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Translational Research : the Journal of... Jul 2022Systemic lupus erythematosus (SLE) is a chronic and often progressive autoimmune disorder marked clinically by a variable constellation of symptoms including fatigue,... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic and often progressive autoimmune disorder marked clinically by a variable constellation of symptoms including fatigue, rash, joint pains, and kidney damage. The lungs, heart, gastrointestinal system, and brain can also be impacted, and individuals with lupus are at higher risk for atherosclerosis, thrombosis, thyroid disease, and other disorders associated with chronic inflammation . Autoimmune diseases are marked by erroneous immune responses in which the target of the immune response is a "self"-antigen, or autoantigen, driven by the development of antigen-specific B or T cells that have overcome the normal systems of self-tolerance built into the development of B and T cells. SLE is specifically characterized by the production of autoantibodies against nucleic acids and their binding proteins, including anti-double stranded DNA, anti-Smith (an RNA binding protein), and many others . These antibodies bind their nuclear-derived antigens to form immune complexes that cause injury and scarring through direct deposition in tissues and activation of innate immune cells . In over 50% of SLE patients, immune complex aggregation in the kidneys drives intrarenal inflammation and injury and leads to lupus nephritis, a progressive destruction of the glomeruli that is one of the most common causes of lupus-related death . To counter this pathology increasing attention has turned to developing approaches to reduce the development and continued generation of such autoantibodies. In particular, the molecular and cellular events that lead to long term, continuous activation of such autoimmune responses have become the focus of new therapeutic strategies to limit renal and other pathologies in lupus patients. The focus of this review is to consider how the innate immune system is involved in the development and progression of lupus nephritis and how a novel approach to inhibit innate immune activation by neutralizing the activators of this response, called Damage Associated Molecular Patterns, may represent a promising approach to treat this and other autoimmune disorders.
Topics: Alarmins; Autoantibodies; Humans; Inflammation; Lupus Erythematosus, Systemic; Lupus Nephritis; Nucleic Acids
PubMed: 35245691
DOI: 10.1016/j.trsl.2022.02.007 -
Frontiers in Immunology 2023T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of... (Review)
Review
T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of T1D poses significant challenges to the healthcare system, particularly in countries with struggling economies. This review paper highlights the multifaceted roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the context of T1D, shedding light on their potential as regulators of immune responses and β-cell biology. Recent research has elucidated the intricate interplay between CD4+ T cell subsets, such as Tregs and Th17, in developing autoimmune diseases like T1D. Th17 cells drive inflammation, while Tregs exert immunosuppressive functions, highlighting the delicate balance crucial for immune homeostasis. Immunotherapy has shown promise in reinstating self-tolerance and restricting the destruction of autoimmune responses, but further investigations are required to refine these therapeutic strategies. Intriguingly, PPARs, initially recognized for their role in lipid metabolism, have emerged as potent modulators of inflammation in autoimmune diseases, particularly in T1D. Although evidence suggests that PPARs affect the β-cell function, their influence on T-cell responses and their potential impact on T1D remains largely unexplored. It was noted that PPARα is involved in restricting the transcription of IL17A and enhancing the expression of Foxp3 by minimizing its proteasomal degradation. Thus, antagonizing PPARs may exert beneficial effects in regulating the differentiation of CD4+ T cells and preventing T1D. Therefore, this review advocates for comprehensive investigations to delineate the precise roles of PPARs in T1D pathogenesis, offering innovative therapeutic avenues that target both the immune system and pancreatic function. This review paper seeks to bridge the knowledge gap between PPARs, immune responses, and T1D, providing insights that may revolutionize the treatment landscape for this autoimmune disorder. Moreover, further studies involving PPAR agonists in non-obese diabetic (NOD) mice hold promise for developing novel T1D therapies.
Topics: Mice; Animals; Diabetes Mellitus, Type 1; Mice, Inbred NOD; Autoimmune Diseases; Cell Differentiation; Inflammation; PPAR alpha
PubMed: 37928539
DOI: 10.3389/fimmu.2023.1292238 -
World Journal of Pediatrics : WJP Jul 2023Aicardi-Goutières syndrome (AGS) is a genetically determined disorder with a variable phenotype. Since the original description of AGS, advances in gene sequencing... (Review)
Review
BACKGROUND
Aicardi-Goutières syndrome (AGS) is a genetically determined disorder with a variable phenotype. Since the original description of AGS, advances in gene sequencing techniques have resulted in a significant broadening of the phenotypic spectrum associated with AGS genes, and new clinical pictures have emerged beyond the classic presentation. The aim of this review is to provide a comprehensive analysis of the clinical spectrum of AGS and report currently available treatments and new immunosuppressive strategies.
DATA SOURCES
Literature reviews and original research articles were collected from databases, including PubMed and ClinicalTrials.gov. Relevant articles about AGS were included.
RESULTS
The involvement of the nervous system certainly represents the major cause of mortality and morbidity in AGS patients. However, other clinical manifestations, such as chilblains, hepatosplenomegaly, and hematological disturbances, may lead to the diagnosis and considerably impact the prognosis and overall quality of life of these patients. Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple comorbidities. However, advances in understanding the pathogenesis of AGS could open new and more effective therapies.
CONCLUSIONS
The over-activation of innate immunity due to upregulated interferon production plays a critical role in AGS, leading to multi-organ damage with the main involvement of the central nervous system. To date, there is no specific and effective treatment for AGS. New drugs specifically targeting the interferon pathway may bring new hope to AGS patients.
Topics: Humans; Quality of Life; Autoimmune Diseases of the Nervous System; Nervous System Malformations; Interferons
PubMed: 36650407
DOI: 10.1007/s12519-022-00679-2 -
Neuroscience and Biobehavioral Reviews May 2022Current knowledge on the general somatic health of individuals with obsessive-compulsive disorder (OCD) is very limited. Here, we critically review the emerging... (Review)
Review
Current knowledge on the general somatic health of individuals with obsessive-compulsive disorder (OCD) is very limited. Here, we critically review the emerging literature on the topic. Rapidly accumulating evidence indicates an association between OCD and autoimmune diseases, which is not limited to streptococcus-related conditions. Similarly, an association with metabolic and circulatory system diseases has been reported, which is at least partially independent from psychiatric comorbidities and familial confounders. Preliminary results also suggest potential links with dementia, insomnia, respiratory diseases, gastrointestinal diseases, migraine, and chronic pain, but replication is warranted. The risk of death by suicide in OCD is now well established. OCD has also been associated to increased mortality due to natural causes, but more research on specific causes of death is needed. Clarification of the mechanisms behind the observed associations will be critical to inform the rational design of prevention efforts. In the meantime, while OCD symptom reduction remains a priority, clinicians should also focus on monitoring the general health and promoting healthy lifestyles of persons with OCD.
Topics: Autoimmune Diseases; Cardiovascular Diseases; Comorbidity; Humans; Morbidity; Obsessive-Compulsive Disorder
PubMed: 35271916
DOI: 10.1016/j.neubiorev.2022.104602 -
Clinical and Experimental Immunology Jul 2023Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly... (Review)
Review
Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects.
Topics: Humans; Pandemics; COVID-19; Autoimmune Diseases; Adjuvants, Immunologic; Vaccines
PubMed: 36881788
DOI: 10.1093/cei/uxad033 -
International Journal of Molecular... Oct 2023Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder clinically presented as Hashimoto thyroiditis (HT) and Graves' disease (GD). The... (Review)
Review
Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder clinically presented as Hashimoto thyroiditis (HT) and Graves' disease (GD). The pathogenesis of AITD is caused by an inappropriate immune response related to genetic, non-genetic, and environmental factors. Pregnancy is one of the factors that have a great influence on the function of the thyroid gland because of the increased metabolic demand and the effects of hormones related to pregnancy. During pregnancy, an adaptation of the maternal immune system occurs, especially of the innate immune system engaged in maintaining adaptive immunity in the tolerant state, preventing the rejection of the fetus. Pregnancy-related hormonal changes (estrogen, progesterone, hCG) may modulate the activity of innate immune cells, potentially worsening the course of AITD during pregnancy. This especially applies to NK cells, which are associated with exacerbation of HD and GD. On the other hand, previous thyroid disorders can affect fertility and cause adverse outcomes of pregnancy, such as placental abruption, spontaneous abortion, and premature delivery. Additionally, it can cause fetal growth retardation and may contribute to impaired neuropsychological development of the fetus. Therefore, maintaining the thyroid equilibrium in women of reproductive age and in pregnant women is of the highest importance.
Topics: Female; Humans; Pregnancy; Hashimoto Disease; Placenta; Thyroid Diseases; Autoimmune Diseases; Graves Disease; Immunity, Innate
PubMed: 37895126
DOI: 10.3390/ijms242015442 -
Frontiers in Immunology 2023Autoimmune blistering diseases (AIBD) are paradigms of autoantibody-mediated organ-specific autoimmune disorders that involve skin and/or mucous membranes. Compared to... (Review)
Review
Autoimmune blistering diseases (AIBD) are paradigms of autoantibody-mediated organ-specific autoimmune disorders that involve skin and/or mucous membranes. Compared to other autoimmune diseases, the pathogenicity of autoantibodies in AIBD is relatively well described. Pemphigus is a potentially lethal autoantibody driven autoimmune disorder with a strong HLA class II association. It is mainly characterized by IgG against the desmosomal adhesion molecules desmoglein 3 (Dsg3) and Dsg1. Several murine pemphigus models were developed subsequently, each allowing the analysis of a characteristic feature, such as pathogenic IgG or Dsg3-specific T or B cells. Thus, the models can be employed to preclinically evaluate potentially novel therapies. We here thoroughly summarize past and recent efforts in developing and utilizing pemphigus mouse models for pathomechanistic investigation and therapeutic interventions.
Topics: Mice; Animals; Pemphigus; Autoantibodies; Skin; Autoimmune Diseases; Blister; Disease Models, Animal; Immunoglobulin G
PubMed: 37180099
DOI: 10.3389/fimmu.2023.1169947 -
Seminars in Immunopathology Feb 2021The conventional perception asserts that immunology is the science of 'discrimination' between self and non-self. This concept is however no longer tenable as effector... (Review)
Review
The conventional perception asserts that immunology is the science of 'discrimination' between self and non-self. This concept is however no longer tenable as effector cells of the adaptive immune system are first conditioned to be tolerant to the body's own antigens, collectively known as self until now. Only then attain these effectors the responsiveness to non-self. The acquisition of this essential state of tolerance to self occurs for T cells in the thymus, the last major organ of our body that revealed its intricate function in health and disease. The 'thymus' as an anatomical notion was first notably documented in Ancient Greece although our present understanding of the organ's functions was only deciphered commencing in the 1960s. In the late 1980s, the thymus was identified as the site where clones of cells reactive to self, termed 'forbidden' thymocytes, are physically depleted as the result of a process now known as negative selection. The recognition of this mechanism further contributed to the belief that the central rationale of immunology as a science lies in the distinction between self and non-self. This review will discuss the evidence that the thymus serves as a unique lymphoid organ able to instruct T cells to recognize and be tolerant to harmless self before adopting the capacity to defend the body against potentially injurious non-self-antigens presented in the context of different challenges from infections to exposure to malignant cells. The emerging insight into the thymus' cardinal functions now also provides an opportunity to exploit this knowledge to develop novel strategies that specifically prevent or even treat organ-specific autoimmune diseases.
Topics: Antigens; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance; Self Tolerance; T-Lymphocytes
PubMed: 33415360
DOI: 10.1007/s00281-020-00831-y -
Liver International : Official Journal... Nov 2022Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with an increased prevalence of extrahepatic autoimmune diseases and an increased mortality...
BACKGROUND AND AIMS
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with an increased prevalence of extrahepatic autoimmune diseases and an increased mortality compared with the general population. The contribution of extrahepatic autoimmune diseases to the increased mortality has not been clarified. Our aim was to determine the effect of extrahepatic autoimmune diseases on mortality in AIH patients.
METHODS
This nationwide register-based cohort study included all Danish patients diagnosed with AIH between 1995 and 2019. We examined the presence of extrahepatic autoimmune diseases and compared the mortality between AIH patients with and without extrahepatic autoimmune diseases. We adjusted our analysis for age, sex, calendar year of AIH diagnosis, cirrhosis, cancer, chronic obstructive pulmonary disease and ischaemic heart disease.
RESULTS
We included 2479 AIH patients of whom 19.8% had one extrahepatic autoimmune disease and 3.3% had multiple. The adjusted 10-year cumulative mortality was 27.2% (95% confidence interval [CI]: 25.2-29.4) for patients with extrahepatic autoimmune diseases and 21.6% (95% CI: 19.9-23.6) for patients without. The adjusted mortality hazard ratio was 1.30 (95% CI: 1.12-1.52) for AIH patients with versus without extrahepatic autoimmune diseases; it was 1.25 (95% CI: 1.06-1.48) for patients with one extrahepatic autoimmune disease and 1.54 (95% CI: 1.15-2.05) for those with more than one.
CONCLUSIONS
Extrahepatic autoimmune diseases increased the mortality in patients with AIH. Patients with multiple extrahepatic autoimmune diseases had a higher mortality than patients with just one extrahepatic autoimmune disease.
Topics: Autoimmune Diseases; Cohort Studies; Hepatitis, Autoimmune; Humans; Liver Cirrhosis; Prevalence; Proportional Hazards Models
PubMed: 35924431
DOI: 10.1111/liv.15382 -
Journal of Thrombosis and Haemostasis :... Jun 2023Since the description of the first case with gray platelet syndrome (GPS) in 1971, this rare inherited platelet disorder has been the focus of extensive clinical and... (Review)
Review
Since the description of the first case with gray platelet syndrome (GPS) in 1971, this rare inherited platelet disorder has been the focus of extensive clinical and basic research. These studies have not only increased our knowledge about the clinical manifestations of GPS but also deepened our understanding of the biogenesis of platelet α-granules and their pathophysiology in hemostasis and thrombosis. The discovery of the causal gene, neurobeachin-like 2, in 2011 was a milestone in hematology. Following this was the rapid diagnosis and phenotyping of many new patients and the further development of experimental models to characterize the pathophysiological relevance of neurobeachin-like 2 in hemostasis and immunity. The impact of altered protein function on cells other than platelets became apparent, including defects in the granules of neutrophils and monocytes and changes in the transcriptomic and proteomic profiles of other immune cells such as T lymphocytes. Besides the previously recognized clinical manifestations of macrothrombocytopenia, splenomegaly, and early-onset bone marrow fibrosis, we now recognize that immunologic abnormalities, including autoimmune diseases and recurrent infections, affect a proportion of patients with GPS. There is a proinflammatory signature of the plasma in GPS, with quantitative alterations of multiple proteins, including many produced by the liver. This review will cover the classical features of GPS and then focus on additional clinical manifestations of immune dysregulation and cellular defects beyond platelets in patients with this rare disorder.
Topics: Humans; Megakaryocytes; Gray Platelet Syndrome; Autoimmunity; Proteomics; Blood Platelets; Autoimmune Diseases; Cytoplasmic Granules
PubMed: 37028650
DOI: 10.1016/j.jtha.2023.03.032