乙型肝炎病毒基因的整合机制及对宿主的影响

乙型肝炎病毒是导致慢性肝炎、肝纤维化、肝细胞癌的主要病因,目前认为乙型肝炎病毒基因整合在其致病机制中具有重要作用,本文试就该领域内目前研究成果做一综述．     

Genetic control of anti-idiotypic vaccination against coronavirus infection

The idiotypic network can be experimentally altered to induce protective immune responses against microbial pathogens. Both internal image and noninternal image anti-idiotypic (anti-Id) antibodies have been shown to trigger antigen (Ag)-specific immune responses. Therefore, mechanisms of anti-Id vaccination appear to go beyond structural mimicry of Ag, but remain undefined. Using the neurotropic murine coronavirus animal model, we have previously shown that a polyclonal noninternal image anti-Id (Ab2) could vaccinate BALB/c mice. To characterize its mode of action, we have examined the immune modulating capability of this Ab2 in vivo in strains of mice with different H-2 haplotypes. Even though only internal image anti-Id are expected to induce non-genetically restricted immunity, this noninternal image Ab2 induced protective immunity in four of eight genetically different strains of mice susceptible to coronavirus infection. These were BALB/c (H-2^d), DBA/1 (H-2^d), DBA/1 (H-2^q), and SWR (H-2^q) mice. Protection was generally correlated with the induction of specific antiviral Ab (Ab3) that showed biological properties, such as virus neutralization in vitro, similar to the initial Ab1. To evaluate the genetic implication of the H-2 haplotypes in protection, congenic mice were also tested. Vaccination profiles suggest that cooperation between background gene(s) of the BALB/c mouse with H-2^d and H-2^q loci is necessary for an optimal protective immune response, although the main genetic element(s) regulating the antiviral response to Ab2 inoculation appeared to be located outside the major histocompatibility complex. These results are consistent with the ability of Ab2 to induce protective antiviral antibodies in genetically different animals by biological mimicry.     

Drosophila ammonium transporter Rh50 is required for integrity of larval muscles and neuromuscular system

Rhesus glycoproteins (Rh50) have been shown to be ammonia transporters in many species from bacteria to human. They are involved in various physiological processes including acid excretion and pH regulation. Rh50 proteins can also provide a structural link between the cytoskeleton and the plasma membranes that maintain cellular integrity. Although ammonia plays essential roles in the nervous system, in particular at glutamatergic synapses, a potential role for Rh50 proteins at synapses has not yet been investigated. To better understand the function of these proteins in vivo, we studied the unique Rh50 gene of Drosophila melanogaster, which encodes two isoforms, Rh50A and Rh50BC. We found that Drosophila Rh50A is expressed in larval muscles and enriched in the postsynaptic regions of the glutamatergic neuromuscular junctions. Rh50 inactivation by RNA interference selectively in muscle cells caused muscular atrophy in larval stages and pupal lethality. Interestingly, Rh50-deficiency in muscles specifically increased glutamate receptor subunit IIA (GluRIIA) level and the frequency of spontaneous excitatory postsynaptic potentials. Our work therefore highlights a new role for Rh50 proteins in the maintenance of Drosophila muscle architecture and synaptic physiology, which could be conserved in other species.     

Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation

Apolipoprotein (apo) E mutants are associated with type III hyperlipoproteinemia characterized by high cholesterol and triglycerides levels. Autosomal dominant hypercholesterolemia (ADH), due to the mutations in the LDLR, APOB, or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to the high levels of low‐density lipoproteins (LDLs). We now report an exceptionally large family including 14 members with ADH. Through genome‐wide mapping, analysis of regional/functional candidate genes, and whole exome sequencing, we identified a mutation in the APOE gene, c.500_502delTCC/p.Leu167del, previously reported associated with sea‐blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p.Leu167del in ADH, with (1) a predicted destabilization of an alpha‐helix in the binding domain, (2) a decreased apo E level in LDLs, and (3) a decreased catabolism of LDLs. Our results show that mutations in the APOE gene can be associated with bona fide ADH.     

Protein kinase C-theta is required for development of experimental cerebral malaria

Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-θ) in experimental CM development was examined. PKC-θ-deficient mice are resistant to CM development. In the absence of PKC-θ, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC-θ-deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8(+) T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-θ. Resistant PKC-θ-deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-θ signaling is crucial for recruitment of CD8(+) T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.     

O等位基因引起ABO基因型与表现型定型差异

保证输血时血清学方面的安全,首要的是对受血者与献血者ABO血型定型,血清学检查通常分两个步骤.正定型通常使用鼠源单克隆抗体检测红细胞表面是否存在A或B抗原.互补的实验即反定型,利用当红细胞上缺乏A或B抗原时,人群可天然产生相对应的抗体的原理,检测血清中是否存在抗-A或者抗-B抗体.确定了受血者红细胞表面的ABO抗原以及血浆中的抗体,便能确定血型,为其提供相合的血液.