Search

Ten years ago, the concept of nanotherapeutics for autoimmunity would have faced significant challenges for even pre-clinical consideration from a broad array of entities; from federal and private funding bodies, to large size, internationally-operating pharmaceutical companies. Five years ago, this thinking changed and today, nanotherapeutics for autoimmunity is receiving increased consideration and support as the technology matures, becomes amenable to target product profile-based quality-by-design, and most importantly, demonstration of pre-clinical efficacy. On the one hand, the technology and the polymer biochemistry behind it has evolved and has spawned some quite clever and very imaginative approaches to formulate a diverse array of therapeutics, from small drugs, to biologics, to nucleic acids and intact genomes [1, 2]. An increasing interest in targeting particular cell populations promises to bridge the gap between systemic untargeted delivery and site-specific, cell-specific drug release [1, 2]. As the polymer biochemistry matures, so have the fields of fundamental biology. Tremendous advances have been made in understanding immune regulations in the past decades. In cancer immunotherapy, the capacities to amplify immune responses generated from intrinsic or extrinsic means have yielded game-changing novel therapeutics for malignancies [3]. At the same time, new tools for downregulating immune responses have emerged rapidly in pre-clinical settings and many are being tested in humans. The advent of cellular and molecular tools aimed for suppressing immune responses have shifted the paradigm from global immunosuppression to antigen-specific tolerance induction as the end-point. Significant obstacles, however, remained in translating emerging molecular technologies to clinical modalities. Bystander effects and complex redundancies of immune mechanisms impose degrees of precision that are not possible with conventional formulations. To target relevant pathways driving disease pathogenesis without sensitizing bystanders, therapeutic entities must be delivered with spatiotemporal precisions. Nanomedicine may provide an answer in meeting the threshold [4]. We responded to the challenge to assist in the publication of a first-in-kind special issue devoted to nanotherapeutics in autoimmunity with the foreknowledge that this would be a pioneering work in the sense that it would open the door to many questions, while leaving even more unanswered. Yet, this is a challenge we eagerly accepted, as science and knowledge moves forward, and solutions to medical problems are solved only when more questions are asked and previously-unadressed areas of investigation are brought to light. In this theme issue, we selected a series of papers in which translational gaps may be met by materials science and bioengineering approaches. The foci of the current collection exemplify the notion that dampening immune-mediated tissue damage can be achieved by exploiting physical features of nanoscaled materials platforms (Hlavaty et al., this issue). These include polymeric particles (Engman et al., Fisher et al., Lewis et al., and Serra and Santamaria, this issue), exosomes (Thanh-Huyen et al., this issue), nanoemulsions (Patel et al., this issue), polymeric prodrug (Ren et al., this issue) and engineered cellular scaffolds (Tajima et al., this issue). The advantages lie in the ability of such entities to avoid rapid renal elimination, penetrate through interstitial space, and enter through plasma membrane efficiently. For type I diabetes (Engman et al., Figueroa et al., Lewis et al., this issue), inflammatory gut diseases (Ren et al., Thanh-Huyen et al., this issue), and allograft rejection (Fisher et al., Hlavaty et al., this issue), antigen-presenting cells (APCs) occupy a centerpiece of the complex immune cascades. Represented chiefly by macrophages and dendritic cells, APCs are targeted because their primary roles in inflammation and steering effector responses (Hlavaty et al., this issue). Polymeric nanoparticles are preferentially taken up by APCs, thereby concentrating the effects of the drug in these cells. Such formulations have particular utilities for biological agents; DNA (plasmid or anti-sense oligonucleotides) and siRNA can be protected from degradation, thereby extending exposure and increasing probability of contact. Enhanced bioavailability of T cell inhibitors, for example rapamycin and tacrolimus, results from micro- and nanoparticle formulations. Proven anti-inflammatory drugs, such as dexamethasone and celecoxib, can be reengineered to enhance target tissues accumulation, and as theranostics (Patel et al., this issue). Cellular therapies may render complex immunological signals that one or a few agents cannot provide (Tajima et al., this issue). Nanomedicine is on the verge of becoming a common reality in the clinic. Merging multifunctional delivery platforms with targeted immune regulators may render pharmacodynamic and pharmacokinetic synergisms beyond what have been conceived thus far. This theme issue thus highlights opportunities for rational convergence of biological and physiochemical approaches in precise tuning of immune dysfunctions. We thank the reader for the time they may allot to the papers in this issue, as we seek their understanding that the many questions the research compels require further work to incisively address.

Autoinflammatory diseases are rare group of conditions manifested by recurrent fevers, systemic inflammation, and dysfunctions of the innate immune system. These conditions are characterized by overproduction or lack of inhibition of various cytokines, and the advent of biologic drugs that block specific cytokines involved in these conditions has revolutionized their treatment. In this review, I will discuss the most common autoinflammatory conditions of adulthood including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), mevalonate kinase deficiency/hyperimmunoglobulinemia D Syndrome (MKD/HIDS), TNF receptor-associated autoinflammatory syndrome (TRAPS), and systemic juvenile idiopathic arthritis/adult-onset Still's disease (SJIA/AOSD). I will discuss how IL-1, IL-6, IL-18, and TNF play pathogenic roles in these conditions and will review the evidence behind cytokine blockade for these diseases. Throughout the paper, I will reflect on gaps in knowledge of autoinflammatory diseases and will highlight the latest advances and newest drugs in development.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy.

Rheumatoid arthritis (RA) is characterized by systemic synovitis leading to joint destruction in which imbalances in pro-inflammatory and anti-inflammatory cytokines promote the induction of autoimmunity. Some pro-inflammatory cytokines can trigger the signaling pathways which responsible for immune-mediated inflammation in RA, and the activated signaling pathways produce pro-inflammatory cytokines, resulting in aggravation of RA. Hence, understanding of the signaling pathways and their inhibitors might be advantageous in the development of therapeutic targets and new drugs for RA. In the current review, we summarize the signaling pathways involved in the pathogenesis of RA as well as the potential role of specific inhibitors in its management. We hope this paper may serve a reference for future studies on signaling pathways implicated in the pathogenesis of RA and benefit the treatment of RA.

This paper is a review, personal memoir, a tribute to Henry Kunkel, and a critique regarding laboratory tests used for the evaluation, diagnosis, and understanding Autoimmune Rheumatic Diseases, in particular systemic lupus erythematosus (SLE).

Laminins are ubiquitous constituents of the basement membranes with major architectural and functional role as supported by the fact that absence or mutations of laminins lead to either lethal or severely impairing phenotypes. Besides genetic defects, laminins are involved in a wide range of human diseases including cancer, infections, and inflammatory diseases, as well as autoimmune disorders. A growing body of evidence implicates several laminin chains as autoantigens in blistering skin diseases, collagenoses, vasculitis, or post-infectious autoimmunity. The current paper reviews the existing knowledge on autoimmunity against laminins referring to both experimental and clinical data, and on therapeutic implications of anti-laminin antibodies. Further investigation of relevant laminin epitopes in pathogenic autoimmunity would facilitate the development of appropriate diagnostic tools for thorough characterization of patients' antibody specificities and should decisively contribute to designing more specific therapeutic interventions.

DNA methylation is now widely recognized as being critical to maintain the function of immune cells. Recent studies suggest that aberrant DNA methylation levels not only can result in immune cells autoreactivity in vitro, but also are related to autoimmunity in vivo. Environmental factors and genetic polymorphisms cause abnormal methylation, which affects the expression of certain immune-related genes, being becoming hot spot of explaining the mechanism of autoimmune diseases. This paper reviews the importance of abnormal methylation during the development of common autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, aiming at a better understanding of the pathogenesis of autoimmune diseases and providing new ideas for the treatment of these diseases.

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.