Anti-DNA antibodies are a major component of the intrathecal B cell response in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of unknown cause that afflicts the central nervous system. MS is typified by a highly clonally restricted antigen-driven antibody response that is confined largely to the central nervous system. The major antigenic targets of this response and the role of antibody in disease pathogenesis remain unclear. To help resolve these issues, we cloned the IgG repertoire directly from active plaque and periplaque regions in MS brain and from B cells recovered from the cerebrospinal fluid of a patient with MS with subacute disease. We found that high-affinity anti-DNA antibodies are a major component of the intrathecal IgG response in the patients with MS that we studied. Furthermore, we show DNA-specific monoclonal antibodies rescued from two subjects with MS as well as a DNA-specific antibody rescued from an individual suffering from systemic lupus erythematosus bound efficiently to the surface of neuronal cells and oligodendrocytes. For two of these antibodies, cell-surface recognition was DNA dependent. Our findings indicate that anti-DNA antibodies may promote important neuropathologic mechanisms in chronic inflammatory disorders, such as MS and systemic lupus erythematosus.

DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state.

Transgenic mice expressing the sequences coding for the envelope proteins of the hepatitis B virus (HBV) in the liver have been used as a model of the HBV chronic carrier state. We evaluated the possibility of inducing a specific immune response to the viral envelope antigens and thus potentially controlling chronic HBV infection. Using HBV-specific DNA-mediated immunization in this transgenic model, we show that the immune response induced after a single intramuscular injection of DNA resulted in the complete clearance of circulating hepatitis B surface antigen and in the long-term control of transgene expression in hepatocytes. This response does not involve a detectable cytopathic effect in the liver. Adoptive transfer of fractionated primed spleen cells from DNA-immunized mice shows that T cells are responsible for the down-regulation of HBV mRNA in the liver of transgenic mice. To our knowledge, this is the first demonstration of a potential immunotherapeutic application of DNA-mediated immunization against an infectious disease and raises the possibility of designing more effective ways of treating HBV chronic carriers.

Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase B (ASB), which is involved in degradation of dermatan sulfate and chondroitin 4-sulfate. A MPS VI mouse model was generated by targeted disruption of the ASB gene. Homozygous mutant animals exhibit ASB enzyme deficiency and elevated urinary secretion of dermatan sulfate. They develop progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age facial dysmorphia becomes overt, long bones are shortened, and pelvic and costal abnormalities are observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals are seen. All major parenchymal organs show storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice are fertile and mortality is not elevated up to 15 months of age. This mouse model will be a valuable tool for studying pathogenesis of MPS VI and may help to evaluate therapeutical approaches for lysosomal storage diseases.

A truncated mutant (residues 58-140) of the hepatitis B virus X protein retains transactivation function.

The hepatitis B virus X protein (HBx) sequence (154 aa) has been divided into six regions (A-F) based on its sequence homology with X proteins of other mammalian hepadnaviruses. Regions A, C, and E are more conserved and include all the four conserved cysteines (C7, C61, C69, and C137). To localize the regions of HBx important for transactivation, a panel of 10 deletion mutants (X5-X14) and 4 single point mutants (X1-X4), each corresponding to a conserved cysteine residue, was constructed by site-directed mutagenesis. A HBx-specific monoclonal antibody was developed and used to confirm the expression of mutants by Western blot. Transactivation property of the HBx mutants was studied on Rous sarcoma virus-long terminal repeat (RSV-LTR) in transient transfection assays. We observed that deletion of the most conserved region A or substitution of the N-terminal cysteine (C7) had no effect on transactivation. Deletion of the nonconserved regions B or F also had no deleterious effects. Deletions of regions C and D resulted in a significant loss of function. Substitution of both C61 and C69 present in region C, caused almost 90% loss of activity that could be partially overcome by transfecting more expression plasmid. The fully conserved 9 amino acid segment (residues 132 to 140) within region E including C137 appeared to be crucial for its activity. Finally, a truncated mutant X15 incorporating only regions C to E (amino acids 58-140) was able to stimulate the RSV-LTR quite efficiently, suggesting a crucial role played by this domain in transactivation function.

Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver.

Hepatitis B virus (HBV) infection is thought to be controlled by virus-specific cytotoxic T lymphocytes (CTL). We have recently shown that HBV-specific CTL can abolish HBV replication noncytopathically in the liver of transgenic mice by secreting tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) after antigen recognition. We now demonstrate that hepatocellular HBV replication is also abolished noncytopathically during lymphocytic choriomeningitis virus (LCMV) infection, and we show that this process is mediated by TNF-alpha and IFN-alpha/beta produced by LCMV-infected hepatic macrophages. These results confirm the ability of these inflammatory cytokines to abolish HBV replication; they elucidate the mechanism likely to be responsible for clearance of HBV in chronically infected patients who become superinfected by other hepatotropic viruses; they suggest that pharmacological activation of intrahepatic macrophages may have therapeutic value in chronic HBV infection; and they raise the possibility that conceptually similar events may be operative in other viral infections as well.

The circumstellar environment and evolutionary status of the supergiant B[e] star Wd1-9

Context. Historically, supergiant (sg)B[e] stars have been difficult to include in theoretical schemes for the evolution of massive OB stars. Aims. The location of Wd1-9 within the coeval starburst cluster Westerlund 1 means that it may be placed into a proper evolutionary context and we therefore aim to utilise a comprehensive multiwavelength dataset to determine its physical properties and consequently its relation to other sgB[e] stars and the global population of massive evolved stars within Wd1. Methods. Multi-epoch R- and I-band VLT/UVES and VLT/FORS2 spectra are used to constrain the properties of the circumstellar gas, while an ISO-SWS spectrum covering 2.45−45μm is used to investigate the distribution, geometry and composition of the dust via a semi-analytic irradiated disk model. Radio emission enables a long term mass-loss history to be determined, while X-ray observations reveal the physical nature of high energy processes within the system. Results. Wd1-9 exhibits the rich optical emission line spectrum that is characteristic of sgB[e] stars. Likewise its mid-IR spectrum resembles those of the LMC sgB[e] stars R66 and 126, revealing the presence of equatorially concentrated silicate dust, with a mass of ~10−4M⊙. Extreme historical and ongoing mass loss (≳ 10−4M⊙yr−1) is inferred from the radio observations. The X-ray properties of Wd1-9 imply the presence of high temperature plasma within the system and are directly comparable to a number of confirmed short-period colliding wind binaries within Wd1. Conclusions. The most complete explanation for the observational properties of Wd1-9 is that it is a massive interacting binary currently undergoing, or recently exited from, rapid Roche-lobe overflow, supporting the hypothesis that binarity mediates the formation of (a subset of) sgB[e] stars. The mass loss rate of Wd1-9 is consistent with such an assertion, while viable progenitor and descendent systems are present within Wd1 and comparable sgB[e] binaries have been identified in the Galaxy. Moreover, the rarity of sgB[e] stars - only two examples are identified from a census of ~ 68 young massive Galactic clusters and associations containing ~ 600 post-Main Sequence stars - is explicable given the rapidity (~ 104yr) expected for this phase of massive binary evolution.

The treatise of al-Jazarī on automata; leaves from a manuscript of the Kitāb fī maʻarifat al-hiyal al handasiya in the Museum of fine arts. Boston, and elsewhere,

Plates, accompanied by unnumbered leaf, laid in.

The A.B.C. of canning : preserving, drying, smoking and pickling of foods /

Includes index.

The foundations of England; or, Twelve centuries of British history (B.C. 55-A.D. 1154)

"List of authorities": v. 1, p. 540-553.

The A B C of cutting and making garments for everyday needs ... /

Mode of access: Internet.

The A B C of the foreign exchanges : a practical guide /

Mode of access: Internet.

The pathology of the vitamin B complex deficiencies in the chicken.

This essay won the Poultry Disease Essay contest for 1949.

Selections from the sources of English history : being a supplement to text-books of English history B.C. 55-A.D. 1832 /

Includes biographical references and index.

The "A.B.C." guide to the making of autotype prints in permanent pigments...

"Revised edition."