Shyi-Jou Chen

Polyglutamine (PolyQ) Diseases: Genetics to Treatments

The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine– adenine–guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado–Joseph disease (MJD/SCA3); Huntingtons disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.

Immunologic regulation in pregnancy: from mechanism to therapeutic strategy for immunomodulation.

The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA), immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy.

Erythropoietin enhances endogenous haem oxygenase-1 and represses immune responses to ameliorate experimental autoimmune encephalomyelitis

Both erythropoietin (EPO) and haem oxygenase‐1 (HO‐1), an anti‐oxidative stress protein, have proven protective roles in experimental autoimmune encephalomyelitis (EAE), a reliable animal model of multiple sclerosis. In this study, EPO delivered intraperitoneally could reduce disease severity in myelin oligodendrocyte glycoprotein (MOG)–EAE mice. To assess the effect of EPO on endogenous HO‐1 in EAE, we investigated expression of HO‐1 mRNA by real‐time polymerase chain reaction (RT–PCR), protein expression centrally and peripherally by Western blot and immunohistochemistry and mean fluorescence intensity of splenic HO‐1 by flow cytometry. A significantly higher expression of HO‐1 in both the central nervous system (CNS) and spleen was shown in EPO‐treated MOG–EAE mice than in controls. We further examined the immunomodulatory effect of EPO in EAE, and via RT–PCR demonstrated significantly lower expression of interferon‐γ, interleukin (IL)‐23, IL‐6 and IL‐17 mRNA, and significantly higher expression of IL‐4 and IL‐10 mRNA in CNS of EPO‐treated MOG–EAE mice than in controls. Using flow cytometry, we also observed a significantly decreased ratio of both T helper type 1 (Th1) and Th17 lymphocyte subsets isolated from CNS and a significantly increased ratio of splenic regulatory CD4 T cells in EPO‐treated MOG–EAE mice. In addition, we demonstrated that MOG‐specific T cell proliferation was lower in the EPO‐treated group than in controls and showed amelioration of EAE by adoptive transfer of splenocytes from EPO‐treated MOG–EAE mice. Together, our data show that in EAE, EPO induction of endogenous HO‐1 and modulation of adaptive immunity both centrally and peripherally may involve the repression of inflammatory responses.

Fatal sepsis and necrotizing pneumonia in a child due to community-acquired methicillin-resistant Staphylococcus aureus: Case report and literature review

Pediatric deaths due to community-acquired methicillin-resistant Staphylococcus aureus are rare. We describe the case of 2-y-old boy with fever and cough followed by comatose state with deteriorated respiration; the boy died of severe sepsis and necrotizing pneumonia. The etiological agent was community-acquired methicillin-resistant Staphylococcus aureus, carrying a type IV staphylococcal mecA gene cassette and the Panton-Valentine Leukocidin gene.

Current Status of the Immunomodulation and Immunomediated Therapeutic Strategies for Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and CD4+ T cells form the core immunopathogenic cascade leading to chronic inflammation. Traditionally, Th1 cells (interferon-γ-producing CD4+ T cells) driven by interleukin 12 (IL12) were considered to be the encephalitogenic T cells in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Currently, Th17 cells (Il17-producing CD4+ T cells) are considered to play a fundamental role in the immunopathogenesis of EAE. This paper highlights the growing evidence that Th17 cells play the core role in the complex adaptive immunity of EAE/MS and discusses the roles of the associated immune cells and cytokines. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS discussed in this paper.

Changes in the nasal colonization with methicillin-resistant Staphylococcus aureus in children: 2004-2009.

Background Staphylococcus aureus is an important cause of infection, particularly in persons colonized with this organism. This study compared the annual prevalence and microbiological characteristics of methicillin-resistant S. aureus (MRSA) nasal colonization in Taiwanese children from 2004 through 2009. Risk factors for MRSA were determined for the overall study period. Methods Children from birth to ≤14 years of age presenting for health maintenance visits or attending 1 of 57 kindergartens were recruited. Nasal swabs were obtained, and a questionnaire was administered. The prevalence and microbiological characteristics of MRSA colonization were also calculated for two 3-year periods: 2004–2006 and 2007–2009. Results Cultures of the anterior nares were positive for S. aureus in 824 (25.8%) of the 3,200 children, and MRSA colonization was found in 371 (11.6%) children. The prevalence of S. aureus colonization decreased from 28.1% in 2004–2006 to 23.3% in 2007–2009 (p<0.01), whereas the prevalence of MRSA colonization increased from 8.1% to 15.1% during this period (p<0.0001). Multivariate analysis revealed that the independent risk factors for MRSA carriage were different for male and female children, and also among age groups. Most MRSA isolates belonged to sequence type 59 (ST59) (86.3%); however, a multiresistant MRSA clone with ST338 background emerged in 2007–2009. Ten (62.5%) of the 16 MRSA isolates expressed the genotypic profile ST338/staphylococcal cassette chromosome mec VT/Panton-Valentine leukocidin-positive/staphylococcal enterotoxin B-positive, and differed only in their antimicrobial susceptibility patterns. Conclusion The prevalence of nasal colonization by MRSA increased among healthy Taiwanese children from 2004–2006 to 2007–2009, despite an overall decrease in the prevalence of nasal colonization by S. aureus. A multiresistant MRSA clone characterized as ST338 was identified from these children.

Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Diseases

Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease.

Decoy receptor 3 ameliorates experimental autoimmune encephalomyelitis by directly counteracting local inflammation and downregulating Th17 cells

To investigate the therapeutic potential of decoy receptor 3 (DcR3) in multiple sclerosis (MS), we used intrathecal (IT) administration of DcR3 into C57/BL6 mice with experimental autoimmune encephalomyelitis (EAE). DcR3 significantly ameliorated EAE symptoms as shown by a lower clinical score and less inflammation in the spinal cord. The expression of TNF-alpha, IFN-gamma, and IL-17 was lower in the spinal cord in IT DcR3-treated mice. Flow cytometry showed a drastic reduction in IL-17-producing CD4 T cells, slightly fewer IFN-gamma producing CD4 T cells and more IL-4-producing CD4 T cells isolated from the central nervous system (CNS) of IT DcR3-treated mice than of controls. Myelin oligodendrocyte glycoprotein (MOG)-specific T cell proliferation was significantly inhibited in DcR3-treated mice. The IL-17 concentration was lower and the IL-4 concentration higher in the supernatants of MOG-stimulated splenocytes from DcR3-treated mice. An adoptive transfer study showed that splenocytes from DcR3-treated mice retained this disease-inhibiting ability. Our data suggest that DcR3 has potential as a suppressor of CNS inflammation in EAE, which may be attributed to either direct inhibition of CNS inflammation or suppression of encephalitogenic Th17 cells. In conclusion, we demonstrate a therapeutic effect of DcR3 in EAE, suggesting its potential for treating human MS.

Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis.

Melatonin is the major product secreted by the pineal gland at night and displays multifunctional properties, including immunomodulatory functions. In this study, we investigated the therapeutic effect of melatonin in experimental autoimmune encephalomyelitis (EAE). We demonstrated that melatonin exhibits a therapeutic role by ameliorating the clinical severity and restricting the infiltration of inflammatory Th17 cells into the CNS of mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Furthermore, melatonin enhances splenic interleukin (IL)-10 expression in regulatory T cells by inducing IL-27 expression in the splenic DC; it also suppresses the expression of IFN-γ, IL-17, IL-6, and CCL20 in the CNS and inhibits antigen-specific T cell proliferation. However, there were no significant differences in the percentage of splenic regulatory T cells. These data provide the first evidence that the therapeutic administration of melatonin is effective in mice with EAE and modulates adaptive immunity centrally and peripherally. Thus, we suggest that melatonin could play an adjunct therapeutic role in treating human CNS autoimmune diseases such as multiple sclerosis. Melatonin merits further studies in animals and humans.

Antimicrobial susceptibility of Staphylococcus aureus in children with atopic dermatitis.

Background:  Skin infection and/or nasal carriage of Staphylococcus aureus in children with atopic dermatitis (AD) is a risk factor for exacerbating disease or subsequent recurrent S. aureus infection. The purpose of the study is to evaluate the antibiotic susceptibilities of S. aureus strains from AD children and determine the most appropriate choice of antibiotics.