1 protein = 2 opposing weight-control hormones

Obesity, a body mass index over 30 kg/m^2, is increasing in America and many western societies. Obesity is correlated with poor health, including diabetes and cardiovascular disease. Body weight is regulated by peptide hormones secreted from the gut and brain. Zhang and colleagues noted that ghrelin, a 28 amino acid, gut-derived peptide that stimulates appetite, is post-translationally trimmed from a larger, 117 amino acid protein. They identified in this larger protein not only a signal sequence but also a whole new, 23 amino acid peptide downstream of a potential convertase cleavage site. They named this second protein obestatin, for obesity-suppressing. They found obestatin in rat gut tissue. Whereas fasting rats had more ghrelin in their blood and fed rats had less, obestatin was stable between the groups. Injecting mice with synthetic obestatin blocked ghrelin-induced weight gains. Finally, they identified the hitherto orphan GPR39 as the G protein-coupled receptor. One gene encodes one protein that yields two antagonist peptides! This story promises to be an interesting and important example of post-translationally regulated protein expression.
Zhang et al., "Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake" Science 11 November 2005.

Interleukin-1 in Systemic Juvenile arthritis

Juvenile idiopathic arthritis (JIA), joint inflammation with unknown cause in children, affects an estimated 250,000 children in the US alone. About 10% of these cases begin with fevers and/or rash that precede joint symptoms by months or years, a subset called systemic onset JIA (SoJIA). These are hard to diagnose and most do not respond to TNF blockade, a therapy that helps many adult rheumatoid arthritis patients. Here, Pascual and colleagues show that the disease is instead driven by the other major proinflammatory cytokine, interleukin 1 (IL-1). They found that activate peripheral blood leukocytes from SoJIA patients make more IL-1 than do those from healthy people. Sera from SoJIA patients increased the expression of immune-related genes by leukocytes from healthy people. Most strikingly, an IL-1 receptor antagonist (IL-1Ra, Anakinra) reduced fever, arthritis, and other symptoms or markers of disease in all 9 SoJIA patients treated.
Pascual et al., J Exp. Med. 201(9) 1479-1486.

Publishing your mistakes?

Most scientists suspect that erroneous results occasionally make their way into publication. Now, Ioannidis confirms these suspicions, and worse, with statistical simulations. In a remarkably readable paper, he shows that "most published research findings are false"! Not surprisingly, bias increases the chances that the finding is false and large effects are more likely to be true than are small effects. Less expected is the conclusion that "a research finding is less likely to be true... when more teams are involved in a scientific field". In other words, "hot" fields have more mistakes published. The analysis is straightforward and may suggest reasonable ways to reduce the errors in publications.
Ioannidis, JPA. August 2005 PLoS Medicine 2(8):696-701

Insulin-Specific T Cells in Long-Term Diabetics

Type 1 diabetes is unusual among autoimmune diseases because diagnosis is greatly aided by laboratory tests. Levels of blood sugar and glycosylated hemoglobin are excellent measures of disease progression. The symptoms of disease are treated with insulin, which would normally be produced by the pancreatic beta cells that are destroyed in the autoimmune process. In common with other autoimmune diseases, the cause of type 1 diabetes is not known, though insulin itself has been a leading candidate autoantigen. Here, Kent and colleagues show they could find insulin-specific T lymphocytes in the lymph nodes draining the pancreas in 2 long-term diabetics, but not in 3 non-diabetic individuals or 1 recently-diagnosed diabetic. They argue against the T cells having been stimulated by therapeutic insulin because none were found in the spleen of one diabetic. They convincingly demonstrate that the T cell response is specific for the insulin peptide (residues 1-15 of the A chain) bound by host histocompatibility molecules (HLA-DR). The insulin-specific T cells were helper (CD4+) cells and, curiously, secreted a suspected tolerogenic helper type 2 cytokine (interleukin-13) and not a proinflamatory helper type 1 cytokine (interferon-gamma) in vitro. These observations strengthen the argument that long-term diabetes correlates with increased immune reactivity against
insulin.
Kent et al., Nature, May 12, 2005. 435(7039):224-8.

Alternate splicing may generate a fly immune receptor

Fruit flies have a large protein called Dscam (Down syndrome cell adhesion molecule) with 24 exons. Four of these exons are alternatively spliced from 12, 48, 33, and 2 variants, potentially generating over 18,000 slightly different Dscam proteins. The protein is expressed by brain cells and cells involved with protection against infectious agents: called fat bodies and hemocytes. Dscam is found on the surface of these cells and the extracellular portion of the protein, clearved from the cytoplasmic portion, is found in the insect equivalent of blood, called the hemolymph. The function of Dscam was not known, but Schmucker and colleagues suspected a role in immune protection. They found that many of the gene variants are expressed in the fat bodies and hemocytes, though even more variants are expressed in the brain. Most strikingly, reducing expression of Dscam with RNA inhibition or using null mutants reduces the phagocytosis of bacteria by hemocytes. Two Dscam variants, but not a third, bind one strain of bacteria, supporting the notion that these variants might protect against different pathogens. Moreover, the alternative splicing of Dscam is conserved in other insects. Although the human homologue is not alternatively spliced, might there be other Dscam-like receptors, analogous to Toll-like-receptors (TLRs) in the mammalian genome?"
Watson et al., Science. 2005 Sep 16 309(5742):1874

Immune Recognition of Vascular Endothelial Cells

Immunologists think about central or peripheral tolerance, depending on whether the potential antigen is found within the lymphoid tissues. The central immune system includes the bloodstream, lymph, and primary lymphoid organs such as the thymus and lymph nodes. From an immunologist's perspective, the "periphery" is all the body's non-lymphoid organs and tissues. This distinction overlooks the interface between these tissues - the endothelium - the single cell layer that lines the blood and lymph vessels. Given the pervasiveness of blood vessels, it is not surprising that endothelial cells (EC) have been implicated in many immune processes, most notably atherosclerosis and transplant rejection. These investigators directly tested the ability of the immune system to recognize a new protein expressed by EC using two strains of transgenic mice that express beta-galactosidase only in their EC because their genomes have the beta-gal gene, lacZ , under control of promoters specific for endothelial cells. One transgenic line, VWF-lacZ, expresses beta-gal only in heart and brain endothelium. A second line, TIE2-lacZ, expresses beta-gal in practically all endothelial cells. Upon immunization with beta-gal protein, these mice responded normally, generating strong antibodies and T cell responses. They also responded normally after immunization with a DNA vector driving expression of beta-gal. After immunization, vascular EC in the transgenic mice continued to express beta-gal and the vessels showed no signs of inflammation when analyzed microscopically. This suggested the EC were simply ignored. However, TIE2-lacZ skin (which contains beta-gal+ EC) stimulated
beta-gal specific antibodies when it was transplanted onto non-transgenic littermates. Moreover, no antibodies were stimulated upon transplantation onto VWF-lacZ mice, suggesting that the immune system in these mice were tolerant, not ignorant, of the beta-gal expressed by EC. They conclude that the immune system subtly tolerates and does not ignore EC proteins.
Annette L Rothermel, Yinong Wang, Jeffrey Schechner, Barry Mook-Kanamori, William C Aird, Jordan S Pober, George Tellides and David R Johnson. Endothelial cells present antigens in vivo BMC Immunology March 2004, 5:5

Mitochondrial tRNA mutant causes metabolic defects

Mitochondria are cellular organelles that use oxidative phosphorylation to convert the energy of reduced dietary carbon into ATP, which provides energy for practically all processes. Human mitochondria possess a mostly vestigial 16 kb genome, which encodes ribosomal and 22 transfer RNAs along with 13 proteins. There are more mitochondria in cells with high energy needs such as heart muscle cells, where mitochondria and myofibrils make up 85% of cell volume. Cardiovascular disease is associated with high blood pressure and high serum cholesterol. These investigators analyzed the genetics of a syndrome that includes hypertension (blood pressure >140/90 mm Hg), hypercholesterolemia (serum cholesterol >200 mg/dl), and hypomagnesemia (serum magnesium below 1.8 mg/dl) in 4 generations of a large family. A genome-wide linkage
analysis yielded no candidates. They found that the 32 family members of both sexes with hypomagnesemia all descended from one female, suggesting a mitochondrial defect. Upon sequencing and single-strand conformational polymorphism analysis, they found 14 variants, 13 of which were previously described, and one new variant at nucleotide 4291 of the mitochondrial genome, within an isoleucine tRNA. This tRNA mutation is found only on this maternal lineage, not among the thousands of previously sequenced mitochondrial genomes.
Wilson et al. Science 306: 1190, November 2004

Common infection might set stage for lupus

Infection is known to trigger certain autoimmune diseases, e.g., rheumatic fever and ankylosing spondylitis. The initial immune response against the pathogen is thought to also recognize "self" proteins called autoantigens and may later spread to recognize additional autoantigens. These investigators wished to test their suspicion that Epstein Barr virus (EBV) triggers systemic lupus erythematosus (SLE). They previously showed that the first SLE autoantigen is the RNA-binding protein Ro. Here, they analyzed blood samples from a repository drawn from more than 5 million people. They found 29 people who later developed lupus and who had donated a blood sample before they developed Ro-specific autoantibodies. Nine of these early sera contained autoantibodies that recognized only a single small portion of Ro. All of these early, Ro-specific antibodies cross-reacted with a completely different small fragment of the EBV nuclear protein EBNA-1, suggesting that the crossreaction could be an early event in the disease. To test this, they immunized rabbits with peptides matching Ro or EBNA-1. Strikingly, both groups of rabbits developed lupus-like symptoms, including reduced numbers of white blood cells (leukopenia), clotting factors (thrombocytopenia) and kidney function. This paper connects a common infection with lupus. It remains to be determined why lupus develops in relatively few of the many EBV infected adults.
McClain et al. Nat.Med. 11, 85 - 89 (2004) "Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry"

Defective Sweet Taste Receptor in Cats

Most mammals can taste bitter, sweet, salty, sour, and amino acids, such as glutamate (umami). The receptors for sweet and umami are paired G proteins, called T1Rs, that are expressed exclusively in the taste buds. T1R1 and T1R3 together respond to the umami taste. Similarly, T1R2 and T1R3 together recognize diverse natural and synthetic sweeteners. T1R2 and T1R3 are encoded by the genes Tas1r2 and Tas1r3. Cats, unlike puppies, do not prefer sweet foods. Previous work had demonstrated that alleles of Tas1r3 predict sugar intake. These investigators tested a simple hypothesis: cats are indifferent to sugar because their sweet taste genes are defective. Here, they show that the cat Tas1r2 gene has a large deletion in the coding region and no messenger RNA can be detected. They found similar deletions in the genes of tiger, cheetah and domestic cats and conclude that this is important in the evolution of the cat as carnivore.
Li et al. PLoS Genetics Volume 1 | Issue 1 | JULY 2005"

Vitamin D and Autoimmunity

Vitamin D deficiency has been implicated in several autoimmune disease, including systemic lupus erythematosus (SLE), type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis (MS). Munger and colleges tested the vitamin D levels in the serum samples collected in the US Army repository. They found that "high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis". When they investigated cause-and-effect, they found:

“Average 25- hydroxyvitamin D levels among individuals who developed MS were stable during the years preceding symptom onset (P=.42 for trend) but significantly decreased after onset of symptoms (P=.002). Mean 25-hydroxyvitamin D levels were 71.8 nmol/L more than 6 years before symptom onset (51 cases),…”

Surprisingly, they continue:

“These results argue against the possibility that the low preclinical 25-hydroxyvitamin D levels among individuals with MS are a consequence rather than a cause of the disease,..."

This finding seems to suggest that MS causes the decrease in vitamin D levels, not vice versa. Also, the average levels preceding the development of symptoms (71.8 nmol/L) is actually protective (figure). This seems inconsistent with a conclusion that low vitamin D contributes to MS (a conclusion they do not draw explicitly, instead stating they have established an “association”).