ABSTRACT
Immune checkpoint inhibitors (ICIs) are associated with multiple endocrine side effects, including thyroid disfunctions. In addition, the efficacy and safety profiles of ICIs in the pediatric population need clarification. Here, we discuss the main evidence regarding the efficacy and thyroid toxicities of ICIs in children.
ABSTRACT
Autoimmune polyglandular syndromes (APS) are classified into four main categories, APS1-APS4. APS1 is caused by AIRE gene loss of function mutations, while the genetic background of the other APS remains to be clarified. Here, we investigated the potential association between AIRE gene promoter Single Nucleotide Polymorphisms (SNPs) and susceptibility to APS. We sequenced the AIRE gene promoter of 74 APS patients, also analyzing their clinical and autoantibody profile, and we further conducted molecular modeling studies on the identified SNPs. Overall, we found 6 SNPs (-230Y, -655R, -261M, -380S, -191M, -402S) of the AIRE promoter in patients' DNA. Interestingly, folding free energy calculations highlighted that all identified SNPs, except for -261M, modify the stability of the nucleic acid structure. A rather similar percentage of APS3 and APS4 patients had polymorphisms in the AIRE promoter. Conversely, there was no association between APS2 and AIRE promoter polymorphisms. Further AIRE promoter SNPs were found in 4 out of 5 patients with APS1 clinical diagnosis that did not harbor AIRE loss of function mutations. We hypothesize that AIRE promoter polymorphisms could contribute to APS predisposition, although this should be validated through genetic screening in larger patient cohorts and in vitro and in vivo functional studies.
Subject(s)
Polyendocrinopathies, Autoimmune , Humans , Syndrome , Mutation , Polymorphism, Single Nucleotide , Promoter Regions, GeneticABSTRACT
Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNωAbs or AIRE mutations (Ferre-Lionakis criteria). Patients and methods: We analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms. Results: Based on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic l-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome. Conclusion: Although Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED.
Subject(s)
Hepatitis, Autoimmune , Intestinal Diseases , Polyendocrinopathies, Autoimmune , Humans , Male , Child , Female , Hepatitis, Autoimmune/diagnosis , Hepatitis, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/genetics , Mutation , Italy/epidemiologyABSTRACT
Type 1 diabetes mellitus (T1D) is a multifactorial autoimmune disease characterized by the selective destruction of pancreatic insulin-producing beta cells due to the aberrant activation of different immune effector cells (reviewed (rev [...].
Subject(s)
Diabetes Mellitus, Type 1 , Insulin-Secreting Cells , Humans , Diabetes Mellitus, Type 1/therapy , ImmunotherapyABSTRACT
Type 1 diabetes (T1D) is a polygenic disease and does not follow a mendelian pattern. Inborn errors of immunity (IEIs), on the other hand, are caused by damaging germline variants, suggesting that T1D and IEIs have nothing in common. Some IEIs, resulting from mutations in genes regulating regulatory T-cell homeostasis, are associated with elevated incidence of T1D. The genetic spectrum of IEIs is gradually being unraveled; consequently, molecular pathways underlying human monogenic autoimmunity are being identified. There is an appreciable overlap between some of these pathways and the genetic variants that determine T1D susceptibility, suggesting that after all, IEI and T1D are 2 sides of the same coin. The study of monogenic IEIs with a variable incidence of T1D has the potential to provide crucial insights into the mechanisms leading to T1D. These insights contribute to the definition of T1D endotypes and explain disease heterogeneity. In this review, we discuss the interconnected pathogenic pathways of autoimmunity, ß-cell function, and primary immunodeficiency. We also examine the role of environmental factors in disease penetrance as well as the circumstantial evidence of IEI drugs in preventing and curing T1D in individuals with IEIs, suggesting the repositioning of these drugs also for T1D therapy.
Subject(s)
Diabetes Mellitus, Type 1 , Humans , Diabetes Mellitus, Type 1/genetics , Autoimmunity/genetics , Mutation , Germ-Line Mutation , T-Lymphocytes, RegulatoryABSTRACT
Context: Bergamot, mainly produced in the Ionian coastal areas of Southern Italy (Calabria), has been used since 1700 for its balsamic and medicinal properties. Phytochemical profiling has confirmed that bergamot juices are rich in flavonoids, including flavone and flavanone glycosides which are responsible for its beneficial effects.Objective: Recently, it was shown that the combination of natural compounds with conventional treatments improves the efficacy of anticancer therapies. Natural compounds with anticancer properties attack cancerous cells without being toxic to healthy cells. Bergamot can induce cytotoxic and apoptotic effects and prevent cell proliferation in various cancer cells.Methods: In this review, the antiproliferative, pro-apoptotic, anti-inflammatory, and antioxidant effects of bergamot are described. Information was compiled from databases such as PubMed, Web of Science, and Google Scholar using the key words 'bergamot' accompanied by 'inflammation' and, 'cancer' for data published from 2015-2021.Results: In vitro and in vivo studies provided evidence that different forms of bergamot (extract, juice, essential oil, and polyphenolic fraction) can affect several mechanisms that lead to anti-proliferative and pro-apoptotic effects that decrease cell growth, as well as anti-inflammatory and antioxidant effects.Conclusions: Considering the effects of bergamot and its new formulations, we affirm the importance of its rational use in humans and illustrate how bergamot can be utilized in clinical applications. Numerous studies evaluated the effect of new bergamot formulations that can affect the absorption and, therefore, the final effects by altering the therapeutic profile of bergamot and enhancing the scientific knowledge of bergamot.
Subject(s)
Anti-Inflammatory Agents , Antineoplastic Agents , Antioxidants , Biological Products , Citrus , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Apoptosis , Biological Products/pharmacology , Biological Products/therapeutic use , Cell Proliferation , Fruit and Vegetable Juices , HumansABSTRACT
Type 1 diabetes mellitus (T1D) is a multifactorial organ specific autoimmune disease which originates from the destruction of insulin-producing beta cells within the pancreatic islets by autoreactive CD8+ T lymphocytes. The autoimmune responses are raised against autoantigenic peptides presented in the context of the Major Histocompatibility Complex (MHC) class I molecules. Peptides are generated in the cytoplasm of the beta cell by degradation through the proteasome activity and other proteases. Proteolytic intermediate protein fragments are then vehicled into the endoplasmic reticulum (ER) by transporters associated with antigen processing TAP1 and TAP2. In the ER, Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the intermediate proteins to produce the optimal peptide size for loading into the MHC class I molecules. Subsequently complexes are shuttled to the cell surface for antigen presentation. Genome Wide Association Studies (GWAS) have identified different SNPs of ERAP1 associated to several autoimmune diseases and in particular the T1D-related ERAP1 SNP rs30187 encoding for K528R ERAP1. An association between the ER stress and the increased exposure of beta cells to the immune system has been hypothesized to further contribute to the etiopathogenesis. In particular in a recent study by Thomaidou et al. 2020 (doi: https://doi.org/10.2337/db19-0984) the posttranscriptional regulation of ERAP1 is shown to shaping the recognition of the preproinsulin (PPI) signal peptide by cytotoxic T lymphocytes. In the light of foregoing ERAP1 inhibitors could potentially prevent the activation of epitope-specific autoimmune-promoting T cells and their cytokine production; further regulating ERAP1 expression at posttranscriptional level under stress conditions of the beta cells could help to reverse autoimmune process through limiting epitope-presentation to autoreactive T cells. In this article we provide a perspective on the role of ERAP1 as implicated in the pathogenesis of insulin-dependent diabetes mellitus by reviewing studies reported in literature and discussing our own experimental evidence.
Subject(s)
Autoimmune Diseases , Diabetes Mellitus, Type 1 , Humans , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/therapy , Genome-Wide Association Study , Aminopeptidases/genetics , Aminopeptidases/chemistry , Aminopeptidases/metabolism , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Antigen Presentation , Autoimmune Diseases/genetics , Autoimmune Diseases/therapy , Peptides , Epitopes , Disease Management , Minor Histocompatibility Antigens/genetics , Minor Histocompatibility Antigens/metabolismABSTRACT
Type 1 diabetes (T1D) is a chronic autoimmune metabolic disorder with onset in pediatric/adolescent age, characterized by insufficient insulin production, due to a progressive destruction of pancreatic ß-cells. Evidence on the correlation between the human gut microbiota (GM) composition and T1D insurgence has been recently reported. In particular, 16S rRNA-based metagenomics has been intensively employed in the last decade in a number of investigations focused on GM representation in relation to a pre-disease state or to a response to clinical treatments. On the other hand, few works have been published using alternative functional omics, which is more suitable to provide a different interpretation of such a relationship. In this work, we pursued a comprehensive metaproteomic investigation on T1D children compared with a group of siblings (SIBL) and a reference control group (CTRL) composed of aged matched healthy subjects, with the aim of finding features in the T1D patients' GM to be related with the onset of the disease. Modulated metaproteins were found either by comparing T1D with CTRL and SIBL or by stratifying T1D by insulin need (IN), as a proxy of ß-cells damage, showing some functional and taxonomic traits of the GM, possibly related to the disease onset at different stages of severity.
Subject(s)
Diabetes Mellitus, Type 1 , Gastrointestinal Microbiome , Insulin-Secreting Cells , Adolescent , Humans , Child , Aged , Gastrointestinal Microbiome/physiology , RNA, Ribosomal, 16S/genetics , Insulin, Regular, Human , InsulinABSTRACT
Alterations of gut microbiota have been identified before clinical manifestation of type 1 diabetes (T1D). To identify the associations amongst gut microbiome profile, metabolism and disease markers, the 16S rRNA-based microbiota profiling and 1H-NMR metabolomic analysis were performed on stool samples of 52 T1D patients at onset, 17 T1D siblings and 57 healthy subjects (CTRL). Univariate, multivariate analyses and classification models were applied to clinical and -omic integrated datasets. In T1D patients and their siblings, Clostridiales and Dorea were increased and Dialister and Akkermansia were decreased compared to CTRL, while in T1D, Lachnospiraceae were higher and Collinsella was lower, compared to siblings and CTRL. Higher levels of isobutyrate, malonate, Clostridium, Enterobacteriaceae, Clostridiales, Bacteroidales, were associated to T1D compared to CTRL. Patients with higher anti-GAD levels showed low abundances of Roseburia, Faecalibacterium and Alistipes and those with normal blood pH and low serum HbA1c levels showed high levels of purine and pyrimidine intermediates. We detected specific gut microbiota profiles linked to both T1D at the onset and to diabetes familiarity. The presence of specific microbial and metabolic profiles in gut linked to anti-GAD levels and to blood acidosis can be considered as predictive biomarker associated progression and severity of T1D.
Subject(s)
Diabetes Mellitus, Type 1 , Gastrointestinal Microbiome , Biomarkers/metabolism , Clostridiales/metabolism , Humans , Hydrogen-Ion Concentration , Isobutyrates , Malonates , Purines , Pyrimidines , RNA, Ribosomal, 16S/geneticsABSTRACT
Autoimmune diseases are a heterogeneous group of disorders of the immune system. They can cluster in the same individual, revealing various preferential associations for polyendocrine autoimmune syndromes. Clinical observation, together with advances in genetics and the understanding of pathophysiological processes, has further highlighted that autoimmunity can be associated with immunodeficiency; autoimmunity may even be the first primary immunodeficiency manifestation. Analysis of susceptibility genes for the development of these complex phenotypes is a fundamental issue. In this manuscript, we revised the clinical and immunologic features and the presence of AIRE gene variations in a cohort of 48 patients affected by high polyautoimmunity complexity, i.e., APECED-like conditions, also including patients affected by primary immunodeficiency. Our results evidenced a significant association of the S278R polymorphism of the AIRE gene with APECED-like conditions, including both patients affected by autoimmunity and immunodeficiency and patients with polyautoimmunity compared to healthy controls. A trend of association was also observed with the IVS9+6 G>A polymorphism. The results of this genetic analysis emphasize the need to look for additional genetic determinants playing in concert with AIRE polymorphisms. This will help to improve the diagnostic workup and ensure a precision medicine approach to targeted therapies in APECED-like patients.
ABSTRACT
The C1858T variant of the protein tyrosine phosphatase N22 (PTPN22) gene is associated with pathophysiological phenotypes in several autoimmune conditions, namely, Type 1 diabetes and autoimmune thyroiditis. The R620W variant protein, encoded by C1858T, leads to a gain of function mutation with paradoxical reduced T cell activation. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes, LiposiRNA) that selectively inhibit variant allele expression. In this manuscript, we functionalize lipoplexes carrying siRNA for variant C1858T with a high affinity ligand of Siglec-10 (Sig10L) coupled to lipids resulting in lipoplexes (LiposiRNA-Sig10L) that enhance delivery to Siglec-10 expressing immunocytes. LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant C1858T PTPN22 mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement, LiposiRNA-Sig10L more significantly restored IL-2 secretion, known to be paradoxically reduced than in wild type patients, than unfunctionalized LiposiRNA in PBMC of heterozygous T1D patients.
Subject(s)
Diabetes Mellitus, Type 1 , Protein Tyrosine Phosphatase, Non-Receptor Type 22 , Autoimmunity , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/therapy , Humans , Immunologic Factors , Immunotherapy , Leukocytes, Mononuclear/metabolism , N-Acetylneuraminic Acid , Phosphoric Monoester Hydrolases , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism , RNA, Small Interfering/genetics , Sialic Acid Binding Immunoglobulin-like LectinsABSTRACT
BACKGROUND: SARS-CoV-2 causes lesions, in addition to lung, in endocrine organs such as the pancreas through ACE2 receptor. Recently the relationship between SARS-CoV-2 exposition and the incidence or evolution of clinical autoimmune diabetes has attracted the attention of diabetologists. CASE PRESENTATION: We report the analysis of the clinical history of a child diagnosed for insulin-dependent diabetes mellitus (Type 1 diabetes) at the time a paucisymptomatic COVID-19 infection occurred, followed by well-controlled metabolic status. As opposite to previous findings SARS-CoV2 did not cause ketosis and ketoacidosis. Polydipsia was reported a few months and weight loss 4 weeks before SARS- CoV-2 infection suggesting that SARS-CoV-2 could not be the trigger of Type 1 diabetes in this patient. CONCLUSIONS: SARS-CoV-2 in this patient was an unexpected event in the course of disease. We advance the hypothesis that the SARS-CoV-2 infection, even if paucisymptomatic could have acted in the present case report as a hypothetical downstream precipitating factor; whilst the inciting triggering event of the autoimmune disease, as confirmed by the presence of circulating autoantibodies, could have occurred even before, as generally assumed for this category of disorders. The precipitating mechanism could have been the acute interaction between virus and the ACE receptor on the beta cells, at the time that hyperglycemia and glycosuria were ascertained, and HbA1c levels confirmed a metabolic dysregulation over the previous 3 months in absence of ketoacidosis.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 1 , Autoantibodies , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/diagnosis , Humans , RNA, Viral , SARS-CoV-2ABSTRACT
Glucocorticoids exert their pharmacological actions by mimicking and amplifying the function of the endogenous glucocorticoid system's canonical physiological stress response. They affect the immune system at the levels of inflammation and adaptive and innate immunity. These effects are the basis for therapeutic use of glucocorticoids. Innate immunity is the body's first line of defense against disease conditions. It is relatively nonspecific and, among its mediators, natural killer (NK) cells link innate and acquired immunity. NK cell numbers are altered in patients with auto immune diseases, and research suggests that interactions between glucocorticoids and natural killer cells are critical for successful glucocorticoid therapy. The aim of this review is to summarize these interactions while highlighting the latest and most important developments in this field. Production and release in the blood of endogenous glucocorticoids are strictly regulated by the hypothalamus-pituitary adrenal axis. A self-regulatory mechanism prevents excessive plasma levels of these hormones. However, exogenous stimuli such as stress, inflammation, infections, cancer, and autoimmune disease can trigger the hypothalamus-pituitary-adrenal axis response and lead to excessive systemic release of glucocorticoids. Thus, stress stimuli, such as sleep deprivation, intense exercise, depression, viral infections, and cancer, can result in release of glucocorticoids and associated immunosuppressant effects. Among these effects are decreases in the numbers and activities of NK cells in inflammatory and autoimmune diseases (e.g., giant cell arteritis, polymyalgia rheumatica, and familial hypogammaglobulinemia).
Subject(s)
Autoimmune Diseases , Glucocorticoids , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Hypothalamo-Hypophyseal System , Inflammation , Killer Cells, Natural , Pituitary-Adrenal SystemABSTRACT
Carcinomas evade the host immune system by negatively modulating CD4+ and CD8+ T effector lymphocytes through forkhead box protein 3 (FOXP3) positive T regulatory cells' increased activity. Furthermore, interaction of the programmed cell death 1 (PD1) molecule and its ligand programmed cell death ligand 1 (PDL1) inhibits the antitumor activity of PD1+ T lymphocytes. Immunotherapy has become a powerful strategy for tailored cancer patients' treatment both in adult and pediatric patients aiming to generate potent antitumor responses. Nevertheless, immunotherapies can generate autoimmune responses. This study aimed to investigate the potential effect of the transformation-related protein 53 (p53) reactivation by a peptide-based inhibitor of the MDM2/MDM4 heterodimer (Pep3) on the immune response in a solid cancer, i.e., thyroid carcinoma frequently presenting with thyroid autoimmunity. In peripheral blood mononuclear cell of thyroid cancer patients, Pep3 treatment alters percentages of CD8+ and CD4+ T regulatory and CD8+ and CD4+ T effector cells and favors an anticancer immune response. Of note that reduced frequencies of activated CD8+ and CD4+ T effector cells do not support autoimmunity progression. In evaluating PD1 expression under p53 activation, a significant decrease of activated CD4+PD1+ cells was detected in thyroid cancer patients, suggesting a defective regulation in the initial activation stage, therefore generating a protective condition toward autoimmune progression.
Subject(s)
Antineoplastic Agents/pharmacology , Autoantibodies/blood , Autoimmunity/drug effects , Leukocytes, Mononuclear/drug effects , Peptides/pharmacology , T-Lymphocytes, Regulatory/drug effects , Thyroid Neoplasms/drug therapy , Tumor Suppressor Protein p53/metabolism , Adult , Biomarkers/blood , Case-Control Studies , Cells, Cultured , Female , Humans , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Male , Middle Aged , Phenotype , Programmed Cell Death 1 Receptor/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Thyroid Neoplasms/immunology , Thyroid Neoplasms/metabolismABSTRACT
Siglecs are sialic acid-binding immunoglobulin-like lectins. Most Siglecs function as transmembrane receptors mainly expressed on blood cells in a cell type-specific manner. They recognize and bind sialic acids in specific linkages on glycoproteins and glycolipids. Since Sia is a self-molecule, Siglecs play a role in innate immune responses by distinguishing molecules as self or non-self. Increasing evidence supports the involvement of Siglecs in immune signaling representing immune checkpoints able to regulate immune responses in inflammatory diseases as well as cancer. Although further studies are necessary to fully understand the involvement of Siglecs in pathological conditions as well as their interactions with other immune regulators, the development of therapeutic approaches that exploit these molecules represents a tremendous opportunity for future treatments of several human diseases, as demonstrated by their application in several clinical trials. In the present review, we discuss the involvement of Siglecs in the regulation of immune responses, with particular focus on autoimmunity and cancer and the chance to target the sialic acid-Siglec axis as novel treatment strategy.
Subject(s)
Autoimmunity , Immunologic Factors , N-Acetylneuraminic Acid/metabolism , Neoplasms/immunology , Sialic Acid Binding Immunoglobulin-like Lectins/metabolism , Animals , Disease , Glycoproteins , Humans , Immunity, Innate , Neoplasms/metabolism , Neoplasms/therapyABSTRACT
BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome Type 1 is a rare autosomal recessive syndrome. The disorder is caused by mutations in the AIRE (AutoImmune Regulator) gene. According to the classic criteria, clinical diagnosis requires the presence of at least two of three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Furthermore, patients are often affected by other endocrine or non-endocrine associated autoimmune conditions. The enrichment of the non-classical triad seems to occur differently in different cohorts. Screenings of the population revealed that homozygous AIRE mutations c.769C > T, c.415C > T and c.254A > G have a founder effect in Finnish, Sardinian and Iranian Jew populations respectively. CASE PRESENTATION: We report here the clinical and genetic characteristics of two new Serbian APECED siblings, one male and one female, actual age of 27 and 24 respectively, born from non-consanguineous parents. Addison's disease was diagnosed in the male at the age of 3.5 and hypoparathyroidism at the age of 4. The female developed hypoparathyroidism at 4 years of age. She presented diffuse alopecia, madarosis, onychomycosis, teeth enamel dysplasia. She further developed Addison's disease at the age of 11 and Hashimoto's thyroiditis at the age of 13.5. She had menarche at the age of 14 but developed autoimmune oophoritis and premature ovarian failure at the age of 16. A treatment with hydrocortisone, fludrocortisone and alfacalcidiol was established for both siblings; L-T4 (levo-thyroxine) for thyroid dysfunction and levonorgestrel and etinilestradiol for POF were also administered to the female. Genetic screening revealed a homozygous c.769C > T (R257X (p.Arg257X)) AIRE mutation. We additionally reviewed the literature on 11 previously published Serbian patients and evaluated the frequency of their main diseases in comparison to Finnish, Sardinian, Turkish, Indian and North/South American cohorts. CONCLUSION: A founder effect was discovered for the R257X genotype detected in the DNA of 10 homozygous and 2 heterozygous patients. Of note, all Serbian APECED patients were affected by adrenal insufficiency and 10 out of 13 patients presented CMC.
Subject(s)
Founder Effect , Genotype , Mutation , Polyendocrinopathies, Autoimmune/genetics , Siblings , Transcription Factors/genetics , Adult , Female , Humans , Male , Serbia , Young Adult , AIRE ProteinABSTRACT
The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene, located in the chromosomal region 21q22.3. The related protein, AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin and anchorage to multimolecular complexes involved in the initiation and post-initiation events of tissue-specific antigen-encoding gene transcription. Once synthesized, the self-antigens are presented to, and cause deletion of, the self-reactive thymocyte clones. The clinical diagnosis of APS1 is based on the classic triad idiopathic hypoparathyroidism (HPT)-chronic mucocutaneous candidiasis-autoimmune Addison's disease (AAD), though new criteria based on early non-endocrine manifestations have been proposed. HPT is in most cases the first endocrine component of the syndrome; however, APS1-associated AAD has received the most accurate biochemical, clinical, and immunological characterization. Here is a comprehensive review of the studies on APS1-associated AAD from initial case reports to the most recent scientific findings.
Subject(s)
Addison Disease/diagnosis , Addison Disease/immunology , Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/immunology , Addison Disease/epidemiology , Adolescent , Adult , Age of Onset , Animals , Autoantigens/immunology , Autoimmune Diseases/diagnosis , Autoimmune Diseases/immunology , Autoimmunity , Biomarkers , Child , Child, Preschool , Diagnosis, Differential , Disease Management , Disease Models, Animal , Disease Susceptibility/immunology , Female , Humans , Immunity, Cellular , Immunity, Humoral , Infant , Infant, Newborn , Male , Middle Aged , Phenotype , Polyendocrinopathies, Autoimmune/epidemiology , Prevalence , Proteomics/methods , Young AdultABSTRACT
Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.
Subject(s)
Autoimmune Diseases/etiology , Autoimmune Diseases/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Autoantibodies/immunology , Autoimmune Diseases/diagnosis , Autoimmune Diseases/therapy , Biomarkers , Disease Management , Disease Susceptibility , Humans , Immunomodulation/drug effects , Killer Cells, Natural/drug effects , Ligands , Lymphocyte Activation/immunology , Molecular Targeted Therapy , Organ Specificity/immunology , Receptors, KIR/metabolismABSTRACT
Autoimmune endocrine disorders, such as type 1 diabetes (T1D) and thyroiditis, at present are treated with only hormone replacement therapy. This emphasizes the need to identify personalized effective immunotherapeutic strategies targeting T and B lymphocytes. Among the genetic variants associated with several autoimmune disorders, the C1858T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, encoding for Lyp variant R620W, affects the innate and adaptive immunity. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes) that selectively inhibit variant allele expression. In this manuscript, we improved lipoplexes carrying siRNA for variant C1858T by functionalizing them with Fab of Rituximab antibody (RituxFab-Lipoplex) to specifically target B lymphocytes in autoimmune conditions, such as T1D. RituxFab-Lipoplexes specifically bind to B lymphocytes of the human Raji cell line and of human PBMC of healthy donors. RituxFab-Lipoplexes have impact on the function of B lymphocytes of T1D patients upon CpG stimulation showing a higher inhibitory effect on total cell proliferation and IgM+ plasma cell differentiation than the not functionalized ones. These results might open new pathways of applicability of RituxFab-Lipoplexes, such as personalized immunotherapy, to other autoimmune disorders, where B lymphocytes are the prevalent pathogenic immunocytes.