Citations

The major predisposing genetic component in type 1 diabetes maps to the major histocompatibility complex locus in both mice and humans. To verify the HLA class II association with disease pathogenesis, we adopted the transgenic approach. Expression of HLA-DQ8, the molecule showing the strongest association with human type 1 diabetes, in the diabetes-predisposing milieu of NOD mice in the absence of the endogenous class II molecule I-Ag7 did not render susceptibility to type 1 diabetes. To study if providing a local proinflammatory environment would lead to diabetes in these mice, Aβo.NOD.DQ8 were bred with C57BL/6 mice expressing tumor necrosis factor (TNF)-α in the β-cells of the islets of Langerhans. Surprisingly, although diabetes was evident in the F1 intercross expressing rat insulin promoter (RIP)-TNF, offspring lacking either endogenous or transgenic class II molecules developed accelerated diabetes with high frequency in both sexes. Moreover, expression of any functional class II molecule seemed to confer significant protection from diabetes in this model. Thus, neonatal expression of TNF-α in an islet-specific manner bypassed the requirement of CD4+ T-cells and resulted in diabetes that could be mediated by CD8+ T-cells. We also show for the first time that diabetes in NOD.RIP-TNF mice can occur independent of inheritance of NOD-derived idd1.

ABSTRACT Conjunctival exposure to the Staphylococcus aureus superantigen staphylococcal enterotoxin B (SEB) may occur accidentally, as a result of bioterrorism, or during colonization or infection of the external eye. Using human leukocyte antigen class II transgenic mice, we show for the first time that conjunctival exposure to SEB can cause robust systemic immune activation.

ABSTRACTStaphylococcus aureusis widely prevalent in the nasopharynges of healthy individuals (carriers) but can also cause serious infections.S. aureuscan elaborate a variety of superantigen exotoxins in “carrier” or “pathogenic” states.Streptococcus pyogenescan also colonize the nasopharynx and elaborate superantigens. Unlike the acute effects of superantigen exotoxins absorbed through the gut or vaginal mucosa, little is known regarding the pathogenesis of superantigens entering through the intranasal route. In the current study, we evaluated the local and systemic effects of staphylococcal enterotoxin B (SEB) and streptococcal pyrogenic exotoxin A (SPEA) delivered through the intranasal route. Superantigens were administered intranasally on multiple occasions, and experimental animals were sacrificed on day 8 for experimental analyses. SEB-induced airway inflammation was more pronounced for HLA-DR3 transgenic mice than for BALB/c mice, consistent with bacterial superantigens binding more efficiently to human than murine major histocompatibility complex class II. The nature of the airway inflammation in HLA-DR3 mice was determined by the concentration of SEB applied intranasally. Low concentrations (20 ng) induced eosinophilic airway inflammation as well as eosinophil degranulation, whereas intranasal exposure to higher concentrations (2,000 ng) resulted in neutrophilic airway inflammation, permanent airway destruction, toxic shock, and mortality. SEB-induced eosinophilic inflammatory response was enhanced in signal transducer and activator of transcription (STAT)-4-deficient HLA-DQ8 transgenic mice with defective interleukin-12 signaling. Intranasal administration of SPEA induced airway inflammation and systemic immune activation in HLA-DQ8 transgenic mice. In conclusion, repeated chronic intranasal exposure to bacterial superantigens causes airway inflammation and systemic immune activation.

Data and simulated data from circumscribing and linear sampled arrays has been used to form high resolution reflection images by two techniques. The first technique (synthetic focusing) uses the mathematical equivalent of a lense to focus the image at each point by adding either linear (uncompressed) or nonlinear (compressed) transforms of the data. Logarithmic and square root compression is studied. The lense effect is obtained by backprojecting convolved or other linear transformed versions of the data along equal time propagation surfaces in the image with appropriate corrections for refraction and frequency dependent attenuation. The choice of apodizing function and different wave forms can greatly improve image resolution. The second technique (reflection ART) is not based on a focusing model but rather on direct inversion of a matrix (linear transform) model of the object-acoustic field interaction and data acquisition process by a Kacmarz iterative inversion method. The two methods are compared.

Quantitative images of acoustic speed distribution in excised human tissues, in excised dog myocardium, and in in vivo female breasts were obtained by ultrasound computerized tomography. The in vitro study was carried over a temperature from 20° to 40 °C. Results indicate (1) acoustic speed in human tissues (except fat) increase monotonically with temperature in this range, (2) fat shows an anomalous decrease in acoustic speed around 35 °C, (3) average acoustic speed is higher in breasts with cancer and with fibrocystic disease compared to normal breasts, and (4) acoustic speed is a function of age. The reconstruction problem in ultrasound computerized tomography is unlike its x-ray analog because of the refraction and diffraction effects. Methods to correct for the consequent degradation are discussed. The backscattering properties of in vivo myocardial tissue of dogs were studied by a high-resolution B-scanner and the potential of (renovist and indocyanine green) as ultrasound contrast agents to quantitate perfusion in the myocardium will be discussed. [Work supported by NCI-CB-64041, HV 72928, HL-07111, HL-00060, HL-00170.]

ABSTRACT Endogenous superantigen-mediated thymic negative selection resulted in a paucity of mature T cells bearing T-cell receptor (TCR) Vβ8 in the periphery. Consequently, the magnitude of immune response to exogenous superantigen staphylococcal enterotoxin B, which activates TCR Vβ8 + T cells, was significantly reduced and conferred protection from superantigen-induced mortality.

ABSTRACTSuperantigen peptide antagonists failed to block T-cell activation and cytokine production as well as toxic shock induced by staphylococcal enterotoxin B (SEB) in HLA class II transgenic mice. They also failed to inhibit the binding of SEB to HLA class II molecules as well as activation of human T lymphocytes in vitro.