Abstract: Psoriatic arthritis (PsA) occurs in approximately 30% of psoriasis patients. Understanding the similarities and differences in the etiology of these related diseases may highlight pathways for intervention and allow risk prediction in the future. Both are complex diseases in which environmental susceptibility factors trigger disease in genetically susceptible individuals. In recent years, genome-wide association studies have been highly successful in identifying genetic susceptibility factors for psoriasis. Most of the psoriasis loci tested so far are also associated with PsA. For example, associations of HLA-Cw*06 and the IL12B and IL23R genes are well-established with both conditions. More recently, analysis of psoriasis genome-wide association studies in a PsA subgroup has also implicated IL23A, TNFAIP3, and TNIP1 genetic variants as conferring risk to PsA. One study has suggested that late cornified envelope (LCE) gene polymorphisms are associated with psoriasis but not PsA. However, this finding was not confirmed by a second study. Similarly, association of the 5q31 gene region encompassing the IL13 gene has been reported with PsA but not psoriasis by one group, but this awaits confirmation in other series. Dedicated genome-wide association studies of PsA are underway and are likely to reveal further insights into why some patients with psoriasis develop arthritis whilst the majority do not. ... Read more

Abstract: Diabetes, a disorder of glucose homeostasis, has risen to near epidemic proportions world-wide and may be the single most important risk factor for cardiovascular, kidney, and eye disease. Dysfunction and destruction of islet β cells, caused in part by the systemic or local release of pro-inflammatory cytokines, underlies all forms of diabetes. A major effort in diabetes research in recent years has been to identify new factors or pathways that can be therapeutically targeted to reduce cytokine action on the β cell. Recent studies have suggested that an ancient and poorly understood protein, eIF5A, may be critical to cytokine release and signaling. Interestingly, eIF5A is the only protein to contain the unique amino acid hypusine, which is a polyamine-derived modification of amino acid lysine residue. This modification is catalyzed by the sequential actions of the inhibitable enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase. Because the hypusine modification is absolutely required for eIF5A action in cytokine signaling, we propose that this modification could serve as a new drug target for islet β cell protection in the setting of diabetic inflammation. ... Read more

Abstract: Nearly all therapeutic proteins induce antibodies in patients. However this immunogenicity has been neglected in the use of these products, even though the antibodies may have severe consequences. During the last few years, progress has been made in understanding why patients do not tolerate these protein therapeutic products and also how to manage the problem of immunogenicity. ... Read more

Abstract: CD8⁺ CTL responses are critical for eliminating virus infected cells in acute infection and in controlling virus replication during chronic infection. Despite evidence of potent HIV-1-specific CD8⁺ CTL responses during the earliest stage of acute infection leading to replacement of founder virus sequence(s) and resolution of peak viral load, in the majority of infected individuals, these responses are inadequate to prevent the establishment or control of persistent infection. Protective CD8⁺ CTL responses have yet to be achieved by vaccine approaches for HIV-1 or other viruses causing persistent infections, Mycobacterium tuberculosis, malaria, and cancer. Understanding the limitations of CD8⁺ CTL responses to keep pace with the diversity of rapidly evolving virus in the case of HIV-1 and HCV and to overcome the diverse and complex mechanisms persistent pathogens employ to escape immune recognition should lead to more effective prophylactic and therapeutic approaches for these diseases. Recent technological advances including single genome amplification (SGA) of plasma viral RNA along with direct amplicon sequencing to identify virus quasispecies, bioinformatics, and statistical methods for the systematic identification of HLA-class I associated escape mutations, and mathematical models that better define the kinetics of virus replication and decay, have provided significant insight into mechanisms of viral transmission and sequence evolution, virus-host interactions, and HIV-1 pathogenesis. In this review we attempt to integrate recent findings from studies in HIV-1, persistent virus infections, and cancer that predict effective T cell responses and suggest approaches that could shift the balance of control in favor of the host immune response. Here, we highlight factors considered essential for effective HIV-1 vaccine CD8⁺ T cell responses: vaccine antigens, quality, magnitude and breadth, mucosal targeting, and formation of CD8⁺ T cell mucosal memory. ... Read more

Abstract: Erosive osteoarthritis (EOA) represents a subset of symptomatic osteoarthritis of hand, characterized by intermittent and often frequent inflammatory episodes and progressive joint damage. A greater degree of inflammation and the presence of subchondral bone erosions on plain radiographs help distinguish EOA from generalized osteoarthritis of hand. High resolution ultrasound and magnetic resonance imaging (MRI) have demonstrated the presence of synovitis and MRI has additionally highlighted the role of inflammation in bone, tendons, and ligaments in EOA. Further evidence for the crucial role of inflammation comes from recent studies that have unraveled the roles for several cytokines in the pathogenesis of EOA. Despite these advances, treatment options for EOA to date have been of modest benefit. Additional research is therefore needed to better understand the pathogenesis of EOA and lead to the development of novel therapeutic agents for this disabling form of arthritis. ... Read more

Abstract: The use of Lactococcus lactis in novel biomedical applications is a fast evolving area of interest. Quite distinct from its traditional use in the dairy industries, L. lactis has emerged as a potential delivery vector for various antigens as well as therapeutic and immunomodulatory proteins. Many recent studies have shown promising results using in vitro or animal models. In addition, the oral administration of human interleukin 10 (hIL-10)-secreting L. lactis for the management and treatment of inflammatory bowel disease (IBD) has been the subject of recent clinical trials. These trials represent the first steps for the use of genetically modified L. lactis in clinical practice. In the present review we discuss some of the recent studies which investigate the use of L. lactis as an in vivo protein delivery system. The concept of biological containment in L. lactis using pyrimidine synthesis knock-out systems is also discussed. Finally we describe recent work evaluating living versus dead L. lactis vectors with particular emphasis on the use of Gram-positive Enhancer Matrix (GEM) particles as a novel delivery system. ... Read more

Abstract: While asthma is an inflammatory disorder of the conducting airways, most frequently therapeutics directed specifically at components of these pathways have had limited or no success in the clinic. Part of the problem lies in over-reliance on simple animal models of antigen sensitization and challenge to select therapeutic candidates, and partly because allergic mechanisms have been studied out of context of the formed elements that make up the structure of the airways such as the epithelium and underlying vasculature and mesenchyme. This review covers recent experience with some new therapeutics that include biologics and concludes by presenting a new paradigm for the disease that embraces heterogeneity and greater consideration of the role played by functionally active structural components. Since asthma was originally described in terms of reversible airflow obstruction, this moves away from placing inflammation at the center of the disease more towards a parallel involvement of the epithelial mesenchymal trophic unit to provide the context within which the inflammatory response occurs. ... Read more

Abstract: The application of RNA interference-based gene silencing technologies has the potential to treat a variety of illness. Preclinical studies and some early clinical trials have already demonstrated the utility of small interfering RNAs (siRNAs) as a potential novel therapy for the treatment of cancer, viral infections, as well as a wide range of additional diseases. To be effective, an siRNA must be taken up by specific cells, enter the cytoplasm, and be loaded onto the Argonaute protein, the catalytic core of the RNA induced silencing complex (RISC) to direct the cleavage of the homologous transcripts. To meet this need, a variety of novel siRNA delivery strategies have been developed. As our understanding of the molecular mechanisms underlying the RNAi pathway has increased so has the ability to rationally design effective silencing and delivery strategies. This review will examine the latest advances in non-viral delivery of siRNA, with special reference to targeted siRNA delivery to specific target tissues and cell types in vivo in preclinical animal models. ... Read more

Abstract: Rheumatoid arthritis (RA) is the most common inflammatory musculoskeletal disease and an important cause of diminished quality-of-life for the affected individuals and with a major impact on society because of decreased work-force participation. Treatment of RA has been advanced dramatically during the past two decades by the advent of biological therapies. A large number of such agents have been approved and several additional ones are in late-stage clinical developments. Because of the high price of biologics, pharmacoeconomical considerations have become an important part of the appraisal of such medications. Current therapeutic developments include the development of additional biologics with various specific targets, the development of small-molecule compounds with similar efficacies, and entirely new approaches to treat autoimmune inflammatory diseases such as RA. ... Read more

Abstract: One-third of humans carry Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) where microbe/host immune response interactions result in persistence or active TB. However, immune mediators associated with human TB remain poorly defined. Through a series of comparative studies of lung immune response of TB cases at the time of diagnosis and patients with other infectious lung diseases and volunteers, we found that TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity critical for containment of M. tuberculosis. Despite the concomitant heightened levels of Th1-type mediators, they are likely rendered ineffectual by high levels of intracellular (e.g., SOCS) and extracellular (e.g., IL-10) immune suppressors. These modulators are a direct response to M. tuberculosis as many suppressive factors declined to the levels of controls by 30 days of anti-TB treatment while most Th1-type and innate immune mediators rose above the pre-treatment levels. Parallel laboratory studies and monitored lung alveolar macrophage effector, nitric oxide synthase-2 (being shown critical for killing M. tuberculosis), support that M. tuberculosis actively promotes down-modulatory mediators to counteract Th1-type/innate immunity as an immunopathological strategy. Our studies highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response. ... Read more