Mechanisms of antibacterial immunity of mucous membranes

A survey based on both literary data and the authors own results, concerning the mechanisms of sIgA-mediated antibacterial immunity, is presented. Secretory IgA is characterized as a specific component of the immune system of mucous membranes, which can recognize harmful bacterial and distinguish them from indigenous microflora physiologically colonizing the mucous membranes, to fix them to the mucous membrane surface and to direct further factors, such as mucin, lysozyme,etc. (which form the effector component of the mucous membrane immunity system) for thvir final inactivation and neutralization.     

Insect immunity. Attacins,a family of antibacterial proteins from Hyalophora cecropia.

Six closely related antibacterial proteins, attacins A-F, were isolated from the hemolymph of immunized pupae of the Cecropia moth, Hyalophora cecropia. Chromatofocusing separated attacins A-F, with isoelectric points between 5.7 and 8.3. Immunological experiments show that the attacins constitute antibacterially active forms of the previously isolated inducible immune protein P5. Their mol. wts., 20-23 K, are similar to that of protein P5, but significantly lower than 28 K found for preP5 synthesized in vitro (see accompanying paper). The six attacins can be divided into two groups according to their amino acid composition and amino-terminal sequences, attacins A-D constitute a basic group and attacins E and F an acidic one. Within each group the forms are very similar. The attacins efficiently killed Escherichia coli and two other Gram-negative bacteria isolated from the gut of a silk worm but they did not act on other Gram-positive and Gram-negative bacteria tested. Only growing cells of E. coli were attacked; cells suspended in phosphate buffer were inert. Besides the cecropins and lysozyme, the attacins represent a third class of antibacterial proteins in the humoral immune system of H. cecropia.     

肽聚糖识别蛋白抗菌活性及参与炎症的免疫作用

哺乳动物肽聚糖识别蛋白(peptidoglycan recognition proteins, PGRPs)是一类可识别肽聚糖的模式识别受体,在先天免疫应答中发挥重要的识别和调节功能。PGRPs通过与肽聚糖结合,诱导激活细菌双组分系统(two-component systems, TCSs)如CssR-CssS、CpxA-CpxR等,诱导氧化应激、硫醇应激和金属应激等反应发挥抗菌活性。现对PGRPs的抗菌活性及其与抗生素的杀菌机制进行比较,旨在为疾病的防治提供理论依据。     

Nucleoside hydrolase from Crithidia fasciculata. Metabolic role, purification, specificity, and kinetic mechanism

Crithidia fasciculata cells grown on complex medium with added [8-14C, 5'-3H]inosine or [8-14C,5'-3H]adenosine metabolize greater than 50% of the salvaged nucleosides through a pathway involving N-glycoside bond cleavage. Cell extracts contain a substantial nucleoside hydrolase activity but an insignificant purine nucleoside phosphorylase. The nucleoside hydrolase has been purified 1000-fold to greater than 99% homogeneity from kilogram quantities of C. fasciculata. The enzyme is a tetramer of Mr 34,000 subunits to give an apparent holoenzyme Mr of 143,000 by gel filtration. All of the commonly occurring nucleosides are substrates. The Km values vary from 0.38 to 4.7 mM with purine nucleosides binding more tightly than the pyrimidines. Values of Vmax/Km vary from 3.4 x 10(3) M-1 s-1 to 1.7 x 10(5) M-1 s-1 with the pyrimidine nucleosides giving the larger values. The turnover rate for inosine is 32 s-1 at 30 degrees C. The kinetic mechanism with inosine as substrate is rapid equilibrium with random product release. The hydrolytic reaction can be reversed to give an experimental Keq of 106 M with H2O taken as unity. The product dissociation constants for ribose and hypoxanthine are 0.7 and 6.2 mM, respectively. Deoxynucleosides or 5'-substituted nucleosides are poor substrates or do not react, and are poor inhibitors of the enzyme. The enzyme discriminates against methanol attack from solvent during steady-state catalysis, indicating the participation of an enzyme-directed water nucleophile. The pH profile for inosine hydrolysis gives two apparent pKa values of 6.1 with decreasing Vmax/Km values below the pKa and a plateau at higher pH values. These effects are due to the pH sensitivity of the Vmax values, since Km is independent of pH. The pH profile implicates two negatively charged groups which stabilize a transition state with oxycarbonium character.     

Serological changes in adjuvant-treated mice,their specificity and relevance to tumor immunity

Summary The effects of a variety of adjuvant protocols on immunoglobulin levels in normal and tumor bearing CBA mice have been investigated together with their ability to elicit immunoglobulin which bind to tumor cells in vitro and inhibit the growth of a transplanted syngeneic MC-induced fibrosarcoma.A marked increase in serum levels of certain immunoglobulins (especially IgG_2a, IgG_2b and IgM) and immunoglobulin interacting with tumor cells in vitro was noted in normal and tumor bearing mice following the administration of C. parvum (strain No. CN6134 and 10387), P. freudenreichii (strain No. 10470) and B. pertussis while a modest increase in some of these accompanied BCG injection. The Freund's complete and incomplete adjuvant protocols adopted had little effect on any of these parameters. The C. parvum protocols alone inhibited tumor growth.The immunoglobulins evoked by C. parvum strain No. 6134 which bound to tumor cells in vitro were extremely heterogeneous, activity being detected in all Ig classes and subclasses. This organism also evoked immunoglobulins which interacted with syngeneic embryonic fibroblasts, and adult syngeneic kidney and spleen cells.Tumor cells which had been preincubated in sera rich in immunoglobulins binding to tumor cells in vitro (i.e. from C. parvum-treated mice) did not exhibit reduced growth following i.v. or s.c. transplantation to syngeneic recipients.     

The contact system--a novel branch of innate immunity generating antibacterial peptides

Activation of the contact system has two classical consequences: initiation of the intrinsic pathway of coagulation, and cleavage of high molecular weight kininogen (HK) leading to the release of bradykinin, a potent proinflammatory peptide. In human plasma, activation of the contact system at the surface of significant bacterial pathogens was found to result in further HK processing and bacterial killing. A fragment comprising the D3 domain of HK is generated, and within this fragment a sequence of 26 amino acids is mainly responsible for the antibacterial activity. A synthetic peptide covering this sequence kills several bacterial species, also at physiological salt concentration, as effectively as the classical human antibacterial peptide LL-37. Moreover, in an animal model of infection, inhibition of the contact system promotes bacterial dissemination and growth. These data identify a novel and important role for the contact system in the defence against invasive bacterial infection.     

Serum vibriolytic activity as an index of antibacterial immunity in cholera

As a result of study of the vibriolytic activity of the serum during the immunity formation in the vaccinated animals in comparison with the specific antibodies titres and nonspecific immunity factors (complement and lysozyme) there was revealed a dependence of the reaction on the vaccine dose and the immunization method; there was also found a relationship between the vibriolytic activity and the serological indices in the sera of volunteers. On the basis of study a conclusion was drawn that the vibriolytic activity of the serum could serve as an index of antibacterial immunity in cholera.     

Insect immunity shows specificity in protection upon secondary pathogen exposure

Immunological memory in vertebrates, conferring lasting specific protection after an initial pathogen exposure, has implications for a broad spectrum of evolutionary, epidemiological, and medical phenomena . However, the existence of specificity in protection upon secondary pathogen exposure in invertebrates remains controversial . To separate this functional phenomenon from a particular mechanism, we refer to it as specific immune priming. We investigate the presence of specific immune priming in workers of the social insect Bombus terrestris. Using three bacterial pathogens, we test whether a prior homologous pathogen exposure gives a benefit in terms of long-term protection against a later challenge, over and above a heterologous combination. With a reciprocally designed initial and second-exposure protocol (i.e., all combinations of bacteria were tested), we demonstrate, even several weeks after the clearance of a first exposure, increased protection and narrow specificity upon secondary exposure. This demonstrates that the invertebrate immune system is functionally capable of unexpectedly specific and durable induced protection. Ultimately, despite general broad differences between vertebrates and invertebrates, the ability of both immune systems to show specificity in protection suggests that their immune defenses have found comparable solutions to similar selective pressures over evolutionary time.     

A graph model for the evolution of specificity in humoral immunity

The immune system protects the body against health-threatening entities, known as antigens, through very complex interactions involving the antigens and the system's own entities. One remarkable feature resulting from such interactions is the immune system's ability to improve its capability to fight antigens commonly found in the individual's environment. This adaptation process is called the evolution of specificity. In this paper, we introduce a new mathematical model for the evolution of specificity in humoral immunity, based on Jerne's functional, or idiotypic, network. The evolution of specificity is modeled as the dynamic updating of connection weights in a dynamic graph whose nodes are related to the network's idiotypes. At the core of this weight-updating mechanism are the increase in specificity caused by clonal selection and the decrease in specificity due to the insertion of uncorrelated idiotypes by the bone marrow. As we demonstrate through numerous computer experiments, for appropriate choices of parameters the new model correctly reproduces, in qualitative terms, several immune functions.