A study in this issue of the JCI shows that in response to autoantigens consisting of peptides from normal proteins, patients with diabetes mount a T cell response characterized by production of IFN-γ . However, in response to these same antigens, T cells from normal control subjects produce IL-10. The antigen-specific response characterized by release of a regulatory cytokine suggests a mechanism for the control of autoimmunity that is initiated at the time of antigen presentation.
Kevan C. Herold
Mutations in lamins A and C, nuclear intermediate-filament proteins in nearly all somatic cells, cause a variety of diseases that primarily affect striated muscle, adipocytes, or peripheral nerves or cause features of premature aging. Two new studies use lamin A/C–deficient mice, which develop striated muscle disease, as a model to investigate pathogenic mechanisms. These reports provide evidence for a stepwise process in which mechanically stressed cells first develop chromatin and nuclear envelope damage and then develop secondary alterations in the transcriptional activation of genes in adaptive and protective pathways.
Howard J. Worman, Jean-Claude Courvalin
A shortcoming in the clinical use of organic nitrates is the development of tolerance. Recent data have suggested that the denitrification of organic nitrates is mediated by mitochondrial aldehyde dehydrogenase and that dysfunction of this enzyme is an important cause of tolerance. In this issue of the JCI, evidence in support of this hypothesis is presented in an in vivo model of nitrate tolerance.
John D. Parker
Genetic disorders of amino acid and fatty acid metabolism can be detected with tandem mass spectrometry (MS/MS). MS/MS screening of mice subjected to chemical mutagenesis defined a new disorder of branched-chain amino acid metabolism resembling human maple syrup urine disease. This approach has general application to the discovery of gene function in developmental and metabolic disorders.
Arnold W. Strauss
Excess collagen deposition occurs in pulmonary fibrosis. A new study suggests that collagen overproduction may originate from cells derived from bone marrow precursors rather than parenchymal lung fibroblasts .
Sarah E. Dunsmore, Steven D. Shapiro
Conserved pairs of CBS sequence motifs (named after cystathionine β-synthase) found in a wide variety of proteins associate to form Bateman domains. A new study establishes that Bateman domains bind adenosyl compounds and regulate IMP dehydrogenase, CBS, chloride channels, and AMP-activated protein kinase. This discovery reveals how mutations in CBS sequences in these proteins cause hereditary diseases and provides a rich vista of conceptual opportunities for therapies in energy metabolism, obesity, diabetes, cancer, antivirals, and immunosuppression.
Bruce E. Kemp
The family of neurodegenerative diseases known as hereditary spastic parapareses have diverse genetic loci, yet there is a remarkable convergence in the neuropathologic and neurologic phenotype. A report describing the construction of a transgenic mouse with a deletion of a nuclear-encoded mitochondrial protein involved in the regulation of oxidative phosphorylation suggests that this family of diseases may reflect activation of a final common pathway involving synaptic dysfunction that progresses to destruction of the presynaptic nerve terminal and axon .
Harris A. Gelbard
While it has long been known that the reduction of nitrite to nitric oxide (NO) forms iron-nitrosyl-myoglobin and is the basis of meat curing, a greater biological activity of the nitrite anion has only recently been appreciated. In the stomach, NO is formed from acidic reduction of nitrite and increases mucous barrier thickness and gastric blood flow (see the related study beginning on page 106). Nitrite levels in blood reflect NO production from endothelial NO synthase enzymes, and recent data suggest that nitrite contributes to blood flow regulation by reaction with deoxygenated hemoglobin and tissue heme proteins to form NO.
Mark T. Gladwin
Kaposi sarcoma–associated herpesvirus (KSHV) can establish latent infection in host cells. The latently infected cells can survive and proliferate with a few viral genes expressed. However, in some Kaposi sarcoma cells, KSHV undergoes a productive life cycle and causes cell lysis. A new study (see the related article beginning on page 124) demonstrates that, after KSHV infection or introduction of viral plasmids into host cells, viral DNA is rapidly lost. Lytic virus production with ensuing infections could balance the loss of the viral plasmids to maintain the virus in cancer cells.
Chen-Yu Wang, Bill Sugden
Jaundice, which is caused by accumulation of bilirubin, is extremely common in newborn infants. Phototherapy is an effective treatment, but a drug therapy would also be desirable. A Chinese herbal remedy for jaundice called Yin Zhi Huang is now shown to activate a liver receptor that enhances the clearance of bilirubin (see the related article beginning on page 137). This discovery could lead to improved pharmaceutical treatments for neonatal jaundice.
Mitchell A. Lazar
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