CONTENTS
Review
- Extrathymic Pathways of T Cell Differentiation
TORU ABOAbstract. Department of Immunology, Niigata University School of Medicine, Niigata, Japan
Keywords: It is known that the liver is a major hematopoietic organ at fetal stages, but the hematopoiesis of this organ ceases of birth. However, the liver is still found to comprise c-kit+ stem cells and gives rise to extrathymic T cells, NK cells, and even granulocytes after birth. Extrathymic T cells generated in the liver of mice are identified as intermediate TCR (TCRint) cells, which include the NK1.1+TCRint (i.e. NKT cells) and NK1.1-TCRint subsets. Although extrathymic T cells are few in number during youth, they increase in number with advancing age. The number and function of extrathymic T cells are also elevated under conditions of stress, infections, malignancy, pregnancy, autoimmune disease, chronic GVH diseases, etc. Under these conditions, the mainstream of T cell differentiation in the thymus, which produces conventional T cells, is inversely suppressed. Extrathymic T cells comprise self-reactive forbidden clones and mediate cytotoxicity against abnormal self-cells. Therefore, they might be beneficial for the elimination of such cells. However, over-activation of extrathymic T cells might be responsible for the onset of certain autoimmune disease.
- The Receptors Regulating Natural Cytotoxic Effector Functions
MARIA NIKOLOVA (National Center of Infectious and Parasisitic Diseases, 1504 Sofia, Bulgaria), LAURENCE BOUMSELL and ARMAND BENSUSSAN (INSERM 448, 94000 Creteil, France)Abstract. Natural cytotoxic effector functions are regulated by a multitude of opposing signals provided by immunoglobulin and lectin-like functional molecules. While inhibitory receptors possess ITIM cytoplasmic sequences recruiting tyrosine phosphatases, activatory receptors require association with accessory ITAM-bearing molecules. One considerable group of natural cytotoxic cell receptors are specific for classical and non-classical class I antigens and detect both qualitative and quantitative changes in the autologous MHC-I phenotype. Non-MHC-I specific receptors provide signaling in the absence of MHC-I antigens or in response to not well-known stress-induced antigens. NK cell receptors may equally participate in the regulation of target cell functions through contact or soluble mediator-dependent mechanisms. The identification of NK cell-regulating molecules has lead to the elucidation of more general principles underlying immune homeostasis.
Keywords: natural cytotoxicity; NK cells; KIR; MHC-I; BY55.
- Neuropeptides as Modulators of Macrophage Functions. Regulation of Cytokine Production and Antigen Presentation by VIP and PACAP
DOINA GANEA (Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA) and MARIO DELGADO (Departamento Biologia Celular, Facultad de Biologia, Universidad Complutense, Madrid 28040, Spain)Abstract. VIP, and the structurally related neuropeptide PACAP, present in the microenvironment of lymphoid organs, modulate the function of inflammatory cells through specific receptors. VIP and PACAP inhibit the production of the pro-inflammatory agents and stimulate the production of anti-inflammatory cytokines in activated macrophages. The effect is mediated through specific receptors, and involves shedding of the CD14 LPS receptor and the transcriptional regulation of cytokine genes through effects on de novo expression or nuclear translocation of NFkB, CREB, c-Jun, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine modulation, which presumably mediates the protective effect of VIP/PACAP in a high-endotoxic murine model for septic shock. VIP/PACAP reduce the expression of the costimulatory B7.1/B7.2 molecules, and the subsequent stimulatory activity for T helper cells in stimulated macrophages. In contrast, in unstimulated macrophages, VIP/PACAP induce specific B7.2 expression and promote Th2 cell differentiation. We propose that VIP/PACAP act as endogenous factors that regulate immune homeostasis, and that the physiological consequences of the VIP/PACAP presence in the immune microenvironment depends on the timing of the neuropeptide release and the activation stage of the neighboring immune cells.
Keywords: neuropeptides, macrophages, cytokines, B7 molecules, Th1/Th2 cells, VIP/PACAP.
- Modeling the Meta-Dynamics of Lymphocyte Repertoires
RAMIT MEHR (Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel)Abstract. The complexity of biological systems, and the explosion of the quantity of biological information which is rapidly becoming available from experimental and clinical studies, necessitate the use of theoretical tools, namely, mathematical and computational modeling. The vertebrate adaptive immune system, with its learning and memory capabilities, is a particularly rich source of modeling challenges. Most difficult within this area is the study of lymphocyte repertoires – the generation of their diversity and the forces that shape the ever-changing dynamics of lymphocyte clones. I review several examples of problems in lymphocyte repertoire modeling, demonstrate the types of solutions employed, and highlight the contribution of these theoretical studies to immunological research.
Keywords: lymphocyte repertoires; lymphocyte development; mathematical model; computer simulation.
- The Molecular Mechanisms of Post-Adhesive Transmigration of T Cells
JUN-ICHI MASUYAMA (Division of Rheumatology and Clinical Immunology, Jichi Medical School, Minamikawachi-machi Tochigi, 329-0498, Japan)Abstract. Leukocyte extravasation is an essential phenomenon in inflammatory responses of the body. However, less is known about the mechanisms of transendothelial migration of leukocytes subsequent to their adhesion to the endothelium. It could be considered that at least three different cellular responses participate in the transmigration of adherent leukocytes: 1) polarization of adherent cells in cell shape, 2) interactions between adherent cells and molecules bound to the endothelial surface to stimulate migration through the junction between adjacent endothelial cells, and 3) co-ordination with endothelial cells to open the junction. Molecules involved in these events are discussed in this review.
Keywords: transmigration; endothelial cells; T cells; molecular mechanism.
- Molecular Mechanisms of CD40 Signaling
GAIL A. BISHOP and BRUCE S. HOSTAGER (Department of Microbiology, The University of Iowa, Iowa City, IA 52240, USA)Abstract. CD40, a member of the growing tumor necrosis factor receptor (TNF-R) family of molecules, functions as a transmembrane signal receptor in both hematopoietic and non-hematopoietic cell types, although its physiological roles are less well understood in the latter. Much has been learned over the past decade about the role of CD40 signaling in various cellular functions. In addition, some of the molecular events which occur subsequent to CD40 engagement have been characterized, although much remains to be understood. This review will summarize the known important biological roles of CD40, and discuss what is currently known about how CD40 signals.
Keywords: CD40; lymphocyte activation; sugnal transduction; B cell; tumor necrosis family; recptor family.
Clinical Immunology
- Alcohol-Related Cirrhosis with Pancreatitis. The Role of Oxidative Stress in the Progression of the Disease
AGNIESZKA SZUSTER-CIESIELSKA (Department of Virology and Immunology, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland), JADWIGA DANILUK (Clinic and Department of Gastroenterology, University Medical School, Jaczewskiego 8, 20-950 Lublin, Poland) and MARTYNA KANDEFER-SZERSZEŃ (Department of Virology and Immunology, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland)Abstract. To assess the level of oxidative stress, measured as prooxidant-antioxidant imbalance in the blood of patients with alcohol-related injury of the liver and pancreas, we determined superoxide ion (O2•-) production by neutrophils isolated from the peripheral blood of 3 groups of patients. Patients with compensated alcoholic liver cirrhosis (n=16), with alcoholic chronic pancreatitis (n=20), and with concomitant cirrhosis and pancreatitis (n=10) were included in this study. All patients had consumed at least 70 g of pure alcohol per day over 5 years. They had not abstained before admission to hospital. The control group consisted of 16 healthy non-alcohol-abusive subjects. As antioxidative enzymes (AOE) present in sera play a very important role in the regulation of plasma ROS levels and in the protection of plasma compounds against ROS action, we also examined serum activity of CAT, SOD (total activity) and GPx serum concentration. Neutrophils of patients with concomitant alcoholic liver cirrhosis and pancreatitis exhibited, similarly to the neutrophils of patients with chronic alcoholic pancreatitis, an enhanced ability to produce superoxide anions in vitro. In contrast, neutrophils of patients with alcoholic liver cirrhosis exhibited a defect in resting and PMA-induced superoxide anion production. The AOE activity in the sera of patients was also significantly changed. Total SOD activity was enhanced in all groups of patients with alcoholic liver cirrhosis, chronic pancreatitis and with concomitant injury of both organs. CAT activity was only increased in the sera of patients with liver cirrhosis or pancreatitis, but not in the patients with concomitant cirrhosis and pancreatitis. GPx concentration was only diminished in the patients with chronic pancreatitis. It seems likely that oxidative stress, defined as the imbalance between prooxidant and antioxidant activity, is highest in the blood of patients with chronic pancreatitis and, especially, in patients with concomitant liver cirrhosis and pancreatitis.
Keywords: alcohol; cirrhosis; pancreatitis; superoxide anion; catalase; glutathione peroxidase; superoxide dismutase.
- Lactoferrin Regulates Proliferative Response of Human Peripheral Blood Mononuclear Cells to Phytohemaggultinin and Mixed Lymphocyte Reaction
MICHAŁ ZIMECKI, DARIUSZ STĘPNIAK, AGNIESZKA SZYNOL (Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, Poland) and MARIAN L. KRUZEL (Department of Integrative Biology, Pharmacology and Physiology, Health Science Center, Medical School, University of Texas, PO BOX 20708, Houston TX 77225, USA)Abstract. The aim of this study was to investigate the effects of bovine lactoferrin on the proliferative response of human blood lymphocytes induced by PHA and alloantigens in two-way mixed lymphocyte culture at a broad range of BLF concentrations (1.5 – 50 ?g/ml). We found that the effects of BLF in both experimental models were differential and depended on an individual reactivity of lymphocytes with respect to mitogen or alloantigen and BLF concentration. Generally, lymphocytes from donors reactive to BLF exhibited higher proliferation indices compared to nonreactive individuals. Low BLF doses were regulatory and higher ones mostly inhibitory. MLR was in most cases inhibited by all doses of BLF, some MLR stimulated and other not affected by BLF. We conclude that basis for the differential action of BLF is its ability to sense the activation status of lymphocytes. The resultant effects of BLF are probably mediated by monocytes and cytokines.
Keywords: bovine lactoferrin; PBMC; proliferation; PHA; MLR.
- Proinflammatory Cytokine Inhibitors, TNF-a and Oxidative Burst of Polymorphonuclear Leukocytes in Pathogenesis of Sepsis in Newborns
JANUSZ PIOTR SIKORA, DANUTA CHLEBNA-SOKÓŁ (Department of Pediatric Propedeutics, Institute of Pediatrics, Medical University of Łódź), IWONA DĄBROWSKA, DARIUSZ LIPCZYŃSKI (Department of Intensive Care and Anesthesiology, 4th Pediatric Clinical Hospital, Medical University of Łódź) and SŁAWOMIR CHRUL (Department of Child Diseases, Institute of Pediatrics, Medical University of Łodź, Sporna 36/50, 91-738 Łódź, Poland)Abstract. This study was to evaluate the levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-a) and the cytokine inhibitors soluble TNF-a receptor (sTNFR) and IL-1 receptor antagonist (IL-1 ra) as well as the intensity of oxidative metabolism of peripheral blood polymorphonuclear leukocytes in the course of sepsis in newborns. An increase of TNF-a, sTNFR and IL-1 ra concentrations was found in the blood serum of the patients at the time of diagnosis. This was further accompanied by polymorphonuclear leukocyte stimulation and, as a consequence of prolonged bacterial antigen stimulation, functional exhaustion of these cells and their diminished oxidative metabolism was observed. Within the same time period, an enhanced expression of p55 and p75 TNF-a receptors on polymorphonuclear leukocyte cell surfaces was found. It was indicated that the applied pharmacotherapy caused a decrease of the initially elevated concentrations of TNF-a and proinflammatory cytokine inhibitors (sTNFR, IL-1 ra). The intensive therapy of sepsis was associated with the increased oxidative burst of polymorphonuclear leukocytes along with the decrease of p55 and p75 expression on their cell surfaces.
Keywords: sepsis; TNF-a; cytokine inhibitors; oxidative burst; neutrophils.
Immunochemistry
- Structure and Serological Characterization of an Ne-[(R)-1-carboxyethyl]-L-lysine-Containing the O-Chain of the Lipopolysaccharide of Proteus mirabilis O13
ANNA S. ŚWIERZKO, MACIEJ CEDZYŃSKI, ANDRZEJ ZIÓŁKOWSKI, WIESŁAW KACA (Centre of Microbiology and Virology, Polish Academy of Sciences, Lodowa 106, 93-232, Łódź, Poland), SOF’YA N. SENCHENKOVA, ANDREI V. PEREPELOV, YURIY A. KNIREL (N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia)Abstract. In this paper we present the structure and describe serological properties of the O-specific polysaccharide of Proteus mirabilis O13 lipopolysaccharide, which contains a unique component, an amide of D-galacturonic acid (D?GalA) with an unusual amino acid Ne-[(R)-1-carboxyethyl]-L-lysine (alaninolysine, AlaLys). Selective chemical degradations of either GalA or AlaLys resulted in the loss of the serological reactivity of the polysaccharide with anti-O serum against P. mirabilis O13. Neither synthetic stereoisomers of AlaLys nor the isolated amide of GalA with AlaLys inhibited the reaction of the O-antiserum with the homologous lipopolysaccharide. The O-antiserum did not cross-react with the lipopolysaccharide of Providencia alcalifaciens O23 containing an amide of D-glucuronic acid with AlaLys. These data showed that both uronic acid and amino acid components of the amide play an important role in manifesting the P. mirabilis O13-specificity, but the full specific epitope also includes also another OPS component(s). A cross-reactivity of anti-O13 serum with some other P. mirabilis strains was observed and attributed to a common heat-stable antigen(s) different from the lipopolysaccharide
Keywords: Proteus mirabilis; lipopolysaccharide; O-specific polysaccharide; serological reactivity; Ne-[(R)-1-carboxyethyl]-L-lysine
- Neural Cell Adhesion Molecule in Breast, Colon and Lung Carcinomas
ALBINA ŻÓŁTOWSKA, JAN STĘPIŃSKI, BARBARA LEWKO (Department of Immunopathology), KRYSTYNA SERKIES (Department of Oncology and Radiotherapy), BARBARA ZAMORSKA (Department of Immunopathology), ANDRZEJ ROSZKIEWICZ, EWA IŻYCKA-ŚWIESZEWSKA (Department of Pathomorphology) and WIESŁAW J. KRUSZEWSKI (Department of Surgical Oncology Medical University Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland)
Abstract. Neural cell adhesion molecules (NCAM) play an important role in embryogenesis and in some tumors, especially of neuroectodermal origin. In this study, eighteen cases of invasive breast carcinoma, seven cases of sigmoid colon carcinomas and seventeen cases of the non-small cell lung carcinoma were immunostained for NCAM. The NCAM expression, usually focal, was observed in some cases only. NCAM was expressed in the membranes, in a fine granular pattern. In three cases of breast cancers, also cytoplasmic localisation of NCAM was observed, which may suggest its cytoplasmic formation. Furthermore, in three cases expression of NCAM in histologically normal ductal lobular units adjacent to invasive breast cancers without presence of this antigen in cancer tissue was observed. The immunostaining was weak or absent in sigmoid colon carcinomas. In this study we confirm observation of some authors that NCAM expression occurs in some cases of non-small cell lung carcinomas.
Keywords: CD56 (NCAM); breast ca; sigmoid colon ca; squamous cell lung ca.