ABSTRACT
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs ), which had decreased programmed death (PD)-1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage.
Subject(s)
HLA-DR4 Antigen/genetics , HLA-DR4 Antigen/immunology , Hepatitis, Autoimmune/etiology , Hepatitis, Autoimmune/pathology , Ammonia-Lyases , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Autoantibodies/immunology , Autoantigens/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/immunology , Cytokines/metabolism , Disease Models, Animal , Glutamate Formimidoyltransferase , Humans , Hypergammaglobulinemia/immunology , Immunization , Immunoglobulin G/immunology , Inflammation Mediators/metabolism , Mice , Mice, Inbred NOD , Mice, Transgenic , Multienzyme Complexes/genetics , Multienzyme Complexes/immunology , Multifunctional Enzymes , Plasma Cells/immunology , Plasma Cells/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
OBJECTIVE: To determine if a commonly used violence prevention curriculum, Second Step: A Violence Prevention Curriculum, leads to a reduction in aggressive behavior and an increase in prosocial behavior among elementary school students. DESIGN: Randomized controlled trial. SETTING: Urban and suburban elementary schools in the state of Washington. PARTICIPANTS: Six matched pairs of schools with 790 second-grade and third-grade students. The students were 53% male and 79% white. INTERVENTION: The curriculum uses 30 specific lessons to teach social skills related to anger management, impulse control, and empathy. MAIN OUTCOME MEASURES: Aggressive and prosocial behavior changes were measured 2 weeks and 6 months after participation in the curriculum by parent and teacher reports (Achenbach Child Behavior Checklist and Teacher Report Form, the School Social Behavior Scale, and the Parent-Child Rating Scale) and by observation of a random subsample of 588 students in the classroom and playground/cafeteria settings. RESULTS: After adjusting for sex, age, socioeconomic status, race, academic performance, household size, and class size, change scores did not differ significantly between the intervention and control schools for any of the parent-reported or teacher-reported behavior scales. However, the behavior observations did reveal an overall decrease 2 weeks after the curriculum in physical aggression (P=.03) and an increase in neutral/prosocial behavior (P=.04) in the intervention group compared with the control group. Most effects persisted 6 months later. CONCLUSIONS: The Second Step violence prevention curriculum appears to lead to a moderate observed decrease in physically aggressive behavior and an increase in neutral and prosocial behavior in school.
Subject(s)
Child Behavior , Curriculum , Interpersonal Relations , Violence/prevention & control , Aggression , Child , Female , Humans , Male , Schools , Socioeconomic FactorsABSTRACT
Isozymes of lactate dehydrogenase from heart and muscle of Atlantic hagfish show less functional divergence than those from other fishes and higher vertebrates. The enzyme from hagfish heart (B4) displays a higher Michaelis constant for pyruvate and lower substrate inhibition at moderate pyruvate concentrations than heart isozymes from other species. These properties support the hypothesis that the ancestral vertebrate lactate dehydrogenase was a muscle (A4)-type enzyme and also suggest a role for the B4 enzyme in the unusual physiology of hagfish cardiac tissue which functions under sustained hypoxic conditions.
