Immunological discrimination between self and non-self by precursor depletion and memory accumulation

We study processes by which T-lymphocytes "learn" to discriminate "self" from "non-self". We show that intrinsic features of the T cell activation and proliferation process are sufficient to tolerize (self) reactive T-lymphocyte clones. Self vs non-self discrimination therefore develops without any down-regulatory (e.g. suppressive) interactions. T-lymphocyte clones will expand by proliferation only if the IL2 concentration is high enough to induce a proliferation rate larger than the rate of cell decay. This concentration is the proliferation threshold. Because effector T cells are short-lived the proliferation threshold must be quite high. Such high numbers of cells producing IL2 are achieved only when sufficient (memory) precursors are activated. Self and non-self antigens differ with respect the number of (memory) precursor cells they accumulate, as a result of two processes, i.e. precursor depletion and memory accumulation, and can thus be discriminated. Precursor depletion: the dynamics of long-lived precursors can cause tolerization. In neonatal circumstances precursor influx is still low, newborn cells reacting with self antigens are immediately activated, generating (few), i.e. fewer than the proliferation threshold, effectors that decay rapidly. Thus total lymphocyte numbers remain low, yielding self tolerance. Conversely, large doses of similar antigens introduced in mature systems push "their" lymphocyte clone over the proliferation threshold because a large (accumulated) precursor population is rapidly activated. Small doses are however low zone tolerized. Memory accumulation: peripheral T-lymphocyte populations in fact consist of a mixture of virgin precursors and memory cells. If the formation process of (long-lived) memory cells is taken into account and virgin precursors are made short-lived, the proliferation threshold again accounts for self non-self discrimination. Memory cells accumulate when antigenic restimulation is low; it is low when the antigen concentration and/or the antigen affinity is low. Therefore self antigens, which are present in relatively high concentrations, fail to accumulate high affinity memory cells, and are hence tolerated. Memory cells crossreacting to self antigens with low affinity, however accumulate neonatally, pushing those clones over the proliferation threshold whenever "their" high affinity antigen enters the immune system. Thus the model generates differences in the antigenicity (i.e. memory precursor frequency) of self and non-self.(ABSTRACT TRUNCATED AT 400 WORDS)     

Analysis of nucleotide sequences of two ligninase cDNAs from a white-rot filamentous fungus, Phanerochaete chrysosporium

An analysis of nucleotide sequences of two types of ligninase cDNAs isolated from the basidiomycete Phanerochaete chrysosporium, designated CLG4 and CLG5, are presented here. The amino acid sequences of the corresponding ligninase proteins, designated LG4 and LG5, respectively, have been deduced from the cDNA sequences. Mature ligninases LG4 and LG5 are preceded by leader sequences containing 28 and 27 amino acids (aa), respectively, and each contains 344 aa residues. The estimated Mrs of mature LG4 and LG5 are 36,540 and 36,607, respectively. Potential N-glycosylation site(s) with the general sequence Asn-X-Thr/Ser are found in both LG4 and LG5. Nucleotide sequence homology between the coding region of CLG4 and CLG5 is 71.5%, whereas the amino acid sequence homology between the two ligninases is 68.5%. The codon usage of ligninases is extremely biased in favor of codons rich in cytosine and guanine. Amino acid sequences of two tryptic peptides of ligninase H8 have exactly matching sequences in ligninase LG5. Also, the sequences of the oligodeoxynucleotide probes, which correspond to the sequences in the tryptic peptides of ligninase H8 and which were used in isolating the ligninase clones from the cDNA library, have exactly matching sequences in CLG5. The experimentally determined N-terminal sequence of purified ligninase H8 is found in the deduced N-terminal amino acid sequence of LG5. These results suggest that CLG5 encodes ligninase H8 and that CLG4 represents a related but different ligninase gene.     

Self assembly of microtubule associated protein tau into filaments resembling those found in Alzheimer disease

Microtubule associated protein tau factor self-assembles into filamentous structures resembling the paired helical filaments found in Alzheimer disease. Tau polymerization requires of a previous modification; conversion of glutamine into glutamic acid by deamination.     

The membrane-anchoring systems of vertebrate acetylcholinesterase and variant surface glycoproteins of African trypanosomes share a common antigenic determinant

Amphiphilic detergent-soluble acetylcholinesterase (AChE) from Torpedo is converted to a hydrophilic form by digestion with phospholipase C from Trypanosoma brucei or from Bacillus cereus. This lipase digestion uncovers an immunological determinant which crossreacts with a complex carbohydrate structure present in the hydrophilic form of all variant surface glycoproteins (VSG) of T. brucei. This crossreacting determinant is also detected in human erythrocyte AChE after digestion with T. brucei lipase. From these results we conclude that the glycophospholipid anchors of protozoan VSG and of AChE of the two vertebrates share common structural features, suggesting that this novel type of membrane anchor has been conserved during evolution.     

Fractionation and amino acid composition of an aspartic acid-containing thermal proteinoid population

The heterogeneity of an aspartic acid-containing thermal polymer population has been studied by anion exchange chromatography, amino acid analysis of the resulting fractions and data processing by the principal components method. By using stepwise or continuous gradients of ionic strength both saw-toothed or bell-shaped elution profiles were obtained. This behaviour and the amino acid composition of analyzed fractions suggest a relatively high degree of heterogeneity in the polymer population although less than theoretically expected. This conclusion is compared with the findings reported in proteinoids made by similar procedures.     

Adenine nucleotide content and energy charge in dry cells and cysts of Azotobacter vinelandii

Abstract The levels of intracellular adenine nucleotides, energy charge, oxygen consumption and poly-β-hydroxybutyric acid stored, have been investigated in dry vegetative cells and cysts of Azotobacter vinelandii . The data show that under desiccation conditions the cysts retain viability at energy charge values of 0.20 and an ATP/ADP ratio of 0.24, whereas under the same desiccation conditions, vegetative cells die at energy charge values <0.5 and an ATP/ADP ratio of <0.6.     

Subcellular localization of a PhoE-LacZ fusion protein in E. coli by protease accessibility experiments reveals an inner-membrane-spanning form of the protein

Protease accessibility experiments were employed to localize a PhoE-LacZ hybrid protein, encompassing a large N-terminal fragment of the outer membrane PhoE protein of E. coli, fused to beta-galactosidase, at the subcellular level. In previous studies, this protein was shown to co-fractionate with the outer membrane, whereas immunocytochemical methods suggested a cytoplasmic location. The present results confirm the latter localization. Moreover, it appears that a minor amount of hybrid protein spans the inner membrane, with the PhoE moiety in the periplasm and the beta-galactosidase moiety in the cytoplasm. These membrane-spanning proteins might be responsible for the lethal jamming of the export machinery, observed upon induction of synthesis of the protein.     

Androgen receptor predominance in human ovarian carcinoma

Cytosols of 94 untreated common epithelial ovarian cancer tissues were analysed for the presence of estrogen-, progesterone- and androgen receptors. Androgen receptors clearly predominated (90%) over and above estrogen- (55%) and progesterone receptors (52%). Further characterisation particularly of the androgen receptor revealed steroid-receptor complex with the sedimentation coefficient similar to ovalbumin (3,6 S). Only androgens, natural and synthetic, were able to alter the sedimentation profile. Estrogen appeared to slightly lower the peak, while progesterone and cortisol did not alter the profile at all. No difference in receptor concentrations between tumor tissues from pre-, peri- and postmenopausal women was found. The serum hormone levels (estradiol-17 beta, testosterone, FSH, LH) measured preoperatively in 20 postmenopausal patients did not correlate with the receptor status. Majority of the ovarian carcinomas studied contained androgen receptors. We therefore suggest consideration of the addition of anti-androgens to the therapeutic strategies applicable to ovarian cancer.