Hierarchical graph-guided contextual representation learning for Neurodegenerative pattern recognition in MRI.

Auto‐immune diseases are a major health problem in both developed and developing countries: They cause as many deaths as the leading infectious diseases and exact an even greater toll on patients’ quality of life given their chronic nature (Box 1). Reliable data for all auto‐immune diseases are hard to collect, but a 2011 study by the American Autoimmune Related Diseases Association (AARDA) reported that the total annual cost of just seven leading auto‐immune diseases (Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, and scleroderma) was somewhere between US$51.8 billion and US$70.6 billion in the USA alone (http://www.diabetesed.net/page/_ files/autoimmune-diseases.pdf). The AARDA report also drew attention to the indirect societal toll with one example being sufferers from RA in the USA, who experienced a decline in average earnings from US$18,409 to US$13,900 per year, and the number of jobs they were able to perform dropped from 11.5 to 2.6 million. It was also found that approximately 50 percent of RA patients were unable to work at all within ten years after disease onset. ### Box 1: Some common auto‐immune diseases #### Graves’ Disease The most common auto‐immune disease in which the body produces antibodies to the receptor for thyroid‐stimulating hormone (TSH). It usually attacks the thyroid, frequently causing it to enlarge to twice its size or more (goiter) and become overactive, with related hyperthyroid symptoms such as increased heartbeat, muscle weakness, disturbed sleep, and irritability. No ideal cure but it can be controlled, with last resort surgical excision of the gland. Other treatments include anti‐thyroid drugs, which reduce the production of thyroid hormone, and radioiodine to shrink the gland and reduce its activity. #### Hashimoto's thyroiditis Another auto‐immune disease of the thyroid gland that involves a variety of cell‐ and antibody‐mediated immune processes. It was the first disease to be recognized as auto‐immune in 1912. In this case, the …

Autoimmune encephalitis associated with autoimmune blistering diseases: A case series and retrospective review

Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a single patient or in the same family. Numerous autoimmune diseases have been shown to coexist frequently with thyroid autoimmune diseases. AUTOIMMNUNE THYROID DISEASE AND OTHER ORGAN SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: This part of the study reviews the prevalence of autoimmune thyroid disease coexisting with: pernicious anaemia, vitiligo, celiac disease, autoimmune liver disease, miastenia gravis, alopecia areata and sclerosis multiplex, and several recommendations for screening have been given. AUTOIMMUNE THYROID DISEASE AND OTHER ORGAN NON-SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: Special attention is given to the correlation between autoimmune thyroid disease and rheumatoid arthritis, systemic lupus erythematosus, syndrome Sjögren, systemic sclerosis and mixed connective tissue disease. Screening for autoimmune thyroid diseases should be recommended in everyday clinical practice, in patients with primary organ-specific or organ non-specific autoimmune disease. Otherwise, in patients with primary thyroid autoimmune disease, there is no good reason of seeking for all other autoimmune diseases, although these patients have a greater risk of developing other autoimmune disease. Economic aspects of medicine require further analyzing of these data, from cost/benefit point of view to justified either mandatory screening or medical practitioner judgment.

Autoimmune diseases are characterized by immune response dysregulation against self-components, leading to chronic inflammation and tissue damage. Vitamin C (VitC), a water-soluble vitamin with established functions in antioxidant defence and collagen synthesis, has also been of interest based on its potential immunomodulatory effects. This review discusses the role of VitC in the course and progression of (A) autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Sjögren's disease, type 1 diabetes, Hashimoto's thyroiditis, pernicious anaemia, antiphospholipid syndrome), (B) other immune-mediated diseases (Crohn's disease, periodontitis), and (C) Alzheimer's disease, a neurodegenerative disorder with autoimmune features. Results from clinical, observational, and experimental trials show that VitC deficiency is common in many of these diseases and may contribute to increased oxidative stress and immune disequilibrium. Supplementation has been associated with improved antioxidant levels, control of inflammatory mediators, and, in some cases, clinical outcomes like disease activity decrease or symptom load. Although findings vary across conditions and few large, randomized trials are available, the overall evidence indicates that maintaining good VitC status can be useful in maintaining immune homeostasis and reducing inflammation. VitC should be viewed as an adjunct to be employed safely, perhaps and ideally within larger treatment regimens, but not in place of effective therapies. Further research, including large-scale clinical trials, will be required to determine more clearly optimal dosing, timing of treatment, and patient population most likely to benefit. By integration of current knowledge, this review recognizes both promise in VitC for treatment of autoimmune/immune-mediated disease and promise in its potential use within future treatment regimens.

Thanks to advances in research, it may soon be easier to diagnose autoimmune diseases earlier, but therapy remains a tricky problem

A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known as being associated with cellular iron overload, but the mechanism by which HFE H63D might increase the risk of neuron degeneration is unclear. Here, using an inducible expression cell model developed from a human neuronal cell line SH-SY5Y, we reported that the presence of the HFE H63D protein activated the unfolded protein response (UPR). This response was followed by a persistent endoplasmic reticulum (ER) stress, as the signals of UPR sensors attenuated and followed by up-regulation of caspase-3 cleavage and activity. Our in vitro findings were recapitulated in a transgenic mouse model carrying Hfe H67D, the mouse equivalent of the human H63D mutation. In this model, UPR activation was detected in the lumbar spinal cord at 6 months then declined at 12 months in association with increased caspase-3 cleavage. Moreover, upon the prolonged ER stress, the number of cells expressing HFE H63D in early apoptosis was increased moderately. Cell proliferation was decreased without increased cell death. Additionally, despite increased iron level in cells carrying HFE H63D, it appeared that ER stress was not responsive to the change of cellular iron status. Overall, our studies indicate that the HFE H63D mutant protein is associated with prolonged ER stress and chronically increased neuronal vulnerability.

The type I interferon system plays a critical role in host defense in health, and a growing body of literature suggests that type I interferon is a critical mediator of human autoimmune disease (1). Type I interferons function as a bridge between the innate and adaptive immune systems, and as such play an important role in setting thresholds for response against self antigens. Many investigators have focused on the role type I interferons play in autoimmune disease. This fascinating and rapidly growing body of literature encompasses many different autoimmune diseases, including systemic lupus erythematosus, type I diabetes, multiple sclerosis, and others. Type I interferons play differing roles in human autoimmune conditions. For example, in the autoimmune diseases, systemic lupus erythematosus and Sjogren’s syndrome, increased interferon alpha signaling plays a pathogenic role (2, 3). Interestingly, interferon beta is used as a therapeutic in multiple sclerosis, an autoimmune disease of the central nervous system (4). Both interferon alpha and beta signal through the same type I interferon receptor and share many similarities in downstream signaling, suggesting that the disparate activities of type I interferons in lupus and multiple sclerosis relate to differences in the underlying disease processes and immunoregulation in these two diseases. In this Research Topic, a series of articles provides a comprehensive overview of the various roles type I interferons play in autoimmune diseases, with a focus on human immunology. This Research Topic features a number of Original Research Articles, including a study by Mavragani et al. examining type I interferon levels in the organ-specific autoimmune disorders type I diabetes and autoimmune thyroid disease (5). They demonstrate high type I interferon levels in both of these autoimmune conditions, supporting the idea that high levels of type I interferon are detectable in organ-specific autoimmune conditions in addition to systemic autoimmune disorders. Clark et al. investigate genetic polymorphisms in the interferon regulatory factor 5 (IRF5) gene (6). This gene has been associated with susceptibility to systemic lupus erythematosus (7), and they demonstrate four distinct promoter regions have differential activity. Ko et al. study type I interferon-induced gene expression in patients with systemic lupus erythematosus (8). They demonstrate that the expression of type I interferon-induced genes in lupus immune cells differs significantly between ancestral backgrounds, which corresponds to clinical differences in the disease between ancestral backgrounds. A Methods article by Feng et al. examines public domain gene expression data to document patterns of type I interferon-induced gene expression and infer both positive and negative regulation by transcription factors (9). The Research Topic also features a number of Review Articles focusing on various disease states. Liu et al. review murine models of systemic lupus erythematosus that are interferon-inducible, providing model systems of autoimmunity related to type I interferon (10). Wu et al. review the role of type I interferon in systemic sclerosis, a distinct autoimmune disease characterized by thickening and fibrosis of the skin, which shares a type I interferon signature with other autoimmune conditions (11). Li et al. review the evidence supporting a role for type I interferon in the pathogenesis of Sjogren’s syndrome, spanning genetic associations, gene expression studies, and clinical features of the disease (12). Reder et al. review the contrasting role of type I interferon in multiple sclerosis and systemic lupus erythematosus and other autoimmune conditions (13). In multiple sclerosis, type I interferon levels are low (14), and administration of recombinant type I interferon is an effective treatment. They review the evidence supporting multiple sclerosis as a low interferon autoimmune disease, and speculate on immunological features that might underlie this striking difference. Shrivastav et al. review the role of nucleic acid receptors in type I interferon generation in systemic lupus erythematosus (15), a disease characterized by pathological activation of the type I interferon pathway. These articles taken together provide an overview of many of the ways type I interferons have been implicated in human autoimmune disease, providing a fascinating window into the biology of the human immune system gone wrong.

Understanding neurodegeneration: beyond basics

Epidemiology and Estimated Population Burden of Selected Autoimmune Diseases in the United States

Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens and represent a heterogeneous group of disorders that afflict specific target organs or multiple organ systems [1]. The chronic nature of these diseases places a significant burden on the utilization of medical care, direct and indirect economic costs, and quality of life. The fact that ADs share several clinical signs and symptoms (i.e., subphenotypes), physiopathological mechanisms, and genetic factors has been called autoimmune tautology and indicates that they have common mechanisms [2–8]. In clinical practice, there are two conditions supporting this theory: polyautoimmunity and familial autoimmunity. Polyautoimmunity is the presence of two or more ADs in a single patient while familial autoimmunity occurs when different relatives from a nuclear family present with diverse ADs [4]. These conditions indicate that similar genetic, epigenetic, and environmental factors influence ADs [8]. In rhetoric, tautology (from Greek tauto, “the same” and logos, “word/idea”) is an obvious statement. In medical practice, Sjogren's syndrome could be considered the “autoimmune diabetes” or the “celiac disease” of the salivary and lachrymal glands. In logic, tautology is a formula, which is true in every possible interpretation. Thus, autoimmune tautology means that an AD is similar to a second one, to a third one, and so on. Its formula is Vpq = AD1≃AD2≃AD3, where Vpq represents the symbol of tautology. ADs cannot be all identical because the target cell and the affected organ may differ from one AD to another one. In addition, trigger factors as well as the age at onset may vary among them and from one patient to another. Yet, autoimmune mechanisms of injury may be common including predisposing and protective factors. One step forward to the demonstration of this logically valid formula will be a new taxonomy of ADs based on common and specific subphenotypes that will allow us to predict and prevent them, tailor individual medical decisions, and provide personalized healthcare while facilitating patient's participation in their treatment and eventual cure of their disease. In Table 1, ten shared characteristics supporting the autoimmune tautology are summarized. In this special issue of Autoimmune Diseases, a dozen of papers are devoted to these characteristics. Evolution and genetics of ADs, including the biological significance of evolution in autoimmune phenomena, a meta-analysis of HLA class II in six ADs in Latin America, genetic factors of autoimmune thyroid diseases in Japanese, and an in silico approach of the autoimmune tautology are included. An updated review on epigenetics and ADs is also presented. Table 1 Shared characteristics among autoimmune diseases (ADs) supporting the autoimmune tautology*. Environmental factors play an important role in the induction of ADs. This special issue also contains a very interesting hypothesis about local cartilage trauma as a pathogenic trigger factor of autoimmunity, a review about the induction of autoimmunity by microbial infections, and another one on the effect of selenium on HLA-DR expression of thyrocytes. How does age at onset influence the outcome of ADs is also reviewed, and an update on lupus nephritis is offered. Last but not least, a careful analysis of concomitant ADs in patients with systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic sclerosis is reported. Polyautoimmunity is the term proposed for this association of disorders, which encompasses the concept of a common origin for these diseases. A lack of association between spondyloarthropathies (SpAs) and ADs is described, highlighting the fact that SpAs correspond more to autoinflammatory diseases rather than to ADs. We hope that readers of Autoimmune Diseases will find in this special issue not only accurate data and updated reviews on the common mechanisms of ADs, but also important questions to be resolved such as their missing heritability, the antagonisms of some disorders (i.e., RA and MS), their prevention, the effect of ethnicity, socioeconomic status and health care system on their outcome, and the role of the autoimmunologist, among others. Juan-Manuel Anaya Adriana Rojas-Villarraga Mario Garcia-Carrasco

Autoimmune disease in families with multiple sclerosis: a population-based study

Background and Objectives18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with principal component analysis (PCA) has been applied to identify disease-related brain patterns in neurodegenerative disorders such as Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Alzheimer’s disease (AD). These patterns are used to quantify functional brain changes at the single subject level. This is especially relevant in determining disease progression in idiopathic REM sleep behavior disorder (iRBD), a prodromal stage of PD and DLB. However, the PCA method is limited in discriminating between neurodegenerative conditions. More advanced machine learning algorithms may provide a solution. In this study, we apply Generalized Matrix Learning Vector Quantization (GMLVQ) to FDG-PET scans of healthy controls, and patients with AD, PD and DLB. Scans of iRBD patients, scanned twice with an approximate 4 year interval, were projected into GMLVQ space to visualize their trajectory. MethodsWe applied a combination of SSM/PCA and GMLVQ as a classifier on FDG-PET data of healthy controls, AD, DLB, and PD patients. We determined the diagnostic performance by performing a ten times repeated ten fold cross validation. We analyzed the validity of the classification system by inspecting the GMLVQ space. First by the projection of the patients into this space. Second by representing the axis, that span this decision space, into a voxel map. Furthermore, we projected a cohort of RBD patients, whom have been scanned twice (approximately 4 years apart), into the same decision space and visualized their trajectories. ResultsThe GMLVQ prototypes, relevance diagonal, and decision space voxel maps showed metabolic patterns that agree with previously identified disease-related brain patterns. The GMLVQ decision space showed a plausible quantification of FDG-PET data. Distance traveled by iRBD subjects through GMLVQ space per year (i.e. velocity) was correlated with the change in motor symptoms per year (Spearman’s rho =0.62, P=0.004). ConclusionIn this proof-of-concept study, we show that GMLVQ provides a classification of patients with neurodegenerative disorders, and may be useful in future studies investigating speed of progression in prodromal disease stages.

Background: Multiple sclerosis (MS) and autoimmune diseases (AIDs) share immunological underpinnings, leading to frequent co-occurrence. This study investigated the prevalence of AIDs among Polish patients with MS (PwMSs) and its potential effects on disease characteristics. The aims were to compare clinical and demographic characteristics between PwMSs with and without coexisting AIDs. Methods: A retrospective analysis was conducted on data from 580 PwMSs who were treated at the Department of Neurology, University Clinical Center in Katowice, Poland, between February 2018 and August 2023. Variables analyzed included age, sex, MS type, disease duration, treatment, Expanded Disability Status Scale (EDSS) scores, thyroid-stimulating hormone (TSH), and vitamin D3 serum concentrations. Results: AID was identified in 16.9% of PwMSs (n = 98). Compared with PwMSs without AIDs, PwMSs with AIDs exhibited significantly higher mean age (44.61 ± 11.40 vs. 42.24 ± 12.27 years; p = 0.0151), longer disease duration (10.77 ± 6.72 vs. 9.56 ± 7.19 years; p = 0.0102), and higher EDSS scores (2.97 ± 1.43 vs. 2.89 ± 1.84; p = 0.0261). Among PwMSs, the prevalence of AIDs was significantly higher in females (20.24%) compared to males (8.13%; p = 0.0022), and strongly associated with the relapsing-remitting MS subtype (p = 0.0352). Autoimmune thyroid diseases were markedly the most prevalent in PwMSs (hypothyroidism 7.24%). Conclusions: PwMSs with AIDs exhibit distinct characteristics, including older age, increased disease duration, and greater disability. Thyroid disorders are notably the most prevalent AIDs among PwMSs. These findings underscore the intricate interplay between AIDs and MS and highlight the necessity for further research into their long-term impact.

Familial occurrence of multiple sclerosis with thyroid disease and systemic lupus erythematosus