Anti-type 2 transglutaminase antibodies as modulators of type 2 transglutaminase functions: a possible pathological role in celiac disease

Auto-antibodies to the ubiquitous enzyme type-2 transglutaminase (TG2) are a specific hallmark of celiac disease (CD), a widely diffused, multi-factorial disease, affecting genetically predisposed subjects. In CD an inflammatory response, at the intestinal level, is triggered by diet consumption of gluten-containing cereals. Intestinal mucosa displays various degrees of atrophy and hyperplasia, with consequent global intestinal dysfunction and other relevant extra-intestinal symptoms. Through deamidation of specific glutamines of gluten-derived gliadin peptides, TG2 strongly enhances gliadin immunogenicity. In addition, TG2 cross-linking activity may generate complexes between TG2 itself and gliadin peptides, and these complexes seem to cause the auto-immune response by means of an apten-carrier-like mechanism of antigen presentation. Anti-TG2 antibodies can be early detected in the intestinal mucosa of celiac patients and are also abundantly present into the serum, thus potentially reaching other organs and tissues by blood circulation. Recently, the possible pathogenetic role of auto-antibodies to TG2 in CD has been investigated. Here, we report an overview about the genesis of these antibodies, their specificity, their modulating ability toward TG2 enzymatic or non-enzymatic activities and their biological effects exerted by interacting with extracellular TG2 or with cell-surface TG2. We also discuss the auto-immune response occurring in CD against other TG members (i.e. type 3 and type 6) and analyze the occurrence of anti-TG2 antibodies in other auto-immune CD-related diseases. Data now available let us to suppose that, even if antibodies to TG2 do not represent the triggering molecules in CD, they could be important players in disease progression and manifestations.     

Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability

Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.     

The effect of αB-crystallin and Hsp27 on the availability of translation initiation factors in heat-shocked cells

The mechanism of the translational thermotolerance provided by the small heat shock proteins (sHsps) αB-crystallin or Hsp27 is unknown. We show here that Hsp27, but not αB-crystallin, increased the pool of mobile stress granule-associated enhanced green fluorescent protein (EGFP)-eukaryotic translation initiation factor (eIF)4E in heat-shocked cells, as determined by fluorescence recovery after photobleaching. Hsp27 also partially prevented the sharp decrease in the pool of mobile cytoplasmic EGFP-eIF4G. sHsps did not prevent the phosphorylation of eIF2α by a heat shock, but promoted dephosphorylation during recovery. Expression of the C-terminal fragment of GADD34, which causes constitutive dephosphorylation of eIF2α, fully compensated for the stimulatory effect of αB-crystallin on protein synthesis in heat-shocked cells, but only partially for that of Hsp27. Our data show that sHsps do not prevent the inhibition of protein synthesis upon heat shock, but restore translation more rapidly by promoting the dephosphorylation of eIF2α and, in the case of Hsp27, the availability of eIF4E and eIF4G. Received 9 December 2005; received after revision 16 January 2006; accepted 23 January 2006     

Climate change and evolutionary adaptation

Evolutionary adaptation can be rapid and potentially help species counter stressful conditions or realize ecological opportunities arising from climate change. The challenges are to understand when evolution will occur and to identify potential evolutionary winners as well as losers, such as species lacking adaptive capacity living near physiological limits. Evolutionary processes also need to be incorporated into management programmes designed to minimize biodiversity loss under rapid climate change. These challenges can be met through realistic models of evolutionary change linked to experimental data across a range of taxa.