Yao-Hsu Yang

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.

Gastrointestinal manifestations in Henoch-Schönlein purpura: a review of 261 patients.

Aim: Henoch‐Schönlein purpura is an IgA‐mediated autoimmune vasculitis of children. It often presents with symptoms including purpuric rash, abdominal pain, renal involvement or arthritis. Abdominal pain is a frequent symptom in children with HSP and raises the suspicion of intussusception or perforation. We sought to evaluate abdominal pain via stool occult blood and image studies. Methods: A retrospective study of 261 patients diagnosed with Henoch‐Schönlein purpura from December 1991 to December 2001 was conducted. Image studies, including abdominal echo, abdominal CT and panendoscopy, were performed for patients who suffered from abdominal pain. Results: Of the 261 patients, 151 (58%) had abdominal pain, and 46 (17.6%) suffered either overt gastrointestinal bleeding or had positive stool occult blood. Seven patients had gross bloody stools. One acute intussusception and one bowel perforation were noted. One patient suffered from hypovolemic shock due to massive gastrointestinal bleeding. When stool occult blood was 3+ or 4+, the incidence of a positive image finding was high.

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.

Innate immunity and primary biliary cirrhosis: Activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis

Murine models of autoimmunity allow the study of the earliest events in disease pathogenesis. Our laboratory has developed a xenobiotic induced model of primary biliary cirrhosis (PBC) following immunization of mice with 2‐octynoic acid coupled to bovine serum albumin (2‐OA‐BSA), an antigen selected following quantitative structure‐activity relationship analysis of the E2 subunit of the pyruvate dehydrogenase complex (PDC‐E2), the immunodominant autoantigen of PBC. Recent data in humans with PBC has suggested that a major component of liver pathology is due to activation of innate immunity. We took advantage of our 2‐OA‐BSA model and immunized mice with and without the addition of α‐galactosylceramide (α‐GalCer), an invariant natural killer T cell activator. Importantly, we report herein that 2‐OA‐BSA‐immunized mice exposed to α‐GalCer develop a profound exacerbation of their autoimmune cholangitis, including significant increases in CD8+ T‐cell infiltrates, portal inflammation, granuloma formation, and bile duct damage. Furthermore, such mice produce increased levels of antimitochondrial antibodies and have evidence of fibrosis, a feature not previously reported in the murine models of PBC. Conclusion: Our data suggests a primary role of innate immunity in the exacerbation of autoimmune cholangitis and also become a logical explanation for the recurrence of PBC following liver transplantation in the absence of major histocompatability complex compatibility. We submit that PBC begins with loss of tolerance to PDC‐E2 and a multilineage antimitochondrial response in which autoreactive CD8+ T cells are critical. However, the perpetuation of disease and its exacerbation will also be modulated by innate immune mechanisms. (HEPATOLOGY 2011;)

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.

Increased transforming growth factor-beta (TGF-β)-secreting T cells and IgA anti-cardiolipin antibody levels during acute stage of childhood Henoch–Schönlein purpura

Henoch–Schönlein purpura (HSP) is a small vessel vasculitis characterized by increased serum IgA and IgA‐dominant immune complex deposition in lesions. The involvement of IgA implies a probable role for TGF‐β, a major factor in IgA production, in the pathogenesis of HSP. Among IgA antibodies, serum IgA anti‐cardiolipin antibodies (aCL) have been found in many diseases, including vasculitis. In addition to the clinical presentations and laboratory parameters, we further investigated the roles of IgA aCL and TGF‐β in childhood HSP. Twenty‐six Chinese children with the diagnosis of HSP were enrolled. Blood samples from these patients were collected at both acute and convalescent stages. Intracellular staining of lymphocytes was performed to enumerate type 1 (interferon‐gamma‐secreting), type 2 (IL‐4‐secreting), and type 3 (TGF‐β‐secreting) helper T cells. Serum levels of TGF‐β were detected by ELISA. Serum IgA aCL of 21 of 26 patients at the acute stage, 11 of them at the convalescent stage, were measured by ELISA. The data showed that IgA aCL serum levels were significantly elevated in patients compared with healthy controls (P < 0·001), and those patients at the convalescent stage (P < 0·001). In addition, TGF‐β‐secreting T cells were significantly elevated during the acute stage, and decreased at the convalescent stage. Although more studies are needed, the high prevalence of IgA aCL and increased TGF‐β‐secreting T cells in children with acute HSP revealed some points which should permit a better understanding of the pathogenesis of HSP.

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.