CONTENTS
Review
- Targeting Janus kinase 3 in the treatment of leukemia and inflammatory diseases
Marina Cetkovic-Cvrlje1, Fatih M. Uckun1, 2 (1Department of Immunology, Parker Hughes Institute, St. Paul, MN 55113, USA, 2Drug Discovery Program, Parker Hughes Institute, St. Paul, MN 55113, USA)Abstract. Janus tyrosine kinases (JAKs) are cytoplasmic protein tyrosine kinases that play a crucial role in the initial steps of cytokine signaling. JAK3, a member of JAK kinase family of four (JAK1, JAK2, JAK3 and TYK2), is abundantly expressed in lymphoid cells. JAK3 has been found to initiate signaling of interleukin (IL)-2, IL-4, IL-7, IL-9, IL-13 and IL-15. Indispensable role of JAK3 in lymphocyte development and function has been revealed recently. Because of the involvement of JAK3 in T cell activation and proliferation, and the documented genetic evidence for the role of JAK3 in autoimmune or transplant-induced inflammatory disorders, the selective targeting of JAK3 in T cells may potentially be clinically beneficial in T cell-derived pathologic disorders. In this review we discuss inhibitors of JAK3 as a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory, anti-allergic, and anti-leukemic properties. Preclinical data from multiple experimental model systems of autoimmune diabetes, allergy, solid organ transplantation, pancreatic islet transplantation and bone marrow transplantation are discussed in the context of the clinical need for new immunomodulatory agents with such properties.
Keywords: Janus kinase 3 (JAK3); JAK3 inhibitors; type 1 diabetes; allogeneic transplantation; allergy.
- Functions of human complement inhibitor C4b-binding protein in relation to its structure
Anna M. Blom1, Bruno O. Villoutreix2 and Björn Dahlbäck1, (1 Lund University, University Hospital Malmö, S-205 02 Malmö, Sweden, 2 INSERM U428, University of Paris V, Paris, France)Abstract. Considering the destructive potential of the complement cascade, it is no surprise that there are several complement inhibitors present in blood and expressed on virtually all cells of the body to protect self tissue. C4b-binding protein (C4BP) is a potent soluble inhibitor of the classical and lectin pathways of complement. This large (500 kDa) plasma glycoprotein consists of seven identical 75 kDa ?-chains and a unique 40 kDa??-chain that are held together by disulphide bridges. Both types of subunit are almost exclusively composed of complement control protein (CCP) domains. In recent years, detailed studies of structure-function relationships have yielded new understanding of the interactions between C4BP and the activated complement factors C4b and C3b, heparin, and vitamin K-dependent anticoagulant protein S. This review describes the localization of binding sites for a number of C4BP ligands in relation to well-established and novel functions of C4BP such as complement inhibition, protection of apoptotic cells from complement, CD40-dependent stimulation of B cells, and the contribution of a number of human pathogens to pathogenesis.
Keywords: complement; C4b-binding protein; protein S; coagulation; heparin; B cells; CD40; apoptosis; C3b; C4b.
- Anti-GBM glomerulonephritis: a T cell-mediated autoimmune disease?
Ya-Huan Lou, (University of Texas Health Science Center at Houston, Houston, TX 77030, USA)Abstract. Anti-glomerular basement membrane (GBM) glomerulonephritis, which was among the earliest recognized human autoimmune diseases, is characterized by the presence of anti-GBM antibody. It has been a prototypical example of autoantibody-mediated autoimmune disease. However, decades of research on this disease, based either on clinical observations or experimental models, have revealed that T cell-mediated cellular immunity may potentially be a more important mediator of glomerulonephritis. We have made several breakthroughs in understanding the T cell-mediated mechanism causing this disease in a rat model based on Goodpasture’s antigen, non-collagen domain 1 of ?3 chain of type IV collagen (Col4?3NC1). We demonstrated that anti-GBM glomerulonephritis was induced by either passive transfer of Col4?3NC1-specific T cells or active immunization with the nephritogenic T cell epitope of Col4?3NC1. Immunization with the T cell epitope also triggered production of anti-GBM antibodies to diversified GBM antigens. Thus, a single nephritogenic T cell epitope alone is sufficient to induce the clinical spectrum of anti-GBM glomerulonephritis, including proteinuria, glomerular injury, and anti-GBM antibody. A possible T cell-mediated mechanism for causing human anti-GBM disease is proposed.
Keywords: autoimmunity; T cells; autoantibody; glomerulonephritis.
- Leucine-rich repeats in host-pathogen interactions
Łukasz Kędzierski, Jacqui Montgomery, Joan Curtis and Emanuela Handman, (The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia)Abstract. Leucine-rich repeats (LRRs) are versatile binding motifs found in a variety of proteins and are involved in protein-protein interactions. The LRR domain is composed of repeats forming a characteristic solenoid horse-shoe structure, which provides a scaffold for numerous insertions involved in binding to pathogen-associated molecular patterns and surface receptors. LRRs have been shown to be involved in the host defense systems of both plants (resistance genes) and mammals (Toll-like receptors and nucleotide-binding oligomerisation domain proteins), where they sense specific pathogen-associated molecules and activate the innate immune system. Paradoxically, LRRs have also been shown to be part of microbial virulence factors involved in the interaction with host cells and establishment of infection. The potential of LRRs to bind a vast array of structurally unrelated ligands and their well-documented involvement in microbial pathogenesis make them a potential target for vaccines and new drugs. The recent identification of LRRs in the obligate intracellular protozoan parasite Leishmania and their participation in the macrophage-parasite interaction have added new insight into the role of LRRs in the host cell invasion.
Keywords: leucine-rich repeat; host-pathogen interaction; Toll-like receptors; Leishmania.
- Genetic and biochemical background of chronic granulomatous disease
Monika Jurkowska1,2, Ewa Bernatowska3 and Jerzy Bal1, (1National Research Institute of Mother and Child, Warsaw, Poland,2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland,3 Children’s Memorial Health Institute, Warsaw, Poland)Abstract. Chronic granulomatous disease (CGD) is a rare inherited immunodeficency syndrome caused by a profound defect in the oxygen metabolic burst machinery. Activity of NADPH oxidase is absent or profoundly diminished, as at least one of its components (gp91phox, p22phox, p47phox and p67phox) is lacking or non-functional. This review explains the molecular basis of NADPH oxidase dysfunction by the effects of mutations in genes coding for particular oxidase components. Among the four types of CGD, the most common is X-linked CGD (approximately 65%), with defects in the CYBB gene encoding gp91phox. A wide spectrum of mutations has been described in the CYBB gene with no predominant genotype. The second most common subtype of CGD caused by NCF1 mutation accounts for 30% of CGD patients and is inherited in an autosomal recessive manner, with predominance of a homozygotous ?GT deletion in the genotype. The other two CGD subtypes having an autosomal recessive pattern together account for no more than 10% of CGD cases. A strategy for the molecular diagnostics in CGD patients is proposed and principles of genetic counseling are discussed here.
Keywords: CGD; NADPH oxidase; genes; molecular diagnostics.
Original Article
- Characterization and serological classification of a collection of Proteus penneri clinical strains
Dominika Drzewiecka, Krystyna Zych and Zygmunt Sidorczyk, (Department of General Microbiology, Institute of Microbiology and Immunology, University of Łódź, Łódź, Poland)Abstract.
Introduction:
Bacteria of the genus Proteus, which are a common cause of urinary tract infections, are divided into four species: P. mirabilis, P. vulgaris, P. penneri, and P. hauseri, and three unnamed genomospecies, Proteus 4, 5, and 6 (single-strain species P. myxofaciens was isolated from the gypsy moth). Establishing the serological classification of these species would aid in completing the classification scheme of the whole genus Proteus and in applying serological methods in diagnostic procedures and epidemiological investigations for these opportunistic pathogens. The aim of this research was a serological characterization and classification of 57 Proteus penneri clinical strains, isolated from patients from different countries all over the world, into Proteus O serogroups.Materials and Methods:
Purified lipopolysaccharides (LPSs) extracted from 57 P. penneri strains were used as antigens in enzyme immunosorbent assay (EIA), SDS/PAGE, and Western blot techniques, and alkali-treated LPSs in passive immunohemolysis test (PIH), inhibition of PIH, and absorption of rabbit polyclonal O-antisera.Results and Conclusions:As a result of serological studies of LPSs extracted from the P. penneri strains, one new Proteus serogroup, represented by the P. penneri 97 strain, was established. Three further strains were classified into the Proteus serogroup O8, which had not contained any P. penneri strains before. All the remaining strains were classified into 11 already existing Proteus O serogroups. It is important to emphasize that 72% of studied strains were classified into serogroups that contain P. penneri strains only. That result confirms the serological distinction of this species within the genus Proteus, and may have diagnostic significance.
Keywords: Proteus penneri; O antigen; lipopolysaccharide; O serogroups; O serotyping; serological classification.
- Effect on peripheral blood natural killer cytotoxic cell activity in rats after intraperitoneal implantation of double veloured polyester (Dacron) prosthesis
Marek K. Jurkowski1, Barbara Bobek-Billewicz2, Małgorzata Ćwiklińska-Jurkowska3 and Piotr Jurkowski4, (1Department of Pediatrics, Hematology and Oncology, University of Medical Sciences, Bydgoszcz, Poland, 2Regional Cancer Center, Bydgoszcz, Poland, 3Department of Computer Science, University of Medical Sciences, Bydgoszcz, Poland, 4Department of Computer Science and the Methodology of Scientific Research, University of Medical Sciences, Bydgoszcz, Poland)
Abstract.
Introduction:
The aim of this study was to assess the changes affecting natural killer cytotoxic cell (NKCC) activity following intraperitoneal implantation of a double veloured polyester prosthesis in a rat model.
Materials and Methods:
Blood samples were taken by cardiac puncture 1 h before (base line) and 14, 28, 100 and 180 days post-implantation. Peripheral blood mononuclear cells were separated from heparinized blood by density centrifugation. A standard, 4 h 51Cr-release assay against YAC-1 target cells at effector to target ratios of 12:1; 25:1 and 50:1 was performed and the number of total leukocytes, lymphocytes, granulocytes, monocytes, and large granular lymphocytes (LGLs), as well as serum corticosterone levels (radioimmunoassay method) were determined.
Results:
Comparative analysis of the results obtained from animals with implants, baseline samples, and a control group (laparotomy only) revealed lower NKCC, LGL, leukocyte and lymphocyte counts and elevated plasma corticosterone levels in animals receiving the implant on the 14th day post-implantation.
Conclusions:
Our findings indicate that the polyester implant can transiently modulate immune system activities. Since NK cells are important in the control of viral infection and carcinogenesis in humans, it is possible that the stress generated by polyester prostheses can exacerbate the surgical stress and put patients at a higher risk for viral infection and/or metastases.
Keywords: Dacron • NKCC • LGL • rat • lymphocytes • leukocytes