Vol. 53, No. 3, 2005

Riana Cockeran¹, Ronald Anderson¹ and Charles Feldman² (¹ Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria and Tshwane Academic Division of the National Health Laboratory Service, Pretoria, South Africa ² Division of Pulmonology, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa)

Abstract. Streptococcus pneumoniae (the pneumococcus) remains one of the major human pathogens and one of the most common causes of community-acquired pneumonia, otitis media, sinusitis, and meningitis. Aside from the threats posed by emerging antibiotic resistance and infection with the human immunodeficiency virus, the mortality rate among those patients with severe pneumococcal disease who receive seemingly appropriate antimicrobial chemotherapy remains unacceptably high. Because of its involvement in the pathogenesis of invasive disease, pneumolysin, one of the best-characterized virulence factors of the pneumococcus, represents not only a potential vaccine target, but also a target for adjunctive therapy to antibiotics in patients with acute pneumococcal disease. In this paper we review the cytolytic and pro-inflammatory properties of pneumolysin and their involvement in subversion of host defenses and extra-pulmonary dissemination of the pneumococcus, as well as strategies, both immunological and pharmacological, which may counter these harmful activities of the toxin.

Keywords: antibiotics • anti-inflammatory agents • community acquired pneumonia • conjugate vaccines • invasive pneumococcal disease • pneumolysin

Jamel El-Benna, Pham My-Chan Dang, Marie-Anne Gougerot-Pocidalo and Carole Elbim Unité Inserm U479, Centre Hospitalo-Universitaire Xavier Bichat, Paris, France

Abstract. Phagocytes such as neutrophils and monocytes play an essential role in host defenses against microbial pathogens. Reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, the hydroxyl radical, and hypochlorous acid, together with microbicidal peptides and proteases, constitute their antimicrobial arsenal. The enzyme responsible for superoxide anion production and, consequently, ROS generation, is called NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of cytosolic proteins (p47phox, p67phox, p40phox, and rac1/2) and membrane proteins (p22phox and gp91phox, which form cytochrome b₅₅₈) which assemble at membrane sites upon cell activation. The importance of this enzyme in host defenses is illustrated by a life-threatening genetic disorder called chronic granulomatous disease in which the phagocyte enzyme is dysfunctional, leading to life-threatening bacterial and fungal infections. Also, because ROS can damage surrounding tissues, their production, and thus NADPH oxidase activation, must be tightly regulated. This review describes the structure and activation of the neutrophil NADPH enzyme complex.

Keywords: NADPH oxidase • neutrophils • phagocyte • CGD

Tamika Henry and Chandra Mohan Department of Rheumatology and the Center for Immunology, University of Texas Southwestern Medical School, Dallas, TX, USA

Abstract. Systemic lupus erythematosus is a polycongenic autoimmune disease characterized by the production of antinuclear antibodies that lead to subsequent end organ damage. The study of lupus is complicated by its polycongenic origin, contributions from hormones and the environment, epistasis among susceptibility loci, suppressive modifiers, and the fact that a single susceptibility locus may encompass multiple susceptibility genes. Murine models that develop lupus spontaneously have greatly contributed to our understanding of this disease. In particular, the advent of “congenic strains” has greatly simplified the study of this complex autoimmune disease. Thus, congenic strains bearing NZB/NZW/NZM2410, BXSB, and MRL lupus susceptibility loci are steadily replacing the traditionally studied murine lupus models as the models of choice for research. This review summarizes how researchers have used congenic strains over the past few years to dissect out and reconstruct the individual elements contributing to lupus pathogenesis.

Keywords: lupus • murine lupus • congenic strains • autoantibodies

Andrew N. Clarkson, Brad A. Sutherland and Ian Appleton Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand

Abstract. After an hypoxic-ischemic (HI) insult, a multi-faceted complex cascade of events occurs that ultimately causes cell death and neurological damage to the central nervous system. The various cascades include, amongst others: immunological changes, such as the activation of the complement system and the generation of antibodies; increased inflammation through the actions of pro-inflammatory cytokines and chemokines; the production of reactive oxygen species leading to oxidative stress; and diminished mitochondrial function leading to the activation of apoptotic pathways and subsequent alteration in the function of neurons within the contralateral hemisphere. This review addresses the immunological aspects following HI, the role of various cytokines (both pro-inflammatory and anti-inflammatory) and chemokines after the induction of HI. In addition, the role of free radicals in producing HI-induced neurodegeneration and the contribution that mitochondrial dysfunction has in neuronal apoptotic cell death will be discussed. This review also covers the changes that the previously assumed “internal control”, the contralateral hemisphere, undergoes due to HI and describes the difficulties associated with therapy intended to prevent neuronal injury associated with HI.

Keywords: angiogenesis • immunity • inflammation • mitochondria

Fumio Ishikawa¹ and Shuichi Miyazaki² (¹Department of Immunology, Toho University School of Medicine, Omori-nishi, Ota-ku, Tokyo, Japan ²Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Omori-nishi, Ota-ku, Tokyo, Japan)

Abstract. Chemokines and other chemotactic factors induce neutrophils, macrophages, and dendritic cells to migrate to an inflammatory site and efficiently ingest and destroy infective microorganisms. Moreover, antigen-presenting cells, such as macrophages and dendritic cells, present the microbial antigens via major histocompatibility complex class II molecules, resulting in the activation of specific CD4 T cells. Since neutrophils have a short life–span and are highly susceptible to apoptosis, their role in antigen presentation has been questioned. However, various pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor α, and interferon γ, produced at the site of inflammation activate neutrophils and suppress apoptotic death. These cytokine-activated neutrophils show enhanced expression of cell surface molecules and become as competent as dendritic cells and macrophages in their ability of antigen presentation. Traditionally, neutrophils are known to be responsible for innate immunity, and recently they are also considered to be intimately associated with the establishment of acquired immunity. In the present review on the role of neutrophils we describe both classic innate and acquired immunity.

Keywords: neutrophils • chemotaxis • chemokines • antigen presentation

Alain P. Gobert¹, Keith T. Wilson² and Christine Martin¹ (¹Unité de Microbiologie, Institut National de la Recherche Agronomique, Centre de Theix, 63122 Saint-Genés-Champanelle, France ²Department of Medicine, Division of Gastroenterology and Greenebaum Cancer Center, University of Maryland School of Medicine, and Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA)

Abstract. During the last decade, research on attaching-effacing (A/E) bacteria/host cell interactions has revealed much of the molecular basis of colonization and lesion formation. The colonic mucosa represents the first line of defense against these pathogens, and its integrity is required to avoid translocation of bacteria or bacterial soluble factors into the infected host. Therefore, the cellular immune response to A/E pathogens plays an important role in bacterial pathogenesis since it can clear the bacteria or modulate the inflammatory processes. Data obtained from infected patients demonstrate a correlation between the production of pro-inflammatory cytokines and the severity of the disease. In vitro studies of infected epithelial cells have clearly elucidated A/E bacteria-induced host signal transduction events. However, the identification of the bacterial factors responsible for cellular activation remains a subject of controversy. Experimental studies with knock-out mice infected with Citrobacter rodentium, a rodent A/E pathogen, indicate that innate immunity is an essential component of pathogenesis. This review summarizes in vivo and in vitro evidence for the induction and potential role of the innate immune system during infection with A/E bacteria.

Keywords: EHEC • EPEC • inflammation • epithelial cells • macrophage • cytokine • nitric oxide

Zofia Błach-Olszewska Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland

Abstract. Essential differences between the innate and acquired branches of immunity are described. These differences concern the detection system (receptors and pathogen structures) and the cells engaged in both systems as well as the effectory mechanisms. In contrast to those of the acquired system, receptors of the innate system, which developed during evolution, recognize unchanged structures on large groups of pathogens (e.g. lipopolysaccharide in Gram-negative bacteria). Two lineages, natural killer (NK) and dendritic cells (DCs), play important roles in the innate system. Phenotypic and functional differentiation is observed among NKs and DCs, so each of their sublineages plays a different role in the innate system. Every lineage of cells of the innate immune system express different stimulatory and sometimes also inhibitory receptors on their surfaces (e.g. NK cells). Among the stimulatory are Toll-like receptors (TLRs), mannose and scavenger receptors, and the stimulatory receptors of NK cells. All TLRs show similarity in structure and in the kind of molecules involved in intracellular signaling. The immune reactions of the innate system involve cytokine-dependent resistance of cells against infection with pathogen, production of cytokines (tumor necrosis factor, interferons, interleukins, chemokines) and MHC-independent killing. Although these reactions protect the host from invasion by microorganisms, they can also be responsible for significant tissue damage or may stimulate the development of autoimmunity. Therefore innate immunity must be under rigorous control. The possible regulatory mechanisms of innate immunity are discussed.

Keywords: innate immunity • receptors • intracellular signaling • immune reactions • regulation

Agnieszka Rusińska and Danuta Chlebna-Sokół Department of Pediatric Propedeutics and Metabolic Bone Diseases, Institute of Pediatrics, Medical University of Łódź, Poland

Abstract. Introduction: The aim of the study is to determine whether serum concentrations of interleukin (IL)-1 and IL-6 correlate with indices of bone mineral metabolism in children with idiopathic osteoporosis and osteopenia.
Materials and Methods: The study comprised 62 patients aged 6–18 years (20 with idiopathic osteoporosis, 22 with idiopathic osteopenia, and 20 controls). In 10 children, investigations were repeated after one year of treatment. Serum concentrations of IL-1(α, IL-1β, IL-1 receptor antagonist (IL-1ra), as well as IL-6 and its soluble receptor (IL-6sR) were determined by the ELISA method. In patients with decreased bone mass, selected calcium-phosphorus metabolism indices and bone turnover markers were assessed.
Results: Higher values of IL-6 were recorded in those with idiopathic osteoporosis than in controls (2.79 vs. 1.43; p<0.05). In these patients there was also a tendency towards higher values of IL-6sR (p=0.05). IL-1(α and IL-1β were not markedly elevated in any of the patients. No significant differences between groups regarding IL-1ra were observed. Negative correlation between IL-6, IL-1(α, cytokine/receptor indices, and spinal bone mineral density was determined. Positive correlation was found between IL-(α, IL-1/IL-1ra, and parathormon as well as between IL-1(α, IL-6sR, and bone formation markers. Increase in bone mass after treatment was accompanied by a decrease in IL-6sR.
Conclusions: The higher serum levels of IL-6 in children with idiopathic osteoporosis/osteopenia and the decrease in IL-6sR after treatment reveal an involvement of IL-6 in the etiopathogenesis of these disturbances. The results suggest that IL-1 may also participate in the primary decrease of bone mass in children.

Keywords: cytokine · bone mineralization · children

Malgorzata Pietruska¹ , Janusz Żak² , Jan Pietruski³ and Jolanta Wysocka² (¹ Department of Conservative Dentistry, Medical Academy, Białystok, Poland ² Department of Pediatric Laboratory Diagnostics, Medical Academy, Białystok, Poland ³ Private Practice, Białystok, Poland)

Abstract. Introduction: Aggressive forms of periodontitis lead to rapid bone destruction resulting in extensive losses in children’s and young adults’ dentition. Adhesion molecule deficiency syndrome and abnormalities in the expression of various adhesion molecules on peripheral blood leukocytes can be observed in prepubertal and aggressive periodontitis (AP) patients. The aim of the study was thus to assess the expression of selected cell adhesion molecules (CAMs; CD11a, CD11b, CD11c, CD54, and CD62L) on monocytes, neutrophils, and lymphocytes of the peripheral blood in patients with AP.
Materials Methods:The study involved 16 patients with AP and a control group of 13 generally healthy suband jects with healthy periodontium. CAM expressions were determined by flow cytometry and presented as mean fluorescence intensity (MFI) and percentage of cells showing expression of the assessed adhesion molecules.
Results: Neutrophil CAM expressions in AP patients were comparable with those of the control group. MFI of CD62L on monocytes in AP patients was significantly lower than that of the controls. Lymphocytes showed increased CD11b expression compared with the control group. The percentage of leukocytes showing CAM expression in both groups was similar. Only the percentage of lymphocytes with CD11b in AP patients was significantly higher than in healthy controls.
Conclusions: Because of the evident lack of differences between patients and controls and the great amount of individual dispersion of the results, the above CAMs on peripheral blood leukocytes in generally healthy patients with AP do not seem to be characteristic markers of this disease.

Keywords: adhesion molecules · peripheral blood leukocytes · aggressive periodontitis

Jarosław Paśnik¹ , Krzysztof Siniewicz¹ , Jadwiga Anna Moll² , Jacek Moll³ , Zbigniew Baj⁴ , Andrzej Sysa² and Krzysztof Zeman¹ (¹ Department of Pediatrics and Preventive Cardiology and Immunology in Childhood, Medical University, Łódź, Poland ² Department of Cardiology, Institute of the Polish Mother’s Health Center, Łódź, Poland ³ Department of Cardiac Surgery, Institute of the Polish Mother’s Health Center, Łódź, Poland ⁴ Department of Pathophysiology and Clinical Immunology, Medical University, ŁódĽ, Poland)

Abstract. Introduction: The nature of the participation of neutrophils in the post-cardiopulmonary bypass (CPB) inflammatory response is not very clear. The aim of our study was to investigate alterations in neutrophil phagocytic activity and adhesion molecule expression on these cells in children during after CPB.
Materials and Methods: Twenty-one children aged 6–33 months with congenital heart disease, scheduled for priand mary corrective surgery, were enrolled. The expressions of CD11b adhesion molecules and Fcγ receptor on neutrophils and their phagocytic activity were evaluated. The studied markers were sequentially measured before, at the initiation of, and after CPB.
Results: During the course of the operation, CD11b molecule expression on neutrophils showed a slight elevation at the start of CPB (876.5±104.8 mean fluorescence intensity, MFI, vs. 768.1±178.2; p=0.0047), followed by a significant decrease to 689.01±166.7 MFI after completion of the procedure. The expression of CD11b molecule on neutrophils measured at the end of CPB inversely correlated with the duration of CPB (r= –0.68, p=0.00059). The expression of CD16 antigen dropped significantly at the start of CPB (1164.6±307.3 MFI vs. 1327.4±345.3 MFI; p=0.0007) and remained decreased until the end of CPB (814.0±198.1 MFI).
Conclusions: These findings suggest that the characteristics of the neutrophil response to cardiac surgery appear to depend on many factors. We demonstrated a link between the duration of CPB and adhesion molecule expression on neutrophils.

Keywords: cardiopulmonary bypass · systemic inflammatory response syndrome · neutrophil · phagocytic activity