TRAIL-R attenuates innate immunity

drj writes: "TRAIL, officially known as TNFSF10, induces apoptosis of virus-infected or transformed cells but not normal cells, suggesting a potentially "magic bullet" therapeutic. TRAIL expression is inducible on immune effector cells: Natural Killers (NK) and T cells, macrophages, and dendritic cells. TRAIL knockout mice are more susceptible to tumor metastasis and chemical carcinogenesis. TRAIL-R (receptor) expression is apparently induced by transformation or infection.
Here, Diehl and collegues describe the generation and characterization of TRAIL-R knockout (TRAIL-R-KO) mice. (Mice have only one signaling receptor; humans have two: TNFRSF10A, B.) TRAIL-R-KO mice have normal lymphocyte populations but produce more of the cytokines IL-12, IFN-alpha, and IFN-gamma and clear cytomegalovirus more rapidly. TRAIL-R-KO macrophages stimulated with pathogen-derived molecules (e.g., LPS) though the Toll-like receptors show increased TRAIL expression and enhanced cytokine production. Although early signaling is normal, activation of the transciption factor NF-kB and degradation of its inhibitor IkB-a is prolonged (12 h).
What is the point of inhibiting the innate response? Unlike the adaptive response, there are no expanded populations of cells to inactivate and remove." Diehl et al., Immunity 21:877-889, December, 2004
TRAIL-R as a Negative Regulator of Innate Immune Cell Responses

Interleukin-7, T cells, and Rheumatoid Arthritis

drj writes "Transient lymphocyte depletion is an effective therapy for some autoimmune diseases, including
juvenile rheumatoid arthritis and multiple sclerosis (MS). Lymphocytes are usually replenished by treatment with growth factors after depletion or with stem cells after ablation. However, CD4 T cells remain depleted for extended periods following therapy of rheumatoid arthritis (RA). Ponchel and colleagues now demonstrate significantly reduced levels of circulating interleukin-7 (IL-7), a T cell growth factor , in the sera of RA patients. Serum IL-7 increased transiently in cancer patients but not RA patients following lymphocyte depletion and autologous stem cell reconstitution.
It would be relatively easy to supplement RA treatment with recombinant IL-7. As the authors acknowledge, however, this would require careful monitoring since IL-7 has been implicated in MS, lymphoma and other cancers."
Ponchel et al., Arthr. Res. & Ther. 7, 2005
"Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia"

Gut check time?

drj writes "Dieters complain about growing fatter despite eating less and exercising more. Backhed and colleagues now provide surprising support for half this claim. Germ-free mice “conventionalized” with microorganisms from the guts of normal mice increase their body fat 60% in just 2 weeks despite eating less. Activity levels were not reported. The bacteria were transmitted by spreading the contents of the distal intestine from normal mice onto the fur of germ-free mice. The microorganisms apparently act by increasing the uptake of sugars from the gut into the bloodstream. Adaptive immunity is not involved in this response because conventionalized Rag1-knockout animals behave similarly. The authors propose that Western diets may predispose to obesity by promoting certain gut microorganisms.
Will obesity, like ulcers caused by Helicobacter pylori, now be understood as having a key microbiological component? Is there a market for bugs from skinny people?"
"The gut microbiota as an environmental factor that regulates fat storage" Fredrik Backhed, Hao Ding, Ting Wang, Lora V. Hooper, Gou Young Koh, Andras Nagy, Clay F. Semenkovich, and Jeffrey I. Gordon. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15718-23. PMID: 15505215

Deamidation & Deimination in Disease

Julian Banerji writes "Deamidation of ASN residues in Bcl-xl may regulate apoptosis (Zhao). Deimination of histones can regulate their activity (Cuthbert and Wang.) Deiminated ARG in Fibronectin is the target of some autoantibodies in RA (Hida). The involvement of Peptidylarginine deimidase (PAD) in disease is explored in Vossenaar. The location of PAD is characterized in synovial tissue by Chang. A Japanese group has found polymorphisms in PAD linked to RA (Suzuki). The stories speak for themselves. Something else that's pretty cool: large scale unfolding of chromatin by estrogen receptor (Carpenter) "

Pecking Ordered

drj writes "Darwin found on the Galapagos Islands 14 species of finches with different beak shapes. He proposed that their different beaks allowed them to exploit different foods – short and wide for cracking seeds vs. long and narrow for reaching into flowers. Abzhanov et al. now show that expression of the bone morphogenic protein 4 gene (Bmp4) is higher in the upper beak epithelium of embryonic chicks growing shorter, stronger beaks, suggesting that BMP4 shapes beaks. Expression of Bmp2 and Bmp4 message, in contrast, correlated with the size of the beak. Surprisingly, expression of Bmp4 in the lower beak epithelium does not vary despite shape differences that are comparable to those in the upper beak. Infection with a virus expressing BMP4 protein produced shorter, wider beaks whereas infection with a virus expressing Noggin, which antagonizes BMP2/4/7 activity, produced longer, narrower beaks. The authors are also “tempted to speculate” that Sonic hedgehog (shh) and Fibroblast growth factor 8 (fgf8) are the nuclear factors driving expression of bmp4. The accompanying article by Wu et al. also concludes that BMP4 shapes beaks. Who regulates the regulators (ssh, fgf8)?
Bmp4 and Morphological Variation of Beaks in Darwin’s Finches Arhat Abzhanov, Meredith Protas, B. Rosemary Grant, Peter R. Grant, Clifford J. Tabin. Science 305:1462, September 3, 2004

J Exp Med Classics online

drj writes "The Journal of Experimental Medicine has produced pdf (Acrobat) versions of all papers they've published since 1896! Now you can peruse the classic 1944 Avery, MacLeod, and McCarty paper that first showed “desoxyribonucleic acid” (DNA) was the “transforming substance”. Or, one of their follow-up papers, for example an "Improved Method for the Isolation of the Transforming Substance”, very early in a very long string of DNA methods papers. Or here’s one of my favorites, the genetic regulation of the immune response. For a glance backward at less memorable papers, try the I-J era. Three cheers and much appreciation to the publisher, the
Rockefeller University Press, with support from The Medical Library Center of New York. This stuff is too old for PubMed (which covers back to the mid-1960s) and even for OLDMEDLINE, which currently goes back to 1951. You’ve got to seek and find it on your own. Search here for your favorite classics (old and new).
What's your favorite J Exp Med paper?"

Synthetic prions

carbonbasedunit writes "In the 20 years since Prusiner popularized Griffith’s suggestion that infectious protein causes Creutzfeld-Jacob disease, the "protein-only" hypothesis has matured from radical to conventional. The hardy doubters not cowed by the 1997 Nobel prize still argued that the infectious agent in brain preparations had not been proven to be protein but could instead be contaminating nucleic acids (review).
Now Legname et al. show that when polymerized into amyloid fibrils and injected into the brains of mice, recombinant mouse prion protein produced in bacteria induces neurologic disease. They previously showed that disease was accelerated in disease-prone mice treated with a synthetic 55 amino acid peptide matching a fragment of a mutant (P101L) human prion that causes spontaneous disease in younger adults. Here, they produced fibrils from a recombinant, truncated mouse prion in mice that do not develop the disease spontaneously. Rather than having fortuitously refolded in vitro a natural prion form, the authors instead suggest based on histology that a novel strain of prion was created. Is there a potential Pandora’s box of prions?
Synthetic mammalian prions. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB. Science. 2004 Jul 30;305(5684):673-6.

Innate + Adaptive = Immunity

drj writes "Innate immunity is initiated by host cells recognizing stable molecular patterns associated with pathogenic microbes and viruses. These molecular patterns are thought to be reliable triggers because they are required for the life of the pathogen. Here, French et al. show that viruses can change these patterns and evade innate immunity in mice deficient in adaptive immune responses. Early infection by murine cytomegalovirus is controlled by natural killer (NK) cells, which use one form of Ly49H to recognize a viral protein, m157, that is expressed on infected cells. Mice possessing a form of Ly49H that is not activated by this virus die in 6 days. Recombinase-deficient mice without adaptive immunity efficiently suppress viral replication for only about 3 weeks, when they succumb. Viruses recovered from these mice do not trigger Ly49H+ NK cells and nearly all possess mutations in m157, probably allowing them to resist innate immunity. This paper demonstrates an essential role for adaptive immunity in clearing virus, thereby reducing the risk of a mutant evading the innate immune system. Even for this double-stranded DNA virus, mutations occur frequently enough to present a serious health risk. The authors suggest that cytomegalovirus disease, which develops more than a month after transplant in some immune suppressed recipients, may be due to a similar selection of mutant viruses escaping the innate immune response.
Escape of Mutant Double-Stranded DNA Virus from Innate Immune Control Anthony R. French, Jeanette T. Pingel, Markus Wagner, Ivan Bubic, Liping Yang, Sungjin Kim,Ulrich Koszinowski, Stipan Jonjic, and Wayne M. Yokoyama. Immunity, Vol. 20, 747–756, June, 2004

Asthma – the Chitin hypothesis

drj writes "Chitin is a polysaccharide that forms fungal cell walls and the exoskeleton of insects and crustacea. Some 'lower' organisms use enzymes that degrade chitin, chitinases, for defense. Chitinases are also found in mammals but their function is unknown. Here, Zhu et al. show that acidic mammalian chitinase (AMCase) accumulates in the lung epithelium of human asthmatics and in mice treated to induce asthma. In mice, the accumulation depended on "type 2" (allergic) helper T lymphocytes and their characteristic cytokines, IL-4 and IL-13. Most promising was the reduction in inflammation caused by blocking AMCase with specific antibodies, suggesting it is a good target for therapy. The authors discuss the potential links between chitin-containing insects, hygiene, and asthma."
Acidic Mammalian Chitinase in Asthmatic Th2 Inflammation and IL-13 Pathway Activation Zhou Zhu, Tao Zheng, Robert J. Homer, Yoon-Keun Kim, Ning Yuan Chen, Lauren Cohn, Qutayba Hamid, Jack A. EliasScience304: 1678-82 Zhu et al., Science 304:1678-82, April 2004

Splice and die!

drj writes "Cytotoxic T lymphocytes (CTL) are triggered by short peptides (8-10 amino acids) held by MHC class I molecules on the target cell. Peptides often derive from cleaved and trimmed full-length proteins but an
earlier report described a spliced peptide that flanks a 40 amino acid deletion within the protein fibroblast growth factor-5 (FGF-5). Vigneron et al. now report the second example of a spliced peptide, a 4 amino acid deletion within a melanocyte glycoprotein 100 (gp100) peptide. They also found that “highly purified” proteasomes are capable of peptide splicing and suggested that closely spaced threonines within the proteasome catalyze protein cleavage and peptide ligation. They estimate that only 1 spliced peptide is produced from 10,000 gp100 molecules but even this low efficiency is good enough to trigger CTL. This phenomenon expands enormously the universe of potential peptides (and will greatly complicate the prediction of MHC binding peptides).
An Antigenic Peptide Produced by Peptide Splicing in the Proteasome Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde BJ.
Science 304:587-23 APRIL 2004"