Vol. 48, No. 1, 2000
The Immunopathology of Primary Biliary Cirrhosis: Thoughts for the Millennium
MOTOKO SASAKI, AFTAB A. ANSARI, YASUNI NAKANUMA, ROSS L. COPPEL, EMMET B. KEEFFE and M. ERIC GERSHWIN
Abstract. Primary biliary cirrhosis is an organ specific autoimmune disease that produces progressive cholestatic liver failure. It is predominantly a disease of women characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antibodies to mitochondria. The mechanisms by which and if which such antibodies produce liver tissue injury is unknown. However, the presence of these antibodies have allowed detailed immunological definition of the antigenic epitopes, the nature of reacting autoantibodies and the characterization of T cell responses. Several mechanisms may now be proposed regarding the immune mediated bile duct damage in PBC, including the possible role of T cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies (AMA) and mitochondrial autoantigens. The advent of molecular biology, the ability to clone and define epitopes, and the use of in situ nucleic acid hybridization, have all led to advances in understanding the natural history of immunopathology in PBC. There are major questions which remain unanswered, including, of course, etiology, but also including the questions of why there is female predominance, the absence of PBC in children, the relative ineffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. In this review, we focus on these issues and particularly on the immunobiology of patients with this disease.
Keywords: primary biliary cirrhosis; autoimmunity; mitochondria; pyruvate dehydrogenase.
Molecular Aspects in the Pathogenesis of Human Systemic Lupus Erythematosus
STAMATIS-NICK C. LIOSSIS, and GEORGE C. TSOKOS
Abstract. Systemic lupus erythematosus is a common and often devastating systemic autoimmune disease of unknown etiology. In this communication we review the latest developments of the molecular pathogenesis of human lupus. Novel genetic studies of multiplex lupus families have revealed potential disease-associated genome intervals, put special emphasis on genetic loci mapping in the long arm of chromosome 1 and have underscored the complexity of the underlying genetic background. New data have emerged on the role of estrogens in the function of lymphocytes and a number of studies have recently emphasized the relative Th-1/Th-2 cytokine imbalance in favor of a Th-2 type cytokine immune response. Finally, novel experiments have revealed an abnormal antigen receptor- -mediated signaling process in lupus T and B cells, which may influence the aberrant expression and function of costimulatory molecules as well as of other aspects of immune cell function. It is important to decipher the underlying molecular mechanisms that govern the expression of human lupus, because we may design novel, rational approaches in the treatment of a human lupus, a disease that has high morbidity and mortality.
Keywords: autoimmunity; lymphocytes; antigen receptor; signal transduction; costimulatory molecules.
Preventing Staphylococcal Disease by Disarming the Immune Responses to Infection
ANDREJ TARKOWSKI
Abstract. Use of experimental models of staphylococcal infections clarified several bacterial virulence factors as well as many hematopoetic cell types and their products that are involved in the pathogenesis of infection. For many decades it has been believed that antibody mediated response to staphylococci and their products was the major, if not the only one, hallmark of immune reactivity during infection. Recent studies have documented that T cell mediated responses to superantigens produced by staphylococci are not only prominent but also decisive with respect to sequels. Also the nonantigen specific immune responsiveness to staphylococcal infection is reviewed including roles of neutrophils, complement system and nitric oxide. The knowledge gained regarding staphylococcal virulence factors and the host immune responses has prompted researchers to develop new strategies how to interact in vivo witl the infectious process. Some of these approaches are commented in this review regarding e. g. vaccination procedures in order to prevent severe infections as well as therapeutic procedures to minimize organ damage during an ongoing infectious process.
Keywords: Staphylococcus aureus; vaccination; virulence immunity; T cells; B cells; cytokines; CpG oligonucleotides.
Crosstalk Between G Protein-Coupled Receptors and Tyrosine Kinase Signaling: Src Take Centre Stage
ANDRZEJ PTASZNIK and ALAN M. GEWIRTZ
Abstract. Although the role of G protein-coupled receptors in the regulation of metabolic, secretory and contractile responses is well established, they have only recently been recognized as important mediators of cellular growth and differentiation. G protein-coupled signaling pathways had been previously thought to be totally independent of the tyrosine kinase receptor pathway. It was previously believed that molecular switches responsible for growth factor tyrosine kinase receptor signaling and G protein-coupled signaling were divided into a distinct sets of protein families. Recent evidence has demonstrated, however, that G protein-coupled receptors can crosstalk to tyrosine kinase signaling. In the past few years several groups have found that G protein-coupled receptors utilize non-receptor tyrosine kinases, mostly that of Src family, and some adapter proteins, to regulate tyrosine kinase cascades in cells.
Keywords: signal transduction; Src kinase; Shc protein; PI 3-kinase.
Effective Phage Therapy is Associated with Normalization of Cytokine Production by Blood Cell Cultures
BEATA WEBER-DĄBROWSKA, MICHAŁ ZIMECKI and MARIAN MULCZYK
Abstract. The aim of this study was to investigate the effect of phagotherapy on tumor necrosis factor a (TNF-a) and interleukin 6 (IL-6) serum levels and the ability of blood cells to produce these cytokines in culture. Fifty one patients with long-term, suppurative infections of various tissues and organs were enrolled. The ability of cells to secrete cytokines was tested using whole blood cell cultures, unstimulated or stimulated with lipopolysaccharide (LPS) from E. coli. In addition, cytokine serum levels were determined. Measurement of cytokine activity was performed using bioassays. We showed that TNF-a, but not IL-6 serum levels, were regulated upon division of patients into categories exhibiting initial: low, moderate and high cytokine levels. The low spontaneous production of IL-6 by blood cell cultures was elevated significantly on day 21 of phage therapy, whereas high release of this cytokine was inhibited. No such correlation was observed with LPS-induced IL-6 production in cell cultures when cells from low-, moderately- or highly-reactive patients were studied. Phage therapy modified TNF release according to the initial ability to produce that cytokine: it reduced TNF production in high responders and increased it in low responders. Patients infected only with Gram-positive bacteria demonstrated analogous changes in the spontaneous and LPS-induced TNF-a production as in the whole studied group. A similar kind of regulation was observed in TNF-a and LPS-induced production, i. e. low production was significantly elevated, high strongly inhibited, and moderate only slightly affected. In summary, we demonstrated for the first time that effective phage therapy can normalize TNF-a serum levels and the production of TNF-a and IL-6 by blood cell cultures.
Keywords: phage therapy; TNF-a; IL-6; blood cell cultures.
Abnormal Distribution of gd T Lymphocytes in Graves’ Disease and Insulin-Dependent Diabetes Type 1
ADAM KRĘTOWSKI, JANUSZ MYŚLIWIEC and IDA KINALSKA
Abstract. There is an increasing evidence that CD3+ cells, bearing gd T cell receptors representing a minor subpopulation of T cells in the peripheral blood of humans are involved in the development of autoimmunity. The aim of the present study was determination of the gd T cell subpopulation levels in the peripheral blood of subjects with Graves’ disease and newly diagnosed type 1 diabetes in comparison to age-matched healthy controls. The percentages of CD3+, CD8+, gd TCR+CD8+, gd TCR+CD8– lymphocyte subsets were measured by flow cytometry. In the peripheral blood of newly diagnosed Graves’ disease patients we showed a significant decrease of gd TCR+ cells and gd TCR+CD8– subset content in comparison to the percentages observed in subjects after methimazole treatment and in healthy controls. We also found a significant increase of gd TCR+CD8+ cells in the peripheral blood of subjects with insulin-dependent diabetes, treated with insulin for 3–6 months. The present findings confirm our previous hypothesis that gd TCR+CD8+ lymphocyte subset could play a role in the pathogenesis of diabetes type 1, probably as regulatory T cells and could be induced by delivery of exogenous insulin. Our results suggest that gd T cells (gd TCR+CD8– subset) could also play an important role in the development of Graves’ disease and that their levels are modulated by thyreostatic treatment.
Keywords: gd TCR+ lymphocytes; Graves’ disease; type 1 diabetes mellitus.
Changes in Glucocorticoid-Induced Apoptosis and in Expression of Bcl-2 Protein During Long-Term Culture of Thymic Lymphoma
MARCIN KOBZDEJ, JANUSZ MATUSZYK, EWA ZIOŁO and LEON STRZĄDAŁAMARCIN KOBZDEJ, JANUSZ MATUSZYK, EWA ZIOŁO and LEON STRZĄDAŁA
Abstract. Lymphomagenesis is a multistep process progressively freeing transformed thymocytes from external regulatory signals, i. e. thymic developmental program controlling growth, differentiation or apoptosis. Here we report that cells of thymic lymphoma overexpressing Ras/Raf proteins, initially resistant to TCR-dependent apoptosis but sensitive to dexamethasone- and etoposide-induced cell death, became insensitive to dexamethasone after long-time culture. That transition correlated with a strong increase in the expression of the anti-apoptotic Bcl-2 protein. Interestingly, lymphoma cells were still sensitive to p53-mediated apoptosis induced by etoposide. It suggests that the anti-apoptotic activity of Bcl-2 is correlated with a resistance to glucocorticoid-induced apoptosis but not to p53-mediated apoptosis. The sequence of mutations in the process of lymphomagenesis seems to be composed of at least 3 main hits which equip the cells with independence from external mitogenic signals (activation of Ras/Raf), resistance to inducers of apoptosis (activation of Bcl-2) and generation of cellular heterogeneity (deletion of p53) important in tumor progression.
Keywords: thymic lymphoma; Bcl-2; dexamethasone; apoptosis; long-term culture.
HLA-DR Antigens in Patients with Pulmonary Tuberculosis in Northern Poland. Preliminary Report
ANNA DUBANIEWICZ
Abstract. The aim of the present study was the analysis of the association between particular class II HLA antigens and the incidence of tuberculosis in northern Poland. HLA-DR antigens in a group of 26 patients with pulmonary tuberculosis (PTB) and 58 healthy volunteers were determined. Histocompatibility typing was performed by the PCR-SSP method using primers from the Dynal company. For statistical analysis, the c2 test was used with Yates’ correction. The probability values were weighted for the number of antigens tested (pc). The relative risk (RR) was calculated by Woolf’s method. We found that HLA-DR16(2) antigen expression was significantly higher in patients with tuberculosis than in the tested group of healthy controls (p<0.001, pc< 0.01); the highest relative risk (RR = 12. 4) of tuberculosis incidence was connected with DR16(2) antigen, the prevalence of HLA-DR13(6) antigen was significantly lower in pulmonary tuberculosis (with RR = 0. 09) than the control (p< 0. 001, pc< 0. 01). The results obtained suggest that the presence of HLA-DR16(2) antigen can extend the risk of developing tuberculosis whereas HLA-DR13(6) antigen occurrence was significantly more rare in pulmonary tuberculosis than in healthy individuals and that the relative risk (RR = 0. 09) can be connected to their relation with the genes of insusceptibility to tuberculosis.
Keywords: HLA-DR; pulmonary tuberculosis.
Novel Ru(III), Rh(III), Pd(II) and Pt(II) Complexes with Ligands Incorporating Azole and Pyrimidine Rings. I. Antiproliferative Activity in Vitro
MAREK Z. WIŚNIEWSKI, JOANNA WIETRZYK and ADAM OPOLSKI
Abstract. A number of co-ordination compounds of Ru(III), Rh(III), Pd(II) and Pt(II) with ligands incorporating azole and pyrimidine rings has been synthesized. The in vitro cell proliferation-inhibitory activity of these compounds was examined against human cancer cell lines: A 549 (lung carcinoma), LS-180 (colon cancer) and MCF-7 (breast cancer), using SRB technique. Six out of 13 compounds studied revealed cytotoxic activity in vitro. Inhibitory dose 50% (ID50) was lower than 4 mg/ml, which is an activity criterion accepted in conventional in vitro cytotoxic screening tests. Two compounds revealed weak cytotoxic activity with ID50 higher than 4 mg/ml and five compounds were inactive.
Keywords: azole and pyrimidine complexes; platinum-group metal complexes; cytotoxic activity in vitro; human cancer cell lines.
Vol. 48, No. 2, 2000
The NFkB/IkB System in Acute Inflammation
ALEX B. LENTSCH, PETER A. WARD
Abstract. The transcription factor NFkB is a primary regulator of a wide variety of proinflammatory mediators. Under normal conditions, NFkB is retained in the cytoplasm bound to inhibitory proteins of the IkB family. Following cell activation, a number of signal transduction pathways lead to degradation of IkB proteins which results in nuclear translocation of NFkB and the ensuing transcriptional activation of proinflammatory genes. Several endogenous regulatory mediators, which function to prevent uncontrolled inflammation, exert their effects by blocking the activation of NFkB. Thus, NFkB appears to be at the heart of the acute inflammatory response. The present review discusses the role of NFkB in the induction and propagation of the acute inflammatory response as well as the regulation and resolution of this process.
Keywords: acute inflammatory response; transcription factor; inhibitory IkB proteins.
Chemokines, G Proteins and Natural Killer Cells
AZZAM A. MAGHAZACHI
Abstract. Natural killer (NK) cells are anti-tumor and anti-viral effector cells. Members of C, CC, CXC and CX3C chemokines induce the chemotaxis and enhance the cytotoxicity of NK cells, suggesting that these cells express receptors for chemokines. The ability of members of chemokines to inhibit the replication of HIV-1 strains, combined with the ability of the same chemokines to activate the anti-viral NK cells, provide compelling evidence for the role of NK cells in eradicating HIV-1 infection. In addition, chemokines induce various intracellular signaling pathways in NK cells, which include activation of the heterotrimeric, and perhaps the small guanine nucleotide binding (G) proteins, as well as the mobilization of intracellular calcium, among other activities. Further, chemokines induce the phosphorylation of chemokine receptors through the recruitment of G protein-coupled receptor kinases (GRKs) resulting in the desensitization and turning off the signals. In this review, I will update the knowledge of the effect of chemokines on NK cell motility and the signal transduction pathways induced by chemokines in these cells.
Keywords: chemokines; natural killer cells; G proteins; chemotaxis; cytolysis.
Immune Privilege or Inflammation? The Paradoxical Effects of Fas Ligand
JOE O’CONNELL
Abstract. Fas ligand (FasL) induces apoptosis of cells, including activated lymphocytes, expressing its cognate receptor, Fas (CD95/APO-1). FasL precludes inflammatory reactions from immune privileged sites by triggering Fas-mediated apoptosis of infiltrating proinflammatory cells. Aberrant expression of FasL by cancers inhibits antitumor immune responses. The ability of FasL to impair immune responses may hold therapeutic promise as a means of protecting tissue transplants from immunological rejection. Paradoxically, FasL exhibits proinflammatory activity independent of its ability to mediate immune privilege. FasL has been shown to recruit and activate neutrophils, although the factors that determine whether FasL is pro- or anti-inflammatory are only beginning to emerge. FasL appears to contribute to cell death in Fas-sensitive endorgan cells during inflammation. Blocking of Fas-mediated endorgan apoptosis or enhancing Fas-mediated apoptosis of inflammatory cells represent potential targets for future antiinflammatory therapies.
Keywords: Fas (CD95/APO-1); Fas ligand (FasL); apoptosis; immune privilege; transplantation; inflammation.
Immunotherapy of Inflammatory Bowel Diseases: Current Concepts and Future Perspectives
MARKUS F. NEURATH
Abstract. The etiology and the pathogenesis of inflammatory bowel diseases (IBD), e. g. Crohn’s disease and ulcerative colitis are still not completely understood. However, there is growing evidence that an alteration of the mucosal immune system towards luminal antigens in a genetically susceptible host plays a key role in the pathogenesis of IBD. In particular, cytokines produced by intestinal epithelial cells, lamina propria macrophages and CD4+ T cells appear to contribute to the initiation and perpetuation of intestinal inflammation in IBD. This review focuses on the role of the mucosal immune system in the pathogenesis of IBD and potential novel immunotherapeutic strategies for chronic intestinal inflammation. Such strategies include recombinant antiinflammatory cytokines, neutralizing antibodies or fusion proteins, antisense oligonucleotides and adenoviral gene transfer.
Keywords: Crohn’s disease; ulcerative colitis; cytokines; immunotherapy; gene transfer.
Tumor Vaccines for the Management of Prostate Cancer
DOUGLAS G. MCNEEL and MARY L. DISIS
Abstract. Prostate cancer is a significant health problem and one of the leading causes of cancer-related death among men. Given the typically long natural history of the disease, there is considerable interest in developing new therapies to treat or prevent metastatic disease, and cancer vaccines are a particularly attractive immune-based approach. Early clinical studies using non-specific immunomodulatory treatments have met with limited success, but also suggest that improved immunologic approaches might be useful in treating human prostate cancer. Over the last decade, the identification of immune cells responsible for actual destruction of prostate tissue and advances in immunologic and molecular techniques have led to a variety of vaccination approaches that are currently being evaluated in human clinical trials. The present article discusses the rationale in animal models for particular immunization strategies and describes the vaccines currently being used in patients with prostate cancer. The ongoing identification of tumor antigens and proteins involved in prostate cancer progression and the development of better immunologic animal models suggest a hopeful future for the design of effective prostate cancer vaccines.
Keywords: prostate cancer; tumor vaccines; clinical trials; immunotherapy.
The Genes of Interferons and Interferon-Related Factors: Localization and Relationships with Chromosome Aberrations in Cancer
OLGA HAUS
Abstract. The paper presents a review of data on the localization of interferons (IFNs) and IFN system genes and their relationship with human diseases, mainly cancer. Genes of interferon system proteins are located at the sites of breakpoints of the structural chromosome aberrations in cancer. Thus, any of them are rearranged or translocated in various tumor types. As the activity of these genes plays a role in cancer development, their rearrangements may be one of the crucial points in the pathogenesis of some cancer types. Besides, they also take part in organism immunity against viral infections. Transfection experiments with IFN system genes have proved the influence of these genes on cancer behavior and may serve as a basis for clinical gene therapy. IFN-a and IFN-b genes are located at 9p21-22, the site of frequent homozygotic deletions in cancer. Their loss sensitizes cells to the growth inhibitory actions of exogenous IFNs. The IFN-g gene, a representative of class II genes, is located at 12q24. 1. Transfection of class II IFNs genes to cancer cell lines causes cell proliferation arrest and augments the expression of HLA antigens, which may be clinically useful in stimulating the immune destruction of tumor cells. The interferon regulatory factor 1 (IRF-1) gene is located at 5q31, the site of common deletions in myelodysplastic syndromes (MDS) and secondary leukemias. The loss of heterozygosity of this gene was found in MDS, which proves that IRF-1 may be a tumor suppressor. A transfection of its gene causes neoplastic transformation arrest. The double-stranded RNA-activated protein kinase (PKR) gene is located at 2p21-22, a region which is frequently rearranged in leukemia. Transfection of a wild type PKR gene reverses neoplastic transformation caused by transfection of a mutated PKR gene, proving that PKR acts as a dominant negative cancer suppressor.
Keywords: interferon system; gene localization; gene transfer; cancer; chromosome aberrations.
Interleukin 6, Tumor Necrosis Factor a and Their Soluble Receptors in the Blood Serum of Patients with Denture Stomatitis and Fungal Infection
JAN KRZYSZTOF PIETRUSKI, MAŁGORZATA DOROTA PIETRUSKA, EWA JABŁOŃSKA, PAWEŁ SACHA, MARIA ZAREMBA and WANDA STOKOWSKA
Abstract. Determinations of the blood serum levels of interleukin 6 (IL-6), tumor necrosis factor a (TNF-a) and their soluble receptors (sIL-6R, sTNFR) in denture stomatitis patients (DS) were performed. Serum levels of interleukins and their soluble receptors were measured using the ELISA method. In all examined patients mycological diagnostics were conducted using API 20C AUX stripe tests and an automatic ATB machine. Results were compared with those of healthy denture weares (D), and controls (C). In DS patients, yeasts were isolated in 90. 9%, in D in 66. 7% of cases. The most often isolated species in both groups was Candida albicans. Mean concentrations of IL-6 and TNF-a were statistically significantly higher in D and D groups compared to controls. Mean concentrations of sIL-6R were similar in all groups; however, concentrations of sTNFR in both DS and D groups were significantly lower compared to controls. There were no correlations found between values of IL-6 and TNF-a nor between examined interleukins and their soluble receptors.
Keywords: denture stomatitis; fungal infection; interleukin 6; tumor necrosis factor; soluble receptors.
Histamine Receptor Expression on Peripheral Blood Lymphocytes Is Influenced by Specific and Nonspecific Activation
TERESA ŻAK-NEJMARK, MARIA KRAUS-FILARSKA, JÓZEF MAŁOLEPSZY, RENATA JANKOWSKA, MAREK JUTEL, IWONA A. NOWAK and GRAŻYNA NADOBNA
Abstract. Histamine is a physiological mediator which exerts both effector and regulatory functions through its receptors on various cells. The aim of the study was to investigate changes in histamine receptor expression on peripheral blood lymphocytes affected by stimulation with both specific and nonspecific stimuli. Lymphocytes were obtained from both healthy and allergic subjects. Cells were incubated with various allergens (mixed grass pollen, Lolium perenne, Dermatophagoides pteronyssinus 1, bee venom, phospholipase A2) and nonspecific (fMLP, PMA/ionomycin, LPS) stimuli. The percentage of histamine-binding cells was determined with a fluorescence microscope after incubation with histamine-fluorescein. In control subjects histamine binding after stimulation with allergens was not significantly changed. In contrast, in allergic subjects stimulation with specific allergens resulted in significantly increased histamine binding. Nonspecific stimulation caused increased histamine binding to lymphocytes in both allergic subjects and healthy controls. We conclude that specific and nonspecific activation of lymphocytes is associated with increased expression of histamine receptors.
Keywords: histamine receptors; lymphocytes; specific activation.
The Contribution of Endotoxins Present in the Respiratory Tract to Overproduction of Nitric Oxide Associated with Impaired Interleukin 6 Release in Bronchoalveolar Leukocytes from Lung Cancer Patients
MONIKA CEMBRZYŃSKA-NOWAK, MAŁGORZATA BIEŃKOWSKA, BOŻENA WERYŃSKA, TOMASZ DYŁA and RENATA JANKOWSKA
Abstract. The purpose of the study was to assess the relation between the levels of endotoxins circulating in airways of patients with lung cancer and the ability of bronchoalveolar lavage (BAL) leukocytes for ex vivo release of nitric oxide (NO) and interleukin 6 (IL-6) and for in vitro lipopolysaccharide (LPS) -induced production of the mediators. Leukocytes isolated from the BAL of 11 patients and from 5 healthy individuals were cultured in the absence or presence of LPSE. coli. The levels of endotoxins in the BAL fluids (BALF) and the amounts of NO released ex vivo from unstimulated cells from the patients were highly (p = 0. 0025) elevated in comparison with those from healthy individuals. The release of NO was significantly correlated (Rs = 0. 638, p = 0. 047) with the levels of endotoxins in BALF. In contrast, production of IL-6 remained very low and a negative correlation (Rs = –0. 623, p = 0. 0542) was observed between the amounts of NO and IL-6. It was also found that, in response to LPS, bronchoalveolar leukocytes from patients with lung cancer express a reduced capacity for in vitro production of NO and IL-6. Our data suggest that, in patients with lung cancer, the activation of BAL cells by endotoxins circulating in the airways may contribute, at least in part, to overproduction of spontaneous NO and, subsequently, the NO may reduce IL-6 production. Moreover, the exposure in vivo of the BAL cells to LPS renders them unable to respond to the second signals.
Keywords: endotoxins; respiratory tract; nitric oxide; interleukin 6; bronchoalveolar leukocytes; lung cancer.
T Cell Depleted Haploidentical Bone Marrow Transplantation for the Treatment of Children with Severe Combined Immunodeficiency
ELŻBIETA M. SMOGORZEWSKA, JUDITH BROOKS, GERALYN ANNETT, NEENA KAPOOR, GAY M. CROOKS, DONALD B. KOHN, ROBERTSON PARKMAN and KENNETH I. WEINBERG
Abstract. Severe combined immunodeficiency (SCID) is fatal in early childhood if unrecognized and if not treated. The aim was to determine the efficacy of T cell depleted bone marrow transplantation (TCD BMT) in the treatment of children with SCID. Eleven children diagnosed with SCID received histocompatible related donor bone marrow transplantation – HRD BMT (group I). Thirty seven children diagnosed with SCID who did not have histocompatible donors were treated with TCD haploidentical parental bone marrow transplantation (BMT) (group II). TCD was performed by in vitro soybean lectin agglutination followed by E-rosette depletion. Patients were longitudinally assessed for the presence and function of T and B lymphocytes. In group I all children survived. The mean age of children in this group at the time of HRD BMT was 15. 4 months. All surviving patients normalized their specific T cell function. Two out of 11 require treatment with intravenous immunoglobulin i. v. Ig. In group II 17 out of 37 (46%) children survived. At the time of TCD BMT the mean age of survivors was 7. 5 months, vs. 11. 4 months in patients who died. Death was caused most commonly by opportunistic infections, Epstein-Barr virus induced lymphoproliferative disease (EBV-LPD), and graft versus host disease (GvHD). Seventeen out of 17 surviving patients recovered normal numbers of CD3+ cells and antigen specific T cell function. Five out of 17 never recovered their B cell function and require i. v. Ig injections. Early diagnosis, prevention or treatment of opportunistic infections, and enhancement of immune recovery will be necessary to improve survival in patients with SCID treated with TCD BMT.
Keywords: severe combined immunodeficiency (SCID); histocompatible bone marrow transplantation; T cell depleted haploidentical bone marrow transplantation.
The Contribution of Endotoxins Present in the Respiratory Tract to Overproduction of Nitric Oxide Associated with Impaired Interleukin 6 Release in Bronchoalveolar Leukocytes from Lung Cancer Patients
MONIKA CEMBRZYŃSKA-NOWAK, MAŁGORZATA BIEŃKOWSKA, BOŻENA WERYŃSKA, TOMASZ DYŁA and RENATA JANKOWSKA
Abstract. The purpose of the study was to assess the relation between the levels of endotoxins circulating in airways of patients with lung cancer and the ability of bronchoalveolar lavage (BAL) leukocytes for ex vivo release of nitric oxide (NO) and interleukin 6 (IL-6) and for in vitro lipopolysaccharide (LPS) -induced production of the mediators. Leukocytes isolated from the BAL of 11 patients and from 5 healthy individuals were cultured in the absence or presence of LPSE. coli. The levels of endotoxins in the BAL fluids (BALF) and the amounts of NO released ex vivo from unstimulated cells from the patients were highly (p = 0. 0025) elevated in comparison with those from healthy individuals. The release of NO was significantly correlated (Rs = 0. 638, p = 0. 047) with the levels of endotoxins in BALF. In contrast, production of IL-6 remained very low and a negative correlation (Rs = –0. 623, p = 0. 0542) was observed between the amounts of NO and IL-6. It was also found that, in response to LPS, bronchoalveolar leukocytes from patients with lung cancer express a reduced capacity for in vitro production of NO and IL-6. Our data suggest that, in patients with lung cancer, the activation of BAL cells by endotoxins circulating in the airways may contribute, at least in part, to overproduction of spontaneous NO and, subsequently, the NO may reduce IL-6 production. Moreover, the exposure in vivo of the BAL cells to LPS renders them unable to respond to the second signals.
Keywords: endotoxins; respiratory tract; nitric oxide; interleukin 6; bronchoalveolar leukocytes; lung cancer.
RM-11, a New Izoxasole Derivative, Is a Potent Stimulator of the Humoral and Cellular Immune Responses in Mice
STANISŁAW RYNG, ZOFIA SONNENBERG and MICHAŁ ZIMECKI
Abstract. In this report we describe immunostimulatory properties of RM-11 in several in vivo and in vitro tests in the murine model. We found that RM-11 significantly stimulated the humoral immune response to sheep erythrocytes (SRBC) when given intraperitoneally (i. p.) at doses of 10 and 100 mg or per os (doses of 20 and 200 mg) 3 h before immunization. The compound was also stimulatory with regard to generation of delayed type hypersensitivity (DTH) to SRBC when given i. p. or per os (doses of 10, 100 and 500 mg/mouse). The described immunostimulatory activities of RM-11 were higher compared to that of the reference drug, levamisole. RM-11 stimulated, in addition, concanavalin A (ConA) -induced splenocyte proliferation. Lastly, we showed that RM-11 was not toxic when given to mice per os at doses 250 mg/kg body weight. Taken together, RM-11 appeared to be a universal stimulator of the immune response in mice. Lack of toxicity and the ability to stimulate the immune response, when administered per os, predispose the compound for further preclinical studies.
Keywords: stimulation; humoral; cellular immune response; izoxazole.
Vol. 48, No. 3, 2000
Three-Dimensional Structures of MHC Class I-Peptide Complexes: Implications for Peptide Recognition
KARINA PERSSON and GUNTER SCHNEIDER
Abstract. Over the last decade, the number of crystal structures of major histocompatibility complex (MHC) class I-peptide complexes has increased rapidly. These studies have provided unique and fascinating insights into the structural basis of MHC-peptide interactions and the specificity of peptide recognition by MHC class I molecules.
Keywords: MHC class I; peptide binding; protein crystallography.
A Burgeoning Family of Biological Mediators: Chemokines and Chemokine Receptors
YINGYING LE, WANGHUA GONG, WEIPING SHEN, BAOQUN LI, NANCY M. DUNLOP and JI MING WANG
Abstract. Chemokines are a superfamily of pro-inflammatory polypeptide cytokines that selectively attract and activate different cell types. Most of its members are small proteins that exhibit conserved cysteines in specific positions. Chemokines activate cells through their binding to shared or unique cell surface receptors which belong to the seven-transmembrane (STM), G-protein-coupled receptors (GPCRs). The large number of chemokines and chemokine receptors are indicative of the importance of these molecules in a variety of pathophysiological conditions.
Keywords: chemokines; G protein-coupled receptor; leukocytes.
Listeria monocytogenes as an Alternative Vaccine Vector for HIV
MARIELENA MATA and YVONNE PATERSON
Abstract. The necessity for an HIV vaccine and a brief review of current strategies towards this aim are given here to set into context contemporary studies towards exploiting the bacterium Listeria monocytogenes as an HIV vaccine vector. The cell biology and immunology of this unusual intracellular organism are also reviewed, in addition to its application to introducing viral antigens, including HIV antigens, to the immune system.
Keywords: HIV vaccine; Listeria monocytogenes; vaccine vector.
Beyond a Structural Component: Sphingolipids in Immunology
EVA E. PRIESCHL and THOMAS BAUMRUKER
Abstract. Two major classes of lipids paricipating in signaling cascades in immune cells are known today. One comprises glycerol-based lipids with diacylglycerol as its most prominent member that mediates the activation of classical and novel protein kinase C molecules. The second group contains the sphingolipids, with the best-investigated representatives being sphingosine, sphingosine-1-phosphate, and ceramide. In the last years the latter two molecules have especially received considerable attention for their modulatory capacity in the course of an apoptotic response. Today it is clear that sphingolipids are ubiquitously distributed in all eukaryotic cells, especially in cellular membranes, where they were previously thought to fulfil an exclusively structural role. Recent findings, however, have demonstrated functions beyond this. Sphingolipid specific G-protein coupled receptors were identified and their role as intracellular second messengers has been further elucidated. In addition, glycosphingolipids, in particular, are enriched in certain membrane compartments, known as detergent resistant membranes. These serve as entry sites for several receptor-mediated signaling events by stabilizing receptor/kinase interactions, suggesting an involvement in the initiation of signaling cascades. Altogether, these findings have led to new insights into both the role of these lipids in signaling as well as the underlying pathology of several diseases with imbalances in the sphingolipid metabolism. The development of these disorders has mainly been attributed to the toxic potential of lysosphingolipids up to now. In addition, attempts have been made to develop compounds and drugs containing the sphingolipid backbone for influencing diseases associated with unwanted cell activation (e. g, cancer, inflammatory processes). These novel findings and developments are reviewed in the following.
Keywords: cell signaling; detergent resistant membranes; intracellular second messengers; sphingolipids.
Cytokine-Producing T Cell Subsets in Human Leishmaniasis
KARE KEMP
Abstract. Leishmania specific Th1/Th2 cells have been identified in humans as well as in mice. There is a correlation between the clinical outcome of the infection and the cytokine response profile. Generally, the production of Th2 cytokines leads to severe infection, whereas the production of Th1 cytokines leads to subclinical or mild infections. In mice, an infection leads to a polarisation of either Th1 or Th2 Leishmania antigen specific cells. In contrast, both Th1 and Th2 Leishmania antigen specific cells can be identified in humans cured from L. donovani infections. Theoretically, Th1 cells and Th2 cells mutually down-regulate each other. However, the presence of antigen specific regulatory T cell subsets may provide an environment that allows the presence of both Th1 and Th2 cells.
Keywords: human leishmaniasis; cytokines; T cells.
Current Status and Future Perspectives of DNA Vaccine Delivery by Attenuated Intracellular Bacteria
GUIDO DIETRICH
Abstract. Vaccination by intradermal or intramuscular injection of antigen-encoding plasmid-DNA elicits strong cellular and humoral immune responses. Professional antigen presenting cells (APC) seem to induce these responses, making it, therefore, desirable to deliver the plasmid molecules directly to these cells. The exploitation of attenuated intracellular bacteria as DNA delivery vehicles makes the direct targeting of DNA vaccine vectors to professional APC feasible.
Keywords: DNA vaccines; delivery; attenuated intracellular bacteria.
Prospects for Development of New Antimycobacterial Drugs, with Special Reference to a New Benzoxazinorifamycin, KRM-1648
HARUAKI TOMIOKA
Abstract. In this article, I have thoroughly reviewed the status of development of new antimycobacterial drugs, in particular, rifamycin derivatives (rifabutin, rifapentine, and a new benzoxazinorifamycin, KRM-1648), fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin, gatifloxacin, sitafloxacin, moxifloxacin, and others), new macrolides (clarithromycin, azithromycin, roxithromycin), and others. In this review, I have mainly described the in vitro and in vivo activities of these drugs against Mycobacterium tuberculosis and atypical mycobacteria, especially Mycobacterium avium complex. In addition, therapeutic efficacy of these drugs in cases of clinical treatment of mycobacterial infections have also been briefly mentioned.
Keywords: mycobacterial infection; Mycobacterium tuberculosis; Mycobacterium avium complex; rifamycin; fluoroquinolones; new macrolides.
Immune Phenomena in Echinoderms
ZDZISŁAW GLIŃSKI and JAN JAROSZ
Abstract. Advances in biochemistry and molecular biology have made it possible to identify a number of mechanisms active in the immune phenomena of echinoderms. It is obvious that echinoderms have the ability to distinguish between different foreign objects (pathologically changed tissues, microorganisms, parasites, grafts) and to express variable effector mechanisms which are elicited specifically and repeatably after a variety of non-self challenges. The molecular and biochemical basis for the expression of these variable defense mechanisms and the specific signals which elicit one type of effector mechanism are not, however, yet well known. The high capacity of coelomocytes to phagocytose, entrap and encapsulate invading microorganisms is a valid immune cell-mediated mechanism of echinoderms. The entrapped bacteria, discharged cellular materials and disintegrating granular cells are compacted and provoke the cellular encapsulation reaction. Moreover, humoral-based reactions form an integral part of the echinoderm defense system against microbial invaders. Factors such as lysozyme, perforins (hemolysins) vitellogenin and lectins are normal constituents of hemolymph, while cytokines are synthesized by echinoderms in response to infection.
Keywords: echinoderm immunity; defense molecules; effector cells; amebocyte immune reactions; cell-free immune factors.
Circulating Immune Complexes in Advanced Hodgkin’s Disease: Qualitative Analysis and Prognostic Significance
ZORAN TOMASEVIĆ and SVETISLAV JELIĆ
Abstract. The level of circulating immune complexes (CIC) may be a reflection of the underlying malignancy and appears to be related to the stage of disease, tumor burden and prognosis. Prognostic factors at diagnosis, clinical response, survival and CIC were analyzed in 89 patients with Hodgkin’s disease. All patients were newly diagnosed, in advanced stage and treated with MOPP regimen. The median follow-up was 41 months. CIC were estimated by the polyethylene glycol precipitation test. The median age was 40 years and 52% were under the age of 45. Nodular sclerosis and mixed cellularity were the most common histologies, 36 and 35% respectively. “B” symptoms were present in 65%, bulky disease in 29% and bone marrow involvement in 4% of the total. The erythrocyte sedimentation rate (ESR) was over 30 in 72% of patients and 27% had one or two extranodal localizations. Complete remission (CR) was obtained in 69 patients (77%). The only factor influencing the CR rate was the number of extranodal localizations (p<0.05). The ten-year relapse-free survival (RFS) and overall survival (OS) were 63 and 83%, respectively. RFS was adversely influenced by lymphocyte depletion histology (p=0. 009) and by performance status over 1 (p=0. 003). Elevated CIC levels were detected in 58% of the total. Patients with ESR over 30 had significantly higher values of CIC (p<0. 05). Qualitative analysis of the CIC showed high levels of positivity to immunoglobulin G and M. C-reactive protein (CRP) was identified in 42% of all samples. CRP is an acute phase protein which shows conformational similarity to the immunoglobulin molecule. There were no significant correlations between levels of CIC and the other prognostic factors. Survival was not influenced by the CIC level.
Keywords: Hodgkin’s disease; immune complexes; prognostic factors.
Lymphoid Aggregates in Gastric Biopsies: Relationship to Other Mucosal Lesions
KAZIMIERZ JAŚKIEWICZ and GRAŻYNA KOBIERSKA
Abstract. The purpose of this study is to estimate the prevalence of lymphocyte aggregates (precursor of MALT lymphomas) in gastric mucosal biopsies and to associate gastric lymphoid tissue with the age of patients, Helicobacter-associated gastritis and other gastric mucosal pathology. A consecutive series of gastric mucosal samples from 150 children and 256 adults were assessed for the presence of lymphoid aggregates as well as morphological characteristics, Helicobacter pylori status, signs of gastritis, mucosal atrophy and lymphoepithelial lesions. Fifteen selected samples with prominent lymphoid aggregates and 10 controls were examined immunohistochemically for the immunoglobulins A, G, M, lymphocytes B and T, clonality of B cell population, atypical lymphocytes and Epstein-Barr virus (EBV) antigen. There was an increase of H. pylori infection and mucosal lymphoid aggregates (MALT) rates in parallel with the increasing age of patients noted in the histological assessment of the mucosal samples. A close association of lymphoid aggregates with H. pylori infection and prominent active gastritis was found, but in adults with chronic non-active, particularly atrophic gastritis this association became weaker. No morphological and immunohistochemical signs of MALT lymphoma were present. Lymphoid aggregates in children were larger, with follicles, but less numerous and tended to be located in the intermediate and deeper parts of the gastric mucosa. Immunohistochemical studies showed an increase of IgA, IgM and lymphocytes T in the deeper part of the lamina propria in H. pylori-associated gastritis and lymphocyte T accumulation in the periphery of the lymphoid follicles. No evidence of monoclonality, CD31 positive lymphocytes or EBV antigen was detected. Lymphoid aggregates are related, but not exclusively, to H. pylori infection. Their detection rates achieve a peak in young adults with H. pylori infection. Lymphocytic aggregates are also present in chronic atrophic gastritis without H. pylori infection and may relate to autoimmune inflammatory response to other factors.
Keywords: lymphoid aggregates; Helicobacter gastritis; immune response; children.
Interleukin 1b Decreases the GSH Content and Catalase Activity in the Human Peritoneal Mesothelial Cells in Vitro
ANDRZEJ E. GRZYBOWSKI
Abstract. The object of this study was to assess the effects of the inflammatory cytokine interleukin b (IL-1b) (0. 01–1. 0 ng/ml) on the activity of catalase (CAT), superoxide dismutase (SOD) and the level of glutathione (GSH), all being antioxidant mechanisms, in human peritoneal mesothelial cells (HPMC) in in vitro culture. HPMC were obtained from the omenta of nonuremic donors. The activity of the antioxidant mechanisms was studied on monolayers of HPMC, which were deprived of serum 48 h prior to experiment. The effect of the cytokine was tested in a medium with low serum concentration (0. 1%) or in a medium with 10% fetal calf serum (FCS). Activity of the antioxidant mechanisms was determined by spectrophotometry. The GSH level was decreased in mesothelial cells (MC) after 24 h of exposition to IL-1. However, after 72 h of incubation with IL-1 the GSH level increased in MC in the presence of 10% FCS, p<0.05. The activity of CAT was inhibited after 72 h exposure to IL-1. Interleukin 1 did not affect SOD activity in MC. However, when supplemented with 10% FCS, IL-1 decreased the activity of SOD after 24 and 72 h of incubation. We conclude that the activity of antioxidant mechanisms in MC is decreased by IL-1b in ways that might increase their vulnerability to the cytotoxic effect of free radicals.
Keywords: dialysis; inflammation; interleukin 1; antioxidants; catalase; superoxide.
Identification of Blood Group A and B Antigens in Human Glycophorin
MARIA PODBIELSKA and HUBERT KROTKIEWSKI
Abstract. Glycophorin A (GPA), the major sialoglycoprotein of human erythrocyte membranes, was isolated separately from blood group A and B erythrocytes using phenol-water extraction. After purification, performed as gel filtration in the presence of SDS, two glycophorin samples GPA-A and GPA-B were run, in duplicate, in SDS-PAGE and electroblotted onto Immobilon P. After staining with 1) anti-glycophorin antibody and 2) with relevant anti-blood group (A or B) antibody it was shown that the band pattern of the samples in each duplicate was the same. GPA-A and GPA-B samples were also degraded using Carlson degradation (b-elimination in mild alkaline/strong reducing conditions) and from reaction products the fractions of O-glycans and N-glycans were isolated; they were used in hemagglutination inhibition test. It was shown that both sugar fractions derived from GPA-A did inhibit agglutination of blood group A erythrocytes by anti-A antibody, whereas oligosaccharide fractions derived from GPA-B inhibited agglutination of blood group B erythrocytes by anti-B antibody. These results, obtained using immunochemical methods, confirm the presence of blood group A and B determinants in the carbohydrate moiety of human glycophorin, derived from the blood group A or B erythrocytes, respectively.
Keywords: human glycophorin; blood group A and B antigens; protein glycosylation; O-glycans; N-glycans.
Vol. 48, No. 4, 2000
Differential Effects of CD40 Stimulation on Normal and Neoplastic Cell Growth
JAMIE L. ZIEBOLD, JULIE HIXON, ANN BOYD and WILLIAM J. MURPHY
Abstract. CD40 is a molecule in the tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family that is present on both normal and neoplastic B lineage cells. It is also expressed on carcinoma and melanoma cells and can be augmented with interferon g. CD40 stimulation in normal B cells has been demonstrated to promote normal B cell differentiation and growth in vitro. In contrast to these effects, CD40 stimulation by either anti-CD40 antibodies or a recombinant soluble CD40 ligand can inhibit the growth of human breast carcinomas and aggressive histology B lymphomas in vitro and in vivo. This is believed to occur by activation- -induced cell death (AICD) in which stimuli that promote the growth of normal cell types inhibit the growth of neoplastic counterparts. This occurs through the induction of apoptosis, necrosis and/or cell cycle arrest. Thus, CD40 stimulation may be of potential clinical use in the treatment of carcinomas and B cell lymphomas. This review shall provide an overview of the various effects of CD40 stimulation on both normal and neoplastic cell types.
Keywords: CD40; apoptosis; transformed; lymphoma; interferon g.
Rethinking Globally Relevant Vaccine Strategies to Human Immunodeficiency Virus Type-1
CLIVE M. GRAY and ADRIAN J. PUREN
Abstract. According to the latest UNAIDS figures for 1999 there were an estimated 30. 6 million people living with HIV-1, with 16000 new HIV infections per day. The only global strategy of combating new HIV infections is to make a vaccine that is affordable to developing countries, where greater than 90% of new infections occur, and that has enough efficacy to interrupt high rates of transmission. This review critically examines: 1) important immune parameters that should be considered which will allow an understanding of preventative vaccine design and 2) the mechanisms underlying immune destruction during HIV-1 infection that will facilitate design of therapeutic vaccines. A realistic goal of a preventative vaccine is to elicit protective immune responses in vaccinees that would prevent HIV-1 from replicating extensively in the host. Components of protective immunity are thought to include neutralizing antibodies (NAB) and cytotoxic T lymphocytes (CTL). Rethinking vaccine strategies has to take into account that HIV-1 vaccines must elicit primary cellular and humoral immunity via dendritic cell and Langerhan cell priming. It is only under these conditions that boosting immunity with subsequent vaccinations will allow high enough CTL effector cells and NAB titres to impede or to prevent HIV-1 replication. Success of therapeutic vaccine strategies, has to take into consideration the pathology of persistent immune stimulation by chronic HIV-1 infection. To re-stimulate immunity and re-direct immune responses, chronic immune stimulation by HIV-1 has to be alleviated by reducing high levels of viral antigen presentation by suppressing virus with antiretroviral agents. Such treatment courses may only have to be transient, long enough for immunity to respond to an immunogenic stimulus. Short-course drug therapy may then be an affordable option for many countries already carrying a high burden of HIV-1/AIDS.
Keywords: vaccines; protective immunity; cytotoxic T lymphocytes; neutralizing antibodies; dendritic cells; antiretroviral drugs.
The Immunological Effects of Interleukin 2 Therapy in HIV+ Patients
PAOLO DE PAOLI
Abstract. Human immunodeficiency virus (HIV) infection produces a profound impairment of immune functions that antiretroviral therapy is unable to restore. Because of its immuno-enhancing properties, interleukin 2 (IL-2) has been used as a therapeutic tool in HIV+ subjects. IL-2 produces an increase of CD4 and CD8 lymphocyte absolute counts that is preferentially due to the expansion of the “naive” cells. In addition, IL-2 increases cytokine production from the cells of the immune system and is able to up-regulate the expression of cytokine receptors, such as the chemokine receptors CCR-5 and CXCR-4. Less informations on the IL-2 activity on the CD8 subset are available at the moment. The advent of highly active antiretroviral therapy has changed this scenario, making the IL-2 effects less clear-cut than previously hypothesized. We suggest that the ongoing studies will define the precise role of IL-2 in the therapy of HIV infection.
Keywords: HIV infection; interleukin 2; CD4 lymphocytes; CD8 lymphocytes; immunological function.
Cellular Immune Activation, Neopterin Production, Tryptophan Degradation and the Development of Immunodeficiency
BERNHARD WIDNER, BARBARA WIRLEITNER, GABRIELE BAIER-BITTERLICH, GÜNTER WEISS2 and DIETMAR FUCHS
Abstract. Cellular (Th1-type) immune response is centrally involved in the pathogenesis of various diseases. Within the immunological cascades of Th1-type immunity, interferon g (IFN-g), among other cytokines, is critically involved. It triggers a series of immune-relevant reactions mostly directed towards forward regulation of the antigen specific immune response. However, in chronic states of immune activation, systemically increased IFN-g is no longer antigen specific and is associated with the development of immunodeficiency. IFN-g also stimulates the production of neopterin, a low-mass compound, in human monocytes/macrophages. Accordingly, neopterin concentrations in humans reflect the degree of Th1-type immune activation. Since IFN-g also stimulates the release of reactive oxygen species (ROS) from immunocompetents cells, the amount of neopterin produced also serves as an indirect estimate of oxidative stress. In parallel, IFN-g activates the degradation of tryptophan, which appears to limit the growth of intracellular pathogens and the proliferation of cells, including T lymphocytes. Thus, during persisting states of immune activation, the production of IFN-g is not only associated with forward regulation of the immune response, but also with immunosuppressive mechanisms. The increased formation of neopterin and degradation of tryptophan may result in a drecreased T cell responsiveness and development of immunodeficiency.
Keywords: cellular immune response; neopterin; tryptophan; immunodeficiency.
Role of Immune-Derived Diffusible Mediators in AIDS-Associated Neurological Disorders
FABRIZIO ENSOLI, VALERIA FIORELLI, MARIA DE CRISTOFARO, DONATELLA SANTINI MURATORI, ARIANNA NOVI, ANTONELLA ISGRO and FERNANDO AIUTI
Abstract. Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. This review will first discuss the spectrum of potential interactions between HIV-1 and neural (neuronal and glial) cells, in the face of experimental data. Next, we will focus on the role of immune-derived cytokines and other soluble compounds which have been proposed to act as neurotoxic mediators and appear to play a role in the pathogenesis of AIDS-associated neurodegeneration.
Keywords: AIDS patients; neurological disorders; neural cells.
B Cell Development and Primary Immunodeficiencies with Hypogammaglobulinemia
SHO HOKIBARA, KAZUNAGA AGEMATSU and ATSUSHI KOMIYAMA
Abstract. The differentiation of B cells along the pathway of B cell development has been well characterized. In the bone marrow, the differentiation from pro-B cells to immature B cells can be defined by several surface antigens, such as a surrogate light chain. Immature B cells become mature B cells and then circulate in the peripheral blood as naive B cells. In the peripheral lymphoid tissues, naive B cells differentiate into memory B cells, which express the CD27 molecule, or plasma cells. Primary immunodeficiencies with hypogammaglobulinemia are caused by defects of the specific molecules which are needed for the B cell differentiation. Recent studies of the genes responsible for such immunodeficiencies have clarified B cell development as well as their pathogenesis. We discuss here the molecules affecting the B cell development and primary immunodeficiencies with hypogammaglobulinemia.
Keywords: B cell development; primary immunodeficiency; hypogammaglobulinemia; CD27; memory B cells.
Macrophages and HIV-1-Associated Dementia
LEONIE A. BOVEN
Abstract. One of the strongest predictors for HIV-1-associated dementia is the presence of monocytic infiltration in perivascular areas of the brain. Therefore, macrophages have been suggested to play a major role in the development of this disease. This review focuses on possible mechanisms through which the macrophage may enhance disease progression by mediating neuronal damage.
Keywords: HIV-associated dementia; macrophages.
Ki-67 Reactivity in Primary Fallopian Tube Cancers
JERZY RABCZYŃSKI, AGATA KOCHMAN, PRZEMYSŁAW KOWALSKI and PIOTR ZIÓŁKOWSKI
Abstract. Forty-four cases of primary cancer of the fallopian tube (PFTC) were analyzed as to Ki-67 expression, grade, stage and the cancer histological type. Among patients with an average age of 57. 5 years (range 38–70 years), 27 patients were FIGO I, 7 were FIGO II and 10 were FIGO III. Histological classification of PFTC revealed 18 cases of endometroid type, 9 serous, 7 undifferentiated, 6 urothelial, 2 clear-cell and 2 of other type. Histological grading revealed 11 cases of G1, 16 of G2 and 17 of G3 tumors. The quantity of Ki-67 positive cells was counted on 300 cancer cells in random high-power fields (10×40) and recorded as the labeling index (LI, %). Positive staining for Ki-67 was shown in the nuclei in all cases. Ki-67 LI values ranged from 14. 2 to 97. 2% (median 36. 1). Ki-67 LI values were graded as 3 36. 1% as high and <36. 1% as low. We did not find any significant differences in Ki-67 LI values among tumors of various clinical stages, histological grades and histological types. The p value was statistically significant only for stage as a prognostic factor.
Keywords: primary cancer of fallopian tube; Ki-67.
Effect of Recombinant IFN-g on IgE-Dependent Leukotriene Generation by Peripheral Blood Leukocytes in Patients with Pollinosis and Asthma
MARYLA KRASNOWSKA, WOJCIECH MĘDRALA, JÓZEF MAŁOLEPSZY and RYSZARD KRASNOWSKI
Abstract. Interferon g (IFN-g) is considered one of the causative and intensifying factors in inflammation. The reaction to allergens releases IFN-g, an immunomodulatory cytokine known to inhibit IgE synthesis and Th cell proliferation. The aim of the study was to evaluate the influence of IFN-g on leukotriene (LT) release in vitro, from human leukocytes of atopic patients with pollinosis and asthma. Thirty-eight patients were enrolled in the study: 15 with pollinosis and 23 asthmatics. In the presence of IL-3, leukocytes were stimulated with specific allergens. Other samples of leukocytes were preincubated with different concentrations of IFN-g for 15 min before allergen stimulation. The concentration of LT in supernatants was measured according to the CAST-ELISA procedure. We stated that IFN-g had significantly diminished LT release in a dose-dependent mode from the leukocytes of pollinotics. IFN-g did not change LT release in the asthmatic group, although, in leukocytes the small and medium basic production of LT, IFN-g caused a statistically significant fall in LT generation.
Keywords: asthma; pollinosis; interferon g; leukotriene.
The Influence of Amifostine Used Alone or in Combination with 2-Chlorodeoxyadenosine on Normal and Chronic Myelogenous Leukemia Granulocyte-Macrophage Progenitor Cells in Vitro
ANNA KORYCKA and TADEUSZ ROBAK
Abstract. We evaluated the influence of amifostine used alone or in combination with 2-chlorodeoxyadenosine (2-CdA) on the colony growth of normal and chronic myeloid leukemia (CML) granulocyte-macrophage progenitor cells (CFU-GM) in semisolid culture in vitro. Amifostine at a concentration of 1 mg/ml was either added directly to the culture medium of normal and CML CFU-GM, or mononuclear cells (MNCs) were first preincubated with amifostine at the same concentration, washed in Iscove’s modified Dulbecco minimum essential medium (IDMEM) and then added to the culture medium. Amifostine used alone inhibited the growth of CML CFU-GM colonies to a higher degree than those of normal CFU-GM, but the differences were not statistically significant. Amifostine preincubated with MNCs and used together with the highest concentration of 2-CdA significantly inhibited the colony growth of CML CFU-GM as compared to 2-CdA alone (p<<0.05). In contrast, the colony growth inhibition of normal CFU-GM was not significantly lower compared to 2-CdA used alone. Our studies suggest that 2-CdA used together with amifostine is more toxic to leukemic CFU-GM than to their normal counterparts.
Keywords: amifostine; 2-CdA; interaction; CFU-GM; chronic myelogenous leukemia; culture in vitro.
Serum Levels of Cytokines in Alcoholic Liver Cirrhosis and Pancreatitis
AGNIESZKA SZUSTER-CIESIELSKA, JADWIGA DANILUK and MARTYNA KANDEFER-SZERSZEŃ
Abstract. Although altered cytokine homeostasis has been implicated in the pathogenesis of both alcoholic liver and pancreas diseases, the serum cytokine pattern characteristic of concomitant alcoholic liver cirrhosis and pancreatitis has not been examined. In this paper we examine the serum levels of proinflammatory cytokines, such as IL-6, IL-8, TNF-a, and also antiinflammatory ones, such as IL-10 and TGF-b, in 22 patients with alcoholic liver cirrhosis and 28 patients with chronic pancreatitis and compare them with those detected in the sera of 14 patients with concomitant alcoholic cirrhosis and pancreatitis. All patients were heavy alcohol drinkers, consuming more than 70 g of pure alcohol per day for at least 5 years. The control group consisted of 33 age- and sex-matched healthy subjects receiving an annual health examination. They were not addicted to alcohol and confirmed to be free of major cardiopulmonary, gastrointestinal and hepatobiliary-pancreatic diseases. The results indicated that the cytokine pattern in the sera of patients with concomitant liver cirrhosis and pancreatitis was characterized by increased levels of two proinflammatory cytokines: TNF-a, the concentration of which seemed to be influenced by both liver and pancreas injury, and IL-6, which seemed to be rather connected with pancreas injury. Increased levels of IL-8, which were detected in the sera of patients with cirrhosis, pancreatitis and concomitant cirrhosis and pancreatitis, were rather connected with exacerbation of the disease processes which occurred only in some of the patients. No significant changes in the levels of IL-10 or TGF-b were detected in the sera of patients with chronic pancreatitis and concomitant cirrhosis and pancreatitis, while in patients with cirrhosis significantly decreased levels of IL-10 were found. A significant imbalance between proinflammatory/antiinflammatory signals was especially characteristic of alcoholic cirrhosis and concomitant cirrhosis with pancreatitis.
Keywords: alcohol; compensated cirrhosis; chronic pancreatitis; interleukin 6, 8, 10; tumor necrosis factor a; transforming growth factor b.
Screening for Germline p53 Mutations in Pediatric and Adult Patients of High-Risk Groups in Poland
ŁUCJA FISZER-MALISZEWSKA, JERZY CZERNIK, KRYSTYNA SAWICZ-BIRKOWSKA, DANUTA PEREK, MARIA KOZERA, BEATA WOJCIECHOWSKA, BERNARDA KAZANOWSKA, PIOTR HUDZIEC and EWA KILAR
Abstract. Germline mutations of the p53 gene lead to cell transformation in various tissues. Such a complex cancer phenotype makes it difficult to recognize the carriers of the defective allele. Several studies undertaken to identify high-risk groups found germline p53 mutations in familial cancer aggregations and in patients with multiple tumors. We screened 189 pediatric and 48 adult patients. The high-risk groups comprised 41 patients with a family history of cancer and 35 with multiple neoplasms. Furthermore, 124 tumors were screened for somatic mutations. p53 exons 2 to 11 were analyzed by polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) followed by direct sequencing of abnormal DNA fragments. No germline p53 mutations were found and somatic mutations were detected in 5 of 59 sarcomas, globally, in 8 of 124 tumors. In conclusion, in Poland, p53 alterations do not seem very important for the predisposition to malignancy and development of sarcomas.
Keywords: p53 tumor suppressor gene; germline mutation; Li-Fraumeni syndrome; Li-Fraumeni-like families; PCR-SSCP; direct sequencing.
Epstein-Barr Virus Association in Pediatric Abdominal Non-Hodgkin-Lymphomas from Turkey
MARIANNE TINGUELY, MARIE-ANNE BRÜNDLER, SAFIYE GÖGÜS, KATRIN KERL and BETTINA BORISCH
Abstract. Recent sudies have shown marked geographic variation associated with Epstein-Barr virus (EBV) in pediatric Burkitt’s lymphomas and Hodgkin’s disease. In the present study we investigated 30 cases of pediatric extranodal high grade non-Hodgkin’s lymphomas (NHL) from Turkey with an abdominal localisation. To classify them histologically and to determine the role of EBV in these lymphomas, immunohistochemistry (IHC), in situ hybridisation (ISH) and polymerase chain reaction (PCR) were used. Our series contained two histologic types: the Burkitt’s or Burkitt’s-like lymphomas (BL/BLL) and high grade NHL. They all were of the B cell type. The immunoglobulin heavy chain gene rearrangement revealed monoclonality in 87% of the BL/BLL cases, in contrast to the NHL cases, showing monoclonality in only 43% of the cases. EBV was found in tumor cells in a high frequency, independent of the histological subtype. EBV strains A and B were detected in 9 cases, with a preponderance of the B subtype (4/9 BL/BLL; 4/9 NHL). Our data suggest that high grade NHLs with abdominal localisation of Turkish children show the pattern of immunodeficient lymphomas to some extent.
Keywords: Epstein-Barr virus; non-Hodgkin’s lymphoma; pediatric; Turkey.
Vol. 48, No. 5, 2000
The Paradigms of Causality and Treatment for Autoimmune Disease
Irun R. Cohen, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
Abstract. A key concept in medicine is that rational therapy rests on accurate diagnosis; quite simply, therapy that is not tuned to the cause of the disease will not cure the patient. I do not mean to say that effective treatments cannot emerge from faulty diagnoses. In truth, much of our therapeutic ensemble is composed of drugs developed as a result of chance observation, random, screening, intuition, or pre-scientific tradition. Nevertheless, the way to effective therapy is best paved by understanding. Effects are inherent in their causes; so if we want to cure autoimmune diseases using the scientific method, we are obliged to inquire into their causes. By reducing the discordant complexity of the disease to the single cause that underlies it, we can hope to learn the most efficient way to manipulate the disease process. How do we identify a cause when we see one? Quite simply, a single cause is that which is both necessary and sufficient to produce the effect. Here, I explore the general paradigm of autoimmune causality, using multiple sclerosis as a specific example.
Keywords: autoimmune disease; therapy; causality; multiple sclerosis; diabetes..betes..
Uncovering the Differences between T Cell Tolerance and Immunity
Anthony T. Vella, Department of Microbiology, Oregon State University, Corvallis, Oregon, USA
Abstract. In the last two decades T cell function has been analyzed in vitro from many different angles with a great deal of attention dedicated to the basic requirements of activation. During this time a compendium of information has been collected and has proven to be invaluable. Paradoxically very little is known about T cell activation and function in vivo. In the last decade a number of models have been developed which allow the tracking of Ag-activated T cells in vivo and these studies have been instrumental in advancing the field of T cell biology. In particular, a new and emerging paradigm of T cell immunity is evolving.
Keywords: T cell activation; immunity; immune memory.memory.
The Physiological Role of Regulatory T Cells in the Prevention of Autoimmunity: Generation, Specificity and Mode of Action
Benedict Seddon, Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK
Abstract. Until recently, the traditional view was that tolerance to self antigens was maintained by a combination of physical deletion intrathymically and functional deletion in the periphery of autoreactive T cells. There is now, however, abundant evidence that the normal T cell repertoire contains overtly autoreactive T cells whose pathogenic potential is held in check by the activity of a distinct subset of peripheral T cells, so called regulatory or suppressor T cells. This article examines data from one model of rodent autoimmunity, where autoimmune pathology develops following thymectomy and irradiation of normal laboratory rats, which characterise the development and function of these so called regulatory T cells.
Keywords: regulatory T cells; autoimmunity prevention.ention.
Epitope Spreading: a Mechanism for Progression of Autoimmune Disease
Vincent K. Tuohy and R. Philip Kinkel
Abstract. Autoimmune diseases are typically characterized by a persistent inflammatory self-recognition process that ultimately leads to chronic progressive disability. Over the past several years we have addressed the fundamental question of why autoimmune diseases are chronic. Our working hypothesis in these studies has been that autoimmunity involves a continuous acquisition of new self-recognition events, thereby providing an inflammatory steady-state that leads to chronicity. This acquired T cell neoautoreactivity is commonly referred to as epitope spreading. By studying mulitple sclerosis (MS) and its related animal model, experimental autoimmune encephalomyelitis (EAE), we have found that chronic progression of autoimmune disease is invariably linked to the development of any epitope-spreading process that manifests as a cascade of inflammatory T cell neoautoreactivities to a sequential series of predictable new target self-antigens. However, our most recent observations indicated that the emergence of epitope spreading is accompanied by a concurrent regression of the established primary autoreactivity associated with disease onset. Thus, our studies indicate that progression of autoimmune disease involves a shifting of T cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during progression to chronicity. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an „epitope du jour” and „moving target” perspective.
Keywords: autoimmunity; EAE/MS; T cell; myelin; demyelination.nation.
A Role of NF-kB and the Proteasome in Autoimmunity
Takuma Hayashi and Denise Faustman, Immunobilogy Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Abstract. Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic b cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear facktor-kB (NF-kB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor a (TNF-a). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.
Keywords: type 1 diabetes; proteasome, LMP2; apoptosis; NOD mose; NF-kB. NF-kB.
Complement Regulatory Proteins and Autoimmunity
Mitsuhiro Kawano, Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa, Japan
Abstract. To discriminate self from nonself is an essential issue in the immune system. Autologous cells are protected against complement-mediated cell injury by the self-recognition mechanism using complement regulatory proteins composed of complement receptor type 1 (CR1, CD35), membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF, CD55) and homologous restriction factor (protectin, CD59). Recently, the upregulation of these molecules has been widely shown in inflammatory tissues and organs affected by autoimmune disease, and in vitro assays have revealed that immune complexes or several cytokines, including interferon g, tumor necrosis factor a, interferon 1b and transforming growth factor b can upregulate these molecules. In contrast, it has been found that expression of these complement regulatory proteins is markedly decreased on autologous cells undergoing apoptosis. These findings suggest that complement regulatory proteins have dual roles at inflammatory sites: enhancement of cellular resistance to complement attack and acceleration of clearance of cells injurious to the organism due to complement-mediated mechanisms. To assist the former function, a therapeutic approach using recombinant soluble complement regulatory proteins may provide one promising strategy for the treatment of autoimmune diseases.
Keywords: membrane cofactor protein (CD46); decay accelerating factor (CD55); homologous restriction factor (CD59); complement receptor type 1 (CD35).(CD35).
PATHOGENIC IMMUNITY IN THEILER’S VIRUS-INDUCED DEMYELINATING DISEASE: A VIRAL MODEL FOR MULTIPLE SCLEROSIS
Byung S. Kim, Joann P. Palma, Atsushi Inoue and Chang-Sung Koh
Abstract. Multiple sclerosis involves inflammatory immune responses in the central nervous system and is considered as an autoimmune disease potentially associated with viral infection. The majority of experimental models rely heavily on the autoimmune components since similar diseases can be induced following immunization with various myelin antigens. A very attractive alternative model is the Theiler’s murine encephalomyelitis virus-induced demyelinating disease. This disease is primarily a CD4+ T cell-mediated, inflammatory demyelinating disease, induced following viral infection. Virus-specific inflammatory Th1 cell responses, rather than cytotoxic T lymphocyte response, play a critical role in the pathogenic immune responses. The major pathogenic epitopes have been identified and these are correlated with a Th1 type response to the epitopes following viral infection. In addition, the initial virus-specific immune response is followed by the autoimmune responses to myelin antigens. Assessment of cytokines produced locally in the CNS during the course of disease suggests involvement of inflammatory cytokines in the disease. Furthermore, the manipulation of inflammatory cytokine levels by administration of either recombinant cytokines or antibodies to the cytokines strongly influences the induction and/or progression of disease, supporting the importance of these inflammatory cytokines in this virus-induced demyelinating disease.
Keywords: multiple sclerosis; Theiler’s virus; demyelinating disease.isease.
Evidence that Fas and FasL Contribute to the Pathogenesis of Experimental Autoimmune Encephalomyelitis
Bonnie N. Dittel, Section of Immunobiology, Yale School of Medicine, New Haven, CT 06520-8011, USA
Abstract. The well established and characterized animal model for the human demyelinating autoimmune disease mulitple sclerosis (MS) is known as experimental autoimmune encephalomyelitis (EAE). EAE is clinically characterized by focal areas of inflammation and demyelination and an infiltrate composed of large numers of lymphocytes and macrophages, often found in a perivascular localization but also throughout the central nervous system (CNS). Active immunization of mice with several different protein components of myelin, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), are capable of eliciting an immune response resulting in the quintessential symptoms of EAE: ascending paralysis involving the tail and then the limbs. Depending on this mouse strain and myelin antigen utilized, the disease course can be acute or chronic relapsing, characterized by a rapid onset of hind limb weakness that commonly progresses to paralysis, followed by spontaneous remission starting 7-10 days after the initial appearance of symptoms. EAE can also be induced passively by the adoptive transfer of in vitro activated CD4+ T cell clones or lines, typically of the Th1 phenotype, into irradiated susceptible recipients. The mechanisms involved in the cellular pathogenesis leading to paralysis and demyelination have been extensively studied and are primarily mediated by CD4+ T cells of the Th1 phenotype, with specificity for myelin antigens. Following activation, Th1 CD4 T cells produce in abundance the inflammatory cytokine TNF-a, IFN-g and lymphotoxin-a (LT-a, also known as TNF-b). IFN-g production is highly correlated with encephalitogenicity and may contribute to disease by up-regulation of adhesion molecules on endothelial cells, facilitating migration of lymphocytes into the CNS; by induction of MHC class I and MHC class II molecules on astrocytes, microglial cells and brain endothelium, facilitating Ag presentation in the CNS; and by activation of macrophages, leading to production of nitric oxide, a potent cytotoxic molecule. TNF-a and LT-a are both members of the TNF family of molecules and cause cell death by apoptosis following interaction with their counter-receptors, the TNFR1 and TNF2, leading to a cascade of proteolytic events culminating in the blebbing of the cytoplasmic membrane, nuclear condensation and DNA fragmentation. Consequently, the production of TNF-a and LT-a by Th1 clones has been correlated with encephalitogenic potential and Abs to both prevents EAE upon transfer of encephalitogenic clones. Even though substantial evidence exists for the role of inflammatory cytokines in the pathogenesis of EAE, other mechanisms of myelin destruction are thought to exist. To date, many reports have implicated a role for the cell death-inducing ligand pair Fas and Fas ligand (FasL)
Keywords: Fas; Fas ligand; experimental autoimmune encephalomyelitis.elitis.
The Role of Cytokines in Experimental Autoimmune Encephalomyelitis
Estelle Bettelli and Lindsay B. Nicholson, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Abstract. Experimental autoimmune encephalomyelitis (EAE) is an animal model of the demyelinating disease multiple sclerosis. In EAE cytokines play a critical role in defining the Th1 or Th2 nature of the autoantigen directed immune response, and in propagating and regulating inflammation within the central nervous system. In this review we summarize some of the recent developments in the field of cytokine research that relate to this model of human disease, focusing principally on disease induced with the autoantigens myelin proteolipid protein and myelin oligodendrocyte protein.
Keywords: experimental autoimmune encephalomyelitis; cytokines; proteolipid protein; myelin oligodenodrocyte protein; review.review.
Involvement of Apoptotic Protease Cascade for Tissue Destruction in Sjögren’s Syndrome
Yoshio Hayashi, Kumiko Yayagi and Norio Haneji, Department of Pathology, Tokushima University School of Dentistry, 3 Kuramotocho, Tokushima 770, Japan
Abstract. Sjögren syndrome (SS) is an autoimmune disease characterized by diffuse lymphoid cell infiltrates in the salivary and lacrimal glands, resulting in symptoms of dry mouth and dry eye due to insufficient secretion. Although it has been assumed that a combination of immunologic, genetic and environmental factors may play a key role on the development of autoimmune lesion in the salivary and lacrimal gland, little is known about the disease pathogenesis. We have identified the 120 KD a-fodrin as an important autoantigen on the development of SS in both animal model and SS patients, but the mechanism of a-fodrin cleavage leading to tissue destruction in SS remains unclear. Tissue-infiltrating CD4+ T cells purified from the salivary glands bear a large proportion of Fas ligand and the salivary gland duct cells possess apoptotic receptor Fas. Anti-Fas antibody-induced apoptotic salivary gland cells results in specific a-fodrin cleavage to the 120 KD fragment in vitro. Preincubation with a combination of calpain and caspase inhibitor peptides could be responsible for inhibition of the 120 KD a-fodrin cleavage. Thus, an increase in apoptotic protease activities may be involved in tha progression of a-fodrin proteolysis and tissue destruction in the development of SS.
Keywords: Sjögrens’s syndrome; autoantigen; protease; apoptosis.ptosis.
Is Lack of Peripheral Tolerance Induction a Cause for Diabetes in the Non-Obese Diabetic Mouse?
Torben Lund, Department of Immunology, Windeyer Institute for Medical Sciences, and Jessica Strid, Immunobiology Unit, Institute of Child Health, University College London, London, UK
Abstract. The nonobese diabetic (NOD) mouse is a spontaneous animal model for type 1 diabetes characterized by a selective destruction of the insulin producing b-cells in the pancreas. As in humans, the disease is controlled by several susceptibility genes some of which maps to the major histocompatibility complex on chromosome 17. However environmental factors contributes also to the development of the disease in the NOD mouse presumably through controlling the balance between the Th1 and Th2 response in the animal. Recent observations have shown that the NOD mouse has abnormalities in the development of bone marrow-derived antigen presenting cells. These include the most potent activators of naive T cells, the dendritic cells, which exist in at least two different sub-populations; DC1 cells responsible for activation of Th1 cells and DC2 cells that produce Th2 cells. In addition to activate na?ve T cells, the dendritic cells are also involved in generating central and peripheral tolerance to self-molecules. In this process DC2 cells appear to be more important for development of peripheral tolerance than DC1 cells. Further to abnormalities in development of bone marrow-derived antigen presenting cells, the NOD mouse has also a defect in the thymic selection of T cells leading to a higher concentration of autoreactive T cells. We speculate that the NOD mouse may develop an imbalance in the two subset of dendritic cells with a skewing towards DC1 cells; thus having a reduced ability to generate peripheral tolerance to a number of autoantigens.
Keywords: peripheral tolerance; non-obese diabetic (NOD) mouse; antigen-presenting cellsg cells
Neuro-Endocrine-Immune Axis in Human Rheumatoid Arthritis
Tsuyoshi Sakane and Noboru Suzuki, Department of Immunology and Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan
Abstract. We present an overview of the role of neuro-endocrine-immune mechanisms in the pathophysilogical responses of patients with rheumatoid arthritis (RA). In patients with RA proinflammatory cytokines secreted by synovial cells provoke local inflammation in the joints and, simultaneously, initiate a systemic acute phase response. Thus, profund changes of the neuro-endocrine-immune axis could take place in the patients. Defects in the hypothalamus-pituitary-adrenal axis have been observed in patients with RA. Prolactin levels are often elevated and a abnormal sex hormone levels have been described in RA patients. Defective neural regulation of inflammation involving neuropeptides at least partly plays a pathogenic role in RA.We and others have found that participants of the neuro-endocrine-immune interactions, such as hormones, neurotransmitters and neuropeptides, modulate RA synovial cell functions and that they are actually produced by, and their receptors are expressed on, cells within the inflammatory joint compartment. Thus, neuropeptides and hormones not only affect a systemic acute phase response of RA patients, but also modulate local inflammation directly in RA joints. These results suggest that defects in regulatory processes, which are fundamental to RA, may lie in the immune system, the nervous system, the endocrine system or the interactions of these. A better understanding of neuro-endocrine-immune interactions holds the promise of new approaches to the treatment of RA with the use of hormones, neurotransmitters, neuropeptides and/or their antagonists.
Keywords: neuro-endocrine-immune interactions; rheumatoid arthritis, synovial cells; hupothalamus-pituitary-adrenal axis; inflammation.mation.
The Role of T Cells in Rheumatoid Arthritis
Cornelia M. Weyand, Ewa Bryl and Jörg J. Goronzy, Division of Rheumatology, Mayo Foundation, Rochester, MN 55905, USA
Abstract. In rheumatoid arthritis (RA), T cells infiltrate into the synovial membrane where they initiate and maintain activation of macrophages and synovial fibroblasts, transforming them into tissue-destructive effector cells. The diversity of the disease process and the formation of complex lymphoid microstructures indicates that multiple T cell activation pathways are involved. This model is supported by the association of distinct disease patterns with different variants and combinations of HLA class II molecules. T cell pathology in RA, however, is not limited to the joint. Affected patients have major abnormalities in the T cell pool with a marked contraction in T cell receptor diversity and an outgrowth of large clonal populations. Clonally expanded CD4+ T cells lose expression of the CD28 molecule and gain expression of perforin and granzyme. Consequently, the functional profile of expanded CD4+CD28null T cells is fundamentally changed and is shifted towards tissue-injurious capabilities. CD4+CD28null T cells are particularly important in patients with extraarticular manifestations of RA, where they may have a direct role in vascular injury. Understanding the mechanisms underlying the loss of T cell diversity and the emergence of pro-inflammatory CD4+CD28- T cell clonotypes may have implications for other autoimmune syndromes.
Keywords: HLA; autoimmunity; cytokines, synovitis; oligoclonality; CD4+CD28null.
Vol. 48, No.6, 2000
Immune Balance in Critically Ill Patients
MICHAEL R. PINSKY
Abstract. The systemic inflammatory response reflects the non-specific clinical expression of a profound activation of the body’s immune responsive elements. Immune activation and immune suppression coexist in the blood of patients with severe sepsis. It is their interaction and the resultant host parenchymal responses that ultimately define the course of sepsis. Importantly, neither profound immune activation (pro-inflammatory) or immune suppression (anti-inflammatory) characterize the dominant process. Rather, there is a combined low grade pro-inflammatory state associated with an immune hyporesponsiveness that defines the usual immunologic state of the patient with severe sepsis.
Keywords: inflammatory response; PMN leukocyte activation; inflammatory mediators.
T Cell Integrin Activation by Chemokines in Inflammation
YOSHIYA TANAKA
Abstract. The adhesive function of integrins is regulated through cytoplasmic signaling induced by several stimuli, whose process is designated „inside-out signaling”. A large number of lymphocytes are recruited to the sites of inflammation where they form an essential component of the response to infection, injury, autoimmune disorders, allergy, tumor invasion, atherosclerosis and so on. The recruitment of leukocytes into tissue is regulated by a sequences of interactions between the circulating leukocytes and the endothelial cells. Leukocyte integrins play a pivotal role in leukocyte adhesion to endothelial cells. During the process, the activation of integrins by chemokines, is essential for integrin-mediated adhesion in which a signal transduced to the leukocyte converts the functionally inactive integrin to an active adhesive configuration. The present review documents the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines during inflammatory processes.
Keywords: T lymphocytes; recirculation/recruitment; adhesion molecules; integrins; chemokines; inflammation.
T Cell Chemokine Receptor Expression in Human Th1- and Th2-Associated Diseases
J. DARREN CAMPBELL and KENT T. HAYGLASS
Abstract. The interaction between chemokines and their receptors is an important step in the control of leukocyte migration into sites of inflammation. Chemokines also mediate a variety of effects independent of chemotaxis, including induction and enhancement of Th1- and Th2—associated cytokine responses. Recent studies have shown that human Th1 and Th2 clones, activated under polarizing conditions with polyclonal stimuli in vitro, display distinct patterns of chemokine receptor expression: Th1 clones preferentially express CCR5 and CXCR3 while many Th2 clones express CCR4, CCR8 and, to a lesser extent, CCR3. These differential patterns of chemokine receptor expression suggest a mechanism for selective induction of migration and activation of Th1- and Th2-type cells during inflammation and, perhaps, normal immune homoeostasis. Studies have begun to examine T cell chemokine receptor expression in vivo to determine the relevance of these in vitro observations to human Th1 and Th2-associated diseases. In this review, we critically examine recent reports of T cell chemokine receptor expression in human autoimmune disorders (multiple sclerosis and rheumatoid arthritis) and atopic disorders (allergic rhinitis and asthma) which are believed to arise from inappropriate Th1- and Th2-dominated responses, respectively.
Keywords: multiple sclerosis; rheumatoid arthritis; atopy; chemokines; chemokine receptors; T cells.
Interleukin 15: Its Role in Inflammation and Immunity
LIYANAGE P. PERERA
Abstract. Interleukin-15 (IL-15) is a 14-15 kDa polypeptide that belongs to the four alpha-helix bundle family of cytokines and was originally discovered due to its T cell proliferative activity. It utilizes the signal transducing b/g polypeptides of the IL-2 receptor complex thus sharing many biological activities with IL-2, in addition to its high affinity private receptor subunit IL-15Ra. Accumulating evidence indicates that the biological relevance of IL-15 may not solely be confined to T lymphocytes, but to a variety of cell populations within the immune system as well as outside the immune system of the host. The expression of both IL-15 and its high affinity receptor component, IL-15Ra are readily demonstrable in a wide variety of tissues and appear to be augmented in response to environmental/stress stimuli and infectious agents. There is increasing evidence to suggest that IL-15 may play an important role in protective immune responses, allograft rejection and the pathogenesis of autoimmune diseases where mononuclear cell infiltration is a hallmark feature. Herein, the effects of IL-15 on cells associated with host defense, immunity and inflammation are reviewed and support a central role for this cytokine in orchestrating multiple aspects of effector functions in immunity and inflammation.
Keywords: interleukin 15; natural killer cells; monocytes; dendritic cells.
Cytokines and Costimulatory Molecules: Positive and Negative Regulation of the Immune Response to Cryptococcus neoformans
ANNA VECCHIARELLI
Abstract. Cytokines are small proteins or glycoproteins that transmit information from one cell to another. Most cells in the body secrete and respond to cytokines and their effects have been described on a myriad of cellular functions. Cytokine interactions may not be linear, thus making the system extremely intricate and with unpredictable features. Therefore, each model of disease may be unique with its own mechanism of autoregulation dictated by positive and negative feedback involving cytokines and costimulatory molecules. The emergence of some cytokines over others in the course of C. neoformans infection may characterize a positive or negative outcome of cryptococcosis. Much less is known about the influence of costimulatory molecules in regulating C. neoformans immune response. The available information indicates a critical role for proinflammatory cytokines such as tumor necrosis factor-a and interleukin (IL)-12. The positive role of interferon-g in infected tissue as an inducer of antimicrobial function of innate immune cells and as positive feedback for IL-12 induction appears to be indisputable. In vitro studies indicate that costimulatory molecule expression appears to be regulated on antigen presenting cells by C. neoformans and increased expression of B7-1 and CD40 on these cells may promote a protective response. These studies await confirmation in an in vivo system. The interplay between cytokines and costimulatory molecules has been scarcely explored, and additional details are needed to better understand how they convey positive and negative information to immune cells in response to C. neoformans.
Keywords: C. neoformans; cytokines; costimulatory molecules.
Prostaglandins and Inflammation: the Cyclooxygenase Controversy
OLIVIER MORTEAU
Abstract. Prostaglandins (PGs) are arachidonic acid metabolites produced by the action of the enzyme cyclooxygenase (COX). Although PGs are important mediators of inflammation in various diseases, they also are key factors in the physiological regulation of gastrointestinal and renal homeostasis. The finding that two distinct COX isoforms are responsible for PG synthesis has provided basis to the opposite actions of PGs in inflammation and homeostasis regulation. COX-1-derived PGs are thought to mediate cytoprotective actions on the gastrointestinal mucosa, whereas COX-2-derived PGs are assumed to display pro-inflammatory properties. This dichotomy has led to the development of selective inhibitors of COX-2 activity which are safer for the gastrointestinal mucosa than the classic inhibitors of both COX isoforms. However, some COX-2 antiinflammatory properties have been recently demonstrated in several experimental models of inflammation. These studies have raised some concern about the potential adverse effects of COX-2 selective inhibitors. In addition, there is evidence that COX-1 displays pro-inflammatory properties, depending on the organ and on the stage of the inflammatory response. This review will focus on the roles of COX-1 and COX-2 in inflammation, based on studies involving pharmacologic COX inhibitors as well as COX knockout mice, with a particular emphasis on the gastrointestinal tract.
Keywords: prostaglandins; cyclooxygenase; NSAIDs; inflammation; colitis.
Nuclear Import of Arachidonate 5-Lipoxygenase
THOMAS G. BROCK and ANNETTE M. HEALY
Abstract. Leukotrienes are lipid messenger molecules that are secreted by leukocytes to orchestrate a rapid and prolonged immune response. The enzyme 5-lipoxygnease catalyzes the rate-limiting first two steps in the synthesis of leukotrienes from arachidonic acid. Although it has long been known that 5-lipoxygenase moves from the cytoplasm to a membrane following activation, it has only recently been recognized that the enzyme may shuttle into and out of the nucleus before activation. The regulation of this movement of soluble 5-lipoxygenase between the cytoplasm and the nucleoplasm, as well as its impact on 5-lipoxygenase action, leukotriene synthesis and cell function, is only now being elucidated. This review details the state of our understanding of the nuclear import of 5-lipoxygenase and its potential importance in immunity.
Keywords: leukotrienes; 5-lipoxygenase; nuclear import.
Suppression of Mast Cell Activation by Glucocorticoid
HIDESHI YOSHIKAWA and KACHIO TASAKA
Abstract. Mast cells play a critical role in allergic diseases. When mast cells are activated by cross-linking of their high affinity IgE receptors by the antigen and IgE antibodies, release of chemical mediators is followed by secretion of multiple cytokines. We report that IL-3-dependent mucosal-type mast cells undergo apoptosis when IL-3 is withdrawn. In addition, cross-linking of high affinityIgE receptors prevents apoptosis of mast cells by paractine mechanisms, producing IL-3, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the secretion of endogenous growth factors are not enough for cell survival, whereas IL-4 induces cell aggregation by expressing adhesion molecules such as leukocyte function-associated antigen 1 (LFA-1), and makes it reactive to endogenous growth factors by contact cell to cell interaction. On the other hand, dexamethazone down-regulates the expression of intracellular adhesion molecule 1 (ICAM-1) and IL-4 in activated mast cells, by which the self-aggregation of mast cells is inhibited and poptosis is induced. Thus, glucocorticoids suppress mast cell survival by inhibiting IL-4 production and expression of adhesion molecules.
Keywords: allergy; mast cell; glucocorticoid; cytokine; adhesion molecule.
Pathogenetic Mechanisms of Atopic Dermatitis
SAVERIA PASTORE, MARIA LAURA GIUSTIZIERI, FRANCESCA MASCIA, ALBERTO GIANNETTI and GIAMPIERO GIROLOMONI
Abstract. Atopic dermatitis (AD) is a chronic inflammatory disease which results from complex interactions between genetic and environmental mechanisms. An altered lipid composition of the stratum corneum is responsible of the xerotic aspect of the skin, and determines a higher permeability to allergens and irritants. Keratinocytes of AD patients exhibit a propensity to an exaggerated production of cytokines and chemokines, a phenomenon that can have a major role in promoting and maintaining inflammation. Specific immune responses against a variety of environmental allergens are also implicated in AD pathogenesis with a bias towards Th2 immune responses. In particular, dendritic cells expressing membrane IgE receptors, play a critical role in the amplification of allergen-specific T cell responses. Cross-linkage of specific IgE receptors on dermal mast cells provokes release and synthesis of a vast series of mediators. Following their recruitment and activation into the skin, eosinophils are also thought to contribute relevantly to tissue damage. Thus, a complex network of cytokines and chemokines contributes to establish a local milieu that favors the permanence of inflammation in AD skin.
Keywords: skin; atopy; keratinocytes; dendritic cells; T lymphocytes.
Recent Advances in Understanding How Interleukin 13 Signals Are Involved in the Pathogenesis of Bronchial Asthma
KENJI IZUHARA, RITSUKO UMESHITA, MINA AKAIWA, TARO SHIRAKAWA, KLAUS A. DEICHMANN, KAZUHIKO ARIMA, BIN YU, NAOTAKA HAMASAKI and JULIAN H. HOPKIN
Abstract. The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industralized areas. Allergic disease are disorders of the immune system, the results of complex interactions among various genetic and environmetal factors. Among them, the important role of interleukin 13 (IL-13), a TH2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the infolvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.
Keywords: allergy; interleukin 13; interleukin 3; bronchial asthma; receptor.
The Inflammatory Response in M. tuberculosis Infection
ZAHRA TOOSSI
Abstract. Infection with Mycobacterium tuberculosis (MTB) is accompanied by an intense local inflammatory response which may be critical to the pathogenesis of tuberculosis. Activation of components of the innate immune response, such as recruitment of polymorphonuclear (PMN) and mononuclear phagocytes and induction of pro-inflammatory cytokines, such as tumor necrosis factor a (TNF-a), by MTB occurs early after MTB infection, however, may persist as the organism establishes itself within granulomas. MTB and its protein and non-protein components are potent in induction of cytokines and chemokines from PMN and monocytes. This review focuses on the interaction of MTB and the host with regard to activation of the innate immune response. It also attempts to identify the potential impact of this early response on the subsequent pathogenesis of MTB, and its role in development and extent of tuberculosis. Insights into the initiation and persistent of the inflammatory response may allow the application of anti-inflammatory agents as adjuncts in the treatment of tuberculosis.
Keywords: polymorhonuclear; monocyte; cytokine; chemokine; tumor necrosis factor a; Mycobacterium tuberculosis; tuberculosis.
Mechanisms of Mycobacterium avium Pathogenesis
LUIZ E. BERMUDEZ, DIRK WAGNER and DANUTA SOSNOWSKA
Abstract. Infections caused by M. avium are common in AIDS patients and patients with chronic lung diseases. The bacterium can be acquired both by the intestinal route and respiratory route. M. avium is capable of invading mucosal epithelial cells and translocate across the mucosa. The bacterium can infect macrophages interfering with several functions of the host cell. The host defense against M. avium is primarily dependent on CD4+ T lymphocytes and NK cells. Activated macrophages can inhibit or kill intracellular bacteria by mechanisms that are currently unknown but M. avium can invade resting macrophages and suppress key aspects of its function by triggering the release of TGF-b and IL-10. Co-infection with HIV-1 appears to be mutually beneficial with both organisms growing faster.
Keywords: Mycobacterium avium
The Therapeutic Potential of Interleukin 10 in Infection and Inflammation
ASHOK KUMAR and W. DAVID CREERY
Abstract. Interleukin 10 (IL-10), a cytokine with inhibitory activity on inflammation and cell–mediated immune responses (CMIR), holds enormous potential for the treatment of inflammatory and autoimmune disorders. In addition, IL-10 has also been implicated in the immunopathogenesis of a number of infectious diseases through the use of IL-10 knock-out or IL-10 transgenic mouse models. In this review, we delineate infectious and inflammatory conditions in which IL-10 has shown potential for therapeutic manipulation. Specifically, we review the role of IL-10 in human endotoxemia/sepsis and in HIV infection, conditions for which preliminary phase I trials have recently been undertaken. It is suggested that the therapeutic potential of IL-10 to selectively ameliorate human infectious and inflammatory processes can be realized through a careful selection of the clinical conditions in which patients are undergoing concomitant treatment with anti-microbial regimens.
Keywords: IL-10; IL-10 knock-out mice; infectious diseases; sepsis; HIV.
Idiopathic Pulmonary Fibrosis: Molecular Mechanisms and Possible Therapeutic Strategies
BERNT VAN DEN BLINK, HENK. M. JANSEN and MAIKEL P. PEPPELENBOSCH
Abstract. Idiopathic pulmonary fibrosis (IPF) is a devastating disease with an almost universally terminal outcome. In recent years much insight has been gained into the pathogenesis of IPF from both a bleomycin mice-model as well as ex vivo human tissue studies. Alveolar damage and inflammation of unknown etiology, eventually leading to interstitial fibrosis, characterize IPF. Apoptosis has emerged as an important factor in the pathogenesis of IPF. This review will outline the current understanding of the immunological and molecular mechanisms underlying IPF, and discuss new therapeutic strategies.
Keywords: apoptosis; fibrosis; Fas; inflammation; bleomycin.
Bacteriophage Therapy of Bacterial Infections: an Update of Our Institute`s Experience
BEATA WEBER-DĄBROWSKA, MARIAN MULCZYK and ANDRZEJ GÓRSKI
Abstract. 1307 patients with suppurative bacterial infections caused by multidrug resistant bacteria of different species were treated with specific bacteriophages (BP). BP therapy was highly effective; full recovery was noted in 1123 cases (85.9%). In 134 cases (10.9%) transient improvement was observed and only in 50 cases (3.8%) BP treatment was found to be ineffective. The results confirm the high effectiveness of BP therapy in combating bacterial infections which do not respond to treatment with all available antibiotics.
Keywords: phage therapy; drug resistance; bacterial infections .