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Immune cells can be equipped with a DNA construct that codes for a chimeric antigen receptor (CAR) specific for pathogenic B lymphocytes, or a chimeric autoantibody receptor (CAAR) that can be specifically recognized by pathogenic B lymphocytes. Engineered immune cells have shown preliminary therapeutic promises in both experimental models and clinical trials of lupus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, and Sjögren's syndrome, sometimes without any identified systemic toxicity. Engineered immune cells obtained by integrating mRNA, instead of DNA, can also lead to durable remission in autoimmune patients in the absence of generalized immunosuppression. Next-generation platforms are under development to overcome the resistance mechanisms of target cells, optimize their specificity, tune bioengineered immune cell signaling, and improve safety. Current treatment options for autoimmune disease (AID) are essentially immunosuppressive, inhibiting the inflammatory cascade, without curing the disease. Therapeutic monoclonal antibodies (mAbs) that target B cells showed efficacy, emphasizing the importance of B lymphocytes in autoimmune pathogenesis. Treatments that eliminate more potently B cells would open a new therapeutic era for AID. Immune cells can now be bioengineered to express constructs that enable them to specifically eradicate pathogenic B lymphocytes. Engineered immune cells (EICs) have shown therapeutic promise in both experimental models and in clinical trials in AID. Next-generation platforms are under development to optimize their specificity and improve safety. The profound and durable B cell depletion achieved reinforces the view that this biotherapeutic option holds promise for treating AID. [ABSTRACT FROM AUTHOR]

Les pneumopathies interstitielles diffuses (PID) sont un groupe hétérogène de pathologies respiratoires souvent secondaires aux connectivites. Certains patients vont développer une PID avec stigmates d'auto-immunité sans avoir les critères suffisants pour porter le diagnostic de pathologie auto-immune. Leur prise en charge est difficile car ils sont à la frontière entre PID idiopathique et secondaire. Afin de mieux identifier ces patients, le concept de PID avec manifestations auto-immunes (IPAF : Interstitial Pneumonia with Autoimmune Features) a été proposé. Le diagnostic repose sur la présence d'une PID sans cause secondaire retrouvée et la présence d'un signe ou plus parmi au moins 2 des 3 domaines suivant : clinique, sérologique, et morphologique. Ces patients ont un âge moyen de 60 ans avec un sex-ratio de 1/1 et selon les études près de 20 % vont développer une connectivite selon les critères internationaux. Le pronostic de ces patients est meilleur que celui des patients ayant une PID idiopathique et la survie moyenne à 5 ans est de 70 %. Un âge élevé au diagnostic, un pattern de pneumopathie interstitielle commune ou une altération de la diffusion libre du monoxyde de carbone ont été identifiés comme facteurs de mauvais pronostic. En plus de la prise en charge standard des pathologies respiratoires chroniques, le traitement repose sur un traitement immunosuppresseur et/ou antifibrosant. Cette classification a pour objectif de mieux caractériser ces patients afin d'optimiser leur prise en charge diagnostique et thérapeutique. Interstitial lung diseases (ILD) are a heterogeneous group of respiratory diseases often related to connective tissue diseases. Some patients will develop an ILD with autoimmune features without reaching the recommended criteria for autoimmune diseases. Their management is difficult because they have both features for idiopathic and connective tissue disease. To better identify these patients, the concept of interstitial pneumonia with autoimmune features (IPAF) has been created. The diagnosis relies on ILD without identified cause and the presence of at least one defined criterion among 2 of the 3 following domains: clinic, serologic, and morphologic. The mean age at diagnosis is 60, a sex ratio of 1/1, and depending on the authors close to 20% of patients with IPAF will develop a connective tissue disease according to the international criterion. Their prognosis is better than for patients with idiopathic ILD and with an average 5-year survival of 70%. Older age at diagnosis, a pattern of usual interstitial pneumonia, and an impaired diffusing capacity for carbon monoxide have been identified as poor prognosis factors. The treatment relies on usual care for chronic respiratory diseases and is often associated with immunosuppressive and/or antifibrotic therapies. The objective of this classification is to better characterize these patients and improve their management. [ABSTRACT FROM AUTHOR]

Different CD4+ T cell subsets have been described to have 'stem-like' features, frequently without a clear indication of what that means functionally or devoid of a systematic set of criteria for how to apply the terminology. Bona fide stem cells are themselves varied and their definitions have been evolving recently. CD4+ T cell types with clear stem-like features are naive cells and subsets of memory cells [central memory (Tcm) and stem cell memory (Tscm)]. These also display stability over time, specific niche homing, high replicative potential, and the capacity to differentiate into many other T cell types. Other cells fall along a continuum of more versus less stem-like features. In some cases, more functional characterization of these cells is required before appending a 'stem-like' moniker is justified. For others, substituting 'progenitor' or 'precursor' terminology along the lines of the hematopoietic system is likely to be more accurate. T cells with stem-like features mediate durable immunity to pathogens and tumors but can also promote tissue damage. The complexity of the literature labeling T cells as 'stem-like' suggests that both the criteria for ascribing stem cell character to T cells, and the nomenclature used to relate them to one another, need refinement. This would help systemize the field, allowing better inference of function from name. Mammalian stem cells govern development, tissue homeostasis, and regeneration. Following years of study, their functions have been delineated with increasing precision. The past decade has witnessed heightened widespread use of stem cell terminology in association with durable T cell responses to infection, antitumor immunity, and autoimmunity. Interpreting this literature is complicated by the fact that descriptions are diverse and criteria for labeling 'stem-like' T cells are evolving. Working under the hypothesis that conceptual frameworks developed for actual stem cells can be used to better evaluate and organize T cells described to have stem-like features, we outline widely accepted properties of stem cells and compare these to different 'stem-like' CD4+ T cell populations. [ABSTRACT FROM AUTHOR]

The natural history of type 1 diabetes mellitus (T1DM) is dynamic and nonlinear, presenting episodes of relapsing and remitting autoimmunity. Immunometabolism regulation can transiently restore β cell function, causing an episode of partial remission (PR), also known as the honeymoon phase. During this transient period, the residual β cell mass shows an improved function, contributing to better glycemic control. Several mechanisms by which PR arises are reflected in the periphery as biomarkers, including changes in immune cell subsets and molecules, demonstrating that immune modulation can improve endogenous insulin secretion. Predictive models of remission on T1DM diagnosis may have clinical implications for patient stratification in immune intervention clinical trials and more personalized therapeutic management. Shortly after diagnosis of type 1 diabetes mellitus (T1DM) and initiation of insulin therapy, many patients experience a transient partial remission (PR) phase, also known as the honeymoon phase. This phase presents a potential therapeutic opportunity due to its association with immunoregulatory and β cell-protective mechanisms. However, the lack of biomarkers makes its characterization difficult. In this review, we cover the current literature addressing the discovery of new predictive and monitoring biomarkers that contribute to the understanding of the metabolic, epigenetic, and immunological mechanisms underlying PR. We further discuss how these peripheral biomarkers reflect attempts to arrest β cell autoimmunity and how these can be applied in clinical practice. [ABSTRACT FROM AUTHOR]

The development of autoimmune diseases and the rejection of transplanted organs are primarily caused by an exaggerated immune response to autoantigens or graft antigens. Achieving immune tolerance is crucial for the effective treatment of these conditions. However, traditional therapies often have limited therapeutic efficacy and can result in systemic toxic effects. The emergence of nanomedicine offers a promising avenue for addressing immune-related diseases. Among the various nanoparticle formulations, cationic nanoparticles have demonstrated significant potential in inducing immune tolerance. In this review, we provide an overview of the underlying mechanism of autoimmune disease and organ transplantation rejection. We then highlight the recent advancements and advantages of utilizing cationic nanoparticles for inducing immune tolerance in the treatment of autoimmune diseases and the prevention of transplant rejection. [Display omitted] • Important role of immunomodulation in autoimmune diseases and organ transplantation. • The great promises of cationic nanoparticles in inducing immune tolerance for related diseases therapy. • Illustration the design and optimization of cationic nanoparticles. • Advantages of cationic nanoparticles in modulating immune cell functions. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1) is a chronic disorder characterized by pathological daytime sleepiness and cataplexy due to the disappearance of orexin immunoreactive neurons in the hypothalamus. Genetic and environmental factors point towards a potential role for inflammation and autoimmunity in the pathogenesis of the disease. This study aims to comprehensively review the latest evidence on the autoinflammatory mechanisms and immunomodulatory treatments aimed at suspected autoimmune pathways in NT1. Recent relevant literature in the field of narcolepsy, its autoimmune hypothesis, and purposed immunomodulatory treatments were reviewed. Narcolepsy is strongly linked to specific HLA alleles and T-cell receptor polymorphisms. Furthermore, animal studies and autopsies have found infiltration of T cells in the hypothalamus, supporting T cell-mediated immunity. However, the role of autoantibodies has yet to be definitively established. Increased risk of NT1 after H1N1 infection and vaccination supports the autoimmune hypothesis, and the potential role of coronavirus disease 2019 and vaccination in triggering autoimmune neurodegeneration is a recent finding. Alterations in cytokine levels, gut microbiota, and microglial activation indicate a potential role for inflammation in the disease's development. Reports of using immunotherapies in NT1 patients are limited and inconsistent. Early treatment with IVIg, corticosteroids, plasmapheresis, and monoclonal antibodies has seldomly shown some potential benefits in some studies. The current body of literature supports that narcolepsy is an autoimmune disorder most likely caused by T-cell involvement. However, the potential for immunomodulatory treatments to reverse the autoinflammatory process remains understudied. Further clinical controlled trials may provide valuable insights into this area. • NT1 is characterized by sleepiness, cataplexy, and disappearance of hypothalamic ORX neurons. • NT1 is linked to gene polymorphisms, immune-cell infiltration, and cytokine alterations. • Apart from the immune theory, the role of epigenetic silencing has recently been explored. • The latest research areas are the gut microbiota and potential COVID-19 pandemic impacts. • Case studies have been conducted on immunomodulatory treatment. However, controlled trials are crucial for stronger proof. [ABSTRACT FROM AUTHOR]

Celiac disease (CeD) is a chronic inflammatory disorder that occurs in response to gluten-derived peptides in genetically susceptible individuals. The only currently approved treatment for CeD is life-long dietary exclusion of wheat and related cereal grains. The causative antigens, genetic background, and their interactions have been well characterized in CeD pathogenesis. Recent work has begun to elucidate additional genetic and environmental factors that are important for disease initiation and subsequent tissue damage. This molecular and cellular understanding of CeD pathogenesis has led to the development of numerous putative therapies that are currently being tested in the clinic. Celiac disease (CeD) is a widespread, gluten-induced, autoimmune disorder that lacks any medicinal therapy. Towards the goal of developing non-dietary treatments for CeD, research has focused on elucidating its molecular and cellular etiology. A model of pathogenesis has emerged centered on interactions between three molecular families: specific class II MHC proteins on antigen-presenting cells (APCs), deamidated gluten-derived peptides, and T cell receptors (TCRs) on inflammatory CD4+ T cells. Growing evidence suggests that this pathogenic axis can be pharmacologically targeted to protect patients from some of the adverse effects of dietary gluten. Further studies have revealed the existence of additional host and environmental contributors to disease initiation and tissue damage. This review summarizes our current understanding of CeD pathogenesis and how it is being harnessed for therapeutic design and development. [ABSTRACT FROM AUTHOR]

Les sclérites et épisclérites sont des maladies inflammatoires oculaires rares mais qui méritent d'être connues des internistes du fait de leur association fréquente à des maladies systémiques auto-immunes ou inflammatoires. Leur distinction par l'interrogatoire et l'examen ophtalmologique est importante car leur prise en charge, leur pronostic et leurs complications potentielles sont très différents. L'épisclérite représente une inflammation oculaire superficielle, de bon pronostic visuel avec un traitement souvent local, habituellement sans complication. Elle est très rarement associée à une maladie systémique auto-immune. En revanche, la sclérite est une atteinte ophtalmologique potentiellement grave qui peut menacer le pronostic visuel en l'absence de traitement systémique adapté. Elle est associée à une maladie sous-jacente dans 40 à 50 % des cas, en particulier une maladie systémique auto-immune (25 à 35 % des cas) ou une cause infectieuse (5 à 10 % des cas). La polyarthrite rhumatoïde et les vascularites systémiques, en particulier les vascularites associées aux anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA), sont les principales causes auto-immunes de sclérites et d'épisclérites. Les sclérites peuvent constituer une porte d'entrée révélatrice de la maladie auto-immune sous-jacente et imposent des explorations étiologiques systématiques. Elles nécessitent dans les formes agressives, compliquées, réfractaires ou associées à une maladie systémique auto-immune, le recours à une corticothérapie générale, voire un traitement immunosuppresseur, ainsi qu'une étroite collaboration entre ophtalmologues et internistes. L'avènement des biothérapies offre de nouveaux outils thérapeutiques efficaces dans la prise en charge de ces cas difficiles. Scleritis and episcleritis are rare ocular inflammatory diseases but deserve to be known by internists because of their frequent association with systemic autoimmune diseases. It is important to distinguish them between because their prognosis, therapeutic management and potential complications are very different. Episcleritis represents a superficial ocular inflammation with usually benign visual prognosis, no complication with local treatment, and is associated with a systemic autoimmune disease in rare cases. In contrast, scleritis is a potentially serious ophthalmological condition that can threaten the visual prognosis in the absence of appropriate systemic treatment. It is associated with an underlying disease in 40–50% of cases, in particular a systemic autoimmune disease (25–35% of cases) or an infectious cause (5–10% of cases). Rheumatoid arthritis and systemic vasculitides, particularly antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, are the main autoimmune causes of scleritis and episcleritis. Scleritis can reveal the underlying autoimmune disease and requires systematic etiological investigations. Aggressive, complicated, refractory forms or those associated with a systemic autoimmune disease require glucocorticoids or even immunosuppressants, and close collaboration between ophthalmologists and internists is required. The development of biologic agents offers new effective therapeutic tools in the management of these difficult cases. [ABSTRACT FROM AUTHOR]

• Unusual GI complaints, vasculitis or arthritis may be due to autoimmune processes in people with CF. • Altered immunity, inflammation and dysbiosis in CF create a milieu that can lead to autoimmunity. • Autoimmune markers are increased in CF but are not sufficient to establish an autoimmune diagnosis. • The best-established autoimmune association is in the GI tract; biopsy verifies the diagnosis. Cystic fibrosis (CF) clinicians may see patients who have difficult-to-manage symptoms that do not have a clear CF-related etiology, such as unusual gastrointestinal (GI) complaints, vasculitis, or arthritis. Alterations in immunity, inflammation and intraluminal dysbiosis create a milieu that may lead to autoimmunity, and the CF transmembrane regulator protein may have a direct role as well. While autoantibodies and other autoimmune markers may develop, these may or may not lead to organ involvement, therefore they are helpful but not sufficient to establish an autoimmune diagnosis. Autoimmune involvement of the GI tract is the best-established association. Next steps to understand autoimmunity in CF should include a more in-depth assessment of the community perspective on its impact. In addition, bringing together specialists in various fields including, but not limited to, pulmonology, gastroenterology, immunology, and rheumatology, would lead to cross-dissemination and help define the path forward in basic science and clinical practice. [ABSTRACT FROM AUTHOR]

• Our understanding of lymphoma predisposition has evolved rapidly over the last decades, accelerated by novel technologies. • Lymphoma-predisposing conditions include inborn errors of immunity, autoimmune disease and immunosuppressive treatment. • Shared characteristic features across clinically unique conditions reveal underlying mechanisms for lymphoma predisposition. • New insights in lymphomagenesis provide opportunities for early detection, prevention and tailored treatment of lymphoma. Lymphoma is a heterogeneous group of malignancies arising from lymphocytes, which poses a significant challenge in terms of diagnosis and treatment due to its diverse subtypes and underlying mechanisms. This review aims to explore the shared and distinct features of various forms of lymphoma predisposing conditions, with a focus on genetic, immunological and molecular aspects. While diseases such as autoimmune disorders, inborn errors of immunity and iatrogenic immunodeficiencies are biologically and immunologically distinct, each of these diseases results in profound immune dysregulation and a predisposition to lymphoma development. Interestingly, the increased risk is often skewed towards a particular subtype of lymphoma. Patients with inborn errors of immunity in particular present with extreme forms of lymphoma predisposition, providing a unique opportunity to study the underlying mechanisms. External factors such as chronic infections and environmental exposures further modulate the risk of lymphoma development. Common features of conditions predisposing to lymphoma include: persistent inflammation, recurrent DNA damage or malfunctioning DNA repair, impaired tumor surveillance and viral clearance, and dysregulation of fundamental cellular processes such as activation, proliferation and apoptosis. Our growing understanding of the underlying mechanisms of lymphomagenesis provides opportunities for early detection, prevention and tailored treatment of lymphoma development. [ABSTRACT FROM AUTHOR]

Lichen sclerosus (LS) is a chronic, autoimmune skin disease predominantly located in the anogenital region in women. In recent years, the role of the human microbiota in the pathogenesis of autoimmune diseases, including LS, has received interest. The study aimed to evaluate and compare the composition of the urinary, vaginal and gut microbiota in women with LS versus non-affected controls. Women diagnosed with LS (n = 16) and matched controls (n = 14) were enrolled in the study. From each participant, midstream urine, upper and lower vaginal swabs, as well as faecal samples, were collected. The microbiota composition was assessed using 16S ribosomal RNA (rRNA) gene sequencing of the V4 hypervariable region. We observed no LS-specific clustering in either of the four anatomic niches, using either hierarchical cluster analysis or weighted beta diversity metrics. However, for unweighted UniFrac, significant differences in the urinary and lower vaginal microbiota were observed when comparing women with LS to controls. These findings indicate that while the two groups have microbiota dominated by the same bacteria, variations do occur amongst less abundant bacteria. The LEfSe analysis revealed a higher relative abundance of the genus Streptococcus in the urinary and lower vaginal microbiota in women with LS compared to controls. Additionally, a higher relative abundance of phylum Euryarchaeota was observed in the gut microbiota in women with LS compared to controls. In this study, we demonstrated several differences amongst less abundant bacteria in the urinary, lower vaginal and faecal microbiota when comparing women with LS to controls. However, further research is required to assess whether these microbiota differences are causative or merely a result of the underlying LS disease. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) are complex structures released by activated neutrophils during inflammatory responses. Due to their unique potential for causing tissue damage and modulating immune responses, there is increasing interest in studying these structures as potential targets for the treatment of infectious diseases, autoimmune diseases, and cancer. However, therapeutic targeting of NETs might trigger deleterious effects that may limit treatment efficacy. NET disruption may increase the microbial load in infection; in autoimmunity, NET targeting might impair peripheral tolerance, but it might reduce adaptive immune responses in cancer. In this review, we explore the therapeutic and deleterious effects of NET-targeted therapy while shedding light on novel strategies to overcome treatment-related limitations and enhance treatment efficacy. Neutrophil extracellular traps (NETs) have the potential to cause tissue damage and modulate immune responses, generating interest in their study as potential therapeutic targets for infections, autoimmune diseases, and cancer. Pharmacological targeting of NETs ranges from drugs that prevent NETosis, such as protein arginine deiminase 4 (PAD4) inhibitors, to drugs that target NET components (i.e., DNases). Despite promising results in disease models and safety in clinical trials, therapeutic targeting of NETs can trigger deleterious effects that may limit its use; such effects include increased microbial load in infections, impaired peripheral tolerance in autoimmunity, and reduced adaptive immunity in cancer. The development of new therapeutic approaches or the administration of NET-targeting drugs with cotherapeutics might serve as strategies to overcome the limitations of existing NET-targeted therapy and potentially increase treatment efficacy. [ABSTRACT FROM AUTHOR]

• B cell depletion reduces autoimmune disease symptoms but may induce side effects. • Antigen-specific B cell targeted therapies can be solely directed at pathogenic B cells. • CD22, a druggable receptor, is a key target for antigen-specific B cell targeting. • Molecular and cellular platforms may suit antigen-specific B cell targeting. • Antigen-specific targeting can yield insights into the role of autoreactive B cells. Autoimmune diseases are heterogeneous pathologies characterized by a breakdown of immunological tolerance to self, resulting in a chronic and aberrant immune response to self-antigens. The scope and extent of affected tissues can vary greatly per autoimmune disease and can involve multiple organs and tissue types. The pathogenesis of most autoimmune diseases remains unknown but it is widely accepted that a complex interplay between (autoreactive) B and T cells in the context of breached immunological tolerance drives autoimmune pathology. The importance of B cells in autoimmune disease is exemplified by the successful use of B cell targeting therapies in the clinic. For example, Rituximab, a depleting anti-CD20 antibody, has shown favorable results in reducing the signs and symptoms of multiple autoimmune diseases, including Rheumatoid Arthritis, Anti-Neutrophil Cytoplasmic Antibody associated vasculitis and Multiple Sclerosis. However, Rituximab depletes the entire B cell repertoire, leaving patients susceptible to (latent) infections. Therefore, multiple ways to target autoreactive cells in an antigen-specific manner are currently under investigation. In this review, we will lay out the current state of antigen-specific B cell inhibiting or depleting therapies in the context of autoimmune diseases. [ABSTRACT FROM AUTHOR]

• Age-associated B cells (ABCs) are considered as drivers of autoimmune disease pathogenesis. • SWEF proteins (DEF6 and SWAP-70) regulate ABCs, via a mechanism involving IRF5 and IL-21. • Lack of DEF6 and/or SWAP-70 leads to increased Rho-kinase (ROCK) activity in immune cells. • ROCK inhibitors may deplete ABCs, thus contribute to autoimmune disease management and therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Survivin plays an essential role in both innate and adaptive immune systems. • Aberrant survivin expression has been reported in allergic and autoimmune diseases. • Survivin modulation needs more attention for treatment of allergic and autoimmune diseases. In addition to malignancies, survivin (a member of the apoptosis inhibitor family) has been implicated in the pathogenesis of inflammatory disorders, including autoimmune and allergic diseases. Survivin is constantly expressed in the proliferating hematopoietic progenitor cells, and it is re-expressed in the mature cells of the innate and adaptive immunity, upon activation. Survivin enhances the expression of co-stimulatory molecules and MHC class II molecules in dendritic cells, and promotes the lifespan of macrophages, neutrophils, and eosinophils, while suppressing natural killer (NK) cell activity. Survivin has been implicated in T cell maturation, T cell expansion, effector CD4+ T cell differentiation, maintenance of memory CD4+ T and CD8+ T cells, as well as antibody production. Upregulated expression of survivin was indicated in the T cells as well as various samples collected from allergic patients. Survivin can contribute to the pathogenesis of allergic diseases via the promotion of the Th2 polarization, promoting IL-4 expression, compromising activation-induced cell death (AICD) in Th2 cells, and preventing apoptosis of eosinophils, as well as, amplification of eosinophilia. Moreover, survivin can interfere with clonal deletion of autoreactive T and B cells, as well as suppress Treg cell development and activity supporting the development of autoimmune diseases. This review discusses the role of survivin in immunity, allergy and autoimmunity as well as provides evidence that survivin may be considered as a novel therapeutic target for the treatment of allergic and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Prostaglandin E 2 (PGE 2) plays different roles through the inflammation and resolution cycle, acting in both proinflammatory and anti-inflammatory capacities. Dysregulated PGE 2 production and signaling has been implicated in the progression and chronic nature of certain autoimmune diseases. PGE 2 is produced by and can directly affect both immune cell populations and cells within the target organ/tissue. Recent data indicate that PGE 2 plays a pivotal role in the resolution of inflammation. We hypothesize that enhancing PGE 2 signaling during the resolution phase of inflammation promotes tissue homeostasis, halts the inflammation cycle, and ameliorates certain autoimmune diseases. A better understanding of PGE 2 signaling is needed to realize the therapeutic potential of this pathway in modulating the inflammation cycle, promoting resolution, and restoring tissue homeostasis in settings of autoimmunity. The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess context-dependent immunoregulatory properties, making their role in autoimmunity difficult to decipher. For example, prostaglandin E 2 (PGE 2) can function as an immunosuppressive molecule as well as a proinflammatory mediator in different circumstances, contributing to the expansion and activation of T cell subsets associated with autoimmunity. Recently, PGE 2 was shown to play important roles in the resolution and post-resolution phases of inflammation, promoting return to tissue homeostasis. We propose that PGE 2 plays both proinflammatory and pro-resolutory roles in the etiology of autoimmunity, and that harnessing this signaling pathway during the resolution phase might help prevent autoimmune attack. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease resulting from the demolition of β-cells that are responsible for producing insulin in the pancreas. Treatment with insulin (lifelong applying) and islet transplantation (in rare cases and severe diseases), are standards of care for T1D. Pancreas or islet transplantation have some limitations, such as lack of sufficient donors and longtime immune suppression for preventing allograft rejection. Recent studies demonstrate that autologous hematopoietic stem cells (HSC) can regenerate immune tolerance against auto-antigens. Taking advantage of this feature, autologous HSC transplantation (auto-HSCT) is likely the only treatment for T1D that is associated with lasting and complete remission. None of the other evaluated immunotherapies worldwide had the clinical efficacy of auto-HSCT. Therapy with auto-HSCT is insulin-independent rather than reducing insulin needs or delaying loss of insulin production. This review provided the latest findings in auto-HSCT for treatment of T1D. [ABSTRACT FROM AUTHOR]

Interleukin 2 (IL-2) is a pleiotropic cytokine that elicits both immunogenic and tolerogenic immune response essential for homeostasis. Initial clinical application of IL-2 based therapy was hampered by its function on broad spectrum of cells expressing corresponding receptors, which exerts uncontrolled side effects in clinical trials. While recent progress on structural modification or adjusted regimen of IL-2, revolutionized the use of IL-2 in immunomodulation process that requires stringent selection of effector cells, such as promotion of T REG cells for tolerance or invigoration of CD8+ T cells against infection and cancer. Low-dose IL-2 therapy is amongst these succuss and is proved to be a promising immunotherapy to treat a broad range of autoimmune and inflammatory diseases. This article will review major recent advances in fundamental research on IL-2 as well as significant progress made in clinical trials where patients received low-dose IL-2 therapy. This knowledge also helps design further optimized IL-2 therapies for a broader application in treating human disease. [Display omitted] • Low-dose IL-2 therapy is an emerging immunotherapy to treat a broad range of autoimmune and inflammatory diseases. • These autoimmune and inflammatory diseases include systemic lupus erythematosus, type 1 diabetes and rheumatoid arthritis. • Clinical trials demonstrated the safety and efficacy of low-dose IL-2 therapy in patients with autoimmune diseases. • The repurpose of IL-2 therapy with a lower to ultra-dose in autoimmunity was largely based on the selective promotion of T REG cells for tolerance. • New human and mouse studies found that low-dose IL-2 treatment inhibits the generation of autoreactive T FH and T H 17 cells [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are an emerging class of non-coding RNAs that do not encode proteins. These RNAs have various essential regulatory functions. Irregular expression of lncRNAs has been related to the pathological process of varied diseases, and are considered promising diagnostic biomarkers. LncRNAs can release into the circulation and be stable in body fluids as circulating lncRNAs. A subset of circulating lncRNAs that exist in exosomes are referred to as exosomal lncRNA molecules. These lncRNAs are highly stable and resist RNases. Exosomes have captured a great deal of attention due to their involvement in regulating communications between cells. In conditions of autoimmune disease, exosomes play critical roles in the pathological processes. In this context, circulating lncRNAs have been shown to modulate the immune response and indicated as prognosis and diagnostic biomarkers for autoimmune diseases. This review highlights the role of circulating lncRNAs (particularly exosomal) as diagnostic biomarkers for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and Sjögren's syndrome. [ABSTRACT FROM AUTHOR]

Autoimmune diseases usually arise as a result of an aberrant immune system attack on normal tissues of the body, which leads to a cascade of inflammatory reactions. The immune system employs different types of protective and anti-inflammatory cells for the regulation of this process. Curcumin is a known natural anti-inflammatory agent that inhibits pathological autoimmune processes by regulating inflammatory cytokines and their associated signaling pathways in immune cells. Due to the unstable nature of curcumin and its susceptibility to either degradation, or metabolism into other chemical entities (i.e. , metabolites), encapsulation of this agent into various nanocarriers would appear to be an appropriate strategy for attaining greater beneficial effects from curcumin as it pertains to immunomodulation. Many studies have focused on the design and development of curcumin nanodelivery systems (micelles, dendrimers, and diverse nanocarriers) and are summarized in this review in order to obtain greater insight into novel drug delivery systems for curcumin and their suitability for the management of autoimmune diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis of ibuprofen + paracetamol hybrid mutual prodrug (IBPA) • IBPA promoted reduction in cytokine secretion in PBMC culture supernatant from SSc patients. • IBPA treatment prevented the progression of dermal and pulmonary fibrosis in vivo in a HOCl-induced SSc model. • IBPA alleviated immune dysregulation in the experimental SSc model. Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and progressive fibrosis. The disease's complicated pathophysiology makes it difficult to develop effective therapies, necessitating research into novel therapeutic options. Molecular hybridization is a strategy that can be used to develop new drugs that act on two or multiple targets and represents an interesting option to be explored for the treatment of complex diseases. We aimed to evaluate the effects of a hybrid mutual prodrug of ibuprofen and acetaminophen (IBPA) in peripheral blood mononuclear cells (PBMC) isolated from SSc patients, and in an in vivo model of SSc induced in BALB/c mice by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. The mice were treated at the same time with daily intraperitoneal injections of IBPA (40 mg/kg). Pulmonary and skin fibrosis as well as immune responses were evaluated. IBPA significantly decreased the release of cytokines in PBMC culture supernatants from SSc patients after stimulation with phytohemagglutinin-M (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17A, TNF and IFN-γ).In HOCl-induced SSc, IBPA treatment prevented dermal and pulmonary fibrosis, in addition to reducing CD4 + T and B cells activation and reversing the M2 polarization of macrophages in spleen cells, and inhibiting IFN-γ secretion in splenocyte cultures. These results show the anti-inflammatory and antifibrotic effects of IBPA in SSc and highlight the therapeutic potential of this mutual prodrug, providing support for future studies. [ABSTRACT FROM AUTHOR]

[Display omitted] Autoimmune diseases are burdensome conditions that affect a significant fraction of the global population. The hallmark of autoimmune disease is a host's immune system being licensed to attack its tissues based on specific antigens. There are no cures for autoimmune diseases. The current clinical standard for treating autoimmune diseases is the administration of immunosuppressants, which weaken the immune system and reduce auto-inflammatory responses. However, people living with autoimmune diseases are subject to toxicity, fail to mount a sufficient immune response to protect against pathogens, and are more likely to develop infections. Therefore, there is a concerted effort to develop more effective means of targeting immunomodulatory therapies to antigen-presenting cells, which are involved in modulating the immune responses to specific antigens. In this review, we highlight approaches that are currently in development to target antigen-presenting cells and improve therapeutic outcomes in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Disturbance in neuroendocrine signaling has been consistently documented in multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS) representing the main cause of non-traumatic brain injury among young adults. In fact, MS patients display altered hormonal levels and psychiatric symptoms along with the pathologic hallmarks of the disease, which include demyelination, neuroinflammation and axonal injury. In addition, we have recently shown that extensive transcriptional changes take place in the hypothalamus of mice upon the MS model experimental autoimmune encephalomyelitis (EAE). We also detected structural and functional aberrancies in endocrine glands of EAE animals. Specifically, we described the hyperplasia of adrenal glands and the atrophy of ovaries at disease peak. To further expand the characterization of these phenotypes, here we profiled the transcriptomes of both glands by means of RNA-seq technology. Notably, we identified fatty acid and cholesterol biosynthetic pathways as the most dysregulated molecular processes in adrenals and ovaries, respectively. Furthermore, we demonstrated that key genes encoding neuropeptides and hormone receptors undergo distinct expression dynamics in the hypothalamus along disease progression. Altogether, our results corroborate the dysfunction of the neuroendocrine system as a major pathological event of autoimmune demyelination and highlight the crosstalk between the CNS and the periphery in mediating such disease phenotypes. [ABSTRACT FROM AUTHOR]

[Display omitted] Immunotherapies have been transformative in many areas, including cancer treatments, allergies, and autoimmune diseases. However, significant challenges persist in extending the reach of these technologies to new indications and patients. Some of the major hurdles include narrow applicability to patient groups, transient efficacy, high cost burdens, poor immunogenicity, and side effects or off-target toxicity that results from lack of disease-specificity and inefficient delivery. Thus, there is a significant need for strategies that control immune responses generated by immunotherapies while targeting infection, cancer, allergy, and autoimmunity. Being the outermost barrier of the body and the first line of host defense, the skin presents a unique immunological interface to achieve these goals. The skin contains a high concentration of specialized immune cells, such as antigen-presenting cells and tissue-resident memory T cells. These cells feature diverse and potent combinations of immune receptors, providing access to cellular and molecular level control to modulate immune responses. Thus, skin provides accessible tissue, cellular, and molecular level controls that can be harnessed to improve immunotherapies. Biomaterial platforms – microneedles, nano- and micro-particles, scaffolds, and other technologies – are uniquely capable of modulating the specialized immunological niche in skin by targeting these distinct biological levels of control. This review highlights recent pre-clinical and clinical advances in biomaterial-based approaches to target and modulate immune signaling in the skin at the tissue, cellular, and molecular levels for immunotherapeutic applications. We begin by discussing skin cytoarchitecture and resident immune cells to establish the biological rationale for skin-targeting immunotherapies. This is followed by a critical presentation of biomaterial-based pre-clinical and clinical studies aimed at controlling the immune response in the skin for immunotherapy and therapeutic vaccine applications in cancer, allergy, and autoimmunity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fibronectin's cryptic binding sites modulate cell binding by different cells to influence many biological processes. • Fibronectin is essential for coordinating the immune response, enabling efficient immune surveillance and tissue repair. • Therapeutic technologies targeting fibronectin are beneficial in non-autoimmune and autoimmune fibrotic conditions. Fibronectin (FN) is a critical component of the extracellular matrix (ECM) contributing to various physiological processes, including tissue repair and immune response regulation. FN regulates various cellular functions such as adhesion, proliferation, migration, differentiation, and cytokine release. Alterations in FN expression, deposition, and molecular structure can profoundly impact its interaction with other ECM proteins, growth factors, cells, and associated signaling pathways, thus influencing the progress of diseases such as fibrosis and autoimmune disorders. Therefore, developing therapeutics that directly target FN or its interaction with cells and other ECM components can be an intriguing approach to address autoimmune and fibrosis pathogenesis. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a challenging autoimmune disease, characterized by an immune system assault on insulin-producing β-cells. As insulin facilitates glucose absorption into cells and tissues, β-cell deficiency leads to elevated blood glucose levels on one hand and target-tissues starvation on the other. Despite efforts to halt β-cell destruction and stimulate recovery, success has been limited. Our recent investigations identified Protease-Activated Receptor 2 (Par2) as a promising target in the battle against autoimmunity. We discovered that Par2 activation's effects depend on its initial activation site: exacerbating the disease within the immune system but fostering regeneration in affected tissue. We utilized tissue-specific Par2 knockout mice strains with targeted Par2 mutations in β-cells, lymphocytes, and the eye retina (as a control) in the NOD autoimmune diabetes model, examining T1D onset and β-cell survival. We discovered that Par2 expression within the immune system accelerates autoimmune processes, while its presence in β-cells offers protection against β-cell destruction and T1D onset. This suggests a dual-strategy treatment for T1D: inhibiting Par2 in the immune system while activating it in β-cells, offering a promising strategy for T1D. This study highlights Par2's potential as a drug target for autoimmune diseases, particularly T1D. Our results pave the way for precision medicine approaches in treating autoimmune conditions through targeted Par2 modulation. [Display omitted] • Par2 identified as key in Type 1 diabetes, with contradicting roles. • Par2 knockout mice were used to solve Par2 functions on Type 1 diabetes. • Par2 dual modulation strategy suggested for Type 1 diabetes treatment. • Highlights Par2 as a promising therapeutic target in Type 1 diabetes. • Advances precision medicine for autoimmune diseases via Par2 dual modulation. [ABSTRACT FROM AUTHOR]

[Display omitted] • - Among patients with DME, 32 % were positive for anti-HK1 autoantibodies. • - Among patients with DME, 12 % were positive for anti-HK2 autoantibodies. • - Anti-HK1 positive were also 7 % of patients with DM and 3 % of control subjects. • - Anti-HK1 autoantibodies fail to predict DME onset. • - Anti-HK1 positivity in vitreous humor corresponded only in part to seropositivity. Autoantibodies against hexokinase 1 (HK1) were recently proposed to be associated with diabetic macular edema (DME). We hypothesized that anti-HK1 autoantibodies can be used as DME markers and to predict DME onset. Serum from patients with 1) DME, 2) diabetes mellitus (DM), 3) allergies or autoimmunities, and 4) control subjects was tested for anti-HK1 and anti-hexokinase 2 (HK2) autoantibodies by immunoblotting. Patients with DM were prospectively followed for up to nine years, and the association of anti-HK1 antibodies with new-onset DME was evaluated. The vitreous humor was also tested for autoantibodies. Among patients with DME, 32 % were positive for anti-HK1 autoantibodies (42 % of those with underlying type 1 DM and 31 % of those with underlying type 2 DM), and 12 % were positive for anti-HK2 autoantibodies, with only partial overlap of these two groups of patients. Anti-HK1 positive were also 7 % of patients with DM, 6 % of patients with allergies and autoimmunities, and 3 % of control subjects. The latter three groups were anti-HK2 negative. Only one of seven patients with DM who were initially anti-HK1 positive developed DME. Anti-HK1 autoantibodies can be used as DME markers but fail to predict DME onset. [ABSTRACT FROM AUTHOR]

• CD300e functioned as an immune-activating receptor. • Dysfunction of CD300e was associated with various pathophysiological processes. • CD300e regulated inflammation and autoimmunity through complicated mechanisms. • CD300e was a diagnostic and therapeutic target for infections and autoimmune disorders. As a transmembrane protein, CD300e is primarily expressed in myeloid cells. It belongs to the CD300 glycoprotein family, functioning as an immune-activating receptor. Dysfunction of CD300e has been suggested in many diseases, such as infections, immune disorders, obesity, and diabetes, signifying its potential as a key biomarker for disease diagnosis and treatment. This review is aimed to explore the roles and potential mechanisms of CD300e in regulating oxidative stress, immune cell activation, tissue damage and repair, and lipid metabolism, shedding light on its role as a diagnostic marker or a therapeutic target, particularly for infections and autoimmune disorders. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor signal transducer, initially identified as an essential signaling molecule for B cells, with genetic mutations resulting in a disorder characterized by disturbed B cell and antibody development. Subsequent research revealed the critical role of BTK in the functionality of monocytes, macrophages and neutrophils. Various immune cells, among which B cells and neutrophils, rely on BTK activity for diverse signaling pathways downstream of multiple receptors, which makes this kinase an ideal target to treat hematological malignancies and autoimmune diseases. First-generation BTK inhibitors are already on the market to treat hematological disorders. It has been demonstrated that B cells and myeloid cells play a significant role in the pathogenesis of different autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome. Consequently, second-generation BTK inhibitors are currently being developed to treat these disorders. Despite the acknowledged involvement of BTK in various cell types, the focus on B cells often overshadows its impact on innate immune cells. Among these cell types, neutrophils are often underestimated in the pathogenesis of autoimmune diseases. In this narrative review, the function of BTK in different immune cell subsets is discussed, after which an overview is provided of different upcoming BTK inhibitors tested for treatment of autoimmune diseases. Special attention is paid to BTK inhibition and its effect on neutrophil biology. • BTK is involved in the maturation and signaling of B cells and myeloid cells. • Inhibition of BTK is beneficial in the treatment of autoimmune diseases. • Neutrophil functions are affected by different BTK inhibitors. [ABSTRACT FROM AUTHOR]

Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert a crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential in counteracting cellular aging, modulating metabolism, responding to oxidative stress, inhibiting tumors, and improving cellular microenvironment. These enzymes are intricately linked to the occurrence and treatment of diverse pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Given the significance of histone modification in gene expression and chromatin structure, maintaining the equilibrium of the sirtuins family is imperative for disease prevention and health restoration. Mounting evidence suggests that modulators of SIRTs play a crucial role in treating various diseases and maintaining physiological balance. This review delves into the molecular structure and regulatory functions of the sirtuins family, reviews the classification and historical evolution of SIRTs modulators, offers a systematic overview of existing SIRTs modulation strategies, and elucidates the regulatory mechanisms of SIRTs modulators (agonists and inhibitors) and their clinical applications. The article concludes by summarizing the challenges encountered in SIRTs modulator research and offering insights into future research directions. [Display omitted] • Sirtuins (SIRTs), as key regulatory factors in cellular processes, are deeply involved in many life processes. • SIRTs modulators have shown great potential in treating various diseases and maintaining physiological balance. • The field of SIRTs and its modulators is developing very rapidly. This paper fills the gap in the research summary of SIRTs modulators in time, and provides valuable insights into the challenges encountered in the research field. [ABSTRACT FROM AUTHOR]

Autoimmunity, the reaction of the host against self, is a complex pattern of immunologic response that allows the immune system to react to "normal" tissue. Many such diseases exist in the skin, but in particular, two stand out as visible manifestations of autoimmune cutaneous attack. These are vitiligo, the immune attack on the melanocyte, and alopecia areata, the immune attack of the hair unit. These two illnesses include the prototypes of "simple" attacks on specific components of the skin. Other such illnesses are psoriasis—a complex series of immunologic responses resulting in a characteristic pattern of keratinocyte hyperproliferation—and lichen planus, which is similarly associated with a typical cutaneous skin disease pattern, but these will not be included in this review. In comparison, autoimmune polyendocrinopathies have defined pathways of disease based on single-gene mutations that can result in a variety of autoimmune skin features including vitiligo and alopecia areata. This contribution reviews known patterns of autoimmunity in childhood skin disease with a particular focus on single-gene disorders where they exist, and the more common multifactorial genes that contribute to this breach of the immune system's regulatory checks and balances. Genetic mechanisms that will be covered include innate and adaptive immunity, major histocompatibility complex II class associations, genetic polymorphisms, and major histocompatibility complex I class associations that bridge autoinflammatory and autoimmunity states, as well as alterations in oxidative metabolism promoting tissue destruction. End-organ tissue destruction appears to occur via interferon gamma and cytotoxic mediated activity and is a promising new therapeutic target. Janus kinase inhibitors also have the benefit clinically of both affecting the immune cascade at the cytotoxic T cell level and allowing triggering of melanocyte and hair follicular activity through the signal transducer and activator of transcription pathway, representing an attractive therapeutic with dial activity, among other cytokines implicated in end-organ destruction. Transplacental autoimmunity will not be covered herein. Greater insight into mechanisms of pediatric cutaneous autoimmunity in vitiligo and alopecia areata has yielded better therapeutic options and interventions. Understanding the basis of autoimmune triggering in our patients, that is, personalized medicine, may allow for targeted therapeutics with a goal of induction of remission, regeneration, or rejuvenation of the end-organ with the least toxic side effect profile. [ABSTRACT FROM AUTHOR]

The immune system maintains homeostasis and protects the body from pathogens, mutated cells, and other harmful substances. When immune homeostasis is disrupted, excessive autoimmunity will lead to diseases. To inhibit the unexpected immune responses and reduce the impact of treatment on immunoprotective functions, polymer nanotherapeutics, such as nanomedicines, nanovaccines, and nanodecoys, were developed as part of an advanced strategy for precise immunomodulation. Nanomedicines transport cytotoxic drugs to target sites to reduce the occurrence of side effects and increase the stability and bioactivity of various immunomodulating agents, especially nucleic acids and cytokines. In addition, polymer nanomaterials carrying autoantigens used as nanovaccines can induce antigen-specific immune tolerance without interfering with protective immune responses. The precise immunomodulatory function of nanovaccines has broad prospects for the treatment of immune related-diseases. Besides, nanodecoys, which are designed to protect the body from various pathogenic substances by intravenous administration, are simple and relatively noninvasive treatments. Herein, we have discussed and predicted the application of polymer nanotherapeutics in the correction of autoimmunity, including treating autoimmune diseases, controlling hypersensitivity, and avoiding transplant rejection. [Display omitted] • It is urgent to develop an effective strategy to treat diseases caused by abnormal autoimmunity. • Polymer nanomedicines, nanovaccines, and nanodecoys provide robust tools to correct autoimmunity. • Polymer nanotherapeutics make up for the deficiency of existing immunotherapies and exhibit excellent clinical prospects. [ABSTRACT FROM AUTHOR]

• CD28null T cells exhibit unique characteristics and may play pivotal physiological roles in aging and disease. • This article highlights the potential of CD28null T cells as immunological biomarkers by emphasizing their significant association with age, disease progression, and prognosis. • This review speculates that targeting CD28null T cells represents a promising approach to delay the aging process and prevent or attenuate disease progression. CD28null T cells, an atypical subset characterized by the loss of CD28 costimulatory molecule expression, exhibit functional variants and progressively expand with age. Moreover, T cells with these phenotypes are found in both typical and atypical humoral immune responses. Consequently, they accumulate during infectious diseases, autoimmune disorders, cardiovascular conditions, and neurodegenerative ailments. To provide an in-depth review of the current knowledge regarding CD28null T cells, we specifically focus on their phenotypic and functional characteristics as well as their physiological roles in aging and diseases. While uncertainties regarding the clinical utility remains, we will review the following two crucial research perspectives to explore clinical translational applications of the research on this specific T cell subset: 1) addressing the potential utility of CD28null T cells as immunological markers for prognosis and adverse outcomes in both aging and disease, and 2) speculating on the potential of targeting CD28null T cells as an interventional strategy for preventing or delaying immune aging processes and disease progression. [ABSTRACT FROM AUTHOR]

Pre-capillary pulmonary arterial hypertension (PAH) is hemodynamically characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) > 2. PAH is classified in six clinical subgroups, including idiopathic PAH (IPAH) and PAH associated to connective tissue diseases (CTD-PAH), that will be the main object of this review. The aim is to compare these two PAH subgroups in terms of epidemiology, histological and pathogenic findings in an attempt to define disease-specific features, including autoimmunity, that may explain the heterogeneity of response to therapy between IPAH and CTD-PAH. • IPAH and CTD-PAH are characterized by distinctive histological and pathogenetic features, that may influence the response to therapy. • The Warburg effect and autoimmunity are emerging features of IPAH. • Targeting antibodies against ETAR, AT1R, and centromeric proteins in SSc can represent a therapeutic strategy to counteract PAH. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are caused by malfunctions of the immune system and generally impact women at twice the frequency of men. Many of the most serious autoimmune diseases are accompanied by a dysregulation of T-cell phenotype, both regarding the ratio of CD4+ to CD8+ T-cells and proinflammatory versus regulatory phenotypes. Biomaterials, in the form of particles and hydrogels, have shown promise in ameliorating this dysregulation both in vivo and ex vivo. In this review, we explore the role of T-cells in autoimmune diseases, particularly those with high incidence rates in women, and evaluate the promise and efficacy of innovative biomaterial-based approaches for targeting T-cells. [Display omitted] • Autoimmune diseases impact more women than men and are underrepresented in research. • Imbalance of T-cell populations is inherent to most autoimmune diseases. • Biomaterials have been designed to rebalance the ratio of CD4+/CD8+ T-cells ex vivo. • Biomaterials have been designed to rebalance Treg/Th17 T-cell phenotypes in vivo. • Next-gen materials can target rebalancing CD4+/CD8+ ratio and phenotype concurrently. [ABSTRACT FROM AUTHOR]

[Display omitted] Autoimmune disorders have risen to be among the most prevalent chronic diseases across the globe, affecting approximately 5–7% of the population. As autoimmune diseases steadily rise in prevalence, so do the number of potential therapeutic strategies to combat them. In recent years, fundamental research investigating autoimmune pathologies has led to the emergence of several cellular targets that provide new therapeutic opportunities. However, key challenges persist in terms of accessing and specifically combating the dysregulated, self-reactive cells while avoiding systemic immune suppression and other off-target effects. Fortunately, the continued advancement of nanomedicines may provide strategies to address these challenges and bring innovative autoimmunity therapies to the clinic. Through precise engineering and rational design, nanomedicines can possess a variety of physicochemical properties, surface modifications, and cargoes, allowing for specific targeting of therapeutics to pathological cell and organ types. These advances in nanomedicine have been demonstrated in cancer therapies and have the broad potential to advance applications in autoimmunity therapies as well. In this review, we focus on leveraging the power of nanomedicine for prevalent autoimmune disorders throughout the body. We expand on three key areas for the development of autoimmunity therapies – avoiding systemic immunosuppression, balancing interactions with the immune system, and elevating current platforms for delivering complex cargoes – and emphasize how nanomedicine-based strategies can overcome these barriers and enable the development of next-generation, clinically relevant autoimmunity therapies. [ABSTRACT FROM AUTHOR]

Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like mercury, lead, and aluminum exhibit well-established neurotoxic effects, yet the precise mechanisms by which they elicit autoimmune responses in susceptible individuals remain unclear. Recent studies propose that metal-induced autoimmunity may arise from direct toxic effects on immune cells and tissues, coupled with indirect impacts on the gut microbiome and the blood-brain barrier. These effects can activate self-reactive T cells, prompting the production of autoantibodies, inflammatory responses, and tissue damage. Diagnosing metal-induced autoimmunity proves challenging due to nonspecific symptoms and a lack of reliable biomarkers. Treatment typically involves chelation therapy to eliminate excess metals and immunomodulatory agents to suppress autoimmune responses. Prevention strategies include lifestyle adjustments to reduce metal exposure and avoiding occupational and environmental risks. Prognosis is generally favorable with proper treatment; however, untreated cases may lead to autoimmune disorder progression and irreversible organ damage, particularly in the brain. Future research aims to identify genetic and environmental risk factors, enhance diagnostic precision, and explore novel treatment approaches for improved prevention and management of this intricate and debilitating disease. • Metal exposure, e.g., Hg and Pb, links to autoimmune diseases impacting the CNS, posing diagnostic and treatment challenge • Metal-induced autoimmunity, complex and impacting diverse organs, is influenced by genetic and environmental factors. • The intricate mechanisms of metal-induced autoimmunity in immune cells and tissues are unclear • Chelation therapy and immunomodulatory agents are crucial for treating metal-induced autoimmunity • Treatment involves avoiding causative metals, immunosuppressive medications, and lifestyle changes for symptom management. • Individual outcomes vary, highlighting the need for appropriate care for a healthy life. • Understanding genetics and environment is key for research, diagnostics, and innovative treatments in metal-induced autoimmunity. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is considered as an age-related disease of men with an unknown etiopathophysiology. Chronic inflammation has been proposed as one of the major pathophysiological mechanisms. There is growing evidence for the involvement of autoimmune responses in an inflammatory setting in the prostate. Patients with autoimmune diseases show a significantly elevated prevalence of BPH. Conventional therapy options for BPH are limited, rendering surgery the ultimate alternative. However, immunosuppression via tumor necrosis factor alpha blocker appears to reduce symptoms in patients with BPH and concurrent autoimmune disease due to the reduction of epithelial hyperplasia and macrophage-induced inflammation. New diagnostic options using HEp-2 cells with overexpression of LEDGF/p75 or mitochondrial DNA as autoimmune targets could be used to identify BPH patients with autoimmune responses. Given the presumed involvement of autoimmune responses in BPH and the efficacy of immunosuppression in reducing BPH symptoms, BPH or subvariants of BPH may be candidates for a new autoimmune disease in males. • Autoimmune responses appear to drive the enlargement of the prostate. • TNF - antagonist could be a therapy option for patients with benign prostate hyperplasia. • Diagnostic markers could aid in the identification of BPH patients with autoimmune features. [ABSTRACT FROM AUTHOR]

Anti-CD20 B cell depleting therapies have demonstrated that B cells are important drivers of disease progress in Multiple Sclerosis, although the pathogenic mechanisms are not well understood. A population of B cells accumulates in the inflamed meninges in MS and also some chronic animal models of disease, typically adjacent to demyelinating lesions. The role of these meningeal B cells in disease is not known, nor is their susceptibility to anti-CD20 therapy. Here, we administered anti-CD20 to 2D2 IgHMOG spontaneous experimental autoimmune encephalomyelitis mice in the chronic phase of disease, after the establishment of meningeal B cell clusters. Compared to the circulation, lymph nodes, and spleen, B cell depletion from the meninges was delayed and not evident until 7d post-administration of anti-CD20. Further, we did not find evidence that anti-CD20 accessed meningeal B cells directly, but rather that depletion was indirect and the result of ongoing turnover of the meningeal population and elimination of the peripheral pool from which it is sustained. [ABSTRACT FROM AUTHOR]

Vitamin D plays a critical role in immunomodulation, and its deficiency is implicated in the pathogenesis of several autoimmune diseases. Nevertheless, its relationship with non-infectious uveitis (NIU), an inflammatory ocular disorder, remains inconclusive. A systematic search was conducted in three databases from database inception until May 8, 2023, to investigate the potential relationship between vitamin D deficiency and NIU. We included observational studies reporting the measurement of vitamin D levels in patients with NIU and healthy controls without restriction of language or date of publication. Three pairs of authors independently screened the title and abstracts for potential eligibility and then in full text. A third author resolved disagreements. Three pairs of independent reviewers abstracted the data from the fully reviewed records and evaluated the risk of bias. We followed The MOOSE and PRISMA guidelines. Random effects meta-analyses were used for primary analysis. Studies not included in the meta-analysis were summarized descriptively. This review was registered in PROSPERO: CRD42022308105. Of 933 records screened, 11 studies were included, and five were meta-analyzed, encompassing 354 cases and 5728 controls (mean participant age ranging from 7.1 to 58.9 years). Patients with vitamin D deficiency exhibited an Odds Ratio of 2.04 (95% CI = 1.55–2.68, P < 0.00001) for developing NIU compared to controls. Overall, potential sources of bias were low across most studies. Our findings suggest that vitamin D may play an essential role in the pathophysiology of NIU. While the included studies demonstrated generally low potential bias, additional rigorous prospective studies are necessary to confirm these findings and further elucidate the underlying mechanisms involved. Vitamin D supplementation could represent a possible therapeutic strategy for preventing or managing NIU if substantiated. Clinicians should consider screening for and addressing vitamin D deficiency in patients with or at risk for NIU. • Recent publications have linked vitamin D with non-infectious uveitis (NIU). • Hypovitaminosis D has been associated with 2.5 times more chance to develop NIU. • In this study, vitamin D levels were found to be lower at any time before NIU onset. • Hypovitaminosis D shows an OR of 2.04 (p < 0.00001) for NIU development. • Evidence on hypovitaminosis D impact in NIU still inconclusive. • Consider screening for hypovitaminosis D in NIU patients or at-risk individuals. [ABSTRACT FROM AUTHOR]

Autoimmune disorders represent a heterogeneous spectrum of conditions defined by an immune system's atypical reactivity against endogenous constituents. In the complex anatomy of autoimmune pathogenesis, lncRNAs have appeared as pivotal arbiters orchestrating the mechanisms of ailment initiation, immune cascades, and transcriptional modulation. One such lncRNA, MALAT1, has garnered attention for its potential association with the aetiology of several autoimmune diseases. MALAT1 has been shown to influence a wide spectrum of cellular processes, which include cell multiplication and specialization, as well as apoptosis and inflammation. In autoimmune diseases, MALAT1 exhibits both disease-specific and shared patterns of dysregulation, often correlating with disease severity. The molecular mechanisms underlying MALAT1's impact on autoimmune disorders include epigenetic modifications, alternative splicing, and modulation of gene expression networks. Additionally, MALAT1's intricate interactions with microRNAs, other lncRNAs, and protein-coding genes further underscore its role in immune regulation and autoimmune disease progression. Understanding the contribution of MALAT1 in autoimmune pathogenesis across different diseases could offer valuable insights into shared pathways, thereby clearing a path for the creation of innovative and enhanced therapeutic approaches to address these complex disorders. This review aims to elucidate the complex role of MALAT1 in autoimmune disorders, encompassing rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), type 1 diabetes, systemic lupus erythematosus, and psoriasis. Furthermore, it discusses the potential of MALAT1 as a diagnostic biomarker, therapeutic target, and prognostic indicator. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Autoimmune diseases are a diverse and complex set of chronic disorders with a substantial impact on patient quality of life and a significant global healthcare burden. Current approaches to autoimmune disease treatment comprise broadly acting immunosuppressive drugs that lack disease specificity, possess limited efficacy, and confer undesirable side effects. Additionally, there are limited treatments available to restore organs and tissues damaged during the course of autoimmune disease progression. Cell therapies are an emergent area of therapeutics with the potential to address both autoimmune disease immune dysfunction as well as autoimmune disease-damaged tissue and organ systems. In this review, we discuss the pathogenesis of common autoimmune disorders and the state-of-the-art in cell therapy approaches to (1) regenerate or replace autoimmune disease-damaged tissue and (2) eliminate pathological immune responses in autoimmunity. Finally, we discuss critical considerations for the translation of cell products to the clinic. [ABSTRACT FROM AUTHOR]

CD95/Fas/APO-1 can trigger apoptotic as well as nonapoptotic pathways in immune cells. CD95 signaling in humans can be inhibited by several mechanisms, including mutations in the gene encoding CD95. CD95 mutations lead to autoimmune disorders, such as autoimmune lymphoproliferative syndrome (ALPS). Gaining further insight into the reported mutations of CD95 and resulting alterations of its signaling networks may provide further understanding of their presumed role in certain autoimmune diseases. For illustrative purposes and to better understand the potential outcomes of CD95 mutations, here we assign their positions to the recently determined 3D structures of human CD95. Based on this, we make certain predictions and speculate on the putative role of CD95 mutation defects in CD95-mediated signaling for certain autoimmune diseases. CD95/Fas controls multiple cellular programs in immune cells by triggering apoptotic as well as nonapoptotic pathways. CD95 mutations can lead to immune system defects and certain autoimmune diseases. Mutations in different domains of CD95 affect all stages of CD95 signaling, from CD95L binding to assembly of the receptor complex. Recently resolved 3D crystal structures of human CD95 provide remarkable insights into the presumed effects of mutations on altered CD95-mediated signaling in certain autoimmune diseases. [ABSTRACT FROM AUTHOR]

Markers of autoimmunity, such as autoantibodies, have been found in patients with endometriosis. These include the antinuclear antibodies (ANA). We aimed to evaluate the prevalence of ANA in a sample of patients with endometriosis and its possible clinical associations. Ninety-four patients with endometriosis and 91 controls were studied for ANA and extractable nuclear antigen (ENA; anti-Ro, anti-La, anti-Sm, and anti-RNP) profiles and anti-dsDNA. Epidemiological, clinical, and staging data in endometriosis were obtained. Patients with autoimmune disorders were excluded. Patients with endometriosis had a 21.2% prevalence of positive ANA vs. 5.4% in controls (P = 0.001). The ENA profile and anti-dsDNA were negative. Patients with positive ANA were more asymptomatic (P = 0.03) and had less dysmenorrhea. No associations with disease duration, patient age, or endometriosis stage were found. We found a high prevalence of positive ANA in patients with endometriosis. The presence of this autoantibody may be linked to a milder clinical expression of the disease. [ABSTRACT FROM AUTHOR]

• Enhanced eosinophil numbers in the spinal cord in the course of EAE. • Absence of eosinophils has no impact on clinical development or severity of EAE. • Spinal cord inflammation and demyelination is not affected by eosinophil deficiency. Experimental autoimmune encephalomyelitis (EAE) represents the mouse model of multiple sclerosis, a devastating neurological disorder. EAE development and progression involves the infiltration of different immune cells into the brain and spinal cord. However, less is known about a potential role of eosinophil granulocytes for EAE disease pathogenesis. In the present study, we found enhanced eosinophil abundance accompanied by increased concentration of the eosinophil chemoattractant eotaxin-1 in the spinal cord in the course of EAE induced in C57BL/6 mice by immunization with MOG 35–55 peptide. However, the absence of eosinophils did not affect neuroinflammation, demyelination and clinical development or severity of EAE, as assessed in ∆dblGATA1 eosinophil-deficient mice. Taken together, despite their enhanced abundance in the inflamed spinal cord during disease progression, eosinophils were dispensable for EAE development. [ABSTRACT FROM AUTHOR]

• Autoreactive IgE are described in various antibody-mediated autoimmune diseases (AAID). • FcεRI-bearing cells, such as basophils or mast cells, are key players in these AAID. • Anti-IgE approach may be a relevant therapeutic modality for some AAID in which it has not been investigated yet. Antibody-mediated autoimmune diseases (AAID) involve several isotypes of autoreactive antibodies. In a growing number of AAID, autoreactive IgE are present with a significant prevalence and are often associated with the presence of IgG anti-IgE and/or anti-FcεRIα (high affinity IgE receptor α chain). FcεRI-bearing cells, such as basophils or mast cells, are key players in some of these AAID. Recent advances in the pathophysiology of these diseases led to the passed or current development of anti-IgE strategies that showed very potent effects in some of them. The present review centralizes the information on the relevance of autoreactive IgE and FcεRI-bearing cells in the pathophysiology of different AAID and the ones where the anti-IgE therapeutic strategy shows or may show some benefits for the patients. [ABSTRACT FROM AUTHOR]

For over three decades, methionine aminopeptidase 2 (MetAP2) has been a tentative drug target for the treatment of cancer, obesity, and autoimmune diseases. Currently, no MetAP2 inhibitors (MetAP2i) have reached the clinic yet, despite considerable investment by major pharmaceutical companies. Here, we summarize the key series of MetAP2i developed to date and discuss their clinical development, progress, and issues. We coalesce the currently disparate knowledge regarding MetAP2i mechanism of action and discuss discrepancies across varied studies. Finally, we highlight the current knowledge gaps that need to be addressed to enable successful development of MetAP2 inhibitors in clinical settings. Spanning decades, pharmacological inhibition of methionine aminopeptidase 2 (MetAP2) has been pursued to treat diseases including cancer, obesity, and inflammatory diseases. Irreversible MetAP2 inhibitors have consistently failed in clinical trials due either to lack of efficacy or side effects undermining efficacy, some of which may be due to off-target activity. Limited information regarding mode of action and a lack of consistency between clinical applications and drug development efforts have hindered the progress of MetAP2 inhibitors. Mechanistic insight into MetAP2 inhibitor mode of action, particularly a clear understanding of the MetAP2 substrates driving efficacy, will guide the safe application of MetAP2 inhibitors to treat human disease. [ABSTRACT FROM AUTHOR]