CD36 null mice reveal a key role for CD36 in β-amyloid induced microglial activation

Microglia and macrophages are important antigen-presenting cells (APCs) in the central nervous system (CNS). By virtue of their ability to express class II MHC antigens and costimulatory molecules such as CD40 and B7, microglia/macrophages promote Th1 cell activation and subsequent immune/inflammatory responses within the CNS. We have previously demonstrated that IFN-γ is the most potent inducer of CD40 expression on microglia. Our more recent studies have focused on the molecular basis of IFN-γ induced CD40 expression, and mechanisms by which this gene can be inhibited. The suppressive effects of IL-4 on CD40 expression will be discussed, as will the involvement of SH2 containing proteins called SOCS (for Suppressors Of Cytokine Signalling). Expression of CD40 by activated microglia/macrophages may contribute to the complex neuroimmunologic cascades that result in inflammation, demyelination and neuronal dysfunction. As such, understanding the mechanisms of inhibition of this molecule will be beneficial in diseases such as multiple sclerosis, HIV-1 associated dementia and Alzheimer's disease.     

Arsenic carcinogenicity: Relevance of c-Src activation

Environmental and occupational exposure to arsenic is associated with increased risk of skin, urinary bladder and respiratory tract cancers. Increasing evidence indicates that arsenic acts at the level of tumor promotion by modulating the signaling pathways responsible for cell growth. One of this pathways might include c-Src dependent EGFR and MAPK activation.     

CXCR3 and heparin binding sites of the chemokine IP-10 (CXCL10)

The chemokine IP-10 (interferon-inducible protein of 10 kDa, CXCL10) binds the G protein-coupled receptor CXCR3, which is found mainly on activated T cells and NK cells, and plays an important role in Th1-type inflammatory diseases. IP-10 also binds to glycosaminoglycans (GAGs), an interaction thought to be important for its sequestration on endothelial and other cells. In this study, we performed an extensive mutational analysis to identify the CXCR3 and heparin binding sites of murine IP-10. The mutants were characterized for heparin binding, CXCR3 binding, and the ability to induce chemotaxis, Ca(2+) flux, and CXCR3 internalization. Double mutations neutralizing adjacent basic residues at the C terminus did not lead to a significant reduction in heparin binding, indicating that the main heparin binding site of IP-10 is not along the C-terminal alpha helix. Alanine exchange of Arg-22 had the largest effect on heparin binding, with residues Arg-20, Ile-24, Lys-26, Lys-46, and Lys-47 further contributing to heparin binding. A charge change mutation of Arg-22 resulted in further reduction in heparin binding. The N-terminal residue Arg-8, preceding the first cysteine, was critical for CXCR3 signaling. Mutations of charged and uncharged residues in the loop regions of residues 20-24 and 46-47, which caused reduced heparin binding, also resulted in reduced CXCR3 binding and signaling. CXCR3 expressing GAG-deficient Chinese hamster ovary cells revealed that GAG binding was not required for IP-10 binding and signaling through CXCR3, which suggests that the CXCR3 and heparin binding sites of IP-10 are partially overlapping.     

Cytokine polymorphisms in silicosis and other pneumoconioses

Silicosis and coal workers' pneumoconiosis are complex multifactorial lung diseases whose etiopathogenesis are not well defined. It is generally accepted that fibrotic lung disorders are mediated by macrophage-derived cytokines and growth factors. There is evidence showing a crucial role for tumor necrosis factor-a (TNF-alpha) and interleukin-1 (IL-1) in inflammation caused by silica dust and in the transition from simple to progressive massive fibrosis. In this review we discuss genetic polymorphisms responsible for regulating the production of these proinflammatory cytokines and their role in modifying silicosis severity.     

BDNF stimulates migration of cerebellar granule cells

During development of the nervous system, neural progenitors arise in proliferative zones, then exit the cell cycle and migrate away from these zones. Here we show that migration of cerebellar granule cells out of their proliferative zone, the external granule cell layer (EGL), is impaired in Bdnf(-/-) mice. The reason for impaired migration is that BDNF directly and acutely stimulates granule cell migration. Purified Bdnf(-/-) granule cells show defects in initiation of migration along glial fibers and in Boyden chamber assays. This phenotype can be rescued by exogenous BDNF. Using time-lapse video microscopy we find that BDNF is acutely motogenic as it stimulates migration of individual granule cells immediately after addition. The stimulation of migration reflects both a chemokinetic and chemotactic effect of BDNF. Collectively, these data demonstrate that BDNF is directly motogenic for granule cells and provides a directional cue promoting migration from the EGL to the internal granule cell layer (IGL).     

T-cell trafficking in asthma: lipid mediators grease the way

Recruitment of T cells to the airways is crucial in the pathogenesis of asthma, and it is thought to be mediated mainly by peptide chemokines. By contrast, lipid mediators such as leukotrienes and prostaglandins have classically been thought to contribute to asthma pathogenesis by other mechanisms. However, as we discuss here, the recent molecular identification of leukotriene and prostaglandin receptors, as well as the generation of mice that are genetically deficient in them, has revealed that two of these lipids - leukotriene B(4) and prostaglandin D(2) - also direct T-cell migration and seem to cooperate with chemokines in a non-redundant, sequential manner to recruit T cells to the airways in asthma.     

Polymorphic restriction patterns of ribosomal internal transcribed spacers in the biocontrol fungus Puccinia carduorum correlate with weed host origin.

The internal transcribed spacer (ITS) regions of ribosomal DNA were amplified by PCR and used to develop genetic markers for isolates of Puccinia carduorum being evaluated for biological control of Carduus thoermeri (musk thistle). Unique patterns were produced upon restriction of ITS DNA amplified from four separate Puccinia spp. Restriction patterns of ITS DNA of isolates of P. carduorum from Carduus acanthoides and C. thoermeri were distinct from those of P. carduorum from Carduus tenuiflorus and Carduus pycnocephalus. By this technique, isolates of P. carduorum from four different weed hosts can be differentiated from other Puccinia spp. and separated into two host groups.     

Immunogenetic and ontogenetic studies of chickens with selective IgA deficiency and autoimmune thyroiditis

In addition to spontaneous hypothyroidism and autoimmune thyroiditis, chickens of the obese strain (OS) have a high incidence of selective IgA deficiency. Elevated levels of serum IgM also occur in many OS chickens. The IgA deficiency begins by 2 weeks, the age when hypothyroidism is developing. Like thyroiditis, a greater incidence of IgA deficiency was noted in OS birds homozygous for the B¹ allele than for the B⁴ allele of the major histocompatibility locus. Although IgA deficiency occurs in both sexes, it is found in a higher frequency in females than males (2:1). An abnormal ontogenesis of immunological competence may influence both traits.     

Restoration of IgA synthesis following transplantation of histocompatible bursa cells into cyclophosphamide treated chicks.

High dose cyclophosphamide (CY) administration to newly hatched Line 6 subline 1 (L6₁) chicks resulted in agammaglobulinemic birds. Monitoring of natural agglutinins to rabbit erythrocytes and immunoglobulin class quantitation by radial immunodiffusion analysis indicated that transplantation with 7-day histocompatible bursal cells partially restored the bursa-dependent immune system, including synthesis of IgA. Additionally, the bursa of Fabricius in this strain of birds appears to be highly susceptible to CY treatment as evidenced by the development of a relatively long-term agammaglobulinemia in > 85% of the CY-treated chicks.