Tuesday, December 26, 2006

Toll-free immune responses

Toll receptors mediate invertebrate protection against bacteria and yeast. Homologous mammalian molecules, the “Toll-like receptors” (TLR), were identified almost a decade ago and were immediately implicated in immunity and autoimmunity. TLRs were thought to provide crucial adjuvant stimulation to trigger the specific adaptive immune response. So you can imagine their surprise when Nemazee and colleagues found that mice mice without functional TLRs nevertheless made strong antibody responses against antigens in four typical adjuvants, including Freund’s Complete Adjuvant (FCA) (Figure). These mice were genetically deficient in both MyD88 and TRIF, which mediate all known TLR signaling. Mice were immunized with the antigen trinitrophenol - hemocyanin (TNP-Hy) in Freund's complete adjuvant. Similar results were obtained with another common experimental antigen, TNP-KLH (keyhole limpet hemocyanin). The deficient mice also responded normally following TNP-Hy immunization with the adjuvant alum, which is used in humans. Moreover, the TLR deficient mice also respond strongly against adjuvants containing TLR ligands. The authors modestly state that these findings “may have important implications in the use and development of vaccine adjuvants”.

Thursday, December 21, 2006


The NIH has a treasure of video recordings of biomedical lectures available for viewing. One recent lecture by Dr. James Bassingthwaite (U Washington) was an enjoyable tour of physiology, the thinking man's biology, and introduction to the 'Physiome' Projects. Though physiology is rarely mentioned these days, replaced by newer terms such as "systems" or "integrative" biology, he reminds us that physiology has always focused on connecting different branches of biology, answering the how and why in biology. He makes a strong case for sharing models and working together to improve them. The Physiome projects provide the JSim software and many models that run on JSim. The lecture's scope is broad, ranging from modeling to personalized medicine, always with a foot or two solidly planted on the ground.

Tuesday, December 12, 2006

CNS and centrality of the cytoskeleon

That cytoskeletal proteins provide a fundamental organising principle for a cell has been appreciated for a long time. However, the centrality of these proteins in disease progression and aging has been realised more recently. Ikeda and coworkers have reported that mutations in bIII spectrin, a cytoskeletal protein expressed abundantly in Purkinje cells, result in spinocerebellar ataxia type 5 (SCA5). Interestingly, the pedigree studied was from President Lincoln's family. The mutations reported result in destabilization of the glutamate transporter EAAT4 resulting in impaired glutamate signalling. While mutations in subunits of the EAAT4 have been shown to affect their assembly and therefore their function, this report draws attention to the importance of the cytoskeleton in proper assembly and stability of subcellular organelles and domains.