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PubMed1998

Serpins and regulation of cell death.

Proteolysis is a key feature of programmed cell death. Extracellular proteinases can activate cell surface receptors which trigger apoptosis, and the effector machinery requires the activation and activity of numerous intracellular proteinases (primarily caspases). Effective control of proteolysis is essential for homeostasis and can occur at two levels: regulation of proteinase activation, and regulation of the activated proteinase. Serpins control activated proteinases and several have been implicated in the regulation of cell death. Serpins that inhibit intracellular processes include the viral proteins CrmA and SPI-1, as well as the granzyme B inhibitor, PI-9. Another endogenous serpin, PN-I, prevents the delivery of an apoptotic signal by inhibiting an extracellular proteinase from cleaving a cell surface receptor. There is evidence to suggest that PAI-2 may target an extracellular as well as an intracellular proteinase. Much of our knowledge of proteolysis within apoptotic cells has come from studies using the poxvirus serpin CrmA/SPI-2. CrmA prevents cytokine processing by inhibiting caspase-1, and protects against Fas-, TNF- and TRAIL-mediated apoptosis by inhibiting an unidentified proteinase specific to these pathways. Work with CrmA has also clearly demonstrated that there are separable effector mechanisms within cells, and that those triggered by growth factor withdrawal, matrix dissociation or cytotoxic ligands are different in several respects to those triggered by radiation, chemicals or steroid hormones. It is likely that analysis of other poxvirus serpins with different inhibitory profiles (especially SPI-1) will yield further insights into these processes. Prospecting for intracellular serpin genes in other virus species may also be fruitful. Finally, all of the serpins known to regulate intracellular proteolysis are members of the ovalbumin subgroup. It remains to be seen whether the more recently described "orphan" ovalbumin serpins (Riewald and Schleef 1995; Sprecher et al. 1995; Sun et al. 1997) also have roles in the regulation of cell death.

Animals↗

PubMed2026

Parasites and allergies: a complex bidirectional relationship from evolutionary origins to modern therapeutics.

Parasites and allergic diseases are linked by a complex, bidirectional relationship shaped by long-term host-parasite coevolution. This review discusses how different parasites may either promote or attenuate allergic responses through immunological, epithelial, and microbiome-mediated mechanisms. IgE-mediated immunity, mast cell activation, eosinophilia, and pruritus may have evolved as protective responses against helminths and blood-feeding ectoparasites. In contrast, modern allergies may partly reflect misdirected responses to harmless environmental antigens. The effects of parasites on allergy are not uniform and depend on parasite type, infection site, exposure intensity and chronicity, host immune status, and the degree of host-parasite adaptation. Protozoa such as Giardia intestinalis may contribute to food allergy-related manifestations by disrupting the intestinal barrier, altering gut microbiota composition, and modifying mucosal immune responses, particularly in atopic individuals. In contrast, selected helminths may attenuate allergic inflammation by inducing regulatory T and B cells, anti-inflammatory cytokines, antigen-presenting cell modulation, and IgG4-associated mechanisms that can limit IgE-mediated effector responses. Molecular similarities between parasite-derived antigens and environmental allergens, including conserved protein families and carbohydrate epitopes, may contribute to cross-reactive IgE responses and complicate allergy diagnostics. Therefore, current research is shifting from live helminth therapy toward defined parasite-derived molecules and immunomodulatory pathways that may inspire safer and more controlled therapeutic strategies. A clearer understanding of parasite-allergy interactions may improve diagnostic interpretation and support the development of new approaches to the management of allergic disease.

Humans↗

PubMed1999

Bacterial transcription factors involved in global regulation.

The presence of intricate global cell regulation mechanisms may be one reason for the exceptional environmental and evolutionary success of microbes. Promoters, the cis-acting signals, are responsive to several stimuli related to growth, stress and substrate specificity. Their response is mediated by a wide variety of trans-acting regulators that sense the environment and the physiological state of the cell and adjust the transcription of specific genes. One of the main transcriptional regulation webs operates in the transition from affluent to barren conditions, with sigmaS being the chief actor in a company of players that stage a competition for the sparsely available RNA polymerase molecules. In this role, sigmaS may be assisted by several factors, including nucleoid-related proteins and metabolites. In addition, the levels of sigmaS itself are regulated by mechanisms that include inactivation and degradation. Several transcription factors, belonging to different regulatory pathways, may operate in the same promoter. In such a case, the final transcriptional output depends both on the interplay of effectors and on the properties of the recruitment of the effector-RNA polymerase complex to the promoter. RNA polymerase itself is also capable of establishing selective interactions with activators and specific promoter regions through the carboxy-terminal domain of its alpha subunit (alphaCTD). Transcriptional regulation controls pervade such crucial events in the life of bacterial cells as Escherichia coli cell division, Bacillus subtilis sporulation and Caulobacter crescentus differentiation. These examples suggest that bacteria have been particularly inventive in adapting gene expression regulation to survive under a diversity of environments and have done so by exploiting the malleable molecular mechanisms involved in transcription, developing complexities that may match those found in eukaryotic cells.

Adaptation, Physiological↗

PubMed1988

An extreme-halophile archaebacterium possesses the interlock type of prephenate dehydratase characteristic of the Gram-positive eubacteria.

The focal point of phenylalanine biosynthesis is a dehydratase reaction which in different organisms may be prephenate dehydratase, arogenate dehydratase, or cyclohexadienyl dehydratase. Gram-positive, Gram-negative, and cyanobacterial divisions of the eubacterial kingdom exhibit different dehydratase patterns. A new extreme-halophile isolate, which grows on defined medium and is tentatively designated as Halobacterium vallismortis CH-1, possesses the interlock type of prephenate dehydratase present in Gram-positive bacteria. In addition to the conventional sensitivity to feedback inhibition by L-phenylalanine, the phenomenon of metabolic interlock was exemplified by the sensitivity of prephenate dehydratase to allosteric effects produced by extra-pathway (remote) effectors. Thus, L-tryptophan inhibited activity while L-tyrosine, L-methionine, L-leucine and L-isoleucine activated the enzyme. L-Isoleucine and L-phenylalanine were effective at micromolar levels; other effectors operated at mM levels. A regulatory mutant selected for resistance to growth inhibition caused by beta-2-thienylalanine possessed an altered prephenate dehydratase in which a phenomenon of disproportionately low activity at low enzyme concentration was abolished. Inhibition by L-tryptophan was also lost, and activation by allosteric activators was diminished. Not only was sensitivity to feedback inhibition by L-phenylalanine lost, but the mutant enzyme was now activated by this amino acid (a mutation type previously observed in Bacillus subtilis). It remains to be seen whether this type of prephenate dehydratase will prove to be characteristic of all archaebacteria or of some archaebacterial subgroup cluster.

Alanine↗

PubMed2002

A functional role for tyrosine-D in assembly of the inorganic core of the water oxidase complex of photosystem II and the kinetics of water oxidation.

The role of D2-Tyr160 (Y(D)), a photooxidizable residue in the D2 reaction center polypeptide of photosystem II (PSII), was investigated in both wild type and a mutant strain (D2-Tyr160Phe) in which phenylalanine replaces Y(D) in the cyanobacterium Synechocystis sp. (strain PCC 6803). Y(D) is the symmetry-related tyrosine that is homologous to the essential photoactive Tyr161(Y(Z)) of the D1 polypeptide of PSII. We compared the flash-induced yield of O(2) in intact, functional PSII centers from both wild-type and mutant PSII core complexes. The yield of O(2) in the intact holo-enzyme was found to be identical in the mutant and wild-type PSII cores using long (saturating) pulses or continuous illumination, but was observed to be appreciably reduced in the mutant using short (nonsaturating) light pulses (<50 ms). We also compared the rates of the first two kinetically resolved steps of photoactivation. Photoactivation is the assembly process for binding of the inorganic cofactors to the apo-water oxidation/PSII complex (apo-WOC-PSII) and their light-induced photooxidation to form the functional Mn(4)Ca(1)Cl(x)() core required for O(2) evolution. We show that the D2-Tyr160Phe mutant cores can assemble a functional WOC from the free inorganic cofactors, but at a much slower rate and with reduced quantum efficiency vs wild-type PSII cores. Both of these observations imply that the presence of Y(D)(*) leads to a more efficient photooxidation of the Mn cluster relative to deactivation (reductive processes). One possible explanation for this behavior is that the phenolic proton on Y(D) is retained within the reaction center following Y(D) oxidation. The positive charge, likely shared by D2-His189 and other residues, raises the reduction potential of P(680)(+)/P(680), thereby increasing the driving force for the oxidation of Mn(4)Y(Z). There is, therefore, a competitive advantage to organisms that retain the Y(D) residue, possibly explaining its retention in all sequences of psbD (encoding the D2 polypeptide) known to date. We also find that the sequence of metal binding steps during assembly of apo-WOC-PSII centers in cyanobacteria cores differs from that in higher plants. This is seen by a reduced calcium affinity at its effector site and reduced competition for binding to the Mn(II) site, resulting in acceleration of the initial lagtime by Ca(2+), in contrast to retardation in spinach. Ca(2+) binding to its effector site promotes the stability of the photointermediates (IM1 and above) by suppressing unproductive decay.

Amino Acid Substitution↗

PubMed2002

Evolutionary relationship between different subgroups of restriction endonucleases.

The type II restriction endonuclease SsoII shows sequence similarity with 10 other restriction endonucleases, among them the type IIE restriction endonuclease EcoRII, which requires binding to an effector site for efficient DNA cleavage, and the type IIF restriction endonuclease NgoMIV, which is active as a homotetramer and cleaves DNA with two recognition sites in a concerted reaction. We show here that SsoII is an orthodox type II enzyme, which is active as a homodimer and does not require activation by binding to an effector site. Nevertheless, it shares with EcoRII and NgoMIV a very similar DNA-binding site and catalytic center as shown here by a mutational analysis, indicative of an evolutionary relationship between these three enzymes. We suggest that a similar relationship exists between other orthodox type II, type IIE, and type IIF restriction endonucleases. This may explain why similarities may be more pronounced between members of different subtypes of restriction enzymes than among the members of a given subtype.

Amino Acid Motifs↗

PubMed2002

Cyclase-associated proteins: CAPacity for linking signal transduction and actin polymerization.

Many extracellular signals elicit changes in the actin cytoskeleton, which are mediated through an array of signaling proteins and pathways. One family of proteins that plays a role in regulating actin remodeling in response to cellular signals are the cyclase-associated proteins (CAPs). CAPs are highly conserved monomeric actin binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. The original CAP was isolated as a component of the Saccharomyces cerevisiae adenylyl cyclase complex that serves as an effector of Ras during nutritional signaling. CAPs are multifunctional molecules that contain domains involved in actin binding, adenylyl cyclase association in yeast, SH3 binding, and oligomerization. Genetic studies in yeast have implicated CAPs in vesicle trafficking and endocytosis. CAPs play a developmental role in multicellular organisms, and studies of Drosophila have illuminated the importance of the actin cytoskeleton during eye development and in establishing oocyte polarity. This review will highlight the critical structural and functional domains of CAPs, describe recent studies that have implied important roles for these proteins in linking cell signaling with actin polymerization, and highlight their roles in vesicle trafficking and development.

Actin Cytoskeleton↗

PubMed1987

Analysis of T-cell subset proliferation at afebrile and febrile temperatures: differential response of Lyt-1+23- lymphocytes to hyperthermia following mitogen and antigen stimulation and its functional consequence on development of cytotoxic lymphocytes.

Poikilotherms are now known to increase their survival by behaviorally induced fevers in response to pathogenic infection. Increased host resistance to viral and bacterial infections has also been noted in homeotherms whose body temperature has been elevated by manipulation of ambient temperature. These observations suggest that fever may increase host resistance by augmenting acquired immunity; thus, this highly conserved response during evolution may provide a survival advantage against environmental pathogens. This possibility has prompted us to investigate the influence of a temperature characteristic of a modest fever in humans (39 degrees C) on T-cell proliferation and function. Our studies revealed that T-cell mitogenesis was enhanced when cultures were incubated at the febrile temperature (39 degrees C). Analysis of T-cell subsets demonstrated that temperature enhanced the mitogenic (Concanavalin A) response of Lyt-1+23- splenocytes; in contrast, hyperthermia was deleterious to lectin-driven proliferation of the Lyt-1-23+ population even in the presence of large quantities of recombinant interleukin-2 (rIL-2). B-cell mitogenesis was invariably inhibited by hyperthermia over a broad range of concentrations of lipopolysaccharide (LPS). Although T-cell mitogenesis was enhanced at the febrile temperature, T-cell proliferation induced by alloantigens or by a murine pathogen, Sendai virus (SV), was diminished at the febrile temperature. Hyperthermia inhibited SV-induced proliferation of Lyt-1+23- lymphocytes, indicating that a febrile temperature can either augment or inhibit T-cell proliferation of the same T-cell subset depending upon the activation signal (i.e., lectin or antigen). Because effector cell development depends upon antigen-induced clonal expansion (proliferation), we evaluated the influence of temperature on primary cytotoxic thymus (T)-derived lymphocyte (CTL) responses against alloantigens and secondary CTL responses against SV under afebrile and febrile conditions. We consistently observed that the induction of alloreactive and virus-specific CTL was diminished in cultures incubated at the elevated temperature, suggesting that a thermosensitive event(s) exists in the progression of CTL derived from either CTL precursors (CTLp) or memory CTL. Furthermore, hyperthermia reduced the number of SV-specific CTL detectable by limiting dilution analysis, suggesting that another event independent of clonal expansion was thermolabile during effector cell development. In view of these results, we suggest that it may be premature to conclude that the observed increase in host resistance induced by a febrile state is mediated by enhanced cell-me

Antigens, Ly↗

PubMed1999

DECAY, a novel Drosophila caspase related to mammalian caspase-3 and caspase-7.

Caspases are key effectors of programmed cell death in metazoans. In Drosophila, four caspases have been described so far. Here we describe the identification and characterization of the fifth Drosophila caspase, DECAY. DECAY shares a high degree of homology with the members of the mammalian caspase-3 subfamily, particularly caspase-3 and caspase-7. DECAY lacks a long prodomain and thus appears to be a class II effector caspase. Ectopic expression of DECAY in cultured cells induces apoptosis. Recombinant DECAY exhibited substrate specificity similar to the mammalian caspase-3 subfamily. Low levels of decay mRNA are ubiquitously expressed in Drosophila embryos during early stages of development but its expression becomes somewhat spatially restricted in some tissues. During oogenesis decay mRNA was detected in egg chambers of all stages consistent with a role for DECAY in apoptosis of nurse cells. Relatively high levels of decay mRNA are expressed in larval salivary glands and midgut, two tissues which undergo histolysis during larval/pupal metamorphosis, suggesting that DECAY may play a role in developmentally programmed cell death in Drosophila.

Amino Acid Sequence↗

PubMedDate not supplied

Interleukin-1-beta activation of cultured glomerular epithelial cells.

In crescentic glomerulonephritis, crescent formation involves the active participation of glomerular epithelial cells (GEC) and macrophages recruited to the glomerulus during the evolution of the disease. Cytokines derived from macrophages may affect many functions of GEC. In this study, we found that interleukin-1 beta (IL-1 beta) inhibited GEC growth (DNA synthesis and cell number) in vitro in a dose- and time-dependent manner. This effect was not mediated by tumor growth factor beta (TGF beta) which is a potent inhibitor of GEC growth in vitro. Treatment of GEC with various concentrations of IL-1 beta induced morphologic changes consisting in the loss of their cobblestone shape and acquisition of a fibroblast-like appearance. Moreover, IL-1 beta was shown to stimulate the expression of interleukin-6 (IL-6) by GEC. The increase in IL-6 secretion by GEC treated with IL-1 beta was observed at both the protein and mRNA levels. IL-1 beta also affected the metabolism of laminin in cultured GEC, inducing a dose-dependent increase in laminin production in culture supernatants harvested from GEC. Finally, we investigated the expression of MHC class II antigens and intercellular adhesion molecule-1 (ICAM-1) in GEC, and found that unstimulated GEC are negative for MHC class II antigens, as detected by flow cytometry. In contrast to the induction of effector functions, expression of MHC class II antigens stringently required interferon-gamma. IL-1 beta did not induce MHC class I antigen expression. The regulation of ICAM-1 expression in that unstimulated GEC expressed ICAM-1, and this expression was upregulated by IL-1 beta. We conclude that IL-1 beta alters many functions of GEC, and these changes may be involved in the initiation and amplification of glomerular injury.

Cell Count↗

PubMed2026

Insect immune systems: same same but different but still same.

Insects are the most diverse group of animals in nature, occupying nearly every ecological niche and playing central roles as pollinators, pests, and disease vectors. Despite this vast diversity, insects rely on a set of conserved yet evolutionarily adaptable immune pathways to defend against pathogens. Early studies in insect immunity have laid the foundation for human immunology, and recent advances in genomic and transgenic technologies have renewed interest in understanding how immune responses vary across insect orders. Insects are highly diverse in their immune systems; each species has unique immune responses that help fight infections from specific pathogens. Nevertheless, they share multiple aspects of recognition, regulation, and effector mechanisms. This review focuses on current knowledge of the immune systems of major insect lineages to highlight both shared signaling pathways, immune cells, and humoral factors, as well as lineage-specific responses that reflect distinct ecological pressures that have shaped the host-microbe interactions. Comparing different insect species and orders not only provides insights into the evolutionary divergences and convergences of immune system features but also offers complementary knowledge among species within the same order, helping fill existing gaps. Understanding these evolutionary patterns not only deepens our understanding of insect immunity but also informs the development of transgenic strategies to disrupt pathogen transmission in key vector species.

Animals↗

PubMed1996

Sea urchin genes expressed in activated coelomocytes are identified by expressed sequence tags. Complement homologues and other putative immune response genes suggest immune system homology within the deuterostomes.

To identify some of the genes expressed in LPS-activated coelomocytes, we sequenced randomly chosen clones from a directionally constructed cDNA library to produce a set of expressed sequence tags (ESTs). Deduced amino acid sequences from 307 ESTs were compared with known protein sequences in GenBank, and significant matches to approximately 30% of the clones were identified. Eighty-nine clones matched to 55 different proteins, including several putative immune effector proteins. In this work, we show the first identification of an invertebrate homologue of a vertebrate C component. Another EST matches to several short consensus repeats that are characteristic of a variety of proteins, including CR/regulatory proteins and clotting factors. Additional putative immune effector genes include 1) a Kazal-type protease inhibitor that may function to inactivate bacterial proteases, 2) a C-type lectin similar to echinoidin, and 3) a serine protease with similarities to thrombin, elastase, haptoglobin, and plasmin. Other EST categories include 1) cell surface proteins and receptors, 2) proteins involved in signaling systems, 3) lysosomal and secreted proteins, 4) cytoskeletal and cytoskeletal modifying proteins, 5) general cell function proteins, 6) proteins with unknown function, and 7) ESTs without significant matches, 25 with open reading frames. Many of the ESTs identified in this study represent the types of genes expected to be used in lower deuterostome immune functions.

Amino Acid Sequence↗

PubMed1995

Interferon gamma, interleukin 4 and transforming growth factor beta in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells.

The potential role of certain important immunoregulatory and effector cytokines in autoimmune neuroinflammation have been studied. We have examined the expression of mRNA, with in situ hybridization, of interferon gamma (IFN-gamma), interleukin 4 (IL-4) and transforming growth factor beta (TGF-beta) both in sections of spinal cords and the antigen-induced expression of these cytokines by lymphoid cells after stimulation with a dominant encephalitogenic peptide of MBP (MBP 63-88) during the course of actively induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats. In spinal cords, the target organ in EAE, cells expressing mRNA for IFN-gamma, first appeared at the onset of clinical signs, i.e., day 10 postimmunization (p.i.), peaked at the height of disease (day 13 p.i.) and then gradually decreased concomitant with recovery. Very few IL-4 mRNA-expressing cells appeared in the spinal cord with no clear relation to clinical signs or histopathology. In contrast, expression of mRNA for TGF-beta did not increase until day 13 p.i., at height of the disease, shortly preceding recovery. These data are consistent with a disease upregulating role of IFN-gamma, while TGF-beta may act to limit central nervous system (CNS) inflammation. In lymphoid organs, primed MBP 63-88 reactive T cells showed an interesting time-dependent evolution of their cytokine production in vitro. Thus, early after immunization there was a conspicuous MBP 63-88-induced production of both IFN-gamma and IL-4. Such cells may act in the initiation and promotion of the disease. Later, in the recovery phase, MBP 63-88 induced lymphoid cells to TGF-beta production. Thus, an autoantigen-specific production of TGF-beta occurred during EAE and hypothetically such a mechanism may serve to downregulate aggressive autoimmunity systemically.

Amino Acid Sequence↗

PubMed1996

Presensitization accelerates allograft arteriosclerosis.

Transplant arteriosclerosis is the major factor influencing allograft survival after the first year posttransplantation. The host's immunologic response is one of the principal effectors responsible for the constitution of this vascular wall lesion, but the effector pathway and the factors influencing the immune injury are not clear. In a rat abdominal aortic allograft model, we used a skin priming method to study the influence of sensitization on the occurrence of vascular wall lesions. Primed rats developed transplant arteriosclerosis lesions involving medial decellularization and intimal proliferation before the 21st day, whereas naive animals had the same lesions at 2 months posttransplantation. A significant difference between primed and naive rats was found for medial thickness (48.00 +/- 2.85 microm versus 79.34 +/- 2.55 microm, P<0.001) and smooth muscle cell content (160 +/- 28 cell/mm versus 466 +/- 19 cell/mm, P<0.001) at 21 days posttransplantation, and intimal hyperplasia was seen in primed animals at that time, whereas it was not observed in naive rats until the 60th day. The immune profile in naive and primed animals was different. The immune cells infiltrating the arterial wall in naive rats, were principally macrophages and CD8+ T-lymphocytes. No Ig or complement deposition was detected. IgG and complement activated fraction were present in the media of primed animals as early as the fifth day posttransplantation and CD4+ T lymphocytes were the dominant immune cell population. In conclusion, sensitization influences the immune mechanisms responsible for the development of transplant arteriosclerosis and alters the rate of its evolution.

Animals↗

PubMed1996

[Clonal B-cell reaction in Sjögren disease and Hashimoto autoimmune thyroiditis].

Autoimmune diseases are defined as specific, adapted immune reactions against self-antigens. These antigens were attacked by activated, autoaggressive T-Cells in most cases. However, since introduction of the MALT concept it became clear, that particularly in the autoimmune diseases of the MALT specific subpopulations of B-cells play an important role. In this study, the B-cells in the thyroid gland of 40 patients suffering from Hashimoto's disease and 25 patients with Sjögrens syndrome and enlargement of the salivary glands were immunophenotyped and molecular-genetically investigated. The molecular-genetical investigation included PCR based amplification of immunoglobulin heavy chain CDR III region and the T-cell receptor gamma chain (TCR-gamma). By immunophenotyping, in the salivary glands monocytoid B-cells could be identified as intraepithelial effector cells in nearly all cases, whereas in the thyroid gland mostly marginal zone cells in the follicle epithelium were observed. In 13 biopsy specimen from salivary gland, clonal rearrangements of TCR-gamma, and in 9 cases of patients with Sjögren's syndrome JH rearrangements could be detected. Monoclonal TCR-gamma rearrangements were identified in 9/40 patients suffering from autoimmunethyroiditis Hashimoto. In 8/40 thyroid gland biopsies a monoclonal JH-rearrangement could be found. Within 11/25 patients with Sjögren's syndrome and in 23/40 patients with M. Hashimoto polyclonal rearrangements were observed. Within all biopsy specimen of patients with monoclonal rearrangements, lymphoepithelial lesions or lymphoepithelial destructions could be identified immunohistochemically. Additionally, in 2 biopsies from salivary gland and in one specimen from thyroid gland the transition from autoimmune disease into a secondary high grade lymphoma was observed. In 26/40 patients with M. Hashimoto and in 11/25 patients with Sjögren's syndrome the transition in a subsequent low grade B cell lymphoma of MALT-type was found. These results lead to the following conclusions: 1. clonal rearrangements of tumor forming B-cells in both autoimmune diseases investigated can be interpreted as facultative malignant. 2. Intraepithelial B-cells probably are the promotors of the autoimmune process and--in case of clonal evolution and immortalisation--can be regard as causative agent in the development of primary extranodal B-cell lymphoma.

B-Lymphocytes↗

PubMed1975

Requirement for vasoactive amines for production of delayed-type hypersensitvity skin reactions.

The skin sites of the mouse where delayed-type hypersensitivity (DTH) reactions are most easily elicited (foot pads and ears) are particularly rich in 5-hydroxytryptamine (5-HT)-containing mast cells. Since mice are deficient in circulating basophils, which play a role in at least some DTH reactions, we investigated the possibility that the mast cells were playing an important role in the evolution of the skin reactions of DTH in mice. We found that reserpine, a drug which depletes mast cells of 5-HT, abolished the ability of the mouse to make DTH reactions in the skin. The suppressive effect of reserpine could be partially blocked by monoamine oxidase inhibitors which prevent the degradation of 5-HT in the cytosol of the mast cell. Spleen cells of immune, reserpine-treated mice transferred DTH reactions to nonimmune mice normally, indicating that the reserpine treatment did not affect immune T cells. DTH reactions could not be transferred into reserpine-treated mice. We suggest that T cells are continually emigrating from the blood, through postcapillary venule endothelium, by a mechanism which does not depend on vasoactive amines. If they are appropriately immune and meet the homologous antigen in the tissue, they induce mast cells to release vasoactive amines which cause postcapillary venule endothelial cells to separate, allowing the egress from the blood of cells which ordinarily do not recirculate. The secondarily arriving vasoactive amine-dependent cells are responsible for the micro- and macroscopic lesions of DTH reactions. Chemotactic factors may also be involved in bringing cells to the DTH reaction sites but we propose that T-cell regulation of vasoactive amine-containing cells allows the effector cells to pass through the endothelial gates after they are called.

Animals↗

PubMed1993

Interferon-alpha-2b enhances the natural killer activity of patients with transitional cell carcinoma of the bladder.

BACKGROUND: Transitional cell carcinoma (TCC) of the bladder is associated with alterations in the immune system of the host. The authors demonstrated that in patients with bladder carcinoma there is a negative correlation between the levels of natural killer (NK) activity and the clinical evolution and pathologic stages of disease. METHODS: The authors investigated the effect of various doses of recombinant interferon-alpha-2b (IFN-alpha-2b) for variable periods of culture on the nonmajor histocompatibility-restricted cytotoxic activity of peripheral blood mononuclear cells (PBMNC) with or without CD16 and CD3-depleted populations from patients with superficial (confined to the mucosa or lamina propria) and infiltrative (those infiltrating beyond the lamina propria) TCC of the bladder using 4-hour 51-sodium chromate (51Cr)-release cytotoxicity assays against both NK-sensitive (K562) and NK-resistant (JY) tumor target cells. RESULTS: The normal NK activity detected in PBMNC from patients with superficial TCC of the bladder can be significantly enhanced by short-term (18-hour) incubation with recombinant IFN-alpha (P < 0.05). The depressed NK cytotoxic activity found in PBMNC from patients with infiltrative TCC can also be significantly enhanced, but not normalized, by short-term (18-hour) incubation with recombinant IFN-alpha (P < 0.05). Short-term recombinant IFN-alpha-incubated PBMNC from patients with superficial, but not infiltrative, TCC of the bladder also showed marked cytotoxic activity against NK-resistant target cells. By selection with CD16 or CD3 monoclonal antibodies and complement, it was also found that the precursor and effector lymphocytes of this recombinant IFN-alpha-promoted cytotoxicity belong to NK lineage. In kinetic studies, it was found that the maximal levels of the recombinant IFN-alpha-promoted cytotoxic activity against NK-sensitive and NK-resistant target cells in PBMNC from patients with TCC were reached after 18 hours of culture. CONCLUSION: Recombinant IFN-alpha can enhance the nonmajor histocompatibility-restricted cytotoxic activity of PBMNC from patients with TCC of the bladder.

Aged↗

PubMed1991

Sensory receptors as a special class of hormonal cells.

Classically, sensory receptors are specialized cells which detect specific environmental disturbances and send out neural signals for the integration, control and/or regulation of effector organs. Recently, a special class of sensory receptors called sensori-hormonal cells which employ hormones as their means of flux of biological information has been proposed. These sensori-hormonal cells are capable of detecting and transducing environmental signals directly into the secretion of hormones within the same cells. Theoretically, all sensory receptors may have examples capable of direct sensori-hormonal transduction. However, only one group of sensori-hormonal cells, the photoendocrine cells, have so far been studied. The photoendocrine cells including the photoreceptors of fish retinas and pinealocytes of bird pineals are capable of detecting light and/or darkness and transducing the electromagnetic radiation energy into a hormonal output. Generally, light suppresses and darkness stimulates the biosynthesis and secretion of melatonin by these photoendocrine cells. Contrary to many hormonal systems which employ principally the feedback mechanism for regulation, the sensori-hormonal cells are predominantly controlled by the feedforward mechanism. However, other factors may serve as additional means of regulation by influencing the system and affecting the transduction processes and/or the synthesis and secretion of the hormone. The ability of sensori-hormonal transduction is suggested to be important for the survival of the organism itself and/or its species and sensori-hormonal cells or their equivalent should appear early in the course of animal evolution. It is further suggested that the sequence of appearance of melatonin functions in the course of evolution would be: hormone--humoral factor--neuromodulator--neurotransmitter.

Animals↗