In the present issue, we are shifting the attention to new areas of fertile research with potential huge implications to understanding molecular pathogenesis of diseases and treatment.
The discovery and subsequent research of miRNA uncovered a fascinating dimension of the living universe, with breathtaking implications to understanding the most fundamental processes of cell regulation, from primitive to the most advanced organisms. During the last few years, evidence indicating that non-protein coding RNA regulates gene expression at various levels, continuously accumulated, culminating with the discovery of a new family of RNAs meeting certain criteria such as direct binding and regulation of mRNAs. The process of deciphering the role of miRNAs in regulating cellular homeostasis is ongoing; but it already resulted in emerging, yet strong, evidence that abnormal expression of select miRNAs—integrated within a veritable regulatory network—may be associated with serious disorders such as inflammation, cancer, cardiovascular, and metabolic diseases.
In this issue, Drs. Vinuesa, Rigby, and Yu provide an extensive review of miRNAs' involvement in basic immune homeostatic mechanisms and fine-tuning the responsiveness of lymphocytes to a variety of endogenous and exogenous threats. Excitingly, they provide a synopsis of current information in support of the association of miRNA with inflammatory diseases, most notably systemic lupus erythematosus (SLE). In fact, many SLE-susceptible loci encompass miRNAs, regulating molecules with stark effect on immune response and self/non-self discrimination. Among those, miRNAs-181, −186, and 590-3p, apparently target over 50% of the mRNAs corresponding to lupus genes—defining a tantalizing regulatory nexus with potential to yield new diagnostics, biomarkers, and therapeutics, through antagonistic or agonistic manipulation.
In another review dedicated to miRNA-mediated regulation of immunity, Drs. Chen, Lu, and Drescher analyze the realm of miRNAs important to morphogenesis and immune function of epithelial barriers. Several miRNAs targeting the production of molecules involved in the mucosal immune defense against infectious agents, may be of considerable importance to understanding the pathogenesis of infectious and inflammatory diseases affecting the gastrointestinal tract, respiratory system, and skin. In addition, accumulating evidence that select miRNAs actually target microbial-derived mRNAs provide a unique glimpse into a universe parallel to the known innate immune system, that is poised to shift paradigms and revolutionize our view on immunity.
In addition to the novel topic of miRNA, in the current volume, we start to tackle some of the newest discoveries, challenges, and opportunities afforded by the ever expanding and complex field of transplantation immunology.
Today, organ transplantation represents the only treatment available for patients suffering from end-stage organ failure. However, in order to attain functional allografts, life-long pharmacologic immunosuppression of the recipient is required. Although, very effective on the short-term, when looking prospectively, immunosuppressive medication remains unspecific and has tremendous negative consequences upon allograft and patient survival (e.g., infections, chronic rejection, cancer). In an effort to eliminate such complications during the last two decades, we have learned from experimental models that the immune system can be manipulated specifically to remain unresponsive towards alloantigens by induction of donor-specific tolerance. Still, although tremendous progress has been made in understanding the core processes governing the immune “ignorance” towards alloantigens after organ transplantation, obtaining clinical operational tolerance still remains elusive.
In this issue, Daniel et al., are reviewing the key role of immune monitoring in clinical organ transplantation. Uniform immunosuppression leads often to over- or under-immunosupressed organ recipients, which in turn are held responsible for major complications such as infection or chronic rejection. In an effort to accurately balance the immune response, the promises and difficulties regarding the development and clinical implementation of monitoring protocols, based on relevant “patient-specific” clinical parameters, are discussed. A wide panel of potential markers, such as NFAT-regulated cytokine genes, cytokine (e.g., IL-2, IFN-gamma) plasma levels, protein, mRNA (e.g., VEGF), or Tregs assays, indoleamine 2,3-deoxygenase (IDO) activity, soluble CD30 antigen, or immmunoregulatory dendritic cell subsets, are assessed in regard of their prediction potential related to acute rejection and graft outcome.
Switching to another actual topic in the field of transplant immunobiology, Loeb et al. are critically reviewing the role of IDO as a potential clinical tool to abrogate the alloimmune response after transplantation. After introducing critical issues, such as the L-tryptophan (TRP) “starvation” vs. TRP “utilization” theories, potential pathways for IDO induction are explored, from cell-signaling scenarios (e.g., B7 activation by CTLA4Ig/CD28 engagement or IFN-gamma IDO induction through the STAT-1/SOCS3) to FoxP3+ Tregs as IDO inducers and transgenic IDO expression on dendritic cells. All the risks and benefits of such IDO-inductive protocols are argued by transposing them into potential clinical settings, thereby taking the experimental evidence from “bench to bed-side” and thus paving the way towards future patient-related applications.
Further, comparative analysis of Toll-like receptor (TLR) pathways across the animal kingdom is of considerable importance to understanding the phylogenesis and functionality of the innate immunity. Drs. Zhu, Li, and Yu provide an in depth analysis of the major innate immune pathways such as those linked to TLRs and advance a model integrating those within a complex, yet finely adjusted, immune network. Finally, in another general article, Dr. Zhou analyzes the key role of IFN-gamma on antigen processing and epitope presentation, as per newest scientific results. This sheds new light on the role of this cytokine in physiologic and pathologic circumstances such as inflammatory, infectious diseases and cancer.
In the upcoming issues, we continue our focus on hot topics such as miRNA and the regulation of immunity, as well as transplantation immunology. In addition, we host new perspectives on immune deficiencies and their molecular substrate along with other articles with a focus on basic and translational immunology.