Presence of hsp65 in bacterial extracts (OM-89): A possible mediator of orally-induced tolerance?

Heat shock proteins (HSP) have been implicated in rodent models of autoimmunity, particularly arthritis, and there is suggestive though inconclusive evidence that they may also play a role in human autoimmune disease. The simplest hypothesis is based on molecular mimicry due to the amino-acid sequence homology between mammalian and microbial HSP. Recently OM-89, an extract of several strains ofEscherichia coli, has shown some efficacy in the treatment of rheumatoid arthritis (RA) when taken orally. Using species-specific antibodies, we show here that OM-89 contains the 65 kDa HSP (hsp65), while hsp65 was not detected in another bacterial extract containing other microorganisms, includingStaphylococcus aureus (OM-85). We suggest that if the human homologue of hsp65 is a relevant target antigen in the human disease, the efficacy of the preparation could be due to induction of oral tolerance or to switching the Th1 response towards Th2. Alternatively, even if the human hsp65 is not a target molecule in RA joints, OM-89 may evoke bystander suppression of joint inflammation via induction of TGF-secreting effector cells. These hypotheses should be tested in further studies.     

Dominant missense mutations in ABCC9 cause Cantú syndrome

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.     

Postcranial evidence from early Homo from Dmanisi, Georgia

The Plio-Pleistocene site of Dmanisi, Georgia, has yielded a rich fossil and archaeological record documenting an early presence of the genus Homo outside Africa. Although the craniomandibular morphology of early Homo is well known as a result of finds from Dmanisi and African localities, data about its postcranial morphology are still relatively scarce. Here we describe newly excavated postcranial material from Dmanisi comprising a partial skeleton of an adolescent individual, associated with skull D2700/D2735, and the remains from three adult individuals. This material shows that the postcranial anatomy of the Dmanisi hominins has a surprising mosaic of primitive and derived features. The primitive features include a small body size, a low encephalization quotient and absence of humeral torsion; the derived features include modern-human-like body proportions and lower limb morphology indicative of the capability for long-distance travel. Thus, the earliest known hominins to have lived outside of Africa in the temperate zones of Eurasia did not yet display the full set of derived skeletal features.