Current Immunology Reviews (v.5, #1)

Editorial by David Lo (1-1).
We begin another year of outstanding reviews in Immunology. We have sought to collect reviews mainly on the clinical aspects of immunology, but we have also included a focus on interdisciplinary aspects of immunology that are not adequately covered by mainstream views of immunology. In this respect, we have been extraordinarily successful in the past few years, with articles discussing the interface between the immune system and the nervous system, the intriguing effects of pharmacological agents not specifically directed toward the immune system, and other interesting and surprising connections. In this first issue of the year, we continue this approach. For example, in the article by Nakamura and Yanagawa, the role of beta-adrenergic signaling on inflammation is explained, along with a discussion on some interesting therapeutic applications. Intriguing connections between conventional immune responses and environmental stimuli are presented in two articles. Hoffman and Steiner discuss the diagnostic antibodies against nucleic acid-protein complexes and how different inflammatory stimuli may influence the development of such specific patterns of autoantibodies. Al-Riyami and Harnett discuss the unusual influences of helminth infections on inflammatory disease, with possible beneficial applications. As the complexity of the immune system is being revealed, some very surprising connections have been found. Thus, many molecules and signals that had previously been relegated to non-immune aspects of biology are increasingly being found to have influences on immunity, and are therefore being lumped in with what has been called and#x201C;innateand#x201D; immunity. This is an increasingly unacceptable situation, as it oversimplifies the different ways in which signaling mechanisms can and must interact with the conventional and#x201C;adaptiveand#x201D; immune response. Two articles illustrate this complexity well, and move us to a clearer understanding of how our overall views of immunity might be organized: Banh and Brossay present a discussion on the interactions between cadherins, thought mainly to be responsible for cellular adhesion, and immune receptors. Eagle, Jafferji and Barrow review stress responses in cells and their induction of ligands for Natural Killer cells.

Immune Receptors, Cadherins and their Interactions by Cindy Banh, Laurent Brossay (2-9).
Cadherins were originally defined as homophilic adhesion molecules, thought specifically to only bind to other cadherins. In contrast to this paradigm, an interaction between E-cadherin and an immune receptor, integrin and#945;E(CD103)and#946;7 was identified over a decade ago to demonstrate the first heterophilic interaction between cadherins and non-cadherin molecules. Recently, E-cadherin was also found to interact with another immune receptor, killer cell lectin like receptor G1 (KLRG1). Both KLRG1 and the integrin and#945;E(CD103)and#946;7 expression have been associated with lymphocyte functions whereas E-cadherin is critical for the formation and maintenance of cellular junctions. The binding of these immune receptors to E-cadherin is intriguing and opens new unanticipated avenues of research. Here we review the current knowledge on KLRG1, integrin and#945;E(CD103)and#946;7 and cadherins. We also discuss the potential consequences of the interaction between KLRG1 and/or integrin and#945;E(CD103)and#946;7 and cadherin on both the immune response and tissue organization.

T Cell Receptor Bias in Humans by John Miles, Rebekah Brennan, Scott Burrows (10-21).
The last decade has seen escalating reports of T cell receptor (TcR) bias across all facets of human immunity. These reports describe a phenomenon whereby certain peptide-bound major histocompatibility complexes (pMHC) elicit T cell expansions which bear TcRs with identical or near-identical sequences across unrelated individuals. These observations are indeed curious given the vastness of the naive T cell repertoire and indicate that powerful Darwinian selection forces influence both thymic and post-thymic pMHC-driven selection. This review catalogues examples of selection bias in the human and#945;and#946; T cell response and presents the proposed mechanisms that steer their supremacy in the blood.

Beyond Stressed Self: Evidence for NKG2D Ligand Expression on Healthy Cells by Robert Eagle, Insiya Jafferji, Alexander Barrow (22-34).
The activity of cytotoxic lymphocytes is regulated by the opposing function of stimulatory and inhibitory cell surface receptors. According to the now classical model of Natural Killer (NK) cell activity, the ligands for inhibitory receptors are constitutively expressed on healthy cells but can be lost on infection and on malignant cells. Loss of inhibitory checks will then allow activating signals to predominate, forming the basis of and#x2018;missing self recognitionand#x2019;. Natural Killer Group 2D (NKG2D) is an important member of the cohort of activating receptors expressed on Natural Killer (NK) cells and subsets of T cells. Ligands for the NKG2D receptor comprise a diverse array of self-proteins structurally related to MHC class I molecules. Expression of NKG2D ligands can be induced in cells during infection with pathogens, tumourigenesis, and by stimuli such as DNA damage, oxidative stress, and heat shock. Consequently NKG2D has been widely described as participating in and#x2018;stressed selfand#x2019; or and#x2018;damaged selfand#x2019; recognition. However, a body of evidence has recently emerged to suggest that this intuitive model of NKG2D function may be an oversimplification. NKG2D ligand expression has now widely been reported on cells that could not be described as stressed or damaged. For example activated T cells can express NKG2D ligands, and constitutive expression of NKG2D ligands has been reported on normal myelomonocytic cells, dendritic cells, and epithelial cells of the gut mucosa. In this article we will review the literature suggesting that NKG2D may function to recognise non-stressed cells and discuss the role NKG2D ligands could be playing in apparently healthy cells.

Helminths are long-lived multicellular organisms that have co-evolved with humans over many thousands of years. The parasites have developed various strategies to evade the host's immune response permitting their long-term survival with minimum pathology caused to the host. Over the past few decades a common trend has been observed linking the high prevalence of helminth infections in lesser-developed countries with lower incidences of autoimmune and allergic diseases. With this in mind many studies have emerged showing the benefits of various helminths and their products in alleviating the inflammatory symptoms of autoimmune and allergic diseases. This review aims to bring together some of the various diseases and the potential treatments that these parasites may naturally harbor.

Advances in Lipid-Based Subunit Vaccine Formulations by Julia Myschik, Thomas Rades, Sarah Hook (42-48).
Advances in vaccine formulation have seen a trend towards the use of subunit antigens, ideally incorporated into particulate carriers. These systems are usually in the nanometer size range to facilitate uptake into antigen-presenting cells and to mimic the nature of pathogens. In addition, adjuvants can be incorporated into the same carrier and therefore result in the simultaneous delivery of antigen and adjuvant to the same antigen-presenting cell. A wide variety of particulate carriers have been investigated for vaccine delivery ranging from biological-based particles such as bacterial ghosts and virus-like particles to more simple polymer- or lipid-based systems. In this review we will focus on lipid-based particulate carriers as these offer great potential as regards immune stimulation and due to the simple formulation techniques involved are likely to be more easily scaled-up for manufacture. Another advantage of such systems is versatility in that in addition to the subcutaneous administration of these vaccine formulations, there is also potential for transdermal or even oral delivery. Examples of such delivery systems include liposomes, ethosomes, transfersomes, bilosomes, and immune stimulating complexes. The physico-chemical properties of such systems will be reviewed as will their potential to stimulate immune responses. In addition, we will summarise the recent developments in lipid-based sustained delivery systems for antigens.

Endotoxemia caused by Gram-negative bacteria can result in sepsis and organ dysfunction, which includes kidney damage and renal failure. The renal and#946;2-adrenoceptor (and#946;2-AR) system has an anti-inflammatory influence on the cytokine network during the course of immunologic responses. The previous reports indicated that the administration of and#946;2-AR agonists was found to attenuate the stimulation of renal TNF-and#945; associated with lipopolysaccharide and Shiga toxin-2 of hemolytic uremic syndrome, which is considered to be a central mediator of the pathophysiologic changes. On the other hand, an altered expression and/or function of and#946;2-AR have been considered to be a pathogenetic factor in some disease states; for example, allergy, heart failure, and renal failure. These observations would suggest that blockade of functional and#946;2-AR activation might be associated with an increase risk for organ dysfunction following severe sepsis. In the present article, we review renal and#946;2-AR pharmacology and new insights into the functional importance of and#946;2-AR signaling cascade in sepsis. In addition, an in vivo and#946;2-AR gene therapy for the replacement of lost receptors as a consequence of sepsis and the genomic information of and#946;2-AR to identify groups of patients with a high risk of developing sepsis-induced acute renal failure are also described.

CTLA-4, expressed by activated T and B lymphocytes, is a co-stimulatory receptor transducing a potent inhibitory signal. Increasing evidence showed CTLA-4 gene as an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4) was recently found and shown to possess CD80/CD86 binding activity and in vitro immuno-regulatory functions. sCTLA- 4 is generated by alternatively spliced mRNA. Low levels of sCTLA-4 have been detected in normal human serum, but increased serum levels have been observed in several autoimmune diseases (e.g. Graves' disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, celiac disease and autoimmune pancreatitis disease). The biological significance of increased sCTLA-4 serum level has not been fully clarified. On one hand, we can hypothesize that sCTLA-4 can specifically inhibit the early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete with membrane-bound CTLA-4 for CD80/CD86, in later T lymphocytes activation phase, causing a reduction of inhibitory signaling. Thus, this doubleedged nature of CD80/CD86 blocking by sCTLA-4 may result in different outcomes during the clinical course of the disease.

Autoimmune responses directed to macromolecular nucleic acid-protein complexes such as the nucleosome or the spliceosome are a hallmark of systemic lupus erythematosus (SLE) and related autoimmune diseases. In SLE and its animal models reactivity to these targets is believed to be caused by a defective apoptotic waste disposal system and is associated with a type I Interferon (IFN) signature. Furthermore, inappropriate activation of nucleic-acid binding Toll-like receptors (TLR) has been revealed in lupus-like conditions. Similar mechanisms may also be relevant for other systemic autoimmune diseases such as systemic sclerosis, poly/dermatomyositis and primary Sjogren's syndrome where autoantibodies to nucleic acid binding proteins are commonly observed. In contrast to these disorders, rheumatoid arthritis (RA), the most severe and most destructive joint disease, is characterized by the presence of rheumatoid factors and antibodies to citrullinated proteins, while autoimmune reactions to nucleic acid-binding proteins occur less frequently. However, data from RA patients and animal models suggest that they may nevertheless play an important role in the pathogenesis of autoimmune arthritis, as recently proposed for the heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2). To address the pathogenic role of these autoantigens animal models are indispensable. Of particular interest are models in which disease develops either spontaneously or is induced by immunization with a non-antigenic compound such as the alkane pristane. Unspecific proinflammatory stimuli such as the mineral oil pristane may trigger pathogenic autoimmune reactions which in genetically susceptible individuals may drive chronic inflammation and eventually lead to the development of disease. This review provides an overview of the involvement of RNA- and DNA-associated antigens in systemic autoimmune disorders and discusses recent data from animal models that point to a fundamental role of nucleic-acid associated autoantigens also in arthritic conditions. We will also outline a role of pristane as an inducer of apoptosis and concomitant trigger of autoimmune events.