Table of Contents

Volume 1, Issue 3

  July/August/September 2010

  Pages 165 - 268

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REVIEWS

Open Access Article

Gene therapy in diabetes

Mary S. Wong, Wayne J. Hawthorne and Nicholas Manolios
Pages 165 - 175
http://dx.doi.org/10.4161/self.1.3.12643
Abstract | PDF

Type 1 diabetes (T1D) is a chronic autoimmune disease, whereby auto-reactive cytotoxic T-cells target and destroy insulin-secreting β-cells in pancreatic islets leading to insulin deficiency and subsequent hyperglycaemia. These individuals require multiple daily insulin injections every day of their life without which they will develop life-threatening diabetic ketoacidosis (DKA) and die. Gene therapy by viral vector and non-viral transduction may be useful techniques to treat T1D as it can be applied from many different angles; such as the suppression of autoreactive T-cells to prevent islet destruction (prophylactic), or the replacement of the insulin gene (post-disease). The need for a better method for providing euglycaemia arose from insufficient numbers of cadaver islets for transplantation and the immunosuppression required post-transplant. Ectopic expression of insulin or islet modification have been examined, but not perfected. This review examines the various gene transfer methods, gene therapy techniques used to date, and promising novel techniques for the maintenance of euglycaemia in the treatment of T1D.

Open Access Article

Self/nonself perception, reproduction, and the extended MHC

Andreas Ziegler, Pablo Sandro Carvalho Santos, Thomas Kellermann and Barbara Uchanska-Ziegler
Pages 176 - 191
http://dx.doi.org/10.4161/self.1.3.12736
Abstract | PDF

Self/nonself perception governs mate selection in most eukaryotic species. It relies on a number of natural barriers that act before, during, and after copulation. These hurdles prevent a costly investment into an embryo with potentially suboptimal genetic and immunological properties and aim at discouraging fertilization when male and female gametes exhibit extensive sharing of alleles. Due to the fact that several genes belonging to the extended major histocompatibility complex (xMHC) carry out crucial immune functions and are the most polymorphic within vertebrate genomes, it is likely that securing heterozygosity and the selection of rare alleles within this gene complex contributes to endowing the offspring with an advantage in fighting infections. Apart from MHC class I and II antigens, the products of several other genes within the xMHC are candidates for participating in mate choice, especially since the respective loci are subject to long-range linkage disequilibrium. Among these are polymorphic odorant receptor genes that are expressed not only in the olfactory epithelium, but also within male reproductive tissues. They may thus not only be of importance in olfaction-dependent mate choice, by recognizing MHC-dependent individual-specific olfactory signals, but could also guide spermatozoa along chemical gradients to their target, the oocyte. By focusing on the human HLA complex and genes within its vicinity, we show here that the products of several xMHC-specified molecules might be involved in self/nonself perception during reproduction. Although the molecular details are often unknown, the existence of highly diverse, yet intertwined pre- and post-copulatory barriers suggests that xMHC-encoded proteins may be important for various stages of mate choice, germ cell development, as well as embryonic and foetal life in mammals and other vertebrates. Many of these genes should thus be regarded as crucial not only within the immune system, but also in reproduction.

Open Access Article

The SCHOOL of nature. III. From mechanistic understanding to novel therapies


Pages 192 - 224
http://dx.doi.org/10.4161/self.1.3.12794
Abstract | PDF

Protein-protein interactions play a central role in biological processes and thus represent an appealing target for innovative drug design and development. They can be targeted by small molecule inhibitors, modulatory peptides and peptidomimetics, which represent a superior alternative to protein therapeutics that carry many disadvantages. Considering that transmembrane signal transduction is an attractive process to therapeutically control multiple diseases, it is therefore fundamentally and clinically important to mechanistically understand how signal transduction occurs. Uncovering specific protein-protein interactions critical for signal transduction, a general platform for receptor-mediated signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) platform, suggests these interactions as universal therapeutic targets. Within the platform, the general principles of signaling are similar for a variety of functionally unrelated receptors. This suggests that global therapeutic strategies targeting key protein-protein interactions involved in receptor triggering and transmembrane signal transduction may be used to treat a diverse set of diseases. This also assumes that clinical knowledge and therapeutic strategies can be transferred between seemingly disparate disorders, such as T cell-mediated skin diseases and platelet disorders, or combined to develop novel pharmacological approaches. Intriguingly, human viruses use the SCHOOL-like strategies to modulate and/or escape the host immune response. These viral mechanisms are highly optimized over the millennia, and the lessons learned from viral pathogenesis can be used practically for rational drug design. Proof of the SCHOOL concept in the development of novel therapies for atopic dermatitis, rheumatoid arthritis, cancer, platelet disorders and other multiple indications with unmet needs opens new horizons in therapeutics.

Open Access Article

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

Marc Derive, Frédéric Massin and Sébastien Gibot
Pages 225 - 230
http://dx.doi.org/10.4161/self.1.3.12891
Abstract | PDF

The Triggering Receptor Expressed on Myeloid cells (TREM)-1 is a recently identified molecule involved in monocytic activation and inflammatory response. It belongs to a family related to Natural Killer cell-receptors and is expressed on neutrophils, mature monocytes and macrophages. The engagement of TREM-1 synergizes with several Toll Like Receptors (TLR) and/or NOD Like Receptors (NLR) activation in amplifying the inflammatory response mediated by microbial components or danger signals. The implication of TREM-1 during experimental models of acute or chronic inflammatory conditions, as well as during cancer, begins to understand. Furthermore, the modulation of the TREM-1 signalling pathway by the use of small synthetic peptides derived from its extracellular moiety confers interesting survival advantages during experimental murine septic shock, and protects from organ damage during other inflammatory diseases. This review summarizes the recent advances on TREM-1 biology and highlights the promises of its therapeutic modulation.

Open Access Article

CD28 co‐signaling in the adaptive immune response

Pavel Riha and Christopher E. Rudd
Pages 231 - 240
http://dx.doi.org/10.4161/self.1.3.12968
Abstract | PDF

T‐cell proliferation and function depends on signals from the antigen‐receptor complex (TCR/CD3) and by various co‐receptors such as CD28 and CTLA‐4. The balance of positive and negative signals determines the outcome of the T‐cell response to foreign and self‐antigen. CD28 is a prominent co‐receptor in naiÅNve and memory T‐cell responses, and its blockade has been exploited clinically to dampen T‐cell responses to self‐antigen. Current evidence shows that CD28 both potentiates TCR signaling and engages a unique array of mediators (PI 3K, Grb2, FLNa) in the regulation of aspects of T‐cell signaling including the transcription factor NFκb. In this mini‐review, we provide an up‐to‐date over‐view of our understanding of the signaling mechanisms that underlie CD28 function and its potential application to the modulation of reactivity to autoimmunity.

 




CUTTING EDGE VIEW

Open Access Article

Visual analytics for immunologists: Data compression and fractal distributions

Elena N. Naumova
Pages 241 - 249
http://dx.doi.org/10.4161/self.1.3.12876
Abstract | PDF

Visual analytics is the science of analytical reasoning that facilitates research through the use of interactive visual interfaces. New techniques of visual analytics are designed to aid the understanding of complex systems versus traditional blind-context rules to explore massive volumes of interrelated data. Nowhere else is context more important in analysis than in the emerging fields of life sciences, where amounts of collected data grow increasingly in exponential rates. The complexity of systems in immunology makes visual analytics especially important to sufficiently understand how the immune system works. In this context, our efforts should focus on avoiding accurate but often misleading use of visual interfaces. The proposed approach of data compression and visualization that reveal structural and functional features of immune responses enhances systemic and comprehensive description and provides the platform for hypothesis generation. Further, this can evolve into a powerful visual-analytical tool for prospective and real-time monitoring, and provide an intuitive and interpretable illustration of vital dynamics that govern immune responses in an individual and populations. The undertaken explorations demonstrate the critical role of novel techniques of visual analytics in stimulating research in immunology and other life sciences, and in leading us to understanding of complex biological systems and processes.




OPINION

Open Access Article

Glycosylation: an intrinsic sign of "Danger"

Jacob Rachmilewitz
Pages 250 - 254
http://dx.doi.org/10.4161/self.1.3.12330
Abstract | PDF

The "danger" model of immunity posits that the immune system is triggered by endogenous danger signals, rather than exogenous non-self signals per se.  It has been proposed that danger signals may consist of both intracellular "pre-packed" molecules released from damaged cells and stress-induced proteins. Here we focus on glycosylation aberrancies as a unifying concept for danger signaling. According to this proposition glycosylation patterns reliably reflect cellular phenotypic state and appearance of altered carbohydrate structures may constitute a pivotal phenotypic alteration that alarms the immune system to danger and initiate immunity. Viewed from this vantage point, healthy cells avert immune recognition by virtue of their normal terminal glycosylation patterns.  By contrast, abnormal cells display and release glycoproteins and glycolipids with aberrant terminal glycosylation trees, which in turn immunologically flag these cells. In turn, diverse carbohydrate-binding receptors are expressed on immune cells and are used to detect these phenotypic changes. Thus, in addition to the "pre-packed" and stress-induced signals this glycosylation-based signal represent an endogenous signal reliably reflecting the cell phenotypic status, enabling the immune system to monitor the tissue/cell's physical condition and to respond accordingly.




REPORTS

Open Access Article

The self/nonself issue: A confrontation between proteomes

Darja Kanduc
Pages 255 - 258
http://dx.doi.org/10.4161/self.1.3.11897
Abstract | PDF

Defining self and nonself  is the most compelling challenge in science today, at the basis of the numerous questions that remain unanswered in the immunology-pathology-therapy debate. The generation of the antibody repertoire, the complicated scenario offered by tolerance and autoimmunity, natural auto-antibodies and their relationship to autoimmune diseases, and positive and negative selection are only a few examples of the unresolved immunological questions. In this context, we proposed that sequence similarity to the host proteome modulates antigen peptide recognition and immunogenicity. Using the available proteome assemblies of viruses, bacteria, and higher vertebrates, and applying the low-similarity criterion, we are systematically defining  the proteomic similarity of B cell epitopes already validated experimentally. Here, we report further data documenting that a low similarity to the host proteome is the common property that defines the immunological “nonself” nature of antigenic sequences in cancer, autoimmunity, infectious diseases, and allergy.

Open Access Article

The autoimmunity-related GIMAP5 GTPase is a lysosome-associated protein

Vivian W.Y. Wong, Amy E. Saunders, Amanda Hutchings, John C. Pascall, Christine Carter, Nicholas A. Bright, Simon A. Walker, Nicholas T. Ktistakis and Geoffrey W. Butcher
Pages 259 - 268
http://dx.doi.org/10.4161/self.1.3.12819
Abstract | PDF

A mutation in the rat GIMAP5 gene predisposes for autoimmunity, most famously in the BB rat model of autoimmune type 1 diabetes mellitus. This mutation is associated with severe peripheral T lymphopenia, as is mutation of the same gene in mice, but the mechanism by which GIMAP5 normally protects T cells from death is unknown. GIMAP5 is a putative small GTPase, a class of proteins which often fulfil their functions in the vicinity of cellular membranes. The objective of this study was to determine the normal intracellular location of GIMAP5 in lymphoid cells. Combining studies in rat, mouse and human systems, novel monoclonal antibodies (mAbs) were used to examine the localisation of GIMAP5, and the closely-related protein, GIMAP1, in lymphoid cells by means of confocal microscopy and sub-cellular fractionation combined with immunoblotting. Additionally, human Jurkat T cells that inducibly express epitope-tagged GIMAP5 were established and used in electron microscopy (EM). Endogenous GIMAP5 was found to be located in a membraneous compartment/s which was also detected by established markers of lysosomes. GIMAP1, by contrast, was found to be located in the Golgi apparatus. EM studies of the inducible Jurkat T cells also found GIMAP5 in lysosomes and, in addition, in multivesicular bodies. This study establishes that the endogenous location of GIMAP5 is in lysosomes and related compartments and provides a clearer context for hypotheses about its mechanism of action.