CONTENTS
Reviews
- Role of lipid rafts in T cells
Sunil Thomas, Rajeev Kumar S. and Teodor-D. Brumeanu (Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA)Abstract. The plasma membrane of T cells is made up of a combination of phospholipids and proteins organized as glycolipoprotein microdomains termed lipid rafts. The structural assembly of lipid rafts was investigated by various physical and biochemical assays. Depending on the differentiation status of T cells, the lipid rafts seclude various protein receptors instrumental for the early T cell signaling, cytoskeleton reorganization, protein and membrane trafficking, and the entry of infectious organisms into the cells. This review article summarizes recent information on the assembly of lipid rafts in plasma membrane of T cells and their signaling output in mature and thymic precursors towards cell growth and differentiation, and possible modalities by which the function of lipid rafts can be altered by drugs and T cell ligands. The concept of using lipid rafts as a target for pharmaceutical compounds and biological T cell ligands to ultimately alter the T cell function is discussed.
Keywords: lipid rafts; T cells; thymic selection; immune modulation
- Rethinking oxidized low-density lipoprotein, its role in atherogenesis and the immune responses associated with it
Peter X. Shaw University of California, San Diego, La Jolla, CA 92093, USAAbstract. Atherosclerosis is a chronic inflammatory disease, resulting from hyperlipidemia and a complex interplay of many environmental, metabolic, and genetic risk factors. The unregulated macrophage uptake of cholesterol and lipids through modified forms of lowdensity lipoprotein (LDL), such as “OxLDL”, transforms macrophages into “foam cells” to form the initial morphological lesion (the fatty streak). The modification of LDL not only enhances its uptake by macrophages, but also changes the natural structures of these otherwise ubiquitous molecules to generate a variety of modified lipids and proteins that represent highly immunogenic neo-determinants. For example, in ApoE–/– mice, autoantibody titers to epitopes on OxLDL are correlated with the extent of atherosclerosis. Similarly, oxidative stress on cellular membranes could also give rise to “oxidation-specific” epitopes and common autoantibodies. However, OxLDL is not uniform, but rather contains complex structures, ranging from a small conformational change in surface lipids to the breakdown of the peptide chain. Therefore, the immune responses to the variety of OxLDL and their association to atherosclerosis progression are very different. For example, phosphorylcholine (PC) is a natural component of phospholipids and exists in LDL and plasma membranes. “Natural” antibodies against PC can distinctively react to PC on bacteria, OxLDL and apoptotic cells, but not to those on unoxidized phospholipids, native LDL and viable cells, which suggests the broader role of such autoantibodies in maintaining the homeostasis of the host. While malondialdehyde-modified structures resemble more the exogenous changes and associate with advanced stage of lesion, they are more likely to associate with adaptive immunity.
Keywords: oxidized LDL; MDA-LDL; atherosclerosis; immune response; anti-phosphorylcholine; inflammation
- Polymorphisms within the genes encoding TNF-a and TNF-b associate with the incidence of post-transplant complications in recipients of allogeneic hematopoietic stem cell transplants
Katarzyna Bogunia-Kubik (Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland)Abstract. Hematopoietic stem cell transplantation (HSCT) is a curative treatment of many hematological disorders. Recent studies have shown the associations between polymorphic features of cytokine-encoding genes and the incidence of post-transplant complications in the recipients of allogeneic HSCT. This review focuses on the relationship between the polymorphic patterns of patient genes encoding tumor necrosis factor (TNF)-a and TNF-b and the manifestation of post-transplant complications, acute graft-versus-host disease (aGvHD), generation of toxic lesions, and mortality. Discussed in more detail are the relationships of TNFd microsatellites and polymorphisms within the promoter region of the TNF-a-encoding gene (TNFA) in the position (–308) and within the first intron of the TNF-ß-encoding gene (TNFB). It appeared that heterozygosity within the TNFA promoter and the first intron of the TNFB gene increased the susceptibility to severe grades III–IV of toxic complications, while the presence of the TNFd3 homozygous genotype was associated with a higher risk of severe aGvHD and early mortality in patients after allogeneic HSCT. These results imply that donor-recipient genotyping, extended to cytokine loci, may be of prognostic value for transplantation outcome.
Keywords: allogeneic HSCT; TNF polymorphism; GvHD; toxicity
- The role of PTEN in allergic inflammation
Yong C. Lee (Department of Internal Medicine, Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, Jeonju, South Korea)Abstract. Bronchial asthma is a chronic inflammatory disease of the airways, characterized by airway eosinophilia, goblet cell hyperplasia with mucus hyper-secretion, and hyper-responsiveness to inhaled allergens and to non-specific stimuli. Eosinophil accumulation and subsequent activation in bronchial tissues play critical roles in the pathophysiology of bronchial asthma. Many inflammatory mediators attract and activate eosinophils via signal transduction pathways involving an enzyme phosphatidylinositol 3-kinase (PI3-kinase). Studies using wortmannin, a specific inhibitor of PI3-kinase, have revealed the involvement of PI3-kinase in the biochemical transduction of activation signals generated by many inflammatory mediators in eosinophils. Wortmannin prevents the development of airway inflammation, either by inhibiting the eosinophil infiltration of bronchial tissues or their activation on arrival. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN opposes the action of PI3-kinase by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. Recently we have demonstrated that PTEN expression is diminished in airway epithelial cells of antigen-sensitized and -challenged mice. Administration of PI3-kinase inhibitors or adenoviruses carrying PTEN complementary DNA remarkably reduces eosinophil levels and inflammation. One likely mechanism for this reduction is PTEN-mediated eosinophil degranulation and suppression of interleukin (IL)-4 and IL-5. These findings indicate that use of PTEN may be a good therapeutic strategy for the management of allergic inflammation.
Keywords: PTEN; bronchial asthma; eosinophilia; phosphatidylinositol 3-kinase; signal transduction; inflammation
- Mouse Ly-6 proteins and their extended family: markers of cell differentiation and regulators of cell signaling
Anil Bamezai (Biology Department, Villanova University, Villanova, PA 19085, USA)Abstract. The Ly-6 locus on mouse chromosome 15 encodes a family of 10–12 kDa proteins that are linked to the cell surface by a glycosylphosphatidyl-inositol anchor and have cell signaling and cell adhesion properties. Expression of Ly-6 proteins is tightly regulated during development; these proteins continue to serve as excellent differentiation surface markers on normal and abnormal cells, but their role in driving cellular differentiation is still emerging. Recent studies suggest that Ly-6 gene products participate in regulating signaling through other cell type-specific receptors, perhaps by virtue of these proteins being localized in lipid rafts that play a key role in relaying signals from the membrane to the nucleus. Ligands for some Ly-6 proteins have been reported; the consequence of their interactions with the Ly-6 receptor remains to be fully uncovered. Mouse Ly-6-like proteins have also been reported from a variety of life forms ranging from Caenorhabditis elegans to humans that show a limited amino acid dentity and share structural features with members of mouse Ly-6. Despite these similarities, the non-murine Ly-6 proteins bind distinct ligands and appear to have different cellular functions. All members of the Ly-6 super gene family perhaps evolved from an ancestral gene by a gene duplication mechanism.
Keywords: Ly-6; cell adhesion; cell signaling; differentiation marker; disease; lipid raft
- The common gc-cytokines and transplantation tolerance
Minh Diem Vu and Xian Chang Li (Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA)Abstract. Transplant rejection, like tolerance, is a T cell-dependent event. There is compelling evidence to suggest that induction of transplant tolerance is an actively learned process in which T cells need to engage the alloantigens in order to learn to tolerate the allograft. A family of cytokines whose receptors use the same IL-2 receptor g chain (also called the common gc) plays an important role in regulating multiple aspects of the allograft response (i.e. rejection vs. tolerance). It is undeniable that gc-cytokines can drive clonal expansion and effector maturation of alloreactive T cells, and therefore, targeting such cytokines or their receptor components remains an attractive way of blocking transplant rejection. However, we just started to appreciate that gc-cytokines also regulate the acquisition of transplant tolerance via programming activated T cells for apoptotic cell death and via guiding the evolution of regulatory T cells. Thus, understanding precisely the role of gc-cytokines in regulating T cell homeostasis and T cell regulation is critically important in the induction of transplant tolerance.
Keywords: common gc; cytokines; T cell regulation; tolerance; transplantation
Original Articles
- Antichlamydial antibodies in the serum and expressed prostatic secretion in prostatitis
Iwona Ostaszewska-Puchalska1, Bożena Zdrodowska-Stefanow2, Jerzy Badyda3, Violetta Bułhak-Kozioł1 , Katarzyna Puciło1 and Barbara Darewicz4. (1 Center for Sexually Transmitted Disease Research and Diagnostics, Białystok, Poland, 2 Department of Dermatology and Venerology, Medical School, Białystok, Poland, 3 Outpatients Urology Clinic, Białystok, Poland, 4 Department of Urology, Medical School, Białystok, Poland)Abstract. Introduction:The aim of the study was to evaluate the prevalence of anti-Chlamydia trachomatis (C. trachomatis) antibodies in serum and expressed prostatic secretion (EPS) in chronic prostatitis.
Materials and Methods:Thirty-six patients with chronic prostatitis were examined. The presence of C. trachomatis was determined in urethral smears and EPS. Specific antibodies were determined in the serum (IgM, IgA, IgG) and in the EPS (IgA, IgG). In the direct diagnosis of chlamydial infection, the direct immunofluorescence method and the ligase chain reaction were employed, and for the serological diagnosis, the immunoenzymatic method.
Results: C. trachomatis infection was detected in the urethra of 3 (8.3%) patients and in the prostatic gland of 3 (8.3%) patients; only one of these patients was found to have C. trachomatis in both the urethra and the EPS. In the control group, C. trachomatis was detected in the urethra of 1/50 (2%) of the men, but the EPS of all of them was free of C. trachomatis. Specific IgM antibodies were found in 7 (19.4%), IgA in 9 (25%), and IgG in 18 (50%) of the patients’ serum, whereas IgAs were detected in 12 (33.3%) and IgGs in 13 (36.1%) of the patients’ EPS. In the control group, anti-C. trachomatis antibodies of the IgG were detected in the serum of 2/35 (5.7%) of the men, whereas in the EPS neither IgA nor IgG antibodies were detected in any of these patients.
Conclusions: Serological tests of the serum and EPS are useful as a complementary method in the diagnosis of chronic prostatitis.Keywords: prostatitis; Chlamydia trachomatis; IgG; IgM; IgA antichlamydial antibodies; expressed prostatic secretion
- Oxidative modification of type II collagen differentially affects its arthritogenic and tolerogenic capacity in experimental arthritis
Janusz Marcinkiewicz1, Rafał Biedroń1, Katarzyna Maresz1, Beata Kwaśny-Krochin2, Małgorzata Bobek1, Ewa Kontny3, Włodzimierz Maśliński3 and Benjamin Chain4 (1 Department of Immunology, Jagiellonian University Medical College, Kraków, Poland, 2 Department of Rheumatology, Jagiellonian University Medical College, Kraków, Poland, 3 Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland, 4Department of Immunology and Molecular Pathology, The Windeyer Institute for Infectious Diseases, University College London, UK)
Abstract. Introduction: Oxidative modification of proteins affects their biological properties. Previously we have shown that hypochlorite (HOCl), the product of activated neutrophils, enhances protein immunogenecity. Collagen type II, a primary component of cartilage, is commonly use in the induction of arthritis in animals (CIA). The aim of this study was to examine whether HOCl may affect immunogenic, tolerogenic, and arthritogenic properties of collagen.
Materials and Methods: DBA/J mice were injected with either native (CNAT) or chlorinated collagen (CHOCl) to induce arthritis. The effect of chlorination on collagen properties was measured by evaluation of incidence and severity of CIA. Moreover, the concentration of serum anti-collagen IgG antibodies and myeloperoxidase (MPO) activity in inflamed joints was determined.
Results: Mice immunized with CNAT in adjuvant developed arthritis (CIA) with an incidence of 69%. CNAT also exerted tolerogenic properties when injected intravenously either before or shortly after primary immunization, resulting in decreased incidence and severity of CIA, reduced MPO activity in inflamed joints, and lowered serum levels of anti-CNAT IgG antibodies. Chlorination of collagen significantly diminished its ability to induce CIA and to trigger generation of anti-CNAT IgG antibodies. Interestingly, chlorination did not affect tolerogenic properties of collagen administered prior to primary immunization with CNAT.
Conclusions: These results suggest that chlorination of collagen may selectively affect functional epitopes of collagen. It is likely that in inflamed joints, neutrophil-derived HOCl, in some circumstances, will destroy arthritogenic and immunogenic B cell epitopes, while regulatory T cell epitopes will be preserved.
Keywords: collagen-induced arthritis; DBA/1 mice; protein oxidation; neutrophils; myeloperoxidase; hypochlorous acid