Abstract: It is clear that micro-RNAs (miRNAs) are emerging as key players in the control of a multitude of biological processes, from plants to animals, alongside with coding genes. The regulation of miRNA expression is tightly controlled, and often the same rules and regulations that govern coding gene expression apply also to miRNAs. Similar to coding genes, altering the levels and the temporal expression of a specific miRNA clearly affects the proper development and function of the tissue where it is expressed. In this review we discuss seminal studies, which demonstrate the importance of miRNAs in the immune system and a possible link between dysregulated miRNA expression and diseases, such as systemic lupus erythematosus (SLE) and cancer. In addition, we summarize progresses towards targeting miRNAs as therapeutic agents. ... Read more

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: Systemic sclerosis (SSc) is a complex fibrosing autoimmune disease that has variable clinical manifestations and morbidity/mortality secondary to organ damage due to vasculopathy and/or fibrosis. Initial events in the pathogenesis are manifested by fibroproliferative vasculopathy that compromises delivery of blood to critical organs. There is evidence of autoimmunity early in the disease which persists and is accompanied by fibrotic processes that leave large accumulations of collagen and other matrix components in the intima of blood vessels and extracellularly in the connective tissue of organs affected by the disease. It has recently been realized that the lysophospholipids -- lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are elevated in sera of SSc patients, are capable of producing many of the abnormalities observed in the vasculature, immune system, and connective tissue of patients with this disease. This article reviews key abnormalities of the vasculature, immune system, and connective tissue in SSc that could be mediated by LPA/S1P. ... Read more

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by the disturbance of pancreatic insulin-producing cells, which results in hyperglycemia. The disease is associated with severe complications that impair the quality of life of individuals. The cause of T1D is unknown. Development of the disease is the result of interactions between immunological, genetic, and environmental factors. Viruses are thought to play an important role in the initiation or acceleration of the disease. This is an important issue since it opens the possibility to develop new preventive and therapeutic strategies to fight the disease. The role of enteroviruses in the development of T1D, in particular type B coxsackieviruses, is supported by epidemiological observations. It has been demonstrated that enterovirus infections were significantly more common in recently diagnosed diabetic patients, compared with control subjects. Enteroviral RNA and/or proteins can be detected in blood samples and intestine biopsies of patients with T1D. The hypothesis of a relationship between enteroviruses and the disease has been strengthened by the presence of enteroviral components or infectious particles in the pancreas of patients with T1D. In this review, arguments in favor of a relationship between enterovirus infections and T1D and the mechanisms of the enteroviral pathogenesis of the disease are presented. ... Read more

Abstract: Systemic sclerosis (SSc, scleroderma) is an autoimmune disease clinically characterized by progressive fibrosis in the skin and internal organs. While the pathogenesis of SSc is not completely understood, familial studies and genetic studies suggest that SSc is a complex polygenic disease. In the current review, we will discuss recent studies investigating genetic susceptibility to SSc. Candidate gene studies have identified critical immunoregulatory genes and gene regions including BANK1, FAM167A-BLK, IL23R, IRF5, STAT4, TBX21, and TNFSF4 as susceptibility genes for the development of SSc. More recently a genome-wide association study has been performed and identified CD247 (CD3-zeta) as a novel genetic risk factor for the susceptibility to SSc. Together these genetic association studies have substantially advanced our understanding of SSc pathogenesis and form the foundation for future studies seeking to understand the complexities of SSc. ... Read more

Abstract: The term marginal-zone lymphoma (MZL) encompasses three closely related indolent B-cell non-Hodgkin's lymphoma subtypes, namely extranodal MZL or MALT lymphoma, nodal MZL, and splenic MZL. Although these neoplasms may share a common cell of origin, being the marginal zone B-cell, they display different characteristics with evident clinical and biological variations according to the organ where the lymphoma arises. The past 2 decades have spawned an avalanche of new data that encompasses the genetic aberrations and pathogenic mechanisms leading to these diseases. This article briefly addresses each of the MZL. ... Read more

Abstract: The past two years have brought great progress in the genetics of systemic lupus erythematosus (SLE) heralded by the publication of genome-wide association studies in humans and the identification of susceptibility genes in mouse models of spontaneous lupus. This influx of new information has revealed an ever-increasing interdependence between the mouse and human systems for unraveling the genetic basis of lupus susceptibility. SLE is a complex disease in which defects in several functional pathways have been identified. Genetic variants in a number of genes in these pathways have now been directly associated with lupus in both species. These discoveries have lead to a better understanding of the mechanisms of disease, and offer potential novel target for therapeutic intervention. As a large number of susceptibility genes are identified, lupus genetics will focus on mechanistic and molecular studies, in which mouse models will continue to serve a pre-eminent role. ... Read more

Abstract: Epidermal growth factor receptor (EGFR) belongs to a large family of receptor tyrosine kinases that mediates many important physiological processes in both normal and cancerous cells. EGFR is best known for its classical role as a plasma membrane-bound receptor that, upon binding to its ligands, recruits and phosphorylates downstream molecules which subsequently regulate protein functions, protein-protein interactions, and gene expression. Built upon this traditional view of the EGFR pathway, a number of therapeutic agents have been developed aiming to target EGFR by blocking ligand-mediated receptor activation or by inhibiting its kinase activity. Unfortunately, most of these interventions have yielded disappointing clinical results in the majority of cancer types evaluated, with the exception of non-small cell lung cancer that carries specific EGFR mutants. Given the notion that these EGFR mutations are absent or very rare in other cancer types, extensive investigations have been directed at other potential mechanisms. Some of these efforts have led to rationales for EGFR-based combination regimens; however, they also demonstrated limited clinical benefits. In this review, we will focus on an emerging line of research that examines a novel mode of EGFR signaling that takes place in the cell nucleus. Specifically, we will outline the findings from a number of reports that have together established nuclear EGFR to be a functionally diversified molecule that regulates the biology of normal and malignantly transformed cells. In light of the fact that the impact of nuclear EGFR on anti-cancer therapy has recently developed into an area of intensive investigations, this review will also summarize the results of these investigations that suggest a potential role the nuclear EGFR may play in tumor response to radiation, chemotherapy, and EGFR-targeted therapy. ... 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: Autoimmune diseases such as multiple sclerosis, type 1 diabetes, systemic sclerosis, and rheumatoid arthritis affect approximately 5% of the population and are characterized by a destructive immune response directed to self-tissues. Treatments are often designed to dampen the immune system and are therefore associated with unwanted side effects. A major challenge is to find a cure that does not compromise normal immune function. From our understanding of how the immune system develops, it is clear that mechanisms designed to eliminate or maintain control over self-reactive clones are critical for normal health. These key concepts form the crux of many experimental strategies currently aimed at abrogating the autoimmune response. In this review, we focus on the strategy of harnessing the bone marrow compartment through genetic manipulation directed at promoting ectopic autoantigen expression. Our experience with this strategy is presented in the context of reports in the literature and we argue for the potential benefit of translating this approach to the treatment of human autoimmune disease. ... Read more