Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.     

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.     

Rapid responses of British butterflies to opposing forces of climate and habitat change.

Habitat degradation and climate change are thought to be altering the distributions and abundances of animals and plants throughout the world, but their combined impacts have not been assessed for any species assemblage. Here we evaluated changes in the distribution sizes and abundances of 46 species of butterflies that approach their northern climatic range margins in Britain-where changes in climate and habitat are opposing forces. These insects might be expected to have responded positively to climate warming over the past 30 years, yet three-quarters of them declined: negative responses to habitat loss have outweighed positive responses to climate warming. Half of the species that were mobile and habitat generalists increased their distribution sites over this period (consistent with a climate explanation), whereas the other generalists and 89% of the habitat specialists declined in distribution size (consistent with habitat limitation). Changes in population abundances closely matched changes in distributions. The dual forces of habitat modification and climate change are likely to cause specialists to decline, leaving biological communities with reduced numbers of species and dominated by mobile and widespread habitat generalists.     

Biology and conservation of the Coral Pink Sand Dunes tiger beetle, Cicindela limbata albissima Rumpp

This study investigated the distribution, abundance, and biology of Cicindela limbata albissima Rumpp, an endemic tiger beetle known only from the Coral Pink Sand Dunes (CPSD) in southwestern Utah. A recently implemented conservation agreement between BLM, USFWS, Utah State Parks, and Kane County protects most of the known habitat of this beetle from off-highway vehicle (OHV) use. A search of collection records and field surveys of 19 Great Basin sand dune sites indicated that this species occurs only at CPSD. Yearly index counts of adults (1992-1998) during peak season in May ranged from 331 in 1997 to 895 in 1993, but the actual population size is probably 2-3 times higher than the index counts. Nearly all of the population is found in the primary habitat, a 300-m-wide × 2.7-km-long area in the southern part of the dune field. Small numbers of adults and larvae have been found at the far north end of the dune field. Mark-recapture studies indicated that most adults moved only short distances ( Surveys of dominant plant species, arthropod (potential tiger beetle prey) abundance, and OHV activity indicated that these vary throughout the dune field and may explain, in part, the distribution of C. l. albissima . The primary habitat is a transition area between the highly dynamic south end of the dune field and the more stabilized north end. Psoralidium lanceolatum Rybd., Sophora stenophylla Gray, and Stipa hymenoides R.&S. are the dominant plants in the interdunal swales of the primary habitat, but other species are dominant in other parts of the dune field. Numbers of arthropod individuals and taxa are greatest in the primary habitat. Off-highway vehicle activity was greatest at the south end of the dune field and lowest at the far north end. Run-over trials and observational data revealed that adult beetles are killed by OHVs, but more important impacts may be damage to vegetation, reduction of arthropod prey of C. l. albissima , and disturbance and increased desiccation of the larval microhabitat. We anticipate that the conservation agreement will provide long-term protection for this species at CPSD.     

Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism

Morphogens act in developing tissues to control the spatial arrangement of cellular differentiation. The activity of a morphogen has generally been viewed as a concentration-dependent response to a diffusible signal, but the duration of morphogen signalling can also affect cellular responses. One such example is the morphogen sonic hedgehog (SHH). In the vertebrate central nervous system and limbs, the pattern of cellular differentiation is controlled by both the amount and the time of SHH exposure. How these two parameters are interpreted at a cellular level has been unclear. Here we provide evidence that changing the concentration or duration of SHH has an equivalent effect on intracellular signalling. Chick neural cells convert different concentrations of SHH into time-limited periods of signal transduction, such that signal duration is proportional to SHH concentration. This depends on the gradual desensitization of cells to ongoing SHH exposure, mediated by the SHH-dependent upregulation of patched 1 (PTC1), a ligand-binding inhibitor of SHH signalling. Thus, in addition to its role in shaping the SHH gradient, PTC1 participates cell autonomously in gradient sensing. Together, the data reveal a novel strategy for morphogen interpretation, in which the temporal adaptation of cells to a morphogen integrates the concentration and duration of a signal to control differential gene expression.