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Science China. Life Sciences Jul 2023With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between... (Review)
Review
With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.
Topics: Humans; Autoimmune Diseases; Immunity, Innate; Autoimmunity; Adaptive Immunity; Genetic Predisposition to Disease
PubMed: 36738430
DOI: 10.1007/s11427-021-2187-3 -
Journal of Neurology Aug 2023In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the...
In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the subject which reflects the rapid expansion and refinement of associated clinical phenotypes, further autoantibody discoveries, and a more detailed understanding of immunological and neurobiological pathophysiological pathways which mediate these diseases. Increasing awareness around distinctive aspects of their clinical phenotypes has been a key driver in providing clinicians with a better understanding as to how these diseases are best recognized. In clinical practice, this recognition supports the administration of often effective immunotherapies, making these diseases 'not to miss' conditions. In parallel, there is a need to accurately assess patient responses to these drugs, another area of growing interest. Feeding into clinical care are the basic biological underpinnings of the diseases, which offer clear pathways to improved therapies toward enhanced patient outcomes. In this update, we aim to integrate the clinical diagnostic pathway with advances in patient management and biology to provide a cohesive view on how to care for these patients in 2023, and the future.
Topics: Humans; Encephalitis; Autoantibodies; Hashimoto Disease; Autoimmune Diseases of the Nervous System
PubMed: 37115360
DOI: 10.1007/s00415-023-11685-3 -
Frontiers in Immunology 2023Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG... (Review)
Review
Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG to explore their clinical presentations and determine whether the presence of autoimmune diseases affects the disease severity and treatment strategies for MG. We reviewed all the major immune-mediated coexisting autoimmune conditions associated with MG. PubMed, Embase and Web of Science were searched for relevant studies from their inception to January 2023. There is a higher frequency of concomitant autoimmune diseases in patients with MG than in the general population with a marked risk in women. Most autoimmune comorbidities are linked to AChR-MG; however, there are few reports of MuSK-MG. Thyroid disorders, systemic lupus erythematosus, and vitiligo are the most common system autoimmune diseases associated with MG. In addition, MG can coexist with neurological autoimmune diseases, such as neuromyelitis optica (NMO), inflammatory myopathy (IM), multiple sclerosis (MS), and autoimmune encephalitis (AE), with NMO being the most common. Autoimmune diseases appear to develop more often in early-onset MG (EOMG). MS coexists more commonly with EOMG, while IM coexists with LOMG. In addition, MG complicated by autoimmune diseases tends to have mild clinical manifestations, and the coexistence of autoimmune diseases does not influence the clinical course of MG. The clinical course of neurological autoimmune diseases is typically severe. Autoimmune diseases occur most often after MG or as a combined abnormality; therefore, timely thymectomy followed by immunotherapy could be effective. In addition, thymoma-associated AChR MG is associated with an increased risk of AE and IM, whereas NMO and MS are associated with thymic hyperplasia. The co-occurrence of MG and autoimmune diseases could be attributed to similar immunological mechanisms with different targets and common genetic factor predisposition. This review provides evidence of the association between MG and several comorbid autoimmune diseases.
Topics: Humans; Female; Myasthenia Gravis; Thymoma; Comorbidity; Thymus Neoplasms; Neuromyelitis Optica; Multiple Sclerosis; Myositis; Disease Progression
PubMed: 37781409
DOI: 10.3389/fimmu.2023.1223322 -
Cellular & Molecular Immunology Nov 2023Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages... (Review)
Review
Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages that infiltrate the brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies. As such, we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development, homeostasis and disease pathogenesis. In this review, we first outline the critical roles played by brain macrophages during development and healthy aging. We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders, autoimmune diseases, and glioma. Finally, we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.
Topics: Humans; Macrophages; Microglia; Brain; Meninges; Autoimmune Diseases
PubMed: 37365324
DOI: 10.1038/s41423-023-01053-6 -
Nature Reviews. Immunology May 2024The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for... (Review)
Review
The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for the management of autoimmunity, allergy, organ transplantation and gene therapy. Recent breakthroughs in our understanding of immune tolerance mechanisms have opened new research avenues and therapeutic opportunities in this area. Here, we review mechanisms of immune tolerance and novel methods for its therapeutic induction.
Topics: Humans; Immune Tolerance; Animals; Antigens; Autoimmunity; Organ Transplantation; Autoimmune Diseases
PubMed: 38086932
DOI: 10.1038/s41577-023-00970-x -
Frontiers in Immunology 2023Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes,... (Review)
Review
Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet's.
Topics: Humans; Interleukin-6; RNA, Viral; COVID-19; SARS-CoV-2; Arthritis, Juvenile; Cytokines
PubMed: 37841263
DOI: 10.3389/fimmu.2023.1255533 -
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 -
Genes Sep 2023Whether the positive associations of gastric cancer (GC) with autoimmune diseases are causal has always been controversial. This study aims to estimate the causal...
BACKGROUND
Whether the positive associations of gastric cancer (GC) with autoimmune diseases are causal has always been controversial. This study aims to estimate the causal relationship between GC and 12 autoimmune diseases by means of Mendelian randomization (MR) analysis.
METHODS
After rigorous evaluation, potential candidate single nucleotide polymorphisms (SNPs) for GC and 12 autoimmune diseases were extracted from genome-wide association study (GWAS) datasets. We performed the MR analyses using the inverse variance weighted (IVW) method as the primary approach to the analysis. Three sensitivity analysis methods were added to assess the robustness of the results. In addition, heterogeneity was measured using Cochran's Q-value, and horizontal pleiotropy was assessed using MR-Egger regression and leave-one-out analysis.
RESULTS
The IVW result, which is the main method of analysis, shows no evidence of a causal association between GC and any autoimmune disease. The results of IVW analysis show the relationship between rheumatoid arthritis ( = 0.1389), systemic lupus erythematosus ( = 0.1122), Crohn's disease ( = 0.1509), multiple sclerosis ( = 0.3944), primary sclerosing cholangitis ( = 0.9022), primary biliary cirrhosis ( = 0.7776), type 1 diabetes ( = 0.9595), ulcerative colitis ( = 0.5470), eczema ( = 0.3378), asthma ( = 0.7436), celiac disease ( = 0.4032), and psoriasis ( = 0.7622) and GC susceptibility. The same result was obtained with the weighted median and the MR-egger ( > 0.05).
CONCLUSION
Our study did not find a genetic causal relationship between susceptibility to these autoimmune diseases and GC, which suggests that unmeasured confounders (e.g., inflammatory processes) or shared genetic architecture may be responsible for the reported epidemiologic associations. Further studies of ancestral diversity are warranted to validate such causal associations.
Topics: Humans; Stomach Neoplasms; Genome-Wide Association Study; Mendelian Randomization Analysis; Autoimmune Diseases; Arthritis, Rheumatoid
PubMed: 37895193
DOI: 10.3390/genes14101844 -
Seminars in Arthritis and Rheumatism Oct 2023The VITAL trial of vitamin D supplementation suggested a possible protective effect for autoimmune diseases but uncertainties remain. We investigated potential causal...
OBJECTIVE
The VITAL trial of vitamin D supplementation suggested a possible protective effect for autoimmune diseases but uncertainties remain. We investigated potential causal effects of vitamin D on composite and individual autoimmune diseases using Mendelian randomization.
METHODS
We used data from 332,984 participants of the UK Biobank of whom 23,089 had at least one autoimmune disease defined using ICD code and/or self-report. Diseases were further considered in mechanistic subgroups driven by "autoimmunity" (n = 12,774) or "autoinflammation" (n = 11,164), then individually. We selected variants within gene regions implicated in vitamin D biology to generate a weighted genetic score. We performed population-wide analysis using the ratio method, then examined non-linear effects across five quantiles based on 25-hydroxycholecalciferol levels.
RESULTS
Genetically-predicted vitamin D was associated with lower risk of diseases in the autoinflammation group (OR 0.95 per 10 ng/ml increase in 25-hydroxycholecalciferol; 95%CI 0.91-0.99; p = 0.03) but not the autoimmunity group (OR 0.99; 95%CI 0.95-1.03; p = 0.64) or combined. When considering individual diseases, genetically-predicted vitamin D was associated with lower risk of psoriasis (OR 0.91; 95%CI 0.85-0.97; p = 0.005), the most common disease in the autoinflammation group, and suggestively with systemic lupus erythematosus (OR 0.84; 95%CI 0.69-1.02; p = 0.08); results were replicated using data from independent studies. We found no evidence for a plausible non-linear relationship between vitamin D and any outcome.
CONCLUSIONS
We found genetic evidence to support a causal link between 25-hydroxycholecalciferol concentrations and psoriasis and systemic lupus erythematosus. These results have implications for potential disease prevention strategies, and the interpretation and design of vitamin D supplementation trials.
Topics: Humans; Vitamin D; Mendelian Randomization Analysis; Calcifediol; Autoimmune Diseases; Lupus Erythematosus, Systemic; Polymorphism, Single Nucleotide
PubMed: 37437450
DOI: 10.1016/j.semarthrit.2023.152238 -
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