ABSTRACT
Introduction: Ataxia telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies, and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNAs play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study, we investigate the differential expression of miRNAs in samples from AT patients to identify miRNA patterns and analyze how these patterns are related to the disease. Methods: We enrolled 20 AT patients (mean age 17.7 ± 9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls. Results: We observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblast samples. Among these, three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p, were further validated in additional AT samples, confirming their dysregulation. Discussion: We identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control, or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.
Subject(s)
Ataxia Telangiectasia , Leukocytes, Mononuclear , MicroRNAs , Humans , Ataxia Telangiectasia/genetics , MicroRNAs/genetics , MicroRNAs/blood , Male , Female , Adult , Adolescent , Child , Young Adult , Leukocytes, Mononuclear/metabolism , Fibroblasts/metabolism , Gene Expression Profiling , Gene Expression RegulationABSTRACT
Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.
Subject(s)
Induced Pluripotent Stem Cells , Phenotype , Primary Immunodeficiency Diseases , Repressor Proteins , Humans , Induced Pluripotent Stem Cells/metabolism , Primary Immunodeficiency Diseases/genetics , Repressor Proteins/genetics , Repressor Proteins/deficiency , DNA Methylation , Immunologic Deficiency Syndromes/genetics , Male , Mutation , Female , Face/abnormalities , Nuclear ProteinsABSTRACT
Kabuki Syndrome (KS) is a multisystemic genetic disorder. A portion of patients has immunological manifestations characterized by increased susceptibility to infections and autoimmunity. Aiming to describe the clinical and laboratory immunological aspects of KS, we conducted a retrospective multicenter observational study on patients with KS treated in centers affiliated to the Italian Primary Immunodeficiency Network.Thirty-nine patients were enrolled, with a median age at evaluation of 10 years (range: 3 m-21y). All individuals had organ malformations of variable severity. Congenital heart defect (CHD) was present in 19/39 patients (49%) and required surgical correction in 9/39 (23%), with associated thymectomy in 7/39 (18%). Autoimmune cytopenia occurred in 6/39 patients (15%) and was significantly correlated with thymectomy (p < 0.002), but not CHD. Individuals with cytopenia treated with mycophenolate as long-term immunomodulatory treatment (n = 4) showed complete response. Increased susceptibility to infections was observed in 22/32 patients (69%). IgG, IgA, and IgM were low in 13/29 (45%), 13/30 (43%) and 4/29 (14%) patients, respectively. Immunoglobulin substitution was required in three patients. Lymphocyte subsets were normal in all patients except for reduced naïve T-cells in 3/15 patients (20%) and reduced memory switched B-cells in 3/17 patients (18%). Elevated CD3 + TCRαß + CD4-CD8-T-cells were present in 5/17 individuals (23%) and were correlated with hematological and overall autoimmunity (p < 0.05).In conclusion, immunological manifestations of KS in our cohort include susceptibility to infections, antibody deficiency, and autoimmunity. Autoimmune cytopenia is correlated with thymectomy and elevated CD3 + TCRαß + CD4-CD8-T-cells, and benefits from treatment with mycophenolate.
Subject(s)
Abnormalities, Multiple , Face/abnormalities , Hematologic Diseases , Vestibular Diseases , Humans , Female , Retrospective Studies , Male , Child , Hematologic Diseases/immunology , Hematologic Diseases/therapy , Adolescent , Italy , Vestibular Diseases/immunology , Child, Preschool , Young Adult , Abnormalities, Multiple/immunology , Infant , Autoimmunity , AdultABSTRACT
Background and aims: X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A, encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. Methods: We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein-Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. Results: The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. Conclusion: We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.
Subject(s)
Epstein-Barr Virus Infections , Immunologic Deficiency Syndromes , Lymphohistiocytosis, Hemophagocytic , Lymphoma , Lymphoproliferative Disorders , Child , Humans , Herpesvirus 4, Human , Rituximab , Epstein-Barr Virus Infections/genetics , Lymphohistiocytosis, Hemophagocytic/geneticsABSTRACT
Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.
Subject(s)
DiGeorge Syndrome , Heart Defects, Congenital , MicroRNAs , Humans , DiGeorge Syndrome/genetics , Epigenesis, Genetic , Phenotype , Heart Defects, Congenital/geneticsABSTRACT
PURPOSE: Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI. METHODS: Here, we describe the functioning of the IEI-Virtual Consultation System (VCS), an innovative platform created by the Italian Immunodeficiency Network (IPINet). RESULTS: In the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. A final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. CONCLUSION: From our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. These results may help the functioning of other international platforms for the management of complex cases.
Subject(s)
Delayed Diagnosis , Rare Diseases , Humans , Phenotype , Referral and Consultation , ItalyABSTRACT
Background and aims: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with classic form. The risk of developing post-transplant tumors appears to be higher in patients with WAS than in other inborn errors of immunity (IEIs), but the actual incidence is not well defined, due to the scarcity of published data. Methods: Herein, we describe a 10-year-old patient diagnosed with WAS, treated with HSCT in the first year of life, who subsequently developed two rare solid tumors, kaposiform hemangioendothelioma and desmoid tumor. A review of the literature on post-HSCT tumors in WAS patients has been performed. Results: The patient received diagnosis of classic WAS at the age of 2 months (Zhu score = 3), confirmed by WAS gene sequencing, which detected the nonsense hemizygous c.37C>T (Arg13X) mutation. At 9 months, patient underwent HSCT from a matched unrelated donor with an adequate immune reconstitution, characterized by normal lymphocyte subpopulations and mitogen proliferation tests. Platelet count significantly increased, even though platelet count never reached reference values. A mixed chimerism was also detected, with a residual WASP- population on monocytes (27.3%). The patient developed a kaposiform hemangioendothelioma at the age of 5. A second abdominal tumor was identified, histologically classified as a desmoid tumor when he reached the age of 10 years. Both hematopoietic and solid tumors were identified in long-term WAS survivors after HSCT. Conclusion: Here, we describe the case of a patient with WAS who developed two rare solid tumors after HSCT. An active surveillance program for the risk of tumors is necessary in the long-term follow-up of post-HSCT WAS patients.
Subject(s)
Fibromatosis, Aggressive , Hematopoietic Stem Cell Transplantation , Sarcoma, Kaposi , Wiskott-Aldrich Syndrome , Male , Humans , Infant , Child , Wiskott-Aldrich Syndrome/diagnosis , Wiskott-Aldrich Syndrome/therapy , Wiskott-Aldrich Syndrome/genetics , Fibromatosis, Aggressive/etiology , Sarcoma, Kaposi/etiology , Hematopoietic Stem Cell Transplantation/adverse effectsABSTRACT
Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.
Subject(s)
Agammaglobulinemia , Amino Acyl-tRNA Synthetases , Lysine-tRNA Ligase , Primary Immunodeficiency Diseases , Humans , Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Amino Acyl-tRNA Synthetases/genetics , Amino Acyl-tRNA Synthetases/metabolism , Deafness/genetics , Lysine-tRNA Ligase/genetics , Lysine-tRNA Ligase/metabolism , Mutation/genetics , Primary Immunodeficiency Diseases/geneticsABSTRACT
BACKGROUND: Unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. Since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological scenario of unPAD children to adulthood and identification of biomarkers of primary immune deficiency (PID) persistence. METHODS: A total of 23 pediatric unPAD patients underwent clinical and immunological FU for a mean time of 14 years (range 3-32 years, median 16 years). RESULTS: UnPAD diagnosis may change over time. At the last FU, 10/23 (44%) children matched the diagnosis of transient hypogammaglobulinemia of infancy and 13/23 (56%) suffered from a persistent PID. In detail, an unPAD condition was confirmed in 7/23 (30%) patients, whereas 3/23 (13%), 2/23 (9%), and 1/23 (4%) were reclassified as common variable immunodeficiency, selective IgA deficiency, and isolated IgM deficiency, respectively. Low IgA, low specific antibody response to pneumococcus, and lower respiratory tract infections at diagnosis were independently associated with IEI persistence. CONCLUSIONS: Long-term monitoring of unPAD patients is required to define their outcome and possible evolution towards a definitive IEI diagnosis.
ABSTRACT
Job's syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry. This study shows the incidence of manifestations present at the time of diagnosis versus those that arose during follow up at a referral center for IEI. The mean time of diagnostic delay was 13.7 years, while the age of disease onset was < 12 months in 66.7% of patients. Respiratory complications, namely bronchiectasis and pneumatoceles, were present at diagnosis in 46.7% and 43.3% of patients, respectively. Antimicrobial prophylaxis resulted in a decrease in the incidence of pneumonia from 76.7% to 46.7%. At the time of diagnosis, skin involvement was present in 93.3% of the patients, including eczema (80.8%) and abscesses (66.7%). At the time of follow-up, under therapy, the prevalence of complications decreased: eczema and skin abscesses reduced to 63.3% and 56.7%, respectively. Antifungal prophylaxis decreased the incidence of mucocutaneous candidiasis from 70% to 56.7%. During the SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients survived, while three patients died at ages of 28, 39, and 46 years as a consequence of lung bleeding, lymphoma, and sepsis, respectively. Analysis of a cumulative follow-up period of 278.7 patient-years showed that early diagnosis, adequate management at expertise centers for IEI, prophylactic antibiotics, and antifungal therapy improve outcomes and can positively influence the life expectancy of patients.
ABSTRACT
X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.
Subject(s)
COVID-19 , Myeloid Differentiation Factor 88 , Child , Humans , Adaptor Proteins, Signal Transducing , COVID-19/complications , Myeloid Differentiation Factor 88/genetics , SARS-CoV-2 , Toll-Like Receptor 7ABSTRACT
Up to 25% of the patients with inborn errors of immunity (IEI) also exhibit immunodysregulatory features. The association of immune dysregulation and immunodeficiency may be explained by different mechanisms. The understanding of mechanisms underlying immune dysregulation in IEI has paved the way for the development of targeted treatments. In this review article, we will summarize the mechanisms of immune tolerance breakdown and the targeted therapeutic approaches to immune dysregulation in IEI.
Subject(s)
Immune System Diseases , Immune Tolerance , Humans , Immune System Diseases/genetics , Immune System Diseases/therapyABSTRACT
Systemic autoinflammatory diseases (SAIDs) are disorders of innate immunity, which are characterized by unprovoked recurrent flares of systemic inflammation often characterized by fever associated with clinical manifestations mainly involving the musculoskeletal, mucocutaneous, gastrointestinal, and nervous systems. Several conditions also present with varied, sometimes prominent, involvement of the vascular system, with features of vasculitis characterized by variable target vessel involvement and organ damage. Here, we report a systematic review of vasculitis and vasculopathy associated with inborn errors of immunity.
ABSTRACT
Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatment choice should be guided by the underlying disease. The study of the pathogenic mechanisms involved in the genesis of AIC in PID and our growing ability to define the molecular underpinnings of immune dysregulation has paved the way for the development of novel targeted treatments. Ideally, targeted therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway. Actually, the molecular diagnosis or a specific drug is not always available. However, defining the category of PID or the immunological phenotype can help to choose a semi-targeted therapy directed towards the suspected pathogenic mechanism. In this review we overview all the therapeutic interventions available for AIC in PID patients, according to different immunologic targets. In particular, we focus on T and/or B cells targeting therapies. To support decision making in the future, prospective studies to define treatment response and predicting/stratifying biomarkers for patients with AIC and PID are needed.
Subject(s)
Immunologic Deficiency Syndromes , B-Lymphocytes , Biomarkers , Humans , Phenotype , Prospective StudiesABSTRACT
Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.
Subject(s)
Common Variable Immunodeficiency , Apoptosis/genetics , Common Variable Immunodeficiency/genetics , Humans , Programmed Cell Death 1 Receptor/genetics , T Follicular Helper Cells , T-Lymphocytes, Helper-InducerABSTRACT
COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50-60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.
Subject(s)
COVID-19 , Common Variable Immunodeficiency , Adult , COVID-19/complications , COVID-19/epidemiology , Child , Common Variable Immunodeficiency/epidemiology , Female , Hospitalization , Humans , Male , Retrospective Studies , SARS-CoV-2 , Post-Acute COVID-19 SyndromeABSTRACT
Background: Severe skeletal muscle damage has been recently reported in patients with SARS-CoV-2 infection and as a rare vaccination complication. Case summary: On Apr 28, 2021 a 68-year-old man who was previously healthy presented with an extremely severe rhabdomyolysis that occurred nine days following the first dose of SARS-CoV-2 ChAdOx1 nCov-19 vaccination. He had no risk factors, and denied any further assumption of drugs except for fermented red rice, and berberine supplement. The clinical scenario was complicated by a multi organ failure involving bone marrow, liver, lung, and kidney. For the rapid increase of the inflammatory markers, a cytokine storm was suspected and multi-target biologic immunosuppressive therapy was started, consisting of steroids, anakinra, and eculizumab, which was initially successful resulting in close to normal values of creatine phosphokinase after 17 days of treatment. Unfortunately, 48 days after the vaccination an accelerated phase of deterioration, characterized by severe multi-lineage cytopenia, untreatable hypotensive shock, hypoglycemia, and dramatic increase of procalcitonin (PCT), led to patient death. Conclusion: Physicians should be aware that severe and fatal rhabdomyolysis may occur after SARS-CoV2 vaccine administration.
Subject(s)
COVID-19 , Rhabdomyolysis , Thrombocytopenia , Aged , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Humans , Male , Multiple Organ Failure/etiology , RNA, Viral , Rhabdomyolysis/etiology , SARS-CoV-2 , Vaccination/adverse effectsABSTRACT
The epigenome bridges environmental factors and the genome, fine-tuning the process of gene transcription. Physiological programs, including the development, maturation and maintenance of cellular identity and function, are modulated by intricate epigenetic changes that encompass DNA methylation, chromatin remodeling, histone modifications and RNA processing. The collection of genome-wide DNA methylation data has recently shed new light into the potential contribution of epigenetics in pathophysiology, particularly in the field of immune system and host defense. The study of patients carrying mutations in genes encoding for molecules involved in the epigenetic machinery has allowed the identification and better characterization of environment-genome interactions via epigenetics as well as paving the way for the development of new potential therapeutic options. In this review, we summarize current knowledge of the role of epigenetic modifications in the immune system and outline their potential involvement in the pathogenesis of inborn errors of immunity.
ABSTRACT
Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.