Serum concentration of alpha-2-macroglobulin, alpha-1-antitrypsin and alpha-2-antichymotrypsin in patients with lung carcinoma

Serum concentration of alpha-2-macroglobulin, alpha-1-antitrypsin and alpha-2-antichymotrypsin was evaluated in 26 patients with lung carcinoma. We observed an evident decrease in alpha-2-M and alpha-1-antitrypsin level and no differences between tested and control groups in alpha-1-antichymotrypsin concentration. The deficiency of protease inhibitors may be due to the increased level of protease activity in malignant cells. Infiltration of granulocytes near tumor and released enzymes from them may exhaust proteolytic inhibitory capacity, too. Increased protease activity is associated with transformation and uncontrolled proliferation, therefore antiproteases may be accepted as anticancerogenic factors. Further investigations are needed to bring us closer to understanding this question.     

Immunofluorescent evaluation of platelet alpha-1-antitrypsin and alpha-2-macroglobulin.

Rabbit raised anti-alpha-1-antitrypsin or anti alpha-2-macroglobulin antisera at dilution of less than 1:80 yielded non-specific staining on human platelets by indirect immunofluorescent technique. A similar pattern was in fact obtained by using normal rabbit sera at the same dilution and was due to the presence of smooth muscle autoantibodies. This indicates that human platelets do not contain significant quantities of these antigens. In agreement with the above, only microamounts of alpha-1-antitrypsin and alpha-2-macroglobulin were found to be present in human platelets by means of the electroimmunoassay.     

Polymorphisms of alpha-1-acid (orosomucoid), alpha-2-HS-glycoproteins and alpha-1-B among the Parsis of India.

Genetic polymorphisms of plasma alpha 1-acid glycoprotein (oro-somucoid, ORM), alpha 2-HS-glycoprotein (A2HS) and alpha 1-B-glycoprotein (alpha 1B) were studied in a group of Parsis in Bombay, India. The frequencies of ORM1*1, ORM1*2 and ORM1*3 were found to be 0.636, 0.356 and 0.008, respectively. A2HS*1, A2HS*2 and A2HS*3 frequencies were 0.855, 0.135 and 0.010, while the frequencies of A1B*1 and A1B*2 were 0.881 and 0.119, respectively. The phenotype distribution at all three loci was at Hardy-Weinberg equilibrium. The ORM2 locus was monomorphic in the Parsis.     

H-deficient blood groups of Reunion Island. III. alpha-2-L-fucosyltransferase activity in sera of homozygous and heterozygous individuals

Small amounts of H-enzyme activity (from 500 to 1,280 counts per minute [cpm]) were detected in sera of white H-deficient individuals (h/h; Reunion phenotype), while no significant H activity (less than 500 cpm) could be detected in sera of Indian H-deficient individuals (h/h; Bombay phenotype). The H-enzyme levels of the unaffected members of H-deficient pedigrees showed an H-related dosage effect. Heterozygous H/h individuals had only half as much H activity in sera (17,000 +/- 3,400 cpm) compared with homozygous H/H individuals (31,600 +/- 3,700 cpm). Data suggesting interactions between the H enzyme and the other gene specified glycosyltransferases working on the same oligosaccharide chains carrying combined ABH and Lewis antigens are analyzed in terms of their possible genetic or biochemical origin.     

Recognition of the alpha-1 and alpha-2 domains of H-2 molecules by allospecific cloned T cells

Previously we had shown that allospecific bulk cultures of cytolytic T lymphocytes lysed the products of cloned class I major histocompatibility genes expressed after DNA-mediated gene transfer. In these experiments, performed by using cloned allospecific T cell effectors, a T cell hybridoma, and recombinant DNA technology, we have been able to map determinants recognized by these T cell clones to the alpha-1 domain of H-2Dd and the alpha-2 domain of H-2Ld (four of eight clones). Target cells used were L cells (H-2k), expressing wild type or hybrid H-2 antigens of H-2d origin. Thus, for the first time determinants recognized by cloned T cells are found in the recombined alpha-1 and alpha-2 domains.     

Isolation of alpha-1-macroglobulin (alpha 1 M) and alpha-2-macroblogulin (alpha 2 M) from rabbit blood]

A purification process of rabbit alpha 1 M and alpha 2 M from plasma was described: first the platelets, the fibrinogen, the plasminogen and the low-density lipoproteins were eliminated; then alpha 1 M and alpha 2 M were purified by gel filtration on Sephadex G 200 and by chromatography on DEAE-cellulose. These purified materials were then isotopically labeled allowing the study of the proteins metabolism.     

The evolution of alpha-1 and alpha-2-macroglobulin levels in the serum of rabbit fetus and newborn

The study of the evolution of alpha-1 and alpha-2-macroglobulin levels in the rabbit fetus and newborn reveals an analogy between alpha-1-macroglobulin in the rabbit and alpha-2-macroglobulin in humans.     

Polymorphism of alpha-1 antitrypsin in dogs

• 1.1. A genetically determined polymorphism of alpha-1 antitrypsin is demonstrated in dog serum by isoelectric focusing in a pH range of 3.5–5.0, followed by direct immunoblotting using a specific antiserum.
• 2.2. Alpha 1 antitrypsin focuses as two major bands at isoelectric points of 4.60 and 4.64 or 4.67 and 4.7 in presumed homozygous animals. Heterozygotes show both sets of bands.
• 3.3. The results of seven crosses with 33 offspring are best explained by two codominant alleles, Pi^M and Pi^S at a single locus designated as Pi for proteinase inhibitor.
• 4.4. The concentration of alpha-1 antitrypsin in serum of healthy dogs was 2.65 ± 0.42 mg/ml and 2.19 ± 0.38 mg/ml in females andv males respectively.
• 5.5. The higher concentration in female dogs suggests that estrogens may influence the serum level of alpha-1 antitrypsin.

     

Rat plasma murinoglobulin: isolation, characterization, and comparison with rat alpha-1- and alpha-2-macroglobulins

Murinoglobulin, a newly identified mouse plasma protein with trypsin-protein esterase activity (Saito, A. & Sinohara, H. (1985) J. Biol. Chem. 260, 775-781), was also found in rat plasma and purified to apparent homogeneity. The serum level of rat murinoglobulin was 14.1 mg/ml, amounting to 1/3 of the total serum globulin fraction. Rat murinoglobulin was a monomeric glycoprotein (Mr = 210,000) containing 12% carbohydrate. Rat plasma contained two isoforms of murinoglobulin, termed I and II, which showed complete immunological identity on double diffusion analysis using rabbit antiserum raised against isoform I or II. These antisera also showed partial cross-reactivity towards mouse murinoglobulin and rat alpha-1-macroglobulin but not towards rat or human alpha-2-macroglobulin. The chemical compositions, peptide mapping patterns and electrophoretic mobilities of the two isoforms resembled each other but clearly differed from those of rat alpha-1- or alpha-2-macroglobulin. Rat murinoglobulin inhibited the proteolytic activity of trypsin towards casein and remazol brilliant blue hide powder. The inhibition as to the latter substrate was greater than that as to the former. When molar ratios of inhibitor to trypsin were low, murinoglobulin and the two alpha-macroglobulins stimulated the amidolytic activity of trypsin towards a synthetic substrate. At higher ratios, however, murinoglobulin, but not the alpha-macroglobulins, inhibited the same activity. The trypsin-protein esterase activity of murinoglobulin and the two alpha-macroglobulins was impaired by a molar excess of soybean trypsin inhibitor. Murinoglobulin and the two alpha-macroglobulins were inactivated by methylamine with a concomitant unmasking of the thiol group. Murinoglobulin was much more sensitive to soybean trypsin inhibitor and methylamine than the two alpha-macroglobulins.     

The alpha-3 domain of class I MHC proteins influences cytotoxic T lymphocyte recognition of antigenic determinants located within the alpha-1 and alpha-2 domains

An interspecies class I MHC molecule, Kb1+2/A2 (in which the alpha-1 and alpha-2 domains of the H-2Kb molecule have been linked to the alpha-3, transmembrane and intracytoplasmic domains of the HLA-A2 molecule) has been expressed on both human and mouse target cells by gene transfer. Maintenance of serologic determinants has been demonstrated. However, decreased lysis by allospecific CTL populations of cell lines that expressed a hybrid interspecies class I molecule, Kb1+2/A2, as compared with lines that expressed the native Ag, H-2Kb, has been described. An analysis with a limited panel of H-2Kb allospecific clones demonstrated that not all H-2Kb-specific CTL can lyse cells that express Kb1+2/A2 Ag. This suggested that the reduction of lysis by CTL populations was due to the loss of specific alloreactive clones in the population. Each clone used in this study was then defined as having high or low affinity characteristics. No correlation between the affinity of the CTL and the ability to recognize the interspecies hybrid molecule could be shown. Rather, these data suggest that antigenic determinants that are located within the polymorphic domains, alpha-1 and alpha-2, may be conformationally influenced by the alpha-3 domain.     

Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite® software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.     

Distribution of alpha-1-antitrypsin phenotypes in Sweden

The distribution of phenotypes of alpha-1-antitrypsin (Pi) in 1,062 unrelated Swedes was determined by isoelectric focusing with carrier ampholytes. The frequencies calculated were: PiM1 = 0.6940, PiM2 = 0.1384, PiM3 = 0.1139, PiZ = 0.0231, PiS = 0.0245, PiF = 0.0038, Pivar = 0.0024. A mother-child material consisting of 194 pairs is also presented.     

Polymorphism of alpha-1-antitrypsin in hematological malignancies

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ(2) = 4.42, d.f.11, p = 0.96 and χ(2) = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59% and 48%, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant.