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Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.

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Myocarditis is a potentially life-threatening inflammatory disease of the myocardium, often resulting from infectious and immune-mediated responses. Clinical presentation in severe cases often results in a devastating illness requiring extracorporeal membrane oxygenation support as a result of cardiogenic shock. Although endomyocardial biopsy is still considered the gold standard for diagnosis, it often reveals nonspecific lymphocytic infiltration. Because the precise cause is usually unknown, the initial treatment typically involves immunosuppression and frequent assessment of myocardial contractility. This report presents 3 rare cases of autoimmune diseases (polymyositis, immunoglobulin G4-related disease, and systemic lupus erythematosus) that require extracorporeal membrane oxygenation support as a result of fulminant myocarditis, including their follow-up periods.

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A body develops an autoimmune illness when its immune system mistakenly targets healthy cells and organs. Eight million people are affected by more than 80 autoimmune diseases. The public's and individuals' well-being is put at risk. Type 1 diabetes, lupus, rheumatoid arthritis, and multiple sclerosisare autoimmune diseases. Tissue injury, nociceptive responses, and persistent inflammation are the results of these stresses. Concerns about healthcare costs, health, and physical limitations contribute to these issues. Given their prevalence, it is crucial to enhance our knowledge, conduct thorough research, and provide all-encompassing support to women dealing with autoimmune diseases. This will lead to better public health and better patient outcomes. Most bacteria's immune systems employ CRISPR-Cas, a state-of-the-art technique for editing genes. For Cas to break DNA with pinpoint accuracy, a guide RNA employs a predetermined enzymatic pathway. Genetic modifications started. After it was developed, this method was subjected to much research on autoimmune diseases. By modifying immune pathways, CRISPR gene editing can alleviate symptoms, promote immune system tolerance, and decrease autoimmune reactivity. The autoimmune diseases that CRISPR-Cas9 targets now have no treatment or cure. Results from early clinical trials and preclinical studies of autoimmune medicines engineered using CRISPR showed promise. Modern treatments for rheumatoid arthritis,multiple sclerosis, and type 1 diabetes aim to alter specific genetic or immune mechanisms. Accurate CRISPR editing can fix autoimmune genetic disorders. Modifying effector cells with CRISPR can decrease autoimmune reactions. These cells include cytotoxic T and B lymphocytes. Because of improvements in delivery techniques and kits, CRISPR medications are now safer, more effective, and more accurately targeted. It all comes down to intricate immunological reactions and unexpected side consequences. Revolutionary cures for autoimmune problems and highly personalized medical therapies have been made possible by recent advancements in CRISPR.

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Over the past 25 years, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory systemic autoimmune diseases, where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. In addition to autoimmune neurologic diseases, such as multiple sclerosis (MS) or neuromyelitis optica (NMO), rheumatic diseases with central or peripheral nervous system involvement and insufficient response to conventional immunosuppressive or biologic therapies represent a growing indication for autologous HSCT. They most commonly include connective tissue diseases, such as systemic lupus erythematosus (SLE), vasculitides, or rarer diseases from the autoinflammatory spectrum, such as Behçet's disease, where neurologic manifestations may represent the greatest disease burden. Neurologic manifestations may resemble those of MS, including myelitis optic neuropathy, stroke, or seizures. Outcomes of such manifestations are variable after autologous HSCT but most frequently improve or even resolve with the underlying disease, especially in SLE. This article will provide the current evidence and summarize the outcomes of HSCT for rheumatic autoimmune diseases with neurologic manifestations.

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Hematopoietic stem cell transplantation (HSCT) has evolved over the last 25 years as a specific treatment of patients with severe neurologic autoimmune diseases (ADs), through eradication of the pathologic, immunologic memory, and profound immune "resetting." HSCT for ADs is recently facing a unique developmental phase across transplant centers. Data from patients undergoing HSCT and cellular therapies have been captured through the established major transplant registries, such as the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR). The EBMT Autoimmune Diseases Working Party (ADWP) is central to bringing together HSCT and disease-specialist communities. The AD section of the EBMT registry is the largest database of its kind worldwide, reporting more than 3700 transplants. Multiple sclerosis (MS) covers approximately 50% of transplants in AD, HSCT being an integral and standard-of-care part of the treatment algorithm. In the Americas, at least a subset of HSCT is reported to the CIBMTR, as reporting is voluntary. A total of 1400 recipients of autologous HSCT were reported and 1030 were performed for the treatment of neurologic conditions. MS accounts for 96% of all diagnoses among neurologic indications for HSCT. Although the activity of HSCT for MS is low in the United States in relation to its prevalence, the number of transplants has increased in recent years. In contrast, Mexico has reported a sharp increase in the number of these transplants. This chapter provides an overview of the EBMT and CIBMTR registries, then offers the current status and publication outputs in relation to neurologic AD.

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The development of autoimmune diseases (ADs) is thought to be caused by a dysfunction of the intrinsic ability of our immune system for "self-nonself" discrimination. Following the breakdown of "self-tolerance," an orchestrated immune cascade develops, involving B- and T-lymphocytes and autoantibodies that target self-antigens. An imbalance of the regulatory immune network and a suitable genetic background, along with external (infectious and environmental) triggers, are all important contributors to the outbreak of clinical autoimmunity. Immunotherapies for ADs can be classified into treatments that are given continuously (chronic treatments) and therapies that are applied only once or intermittently, aiming to induce partial or complete reconstitution of the immune system [immune reconstitution therapies (IRTs)]. The principle underlying IRTs is based on the depletion of mature immune cells and the rebuilding of the immune system. During this process of immune reconstitution, a substantial change in the lymphocyte repertoire occurs, which may explain the impressive and long-term beneficial effects of IRTs, including the possibility of induction of tolerance to self-antigens. Hematopoietic (or bone marrow) stem cell transplantation (HSCT or BMT) represents the prototype-and the most radical type-of IRT therapy. The rationale for HSCT or BMT for the treatment of severe ADs is based on convincing proof in preclinical studies, utilizing various animal models of autoimmunity. More than 30 years' worth of pioneering experiments in various models of ADs have shown that HSCT can lead to substantial improvement or even cure of the autoimmune syndromes and induction of long-term tolerance to autoantigens. The success of treatment depends on how completely the autoantigen-reactive lymphocytes and memory cells are eradicated by the conditioning chemotherapy, which is administered in a single dose before the transplantation. The most successful conditioning methods in animal models of ADs are total body irradiation (TBI) and high-dose cyclophosphamide (CY). These preclinical studies, summarized in this review, have provided important data about the therapeutic potential of HSCT in human ADs and the associated mechanisms of action and have contributed to the formulation of guidelines for clinical applications of autologous or allogeneic HSCT/BMT in refractory autoimmunity.

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Hematopoietic stem cell transplantation (HSCT) is a medical procedure used mainly for the treatment of onco-hematologic disorders. Over the last two decades, autologous HSCT has been explored for the treatment of neurologic autoimmune diseases (ADs), being multiple sclerosis (MS) the most frequent indication in this setting. HSCT is characterized by the sequential administration of a conditioning regimen (CR) and the infusion of hematopoietic stem cells (HSCs), previously collected either by the individual himself in the autologous transplant (AHSCT), or by a healthy donor in allogeneic HSCT. CR consists of the administration of high-dose chemotherapy and/or total body irradiation (TBI), that in ADs is usually associated with an immunodepleting serotherapy, either by an animal-derived polyclonal serum or a monoclonal antibody (MoAb), to induce intense immunosuppression. CRs are classified according to the European Society for Blood and Marrow Transplantation (EBMT) guidelines for HSCT in ADs in three grades of intensity according to the degrees of depletion of the hemato-lymphopoietic system induced. In the present chapter, after a brief overview of mobilization and CR adopted in the neurologic autoimmune setting, the role of chemotherapy in HSCT will be discussed, providing a historical perspective on the use of different regimens and summarizing the available evidence on potential associations between CR and outcomes.

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Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated significant success in treating cancers. The potential of CAR-T cells is now being explored in the context of autoimmune diseases. Recent clinical trials have shown sustained and profound elimination of autoreactive B cells by CAR-T cells, leading to promising autoimmune disease control with minimal safety concerns. These encouraging results have inspired further investigation into CAR-T cell applications for a broader range of autoimmune diseases and the development of advanced cell products with improved efficacy and safety. In this review, we discuss the mechanisms by which CAR-T cells target autoimmune conditions, summarize current preclinical models, and highlight ongoing clinical trials, including CAR-T therapy design, clinical outcomes, and challenges. Additionally, we discuss the limitations and future directions of CAR-T therapy in the treatment of autoimmune diseases.

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Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have been recognized as promising cytotherapeutics due to their demonstrated immunomodulatory effects in various preclinical models. The immunomodulatory capabilities of EVs stem from the proteins and genetic materials they carry from parent cells, but the cargo contents of EVs are significantly influenced by MSC tissues and donors, cellular age and culture conditions, resulting in functional variations. However, there are no surrogate assays available to validate the immunomodulatory potency of MSC-EVs before in vivo administration. In previous work, we discovered that microcarrier culture conditions enhance the immunomodulatory function of MSC-EVs, as well as the levels of immunosuppressive molecules such as TGF-ß1 and let-7b in MSC-EVs. Building on these findings, we investigated whether TGF-ß1 levels in MSC-EVs could serve as a surrogate biomarker for predicting their potency in vivo. Our studies revealed a strong correlation between TGF-ß1 and let-7b levels in MSC-EVs, as well as their capacity to suppress IFN-γ secretion in stimulated splenocytes, establishing biopotency and surrogate assays for MSC-EVs. Subsequently, we validated MSC-EVs generated from monolayer cultures (ML-EVs) or microcarrier cultures (MC-EVs) using murine models of experimental autoimmune uveoretinitis (EAU) and additional in vitro assays reflecting the Mode of Action of MSC-EVs in vivo. Our findings demonstrated that MC-EVs carrying high levels of TGF-ß1 exhibited greater efficacy than ML-EVs in halting disease progression in mice with EAU as well as inducing apoptosis and inhibiting the chemotaxis of retina-reactive T cells. Additionally, MSC-EVs suppressed the MAPK/ERK pathway in activated T cells, with treatment using TGF-ß1 or let-7b showing similar effects on the MAPK/ERK pathway. Collectively, our data suggest that MSC-EVs directly inhibit the infiltration of retina-reactive T cells toward the eyes, thereby halting the disease progression in EAU mice, and their immunomodulatory potency in vivo can be predicted by their TGF-ß1 levels.

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Chimeric antigen receptor (CAR) T cells are highly effective at targeting and eliminating cells of the B cell lineage. CAR T cell therapy has become a standard-of-care treatment for patients with relapsed or refractory B cell malignancies. In addition, the administration of genetically modified T cells with the capacity to deplete B cells and/or plasma cells has tremendous therapeutic potential in autoimmune diseases. In the past few years, CD19-based and B cell maturation antigen (BCMA)-based CAR T cell therapies have been applied to various B cell-mediated autoimmune diseases including systemic lupus erythematosus, idiopathic inflammatory myopathy, systemic sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis and multiple sclerosis. The scientific rationale behind this approach is that deep depletion of B cells, including autoreactive B cell clones, could restore normal immune function, referred to as an immune reset. In this Review, we discuss important aspects of CAR T cell therapy in autoimmune disease, including considerations relating to patient selection, safety, efficacy and medical management. These considerations are based on the early experiences of CAR T cell therapy in autoimmune diseases, and as the field of CAR T cell therapy in autoimmune diseases continues to rapidly evolve, these issues will remain subject to ongoing refinement and adaptation.

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The mammalian intestine harbors abundant T cells with high motility, where these cells can affect both intestinal and extraintestinal disorders. Growing evidence shows that gut-derived T cells migrate to extraintestinal organs, contributing to the pathogenesis of certain autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). However, three key questions require further elucidation. First, how do intestinal T cells egress from the intestine? Second, how do gut-derived T cells enter organs outside the gut? Third, what is the pathogenicity of gut-derived T cells and their correlation with the gut microenvironment? In this Opinion, we propose answers to these questions. Understanding the migration and functional regulation of gut-derived T cells might inform precise targeting for achieving safe and effective approaches to treat certain extraintestinal autoimmune diseases.

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The International Consensus on ANA Patterns (ICAP) is an ongoing international initiative dedicated to harmonizing technical and interpretation aspects of the HEp-2 IFA test. Comprised of internationally recognized experts in autoimmunity and HEp-2 IFA testing, ICAP has operated for the last 10 years by promoting accurate reading, interpretation, and reporting of HEp-2 IFA images by professionals involved in various areas related to autoimmune diseases, such as clinical diagnostic laboratories, academic research, IVD industry, and patient care. ICAP operates through continuous information exchange with the international community and encourages the participation of younger experts from all over the world. The 7th ICAP workshop has addressed several aspects that originated from this interaction with the international community and has effectively established objective goals and tasks to be delivered over the next two years. Some of these are outlined in this article, including the planning of three audio-visual educational modules to be posted at the www.anapattern.org website, the classification of two novel HEp-2 IFA patterns, the implementation of a project dedicated to continuously updating the information on the clinical and immunologic relevance of the HEp-2 IFA patterns, and the launch of two additional branches of the HEp-2 Clinical and Immunological (HEp-2 CIC) project.

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Tertiary lymphoid structures (TLSs) are defined as lymphoid aggregates formed in non-hematopoietic organs under pathological conditions. Similar to secondary lymphoid organs (SLOs), the formation of TLSs relies on the interaction between lymphoid tissue inducer (LTi) cells and lymphoid tissue organizer (LTo) cells, involving multiple cytokines. Heterogeneity is a distinguishing feature of TLSs, which may lead to differences in their functions. Growing evidence suggests that TLSs are associated with various diseases, such as cancers, autoimmune diseases, transplant rejection, chronic inflammation, infection, and even ageing. However, the detailed mechanisms behind these clinical associations are not yet fully understood. The mechanisms by which TLS maturation and localization affect immune function are also unclear. Therefore, it is necessary to enhance the understanding of TLS development and function at the cellular and molecular level, which may allow us to utilize them to improve the immune microenvironment. In this review, we delve into the composition, formation mechanism, associations with diseases, and potential therapeutic applications of TLSs. Furthermore, we discuss the therapeutic implications of TLSs, such as their role as markers of therapeutic response and prognosis. Finally, we summarize various methods for detecting and targeting TLSs. Overall, we provide a comprehensive understanding of TLSs and aim to develop more effective therapeutic strategies.

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Mesenchymal stem cells (MSCs) are a promising tool that may be used in regenerative medicine. Thanks to their ability to differentiate and paracrine signaling, they can be used in the treatment of many diseases. Undifferentiated MSCs can support the regeneration of surrounding tissues through secreted substances and exosomes. This is possible thanks to the production of growth factors. These factors stimulate the growth of neighboring cells, have an anti-apoptotic effect, and support angiogenesis, and MSCs also have an immunomodulatory effect. The level of secreted factors may vary depending on many factors. Apart from the donor's health condition, it is also influenced by the source of MSCs, methods of harvesting, and even the banking of cells. This work is a review of research on how the patient's health condition affects the properties of obtained MSCs. The review discusses the impact of the patient's diabetes, obesity, autoimmune diseases, and inflammation, as well as the impact of the source of MSCs and methods of harvesting and banking cells on the phenotype, differentiation capacity, anti-inflammatory, angiogenic effects, and proliferation potential of MSCs. Knowledge about specific clinical factors allows for better use of the potential of stem cells and more appropriate targeting of procedures for collecting, multiplying, and banking these cells, as well as for their subsequent use. This article aims to review the characteristics, harvesting, banking, and paracrine signaling of MSCs and their role in diabetes, obesity, autoimmune and inflammatory diseases, and potential role in regenerative medicine.

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Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies.

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We report two patients with autoimmune cerebellar ataxia who fulfilled the diagnostic criteria of multiple system atrophy (MSA) and responded to immunotherapies. Patient 1 was a 72-year-old man who was diagnosed with clinically probable MSA according to Movement Disorder Society criteria. Patient 2 was a 68-year-old man who was diagnosed with clinically established MSA according to Movement Disorder Society criteria. Both patients showed cerebellar ataxia, autonomic dysfunction, and pyramidal tract signs; however, they also had atypical clinical features. Patient 1 exhibited self-|limiting mild improvement of clinical symptoms and had inflammatory findings in his cerebrospinal fluid. Patient 2 showed a rapidly progressive clinical course. We therefore examined anti-neuronal antibodies using tissue-based immunohistochemical assays with frozen rat cerebellum sections. We detected autoantibodies that mainly reacted with the cytoplasm of Purkinje cells. The two patients then underwent immunotherapies, which led to substantial improvements in their clinical symptoms. Our findings indicate that some patients with autoimmune cerebella ataxia have clinical features that resemble MSA, and respond well to immunotherapies.

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The guanine nucleotide exchange factor (GEF) VAV1, a previously 'undruggable' protein integral to T/B lymphocyte antigen-receptor signaling, promotes actin polymerization, immunological synapse formation, T cell activation and differentiation, and cytokine production. With the development of novel modalities for targeting proteins, we hypothesize that interventions targeting VAV1 will have therapeutic potential in T and T/B cell-mediated autoimmune and chronic inflammatory diseases. This opinion is supported by recent CRISPR-Cas9 studies showing VAV1 as a key positive regulator of T cell receptor (TCR) activation and cytokine production in primary human CD4+ and CD8+ T cells; data demonstrating that loss/suppression of VAV1 regulates autoimmunity and inflammation; and promising preclinical data from T and T/B cell-mediated disease models of arthritis and colitis showing the effectiveness of selective VAV1 targeting via protein degradation.

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Efferocytosis is a crucial process whereby phagocytes engulf and eliminate apoptotic cells (ACs). This intricate process can be categorized into four steps: (1) ACs release "find me" signals to attract phagocytes, (2) phagocytosis is directed by "eat me" signals emitted by ACs, (3) phagocytes engulf and internalize ACs, and (4) degradation of ACs occurs. Maintaining immune homeostasis heavily relies on the efficient clearance of ACs, which eliminates self-antigens and facilitates the generation of anti-inflammatory and immunosuppressive signals that maintain immune tolerance. However, any disruptions occurring at any of the efferocytosis steps during apoptosis can lead to a diminished efficacy in removing apoptotic cells. Factors contributing to this inefficiency encompass dysregulation in the release and recognition of "find me" or "eat me" signals, defects in phagocyte surface receptors, bridging molecules, and other signaling pathways. The inadequate clearance of ACs can result in their rupture and subsequent release of self-antigens, thereby promoting immune responses and precipitating the onset of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. A comprehensive understanding of the efferocytosis process and its implications can provide valuable insights for developing novel therapeutic strategies that target this process to prevent or treat autoimmune diseases.

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Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.

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