HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals

The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.     

Possible role of acetylcholinesterase in regulation of postsynaptic receptor efficacy at a central inhibitory synapse of Aplysia

Most of the effects of acetylcholinesterase (AChE) on synaptic transmission are considered to be related to its acetylcholine (ACh) hydrolysing properties. This is clearly apparent from changes which occur in the characteristics of the miniature endplate potential and of the endplate potential at neuromuscular junctions when AChE is inhibited1-4 and during the development of enzymatic AChE activity at maturing synapses5. However, we report here that after inhibiting AChE in a cholinergic synapse in Aplysia, we found an increase not only in postsynaptic responses to presynaptic stimulation and to ionophoretic application of ACh on postsynaptic receptors, but also to ionophoretic application of carbachol. This could not be explained by the inhibition of the ACh hydrolysing function of the enzyme, as carbachol is not hydrolysed by AChE. A possible explanation of these observations is that inhibition of the enzyme affects a property of the ACh receptor (AChR) itself.     

SB-restricted presentation of influenza and herpes simplex virus antigens to human T-lymphocyte clones

The HLA-D region of the human major histocompatibility complex (MHC) has been shown to be homologous to the murine I region in terms of both structure and function. Both regions encode class II MHC molecules which restrict T-lymphocyte interactions with antigen-presenting cells. We have recently described the MHC restriction and antigen specificities of human T-lymphocyte clones directed at strain A influenza virus. The majority of T-lymphocyte clones recognized antigen in the context of cell surface interaction products encoded by HLA-D/DR genes. However, a few clones recognized antigen presented by cells histoincompatible for D/DR antigens. We report here that some of these clones recognized viral antigens in association with antigens encoded by genes identical with or closely linked to the recently described secondary B-cell (SB) locus of the MHC. This is the first report that SB-restricted antigen recognition may form an integral part of normal, human immune responses.     

Steady-state kinetic studies with the polysulfonate U-9843, an HIV reverse transcriptase inhibitor

The tetramer of ethylenesulfonic acid (U-9843) is a potent inhibitor of HIV-1 RT^* and possesses excellent antiviral activity at nontoxic doses in HIV-1 infected lymphocytes grown in tissue culture. Kinetic studies of the HIV-1 RT-catalyzed RNA-directed DNA polymerase activity were carried out in order to determine if the inhibitor interacts with the template: primer or the deoxyribonucleotide triphosphate (dNTP) binding sites of the polymerase. Michaelis-Menten kinetics, which are based on the establishment of a rapid equilibrium between the enzyme and its substrates, proved inadequate for the analysis of the experimental data. The data were thus analyzed using steady-state Briggs-Haldane kinetics assuming that the template:primer binds to the enzyme first, followed by the binding of the dNTP and that the polymerase is a processive enzyme. Based on these assumptions, a velocity equation was derived which allows the calculation of all the specific forward and backward rate constants for the reactions occurring between the enzyme, its substrates and the inhibitor. The calculated rate constants are in agreement with this model and the results indicated that U-9843 acts as a noncompetitive inhibitor with respect to both the template:primer and dNTP binding sites. Hence, U-9843 exhibits the same binding affinity for the free enzyme as for the enzyme-substrate complexes and must inhibit the RT polymerase by interacting with a site distinct from the substrate binding sites. Thus, U-9843 appears to impair an event occurring after the formation of the enzyme-substrate complexes, which involves either an event leading up to the formation of the phosphoester bond, the formation of the ester bond itself or translocation of the enzyme relative to its template:primer following the formation of the ester bond.     

Evolution and ecological correlates of uniparental reproduction in freshwater snails

We review the spatial and temporal correlates of uniparental reproduction in freshwater snails as they pertain to the ecological hypotheses for the maintenance of biparental sex. The biogeographic evidence from two species (Potamopyrgus antipodarum andBulinus truncatus) presently supports the Red Queen hypothesis that biparental reproduction is selected as a way to reduce the risk to progeny of parasite attack. Uniparental reproduction in these species is associated with low levels of infection by parasites (castrating digenetic trematodes), suggesting that parthenogenesis or self-fertilization can replace cross-fertilization when the risk of infection is low. In addition, inB. truncatus, the opportunity for cross-fertilization coincides with the season in which parasite attack is highest. In a third species (Campeloma decisum), parthenogenetic reproduction is correlated with latitude and the presence of a non-castrating trematode that may prevent cross-fertilization; these patterns suggest that parthenogenesis has been selected as a mechanism to assure reproduction. Finally, we discuss the spotty taxonomic distribution of parthenogenetic species.