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Annals of Hematology Mar 2022Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity.... (Review)
Review
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified. Moreover, mutations in FAS often show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern. FAS mutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants in FAS and increased TCR αβ double-negative T cells (DNTs, a hallmark of ALPS) have been identified in multifactorial autoimmune diseases, while FAS itself could play a potential role in carcinogenesis. These findings suggest that alterations of FAS-mediated apoptosis could trespass the universe of inborn errors of immunity and that somatic mutations leading to ALPS could only be the tip of the iceberg of acquired immunodeficiencies.
Topics: Animals; Autoimmune Lymphoproliferative Syndrome; Autoimmunity; Humans; Mutation; Neoplasms; fas Receptor
PubMed: 35059842
DOI: 10.1007/s00277-022-04761-7 -
Frontiers in Immunology 2022The coexistence of neuromyelitis optica spectrum disorder (NMOSD) with other autoimmune diseases has been well recognized. However, the causal association between these...
OBJECTIVES
The coexistence of neuromyelitis optica spectrum disorder (NMOSD) with other autoimmune diseases has been well recognized. However, the causal association between these two conditions has not been fully studied. The etiology and therapies of NMOSD coexisting with autoimmune diseases also need to be elucidated.
METHODS
We performed two-sample Mendelian randomization (MR) analysis to examine the causality. Genome-wide association (GWAS) summary data from NMOSD, autoimmune thyroid disease (AITD), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SS) were used to identify genetic instruments. Causal single-nucleotide polymorphisms (SNPs) were annotated and searched for cis-expression quantitative trait loci (cis-eQTL) data. Pathway enrichment analysis was performed to identify the mechanism of NMOSD coexisting with AITD, SLE, and SS. Potential therapeutic chemicals were searched using the Comparative Toxicogenomics Database.
RESULTS
The MR analysis found that AITD, SLE, and SS were causally associated with NMOSD susceptibility, but not vice versa. Gene Ontology (GO) enrichment analysis revealed that MHC class I-related biological processes and the interferon-gamma-mediated signaling pathway may be involved in the pathogenesis of NMOSD coexisting with AITD, SLE, and SS. A total of 30 chemicals were found which could inhibit the biological function of cis-eQTL genes.
CONCLUSIONS
Our findings could help better understand the etiology of NMOSD and provide potential therapeutic targets for patients with coexisting conditions.
Topics: Humans; Autoimmune Diseases; Genome-Wide Association Study; Interferon-gamma; Lupus Erythematosus, Systemic; Neuromyelitis Optica; Sjogren's Syndrome
PubMed: 36248893
DOI: 10.3389/fimmu.2022.959469 -
International Journal of Molecular... Jan 2021Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic... (Meta-Analysis)
Meta-Analysis Review
Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic factors that lead to overactivation of immune cells and chronic inflammation. Since oxidative stress is a common feature of these diseases, which activates leukocytes to intensify inflammation, antioxidants could reduce the severity of these diseases. In addition to activating leukocytes, oxidative stress increases the production of lipid mediators, notably of endocannabinoids and eicosanoids, which are products of enzymatic lipid metabolism that act through specific receptors. Because the anti-inflammatory CB2 receptors are the predominant cannabinoid receptors in leukocytes, endocannabinoids are believed to act as anti-inflammatory factors that regulate compensatory mechanisms in autoimmune diseases. While administration of eicosanoids in vitro leads to the differentiation of lymphocytes into T helper 2 (Th2) cells, eicosanoids are also necessary for the different0iation of Th1 and Th17 cells. Therefore, their antagonists and/or the genetic deletion of their receptors abolish inflammation in animal models of psoriasis-RA and SLE. On the other hand, products of non-enzymatic lipid peroxidation, especially acrolein and 4-hydroxynonenal-protein adducts, mostly generated by an oxidative burst of granulocytes, may enhance inflammation and even acting as autoantigens and extracellular signaling molecules in the vicious circle of autoimmune diseases.
Topics: Animals; Autoimmune Diseases; Humans; Immunomodulation; Inflammation Mediators; Lipid Metabolism; Oxidative Stress; Reactive Oxygen Species
PubMed: 33450863
DOI: 10.3390/ijms22020723 -
Autoimmunity Reviews May 2023More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of... (Review)
Review
More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis (MS) and new therapeutic options are on the horizon. Due to different underlying therapeutic mechanisms, a more individualized selection of DMTs in MS is possible, taking into account the patient's current situation. Therefore, concomitant treatment of various comorbid conditions, including autoimmune mediated disorders such as rheumatoid arthritis, should be considered in MS patients. Because the pathomechanisms of autoimmunity partially overlap, DMT could also treat concomitant inflammatory diseases and simplify the patient's treatment. In contrast, the exacerbation and even new occurrence of several autoimmune diseases have been reported as a result of immunomodulatory treatment of MS. To simplify treatment and avoid disease exacerbation, knowledge of the beneficial and adverse effects of DMT in other autoimmune disorders is critical. Therefore, we conducted a literature search and described the beneficial and adverse effects of approved and currently studied DMT in a large number of comorbid autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, cutaneous disorders including psoriasis, Sjögren´s syndrome, systemic lupus erythematosus, systemic vasculitis, autoimmune hepatitis, and ocular autoimmune disorders. Our review aims to facilitate the selection of an appropriate DMT in patients with MS and comorbid autoimmune diseases.
Topics: Humans; Multiple Sclerosis; Autoimmunity; Autoimmune Diseases; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic
PubMed: 36924922
DOI: 10.1016/j.autrev.2023.103312 -
Frontiers in Endocrinology 2023The relationship between different autoimmune diseases and bone mineral density (BMD) and fractures has been reported in epidemiological studies. This study aimed to...
OBJECTIVE
The relationship between different autoimmune diseases and bone mineral density (BMD) and fractures has been reported in epidemiological studies. This study aimed to explore the causal relationship between autoimmune diseases and BMD, falls, and fractures using Mendelian randomization (MR).
METHODS
The instrumental variables were selected from the aggregated statistical data of these diseases from the largest genome-wide association study in Europe. Specifically, 12 common autoimmune diseases were selected as exposure. Outcome variables included BMD, falls, and fractures. Multiple analysis methods were utilized to comprehensively evaluate the causal relationship between autoimmune diseases and BMD, falls, and fractures. Additionally, sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and one analysis, were conducted to verify the result's reliability.
RESULTS
Strong evidence was provided in the results of the negatively association of ulcerative colitis (UC) with forearm BMD. UC also had a negatively association with the total body BMD, while inflammatory bowel disease (IBD) depicted a negatively association with the total body BMD at the age of 45-60 years. Horizontal pleiotropy or heterogeneity was not detected through sensitivity analysis, indicating that the causal estimation was reliable.
CONCLUSION
This study shows a negative causal relationship between UC and forearm and total body BMD, and between IBD and total body BMD at the age of 45-60 years. These results should be considered in future research and when public health measures and osteoporosis prevention strategies are formulated.
Topics: Humans; Middle Aged; Genome-Wide Association Study; Mendelian Randomization Analysis; Reproducibility of Results; Osteoporosis; Fractures, Bone; Colitis, Ulcerative; Inflammatory Bowel Diseases; Autoimmune Diseases
PubMed: 37693362
DOI: 10.3389/fendo.2023.1196269 -
Frontiers in Immunology 2021
Topics: Autoimmune Diseases; Comorbidity; Humans; Skin Diseases
PubMed: 33841410
DOI: 10.3389/fimmu.2021.627565 -
Cytokine Aug 2020
Topics: Autoimmune Diseases; Humans; Interferon Type I
PubMed: 32336557
DOI: 10.1016/j.cyto.2020.155109 -
Journal of Hepatology Dec 2023IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of... (Review)
Review
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4 plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8 and CD4 SLAMF7 T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
Topics: Humans; Immunoglobulin G; Immunoglobulin G4-Related Disease; Cholangitis; Autoantigens; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangitis, Sclerosing; Autoimmune Diseases
PubMed: 37598939
DOI: 10.1016/j.jhep.2023.08.005 -
Neurology(R) Neuroimmunology &... Jul 2020
Topics: Autoimmune Diseases of the Nervous System; Humans
PubMed: 32527761
DOI: 10.1212/NXI.0000000000000779 -
International Journal of Molecular... Dec 2020Myelin oligodendrocyte glycoprotein (MOG)-associated disease (MOGAD) is a rare, antibody-mediated inflammatory demyelinating disorder of the central nervous system (CNS)... (Review)
Review
Myelin oligodendrocyte glycoprotein (MOG)-associated disease (MOGAD) is a rare, antibody-mediated inflammatory demyelinating disorder of the central nervous system (CNS) with various phenotypes starting from optic neuritis, via transverse myelitis to acute demyelinating encephalomyelitis (ADEM) and cortical encephalitis. Even though sometimes the clinical picture of this condition is similar to the presentation of neuromyelitis optica spectrum disorder (NMOSD), most experts consider MOGAD as a distinct entity with different immune system pathology. MOG is a molecule detected on the outer membrane of myelin sheaths and expressed primarily within the brain, spinal cord and also the optic nerves. Its function is not fully understood but this glycoprotein may act as a cell surface receptor or cell adhesion molecule. The specific outmost location of myelin makes it a potential target for autoimmune antibodies and cell-mediated responses in demyelinating processes. Optic neuritis seems to be the most frequent presenting phenotype in adults and ADEM in children. In adults, the disease course is multiphasic and subsequent relapses increase disability. In children ADEM usually presents as a one-time incident. Luckily, acute immunotherapy is very effective and severe disability (ambulatory and visual) is less frequent than in NMOSD. A critical element of reliable diagnosis is detection of pathogenic serum antibodies MOG with accurate, specific and sensitive methods, preferably with optimized cell-based assay (CBA). MRI imaging can also help in differentiating MOGAD from other neuro-inflammatory disorders. Reports on randomised control trials are limited, but observational open-label experience suggests a role for high-dose steroids and plasma exchange in the treatment of acute attacks, and for immunosuppressive therapies, such as steroids, oral immunosuppressants and rituximab as maintenance treatment. In this review, we present up-to-date clinical, immunological, radiographic, histopathological data concerning MOGAD and summarize the practical aspects of diagnosing and managing patients with this disease.
Topics: Adrenal Cortex Hormones; Animals; Autoantibodies; Demyelinating Autoimmune Diseases, CNS; Humans; Immunosuppressive Agents; Myelin-Oligodendrocyte Glycoprotein; Plasma Exchange; Rituximab
PubMed: 33374173
DOI: 10.3390/ijms22010100