CONTENTS
Reviews
- Ludwik Hirszfeld Memorial Lecture: HIV-1 reservoirs: major molecular obstacles to viral eradication
Roger J. Pomerantz (Center for Human Virology and Biodefense, Thomas Jefferson University, Philadelphia, PA 19107, USA)Abstract. Over the last 18 years of study in one of our laboratories, we have observed the development of residual disease and latent reservoirs as major problems in the long-term therapy of HIV-1-infected individuals on highly active antiretroviral therapy (HAART). It was shown in the early 1990’s that HAART, as it is presently configured, is unlikely to lead to viral eradication due to several mechanisms of viral persistence. The two general mechanisms involved with persistence during HAART include low-level residual, cryptic replication and proviral latently-infected cells. As such, these are key areas of potential study for depletion and, hopefully in the future, eradication of residual disease in patients on suppressive HAART. To deplete these residual disease mechanisms will require multipronged approaches. These will include induction of HIV-1 latent proviruses, suppression of residual viral replication and destruction of long-lived cellular sanctuaries, such as tissue-bound macrophages.
Keywords: HIV-1; eradication; reservoirs; latency
- Nucleic acid aptamers in human viral disease
Zhiren Zhang1, Michael Blank2 and Hermann J. Schluesener1, (1 Institute of Brain Research, University of Tuebingen, Tuebingen, Germany, 2 NascaCell IP GmbH, München, Germany)Abstract. Nucleic acid aptamers are short, single-stranded oligonucleotides or their modified analogues which avidly and specifically interact with targeted ligands through their 3-dimensional structure. Aptamers can be selected out of a large combinatorial oligonucleotide library through an in vitro evolution process termed SELEX. Since 1990, a wide variety of aptamers targeted to ligands ranging from small molecules to complex mixtures have been isolated. Most selected aptamers have shown high specificity to and affinity for their ligands and are potential detection and/or diagnostic reagents. Furthermore, some aptamers specifically inhibit biological functions of targeted proteins, resulting in potent therapeutic candidates in disease models. Some recent advances to increase the stability of aptamers, extend their in vivo circulation time and their in vivo expression have pushed aptamers closer to therapeutic applications. This review presents recent developments in the field of aptamer research and focuses on their applications to human viral diseases, particularly HIV induced diseases.
Keywords: aptamer; SELEX; therapeutic applications; analytic applications; human viral diseases; HIV; HCV
- Genetics of experimental autoimmune encephalomyelitis in the mouse
Asa Andersson and Jenny Karlsson (Medical Inflammation Research, I11, BMC, Lund University, Lund, Sweden)Abstract. Multiple sclerosis (MS) is an inflammatory, demyelinating disease in the central nervous system (CNS) affecting approximately 0.1% of the population in the northern part of the world. The factors behind the initiation of the inflammatory response are not known at present, but MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the prevailing experimental rodent model for multiple sclerosis (MS). Disease is induced in genetically susceptible mice or rats by immunization with myelin proteins or peptides, which leads to an infiltration of leukocytes into the CNS. EAE has been subjected to investigations of genetic susceptibility to disease development. By the identification of genes predisposing to EAE, the hope is to get clues as to what genetic elements are also important in MS. To date, more than 25 Eae loci have been described in the mouse. The quantitative trait loci are linked to different disease traits and several show sex specificity. Here we discuss the current state of the genetics controlling susceptibility to EAE.
Keywords: autoimmunity;experimental models; genetics; EAE; multiple sclerosis
- Protein catabolism in chronic uremia: is it due to malnutrition?
Tejinder S. Ahuja and William E. Mitch 9University of Texas Medical Branch, Galveston, TX 77555-0562, USA)Abstract. The high prevalence of anthropometric measurements and laboratory values that are similar to those in patients with protein-energy malnutrition has lead to the classification of a large number of dialysis patients as being malnourished. However, malnutrition in the strict sense implies that abnormalities will be reversed if more food is eaten. There is virtually no evidence, however, that simply providing more nutrients in the diet of dialysispatients will reverse the abnormalities attributed to malnutrition. This suggests that the diagnosis of malnutrition is a misdiagnosis. In this review, we discuss mechanisms that will cause the loss of protein stores, including albumin, other plasma proteins, and muscle mass in dialysis patients. We will also review the shortcomings of techniques that are used to measure the nutritional status of these patients.
Keywords: malnutrition; muscle atrophy; dialysis
- New target against inflammatory diseases: transglutaminase 2
Soo-Youl Kim (Department of Neurology and Neuroscience, Weill Medical College of Cornell University and Burke Medical Research Institute, White Plains, NY 10605, USA)Abstract. Transglutaminase (TGase) 2 is an enzyme that is widely used in many biological systems for generic tissue stabilization or immediate defense for wounds. Many reports showed that TGase 2 is aberrantly activated in tissues and cells and contributes to a variety of diseases, including neurodegenerative diseases and autoimmune diseases. In most cases, TGase 2 appears to be a factor in the formation of inappropriate proteinaceous aggregates that may be cytotoxic. However, in other cases, such as celiac disease, arthritis, lupus, and amyotrophic lateral sclerosis, TGase 2 is involved in the generation of autoantibodies. This suggests the possibility that inappropriate expression and/or presentation of TGase 2 to T cells might contribute to these diseases in genetically predisposed individuals. We and others have found that TGase 2 expression is also increased in the inflammation process. Furthermore, we also demonstrated a reversal of inflammation by TGase inhibition. This review will examine a possibility of TGase inhibitors as therapeutic agents in a variety of inflammatory diseases.
Keywords: transglutaminase; transglutaminase inhibitor; inflammation; autoimmune disease
- Neurokinin receptors: relevance to the emerging immune system
Helen S. Kang1, 2, Katarzyna A. Trzaska1, 2, Kelly Corcoran1, 2, Victor T. Chang1, 3 and Pranela Rameshwar1 (1 Department of Medicine, UMDNJ-New Jersey Medical School, Newark, NJ, USA, 2 Graduate School of Biomedical Sciences, UMDNJ, Newark, NJ, USA, 3VA New Jersey Health Care System, East Orange, NJ, USA)Abstract. The adult bone marrow (BM) is the major site of the emerging immune system. Hematopoiesis is the process whereby immune cells are generated from a finite number of hematopoietic stem cells. Hematopoiesis is regulated by soluble mediators and intercellular interactions. A major regulatory mechanism of hematopoiesis involves bidirectional crosstalk with the neural system. This communication mainly occurs by the release of neurotransmitters from innervated fibers. The neurotransmitters interact with specific receptors on BM resident cells and release other hematopoietic regulators such as cytokines. Together, the neurotransmitters and cytokines form a complex network to regulate hematopoiesis. Among BM resident cells, the stromal cells are particularly relevant for two reasons: 1) they represent non-neural sources of neurotransmitters, and 2) stromal cells express specific receptors for neurotransmitters. This review focuses on the hematopoietic effects of neurotransmitters belonging to the tachykinins. The two major tachykinins focused in this review are substance P and neurokinin (NK)-A, 11 and 10 amino acid peptides. In BM, the tachykinins interact with two major NK receptors: NK-1 and NK-2. These two receptors appear to limit tachykinin-mediated effects on hematopoiesis. The central roles of NK receptors within a network comprising of cytokines and tachykinins are reviewed.
Keywords: neurokinin;substance P; cytokines; neuropeptides; hematopoiesis
- b3-Integrin cytoplasmic binding proteins
Renyi Zhao, Alokkumar S. Pathak and George A. Stouffer (Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC, USA)Abstract. Integrins are cell-surface adhesion receptors that play an important role in mediating numerous physiological processes, including inflammation, migration, adhesion, and proliferation. Integrin regulation by events within the cell has been termed “inside-out” signaling; this is a capacity that is unique to integrin receptors. As is typical of other cell-surface receptors, integrins can also transduce signals from outside the cell into the cytoplasm on binding extracellular ligands (“outside-in signaling”). Integrins are composed of an a and a b subunit, which form a heterodimer. The b3-integrin family consists of aIIbb3 found on platelets and megakaryocytes, and the more widely distributed avb3. ß Subunits consist of a large extracellular domain, a single transmembrane segment, and a relatively short cytoplasmic tail. The cytoplasmic domains do not contain intrinsic tyrosine kinase activity, and therefore signaling occurs primarily via recruitment of intracellular signaling molecules. Integrins form transmembrane connections, and the interactions between integrin cytoplasmic domains, intracellular factors (cytoplasmic proteins and intracellular signaling pathways), and membrane-anchored proteins play an important role in integrin- mediated events. There are at least 21 proteins that associate with integrin b tails to regulate cell motility, proliferation, differentiation, and apoptosis. In this review, we will focus on 10 of these proteins and their function in integrin-mediated events.
Keywords: integrinscytoplasmic domains; intracellular factors
- Treatment options for severe lupus nephritis
Oliver Lenz and Gabriel Contreras (Division of Nephrology and Hypertension, University of Miami, Miami, FL 33136, USA)Abstract. Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Landmark trials conducted by the National Institutes of Health established cyclophosphamide as the mainstay of therapy. Since then, the prognosis of patients with lupus nephritis has markedly improved, and 10-year survival rates now surpass 75%. These superior outcomes have come at the expense of adverse events such as serious infections and gonadal failure in a significant number of patients, and the relapsing nature of the disease continues to pose a problem. For these reasons, new treatment protocols, such as mycophenolate mofetil induction or sequential therapies using azathioprine or mycophenolate mofetil in the maintenance phase, have been developed in recent years with the goal to maintain remission and reduce adverse events. In addition, ongoing research into the pathogenesis of lupus nephritis has confirmed the importance of B and T cell activation, leading to the identification of potential new therapeutic targets. This article discusses established and novel treatment options for patients with severe lupus nephritis corresponding to WHO c asses III, IV, and V with III or V with IV.
Keywords: lupus erythematosus; systemic; lupus nephritis; drug therapy
Original Articles
- CTLA-4 (CD152) gene polymorphism at position 49 in exon 1 in Graves’ disease in a Polish population of the Lower Silesia region
Irena Frydecka1, 2 , Jacek Daroszewski3 , Katarzyna Suwalska1 , Magdalena Żołędziewska4 , Anna Tutak1 , Mirosław Słowik5 , Stanisław Potoczek2 and Tadeusz Dobosz4 (1 Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, 2Department of Hematology, Blood Neoplastic Diseases and Bone Marrow Transplantation, Medical University, Wrocław, Poland, 2Department of Endocrinology and Diabetics, Medical University, Wrocław, Poland, 4Department of Forensic Medicine, Medical University, Wrocław, Poland 5 Department of Ophthalmology, Medical University, Wrocław, Poland)
Abstract. Introduction:Graves’ disease (GD) is an autoimmune disease believed to be caused by a combination of environmental and genetic factors. The gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of the candidate genes for conferring susceptibility to thyroid autoimmunity. The aim of the study was to investigate the association between the exon 1 CTLA-4 gene polymorphism A(49)G and susceptibility to GD and Graves’ ophthalmopathy (GO) as well as its severity in a Polish population of the Lower Silesia region.
Materials and Methods: We analyzed the A(49)G exon 1 CTLA-4 gene polymorphism in 99 unrelated Polish patients with GD, of whom 50 had clinically evident GO (NOSPECS class III and higher), and 154 matched healthy subjects from the Lower Silesia region. Genomic DNA was isolated from whole frozen blood using the NucleoSpinR Blood kit. A/G transition was genotyped by polymerase chain reaction followed by labeling with the SnaPshot kit of PE Applied Biosystems and detected usng an ABI PRISM 310 capillary genetic analyzer.
Results: The distribution of CTLA-4 exon 1 A(49)G genotype, allele, and phenotypic frequencies did not differ between patients with GD and healthy subjects. There was a significantly lower frequency of the AA genotype in the group of patients with clinically evident GO than in patients without severe GO (22% vs. 43%; p=0.02, OR=2.6).
Conclusions: Our results showed that the AA genotype in patients with GD is associated with a lower risk of GO severity.
Keywords: CTLA-4;A(49)G; Graves’ disease; Lower Silesia