Japanese population, the allele frequencies of T at rs7951 and G at rs2230201 of the C3 gene were 0.110 and 0.626, respectively, in SLE patients; significantly higher than the frequencies of 0.081 and 0.584, respectively, in controls [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.05-1.86, P = 0.016 and OR=1.19, 95% CI = 1.01-1.41, P = 0.038, respectively]. The mean serum C3 level of carriers of the rs7951 T allele was significantly lower than that of non-carriers of the T allele in 87 SLE patients whose medical records were available (P = 0.0018). CONCLUSION rs7951 T allele of the C3 gene was significantly associated with SLE, and decreased serum level of C3 seems to be correlated with this allele.

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.

Interleukin 4 and STAT6 gene polymorphisms are associated with systemic lupus erythematosus in Chinese patients

An imbalance between T Helper 1 (TH1) and T Helper 2 (TH2) cytokine production is important for the pathogenesis of systemic lupus erythematosus (SLE). We aimed to investigate gene—gene associations of TH1 and T H2 cytokines genes in Chinese patients with SLE. Twenty single nucleotide polymorphisms (SNPs) in eight cytokines genes were genotyped in 110 SLE patients and 138 healthy controls in a case—control association study. The minor allelic frequencies of interleukin4(IL4) -590 T/C, -33 T/C, 9241C/G, and IL10 -592 A/C were significantly increased in SLE patients compared with those in controls (p < 0.05). None of the separate 20 SNPs showed significant association with SLE after Bonferroni correction. An IL4 haplotype -590C/-33C/9241G/14965C was significantly associated with SLE (odds ratio 3.7, 95% confidence interval [CI] 1.5—8.9, p = 0.004, Bonferroni-corrected p = 0.024). A borderline significant three-locus gene—gene interaction among IL4 9241 C/G, IL4 -33 T/C, signal transducer and activator of transcription 6, IL4-induced (STAT6) 2892 C/T was detected by a multifactor dimensionality reduction test (p = 0.051). However, the presence of two at-risk genotypes lead to increased risk of SLE for two-locus interaction using logistic regression method. The risk of SLE increased significantly when a subject has two at-risk genotypes for IL4 -590C and STAT6 2892C (odds ratio, 3.24, 95% CI 1.5—7.0, p = 0.003, Bonferroni-corrected p = 0.009), IL4 -33C and STAT6 2892C (odds ratio 3.06, 95% CI 1.4— 6.7, p = 0.005, Bonferroni-corrected p = 0.015), as well as IL4 9241G and STAT6 2892C (odds ratio 3.34, 95% CI 1.6—7.1, p = 0.002, Bonferroni-corrected p = 0.006). Further, plasma IL-4 concentrations were significantly lower in SLE patients than in healthy controls (1.59 + 3.53 versus 5.67 + 11.28 pg/ml, p = 0.042). These results indicated that IL4 and STAT6 genes might be involved in the etiology of SLE and potentially increased SLE risk through their interaction effect in Chinese patients.

Ribavirin for respiratory syncytial virus bronchiolitis reduced the risk of asthma and allergen sensitization.

Respiratory syncytial virus (RSV) bronchiolitis in early life is a risk factor for later development of asthma and atopy. Ribavirin is the only effective drug currently available against acute RSV bronchiolitis. However, the long‐term effects of ribavirin remain unclear. We investigated a cohort of children hospitalized with RSV bronchiolitis from when they were under 2 yr old until they reached a mean age of 6.2 yr. In total, we enrolled 175 children in this study. Both the group treated with ribavirin and the group not treated with ribavirin included high‐risk young children with congenital heart disease or chronic lung disease. Their respective age‐matched controls, that we labeled groups A and B, both without ribavirin treatment, consisted of previously healthy subjects. Wheezing was either verified by physicians or estimated by a questionnaire. Allergen sensitization was judged by serum allergen‐specific IgE levels. The cumulative incidence of physician‐diagnosed asthma or recurrent wheezing in the ribavirin group (15%) was significantly lower than its incidence in the non‐ribavirin‐treated group (34%, p = 0.049), and in the control A group (43%, p = 0.005). Allergen sensitization was also least frequent in the ribavirin group. Ribavirin therapy was an independent factor in reducing the risk of developing asthma, asthma/recurrent wheezing, and sensitization to D. pteronyssinus/D. farinae. The long‐term value of ribavirin for acute RSV bronchiolitis and its underlying mechanisms deserves further research.

Linoleic acid metabolite levels and transepidermal water loss in children with atopic dermatitis

BACKGROUND It has been suggested that atopic dermatitis (AD) is associated with impaired delta-6 desaturase activity and the subsequent altered composition of n-6 essential fatty acids (EFAs). OBJECTIVE To investigate whether n-6 EFA deficiency accounts for AD by affecting transepidermal water loss or the immune response. METHODS Serum levels of n-6 EFAs were measured using gas chromatography-mass spectrometry in a well-defined group of 35 children with AD (IgE level >150 U/mL); 35 age-matched children with allergic rhinitis, asthma, or both (IgE level >150 U/mL); and 31 nonatopic controls (IgE level <100 U/mL). Skin barrier function was evaluated by measuring transepidermal water loss and severity of AD by computing the Scoring Atopic Dermatitis (SCORAD) index. RESULTS Atopic children had higher levels of linoleic acid (LA) and lower levels of its metabolites. Furthermore, gamma-linolenic acid to LA and dihommo-gamma-linolenic acid to LA ratios were significantly reduced in atopic patients. Transepidermal water loss and the SCORAD index were negatively correlated with serum levels of LA metabolites. There was no correlation between the SCORAD index and IgE level (P = .51) or between n-6 EFA concentrations and IgE level (P > .10). CONCLUSIONS Deficits in n-6 EFAs were correlated with the severity of AD by affecting skin barrier function and cutaneous inflammation. The link between impaired n-6 EFA metabolism and IgE level could not be defined.

Genetics and Immunopathogenesis of IgA Nephropathy

IgA nephropathy (IgAN) is the most common glomerulonephritis in the world. The hallmark of IgAN is underglycosylation in the hinge region of IgA1. Increasing evidence supports the underglycosylated IgA-containing immune-complex including IgG antibodies against the glycans of the hinge region of IgA1 are key factors for mesangial deposition and then trigger inflammation and glomerular injury. The polymeric IgA is produced after aberrant mucosal IgA response. The displacement of mucosal B cells to systemic lymphoid organs and bone marrow may arise from abnormal trafficking of lymphocytes along the mucosa–bone marrow axis involving changes of chemokines and adhesion molecules. This review will summarize the works on the genetics, the mucosal and systemic IgA immune response, mechanism of underglycosylation of IgA1, and the pathological effect of mesangial IgA deposition in IgAN.

Noninvasive in vitro and in vivo assessment of epidermal hyperkeratosis and dermal fibrosis in atopic dermatitis

Atopic dermatitis (AD) is characterized by hyperkeratosis of epidermis and fibrosis within dermis in chronic skin lesions. Thus far, the histology of skin lesions has been evaluated only by examination of excised specimens. A noninvasive in vivo tool is essential to evaluate the histopathological changes during the clinical course of AD. We used Cr:forsterite laser-based multimodality nonlinear microscopy to analyze the endogenous molecular signals, including third-harmonic generation (THG), second-harmonic generation (SHG), and two-photon fluorescence (TPF) from skin lesions in AD. Significant differences in thickness of epidermis and stratum corneum (SC), and modified degrees of fibrosis in dermis (measured by THG signals and SHG signals, respectively), are clearly demonstrated in in vitro studies. Increased TPF levels are positively associated with the levels of the THG signals from the SC. Our in vitro observations of histological changes are replicated in the in vivo studies. These findings were reproducible in skin lesions from human AD. For the first time, we demonstrate the feasibility of preclinical applications of Cr:forsterite laser-based nonlinear microscopy. Our findings suggest that the optical signatures of THG, TPF, and SHG can be used as molecular markers to assess the pathophysiological process of AD and the effects of local treatment.