ABSTRACT
The neonatal immune ontogeny begins during pregnancy to ensure that the neonate is well-suited for perinatal life. It prioritizes Th2/M2 and regulatory responses over Th/M1 activity to avoid excessive inflammatory responses and to ensure immune tolerance and homeostasis. Newborns also present increased Th17/Th22 responses providing effective anti-fungal immunity and mucosal protection. Intrauterine exposure to immune modulatory drugs with the placental transfer may influence the natural course of the fetal immune development. The vertical transfer of both biological therapy and small molecules begins during the first trimester through neonatal Fc receptor or placental diffusion, respectively, reaching its maximum transfer potential during the third trimester of pregnancy. Most of the biological therapy have a prolonged half-life in newborn's blood, being detectable in infants up to 12 months after birth (usually 6-9 months). The use of immunomodulators during pregnancy is gaining global interest. Current evidence mainly reports birth-related outcomes without exhaustive analysis of the on-target side effect on the perinatal immune system ontogeny, the infection risk, or the immune dysregulation. The present review will focus on: (1) the main characteristics of the perinatal immune system to understand its specific features and vulnerabilities to immune modulation; (2) the mechanisms of placental transfer of immunomodulators; and (3) the immune changes reported to date in newborns exposed to immunomodulators with emphasis on the current concerns and gaps in knowledge.
Subject(s)
Immunomodulating Agents , Placenta , Infant , Pregnancy , Infant, Newborn , Humans , Female , ParturitionABSTRACT
Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphohistiocytosis, Hemophagocytic , Mycobacterium Infections , Mycobacterium bovis , Humans , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolismABSTRACT
Congenital disorders of glycosylation (CDG) include 150 genetically and clinically heterogeneous diseases, showing significant glycoprotein hypoglycosylation that leads to pathological consequences in multiple organs and systems whose underlying mechanisms are not yet understood. A few cellular and animal models have been used to study specific CDG characteristics, although they have given limited information due to the few CDG mutations tested and the still missing comprehensive molecular and cellular basic research. Here, we provide specific gene expression profiles, based on ribonucleic acid (RNA) microarray analysis, together with some biochemical and cellular characteristics of a total of nine control Epstein-Barr virus-transformed lymphoblastoid B cell lines (B-LCL) and 13 CDG B-LCL from patients carrying severe mutations in the phosphomannomutase 2 (PMM2) gene, strong serum protein hypoglycosylation and neurological symptoms. Significantly dysregulated genes in PMM2-CDG cells included those regulating stress responses, transcription factors, glycosylation, motility, cell junction and, importantly, those related to development and neuronal differentiation and synapse, such as carbonic anhydrase 2 (CA2) and ADAM23. PMM2-CDG-associated biological consequences involved the unfolded protein response, RNA metabolism and the endoplasmic reticulum, Golgi apparatus and mitochondria components. Changes in the transcriptional and CA2 protein levels are consistent with the CDG physiopathology. These results demonstrate the global transcriptional impact in phosphomannomutase 2-deficient cells, reveal CA2 as a potential cellular biomarker and confirm B-LCL as an advantageous model for CDG studies.
Subject(s)
Congenital Disorders of Glycosylation , Epstein-Barr Virus Infections , Animals , Cell Line , Congenital Disorders of Glycosylation/genetics , Congenital Disorders of Glycosylation/metabolism , Glycosylation , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Humans , Phosphotransferases (Phosphomutases)/deficiency , RNA/metabolismABSTRACT
INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.
Subject(s)
Gain of Function Mutation , Janus Kinase Inhibitors , STAT1 Transcription Factor , Child , Humans , Janus Kinase Inhibitors/therapeutic use , Multicenter Studies as Topic , Retrospective Studies , STAT1 Transcription Factor/geneticsABSTRACT
BACKGROUND: Phosphoglucomutase-3 (PGM3) deficiency is a congenital disorder of glycosylation (CDG) with hyperimmunoglobulin IgE, atopy, and a variable immunological phenotype; most reported patients display dysmorphic features. The aim of the study was to characterize the genotype and phenotype of individuals with newly identified compound heterozygous variants in the phosphate-binding domain of PGM3 in order to better understand phenotypic differences between these patients and published cases. METHODS: We analyzed PGM3 protein expression, PGM3 enzymatic activity, the presence of other gene variants within the N-glycosylation pathway, and the clinical and immunological manifestations of two affected siblings. RESULTS: Patients belonged to a non-consanguineous family, presenting with atopic dermatitis, elevated levels of IgE, and CD4+ lymphopenia (a more severe phenotype was observed in Patient 2), but lacked dysmorphic features or neurocognitive impairment. Compound heterozygous PGM3 variants were identified, located in the phosphate-binding domain of the enzyme. PGM3 expression was comparable to healthy donors, but L-PHA binding in naïve-CD4+ cells was decreased. Examination of exome sequence identified the presence of one additional candidate variant of unknown significance (VUS) in the N-glycosylation pathway in Patient 2: a variant predicted to have moderate-to-high impact in ALG12. CONCLUSIONS: Our analysis revealed that L-PHA binding is reduced in naïve-CD4+ cells, which is consistent with decreased residual PGM3 enzymatic activity. Other gene variants in the N-glycosylation pathway may modify patient phenotypes in PGM3 deficiency. This study expands the clinical criteria for when PGM3 deficiency should be considered among individuals with hyper-IgE.
Subject(s)
Dermatitis , Lymphopenia , Humans , Immunoglobulin E , Mutation , Phenotype , Phosphoglucomutase/geneticsABSTRACT
Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.
Subject(s)
Candidiasis, Chronic Mucocutaneous/immunology , Primary Immunodeficiency Diseases/immunology , Azoles/therapeutic use , Candida/immunology , Candida/isolation & purification , Candidiasis, Chronic Mucocutaneous/diagnosis , Candidiasis, Chronic Mucocutaneous/genetics , Candidiasis, Chronic Mucocutaneous/therapy , Humans , Interleukin-17/genetics , Interleukin-17/immunology , Janus Kinase Inhibitors/therapeutic use , Mutation , Primary Immunodeficiency Diseases/diagnosis , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/therapy , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunology , Th17 Cells/immunology , Th17 Cells/pathologyABSTRACT
Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient's B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.
Subject(s)
Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/genetics , Mutation , Phospholipase C gamma/genetics , Adolescent , Agammaglobulinemia/therapy , Autoimmunity/genetics , Biomarkers , Caspase 1/metabolism , Child , Cytokines/metabolism , DNA Mutational Analysis , Female , Genetic Association Studies , Genetic Predisposition to Disease , Hereditary Autoinflammatory Diseases/therapy , Humans , Inflammasomes/metabolism , Male , Pedigree , Phenotype , Phospholipase C gamma/chemistry , Phospholipase C gamma/metabolism , Structure-Activity RelationshipABSTRACT
The integrity of the interferon (IFN)-γ circuit is necessary to mount an effective immune response to intra-macrophagic pathogens, especially Mycobacteria. Inherited monogenic defects in this circuit that disrupt the production of, or response to, IFN-γ underlie a primary immunodeficiency known as Mendelian susceptibility to mycobacterial disease (MSMD). Otherwise healthy patients display a selective susceptibility to clinical disease caused by poorly virulent mycobacteria such as BCG (bacille Calmette-Guérin) vaccines and environmental mycobacteria, and more rarely by other intra-macrophagic pathogens, particularly Salmonella and M. tuberculosis. There is high genetic and allelic heterogeneity, with 19 genetic etiologies due to mutations in 10 genes that account for only about half of the patients reported. An efficient laboratory diagnostic approach to suspected MSMD patients is important, because it enables the establishment of specific therapeutic measures that will improve the patient's prognosis and quality of life. Moreover, it is essential to offer genetic counseling to affected families. Herein, we review the various genetic and immunological diagnostic approaches that can be used in concert to reach a molecular and cellular diagnosis in patients with MSMD.
Subject(s)
Genetic Predisposition to Disease/genetics , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Interferon-gamma/genetics , Molecular Diagnostic Techniques , Mycobacterium Infections/genetics , BCG Vaccine , Humans , MycobacteriumABSTRACT
PURPOSE: Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient's prognosis. METHODS: We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rß1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species. RESULTS: We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rß1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response. CONCLUSIONS: We report the first Peruvian patient with IL-12Rß1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.
Subject(s)
BCG Vaccine/immunology , Disease Susceptibility , Mycobacterium tuberculosis/immunology , Receptors, Interleukin-12/deficiency , Tuberculosis, Multidrug-Resistant/genetics , Tuberculosis, Multidrug-Resistant/immunology , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Child , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Humans , Male , Mutation , Mycobacterium tuberculosis/drug effects , Peru , Prognosis , Severity of Illness Index , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/microbiologyABSTRACT
BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.
Subject(s)
Immunologic Deficiency Syndromes/complications , Immunosuppressive Agents/therapeutic use , Lung Diseases, Interstitial/drug therapy , Sirolimus/therapeutic use , T-Lymphocytes, Regulatory/metabolism , Abnormalities, Multiple/immunology , Adolescent , Biomarkers/metabolism , Child , Face/abnormalities , Female , Hematologic Diseases/complications , Hematologic Diseases/immunology , Humans , Immunologic Deficiency Syndromes/immunology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/immunology , Male , Vestibular Diseases/complications , Vestibular Diseases/immunologyABSTRACT
Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical uterus to a world full of antigens and the rapid microbial colonization of the mucosa. B regulatory (Breg) cells are a recently discovered B cell subset thought to play a pivotal role in different conditions such as chronic infections, autoimmunity, cancer, and transplantation among others in addition to pregnancy. This review focuses on the role of Breg cells in pregnancy and early infancy, two special stages of life in which recent studies have positioned Breg cells as important players.
Subject(s)
B-Lymphocytes, Regulatory/metabolism , Disease , Female , Health , Humans , Immune System/metabolism , Infant, Newborn , PregnancyABSTRACT
BACKGROUND: Evans syndrome (ES) is a rare immune disorder in children, manifested by simultaneous or sequential autoimmune cytopenias (ACs) of unknown cause and having a chronic course with periods of exacerbation and remission. Some primary immunodeficiencies (PIDs) may present with autoimmune manifestations without infections, masking suspicion of them. The PIDs that can typically manifest as ES are autoimmune lymphoproliferative syndrome and common variable immunodeficiency (CVID). MATERIALS AND METHODS: Review of clinical charts and laboratory results of pediatric patients followed-up in the outpatient clinic of PID with a diagnosis of ES and humoral immunodeficiency. RESULTS: Three pediatric patients, a boy and 2 girls, presented with corticosteroid-dependent ES. In the diagnostic approach, autoimmune lymphoproliferative syndrome was ruled out, and during follow-up, patients showed laboratory signs of humoral immune deficiency and were diagnosed with CVID. After initiating the recommended treatment for CVID with AC, patients improved without new exacerbations. CONCLUSIONS: These cases highlight the importance of detection of possible PID in the context of ES and the establishment of CVID treatment to control AC.
Subject(s)
Anemia, Hemolytic, Autoimmune/immunology , Common Variable Immunodeficiency/diagnosis , Immunologic Deficiency Syndromes/pathology , Thrombocytopenia/immunology , Autoimmune Lymphoproliferative Syndrome , Child , Child, Preschool , Common Variable Immunodeficiency/therapy , Diagnosis, Differential , Female , Humans , MaleABSTRACT
Background: We sought to identify resistance patterns and key drivers of recent multidrug-resistant tuberculosis (MDR-TB) transmission in a TB-prevalent area in Peru. Methods: Cross-sectional study including MDR Mycobacterium tuberculosis complex (Mtbc) strains identified in Callao-Peru between April 2017 and February 2019. Mtbc DNA was extracted for whole genome sequencing which was used for phylogenetic inference, clustering, and resistance mutation analyses. Clusters indicative of recent transmission were defined based on a strain-to-strain distance of ≤5 (D5) single nucleotide polymorphisms (SNPs). Epidemiologic factors linked to MDR-TB clustering were analyzed using Poisson regression. Findings: 171 unique MDR-Mtbc strains were included; 22 (13%) had additional fluoroquinolone resistance and were classified as pre-XDR. Six strains (3.5%) harboured bedaquiline (BDQ) resistance mutations and were classified as MDR + BDQ. 158 (92%) Mtbc strains belonged to lineage 4 and 13 (8%) to lineage 2. Using a cluster threshold of ≤5 SNPs, 98 (57%) strains were grouped in one of the 17 D5 clusters indicative of recent transmission, ranging in size from 2 to the largest cluster formed by 53 4.3.3 strains (group_1). Lineage 4.3.3 strains showed the overall highest cluster rate (43%). In multivariate analyses, current or previous imprisonment was independently associated with being part of any MDR-TB transmission clusters (adjusted prevalence ratio [aPR], 1.45; 95% CI, 1.09-1.92). Interpretation: Pre-XDR-TB emerged in more than 10% of the MDR-TB strains investigated. Transmission of 4.3.3 Mtbc strains especially of the dominant group_1 clone is a major driver of the MDR-TB epidemic in Callao. Current or previous imprisonment was linked to recent MDR-TB transmissions, indicating an important role of prisons in driving the MDR-TB epidemic. Funding: This work was supported in part by the ERANet-LAC Network of the European Union, Latin America and the Caribbean Countries on Joint Innovation and Research Activities, and FONDECYT. Additional support was received from Leibniz Science Campus Evolutionary Medicine of the Lung, the Deutsche Forschungsgemeinschaft (German Research Foundation, under Germany's Excellence Strategy-EXC 2167 Precision Medicine in Inflammation), and the Research Training Group 2501 TransEvo.
ABSTRACT
AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5-6 dimerization domain, but was still able to homodimerize with WT AIOLOS and negatively regulate DNA binding through ZF1, a previously unrecognized function for this domain. Missense mutant E82K showed overall normal AIOLOS functions; however, by affecting a redefined AIOLOS protein stability domain, it also led to haploinsufficiency. Patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent infections, autoimmunity, and allergy, but with incomplete clinical penetrance. Altogether, these data redefine the AIOLOS structure-function relationship and expand the spectrum of AIOLOS-associated diseases.
Subject(s)
Haploinsufficiency , Trans-Activators , Humans , DNA , Gene Expression Regulation , Trans-Activators/metabolism , Transcription Factors/geneticsABSTRACT
The interpretation of clinical diagnostic results in suspected inborn errors of immunity, including Tregopathies, is hampered by the lack of age-stratified reference values for regulatory T cells (Treg) in the pediatric population and a consensus on which Treg immunophenotype to use. Regulatory B cells (Breg) are an important component of the regulatory system that have been poorly studied in the pediatric population. We analyzed (1) the correlation between the three immunophenotypic definitions of Treg (CD4+CD25hiCD127low, CD4+CD25hiCD127lowFoxP3+, CD4+CD25hiFoxP3+), and with CD4+CD25hi and (2) the changes in Treg and Breg frequencies and their maturation status with age. We performed peripheral blood immunophenotyping of Treg and Breg (CD19+CD24hiCD38hi) by flow cytometry in 55 healthy pediatric controls. We observed that Treg numbers varied depending on the definition used, and the frequency ranged between 3.3-9.7% for CD4+CD25hiCD127low, 0.07-1.6% for CD4+CD25hiCD127lowFoxP3+, and 0.24-2.83% for CD4+CD25hiFoxP3+. The correlation between the three definitions of Treg was positive for most age ranges, especially between the two intracellular panels and with CD4+CD25hi vs CD4+CD25hiCD127low. Treg and Breg frequencies tended to decline after 7 and 3 years onwards, respectively. Treg's maturation status increased with age, with a decline of naïve Treg and an increase in memory/effector Treg from age 7 onwards. Memory Breg increased progressively from age 3 onwards. In conclusion, the number of Treg frequencies spans a wide range depending on the immunophenotypic definition used despite a good level of correlation exists between them. The decline in numbers and maturation process with age occurs earlier in Breg than in Treg.
Subject(s)
B-Lymphocytes, Regulatory , T-Lymphocytes, Regulatory , Humans , Child , Child, Preschool , Flow Cytometry , Antigens, CD19 , Forkhead Transcription Factors/geneticsABSTRACT
Regulatory T cells (Treg) are essential for immune balance, preventing overreactive responses and autoimmunity. Although traditionally characterized as CD4+CD25+CD127lowFoxP3hi, recent research has revealed diverse Treg subsets such as Tr1, Tr1-like, and CD8 Treg. Treg dysfunction leads to severe autoimmune diseases and immune-mediated inflammatory disorders. Inborn errors of immunity (IEI) are a group of disorders that affect correct functioning of the immune system. IEI include Tregopathies caused by genetic mutations affecting Treg development or function. In addition, Treg dysfunction is also observed in other IEIs, whose underlying mechanisms are largely unknown, thus requiring further research. This review provides a comprehensive overview and discussion of Treg in IEI focused on: A) advances and controversies in the evaluation of Treg extended subphenotypes and function; B) current knowledge and gaps in Treg disturbances in Tregopathies and other IEI including Treg subpopulation changes, genotype-phenotype correlation, Treg changes with disease activity, and available therapies, and C) the potential of Treg cell-based therapies for IEI with immune dysregulation. The aim is to improve both the diagnostic and the therapeutic approaches to IEI when there is involvement of Treg. We performed a non-systematic targeted literature review with a knowledgeable selection of current, high-quality original and review articles on Treg and IEI available since 2003 (with 58% of the articles within the last 6 years) in the PubMed database.
Subject(s)
Autoimmune Diseases , T-Lymphocytes, Regulatory , Humans , Autoimmunity , Databases, Factual , MutationABSTRACT
Purpose: To describe SARS-CoV-2 infection outcome in unvaccinated children and young adults with inborn errors of immunity (IEI) and to compare their specific acute and long-term immune responses with a sex-, age-, and severity-matched healthy population (HC). Methods: Unvaccinated IEI patients up to 22 years old infected with SARS-CoV-2 were recruited along with a cohort of HC. SARS-CoV-2 serology and ELISpot were performed in the acute phase of infection (up to 6 weeks) and at 3, 6, 9, and 12 months. Results: Twenty-five IEI patients (median age 14.3 years, min.-max. range 4.5-22.8; 15/25 males; syndromic combined immunodeficiencies: 48.0%, antibody deficiencies: 16.0%) and 17 HC (median age 15.3 years, min.-max. range 5.4-20.0; 6/17 males, 35.3%) were included. Pneumonia occurred in 4/25 IEI patients. In the acute phase SARS-CoV-2 specific immunoglobulins were positive in all HC but in only half of IEI in whom it could be measured (n=17/25): IgG+ 58.8% (10/17) (p=0.009); IgM+ 41.2% (7/17)(p<0.001); IgA+ 52.9% (9/17)(p=0.003). Quantitative response (index) was also lower compared with HC: IgG IEI (3.1 ± 4.4) vs. HC (3.5 ± 1.5)(p=0.06); IgM IEI (1.9 ± 2.4) vs. HC (3.9 ± 2.4)(p=0.007); IgA IEI (3.3 ± 4.7) vs. HC (4.6 ± 2.5)(p=0.04). ELISpots positivity was qualitatively lower in IEI vs. HC (S-ELISpot IEI: 3/11, 27.3% vs. HC: 10/11, 90.9%; p=0.008; N-ELISpot IEI: 3/9, 33.3% vs. HC: 11/11, 100%; p=0.002) and also quantitatively lower (S-ELISpot IEI: mean index 3.2 ± 5.0 vs. HC 21.2 ± 17.0; p=0.001; N-ELISpot IEI: mean index 9.3 ± 16.6 vs. HC: 39.1 ± 23.7; p=0.004). As for long term response, SARS-CoV-2-IgM+ at 6 months was qualitatively lower in IEI(3/8, 37.5% vs. 9/10 HC: 90.0%; p=0.043), and quantitatively lower in all serologies IgG, M, and A (IEI n=9, 1.1 ± 0.9 vs. HC n=10, 2.1 ± 0.9, p=0.03; IEI n=9, 1.3 ± 1.5 vs. HC n=10, 2.9 ± 2.8, p=0.02; and IEI n=9, 0.6 ± 0.5 vs. HC n=10, 1.7 ± 0.8, p=0.002 -respectively) but there were no differences at remaining time points. Conclusions: Our IEI pediatric cohort had a higher COVID-19 pneumonia rate than the general age-range population, with lower humoral and cellular responses in the acute phase (even lower compared to the reported IEI serological response after SARS-CoV-2 vaccination), and weaker humoral responses at 6 months after infection compared with HC.
Subject(s)
COVID-19 , Primary Immunodeficiency Diseases , Male , Humans , Child , Young Adult , Adolescent , SARS-CoV-2 , COVID-19 Vaccines , Immunoglobulin M , Immunity , Immunoglobulin A , Immunoglobulin GABSTRACT
It is unclear why COVID-19 ranges from asymptomatic to severe. When SARS-CoV-2 is detected, interferon (IFN) response is activated. When it is insufficient or delayed, it might lead to overproduction of cytokines and severe COVID-19. The aim was to compare cytokine and IFN patterns in children and adults with differing severity with SARS-CoV-2.It was a prospective, observational study, including 84 patients. Patients with moderate/severe disease had higher cytokines' values than patients with mild disease (p< 0.001).Two IFN genes were selected to build a decision tree for severity classification: SOCS1 (representative of the rest of the IFN genes) and CIITA (inverse correlation). Low values of CIITA and high values of SOCS1 indicated severe disease. This method correctly classified 33/38(86.8%) of children and 27/34 (79.4%) of adults. To conclude, patients with severe disease had an elevated cytokine pattern, which correlated with the IFN response, with low CIITA and high SOCS1 values.
ABSTRACT
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is a T-cell hyperactivation disorder that can manifest with both immunodeficiency and immune dysregulation. Approximately one-third of patients may present mild symptoms and remain stable under supportive care. The remaining patients may develop severe multiorgan autoimmunity requiring lifelong immunosuppressive treatment. Hematopoietic stem cell transplantation (HSCT) is potentially curable for patients with treatment-resistant immune dysregulation. Nevertheless, little experience is reported regarding the management of complications post-HSCT. We present case 1 (CTLA-4 haploinsufficiency) and case 2 (CTLA-4 insufficiency-like phenotype) manifesting with severe autoimmunity including cytopenia and involvement of the central nervous system (CNS), lung, and gut and variable impairment of humoral responses. Both patients underwent HSCT for which the main complications were persistent mixed chimerism, infections, and immune-mediated complications [graft-versus-host disease (GVHD) and nodular lung disease]. Detailed management and outcomes of therapeutic interventions post-HSCT are discussed. Concretely, post-HSCT abatacept and human leukocyte antigen (HLA)-matched sibling donor lymphocyte infusions may be used to increase T-cell donor chimerism with the aim of correcting the immune phenotype of CTLA-4 haploinsufficiency.