Last year, the National Institute of Allergy and Infectious Diseases (NIAID) estimated that about 8% of the US population (~29 million people) suffer from autoimmune diseases (AID) of which there are between 80-150 recognized types. Most of these illnesses are chronic, affect more than one organ, are associated with substantial morbidity and patient care often involves family members. AIDs have emerged as a global health concern. In the US alone, health care costs related to AIDs have reached over 100 billion per year, according to a recent NIH study (1). and AIDs contribute substantially to premature death (2). The spectrum of AIDs covers almost every organ in the body and while the etiology of these diseases is based on some shared environmental, immunological and genetic factors (3), the devil is in the complex detail of the combinations of these and additional factors, such as gender. Due to this complexity drug therapies for AIDs have, historically, sought to treat common components across the spectrum of disorders. A good example is the use of steroids to control aberrant, self-directed immune responses, a common feature of these diseases. However, the long-term use of steroids is associated with a list of adverse effects related to panimmunosuppression, despite a drop in recommended doses over recent years (4). And side effects need to be treated, which has led to an increase in polypharmacy that carries its own adverse outcomes (5). Drug therapy for autoimmune diseases is focused on controlling symptoms rather than curing the underlying pathology, exemplified by the use of anti-coagulants in patients with Anti-Phospholipid Syndrome (APS). AIDs pose a significant challenge in the field of immunology; to decipher the immune system's failure to distinguish between self and non-self. Despite extensive research, the precise mechanisms that disrupt immune tolerance to self remain elusive, and there is a pressing need for novel therapeutics that can effectively target the underlying causes of AIDs. Traditionally, AIDs have been ranked as specific or non-specific according to the tissue restriction of their clinical symptoms. Given the significance of the dysfunctional regulation of the immune response in the pathology of these diseases, this system of cataloging is misleading and undermines the complexity of the immune response. On the one hand, AIDs are (often) characterized by the production of a series of autoantibodies, some of whose targets are not disease specific. For example, anti-dsDNA antibodies are a hallmark of Systemic Lupus Erythematosus (SLE) where they form immune complexes and induce nephritis; however, this process also occurs in other AIDs (6). On the other hand, T cell responses are tissue-specific, even in multi-system diseases such as SLE, both at the level of autoreactive T cells (7), and for T regulatory cells (8). Enter antigen-targeted B-cell and T-cell immunotherapies, which, after decisive and life-saving proofs-of-concept in cancer therapy, are also now being applied to restore immune homeostasis by targeting specific self-antigens implicated in these diseases. However, the development and clinical application of such targeted immunotherapies are still in their nascent stages, necessitating further exploration and validation. Antigen-targeted immunotherapies raise the opportunity to develop more effective and controlled therapies for AIDs rather than deferring to pan-immunotherapies which, while effective may carry long-term safety issues (9), (10). With these issues in mind, the current special issue of Frontiers in Immunology entitled "Advances in antigen-specific immunotherapies for autoimmune disease management", aims to explore the development and application of targeted immunotherapies for autoimmune diseases, with a focus on antigen-specific approaches. The primary objective for selection of the 16 articles in this issue was to investigate how these therapies can be harnessed to restore immune homeostasis and provide more effective treatment options for patients suffering from AIDs. Key questions addressed by the authors include understanding the mechanisms leading to immune dysfunction in particular AIDs, and the efficacy of targeted immunotherapies, both in more common and rare AIDs. Understanding the molecular machinery responsible for effector immune responses has led to several breakthrough technologies that are impacting patient survival and quality of life. This is particularly the case with the ever expansion in the spectrum of humanized therapeutic monoclonal antibodies. This is described in the papers by Lee and Kahaly and Chen et al, who reviewed the effect targeted immunotherapies in the treatment of patients with Graves' hyperthyroidism and in the rare AID Generalized pustular psoriasis, respectively. initially termed "T-bodies" by its inventor Zelig Eshhar (11). Several CAR-T cell therapies have received FDA approval for B-cell hematological cancers (12) and there is keen interest in Based on the successful use of the anti-CD20 monoclonal antibody Rituximab in eliminating disease-related B-cells such as in B-cell leukemia, Li and colleagues reasoned that this approach would reduce the production of anti-PLA2R antibodies, which are crucial in the development of nephrotic syndrome. The aim of the study was to overcome the dependance on calmodulin inhibitors (CNI) id patients with primary membranous nephropathy (PMN). They found that Rituximab therapy led to complete clinical and immunological remission in PMN patients dependent on or partially responsive to long-term CNI therapy, reducing recurrence and minimizing prolonged immunosuppressive therapy risks. Returning to the problem of long-term use of corticosteroids mentioned earlier, Shirai and colleagues tested the feasibility of the drug's removal from patients with Takayasu arthritis (TA), a rare, chronic large-vessel vasculitis that causes inflammation, stenosis, and aneurysms in the aorta and its main branches. Patients with TA were treated with Tocilizumab, a monoclonal antibody to the IL-6 receptor, while tapering off prednisone, resulting in 44. 4% of the patients achieving corticosteroid withdrawal. This study highlights the potential of replacing a nonspecific pan-immunosupressive drug with a immunotherapy directed at disease pathology. showcase the potential of replacing many of the current symptom-based therapies for patients with AIDS with those that focus on the cellular mechanisms that lead to the breaking of immune tolerance to specific self-antigens. We are still in the early days of this transformation. While some of these approaches are progressing through clinical evaluation, basic research must continue to focus of the basic immunology of autoimmunity in collaboration with biotechnology to develop applications that are translatable and will lead to improved quality of life for patients. In conclusion, we would like to thank to Editorial team of Frontiers in Immunology for the opportunity to edit this special issue, and in their helpful and professional processing of the articles.
Firer et al. (Mon,) studied this question.