ABSTRACT
The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.
Subject(s)
Agammaglobulinemia , Common Variable Immunodeficiency , Humans , Female , Alleles , Antibodies , CD40 Ligand , Chromosomes , I-kappa B KinaseABSTRACT
Intrathecal production of kappa free light chains occurs in multiple sclerosis and can be measured using the kappa free light chain index. Kappa free light chain index values can be determined more easily than oligoclonal bands detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of oligoclonal bands, kappa free light chain index cut-offs 5.9, 6.6 and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome inception cohort. We selected patients with sufficient data to determine oligoclonal bands positivity, MRI dissemination in space and time, IgG index and sufficient quantities of paired CSF and blood samples to determine kappa free light chain indexes (n = 214). We used Kendall's Tau coefficient to estimate concordance, calculated the number of additional diagnoses when adding each positive index to dissemination in space and positive oligoclonal bands, performed survival analyses for oligoclonal bands and each index with the outcomes second attack and 2017 MRI dissemination in space and time and estimated the diagnostic properties of oligoclonal bands and the different indexes for the previously mentioned outcomes at 5 years. Oligoclonal bands were positive in 138 patients (64.5%), kappa free light chain-5.9 in 136 (63.6%), kappa free light chain-6.6 in 135 (63.1%), kappa free light chain-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between oligoclonal bands and kappa free light chain-6.6 (τ = 0.727) followed by oligoclonal bands and kappa free light chain-5.9 (τ = 0.716). Combining dissemination in space plus oligoclonal bands or kappa free light chain-5.9 increased the number of diagnosed patients by 11 (5.1%), with kappa free light chain-6.6 by 10 (4.7%), with kappa free light chain-10.61 by 9 (4.2%) and with IgG index by 3 (1.4%). Patients with positive oligoclonal bands or indexes reached second attack and MRI dissemination in space and time faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [adjusted hazard ratio (95% confidence interval)], the risk for second attack was very similar between kappa free light chain-5.9 [2.0 (0.9-4.3), P = 0.068] and kappa free light chain-6.6 [2.1 (1.1-4.2), P = 0.035]. The highest risk for MRI dissemination in space and time was demonstrated with kappa free light chain-5.9 [4.9 (2.5-9.6), P < 0.0001], followed by kappa free light chain-6.6 [3.4 (1.9-6.3), P < 0.0001]. Kappa free light chains-5.9 and -6.6 had a slightly higher diagnostic accuracy than oligoclonal bands for second attack (70.5, 71.1 and 67.8) and MRI dissemination in space and time (85.7, 85.1 and 81.0). Kappa free light chain indexes 5.9 and 6.6 performed slightly better than oligoclonal bands to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between oligoclonal bands and these indexes, we suggest using dissemination in space plus positive oligoclonal bands or positive kappa free light chain index as a modified criterion to diagnose multiple sclerosis.
Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Humans , Oligoclonal Bands , Immunoglobulin kappa-Chains , Demyelinating Diseases/diagnosis , Multiple Sclerosis/diagnostic imaging , Immunoglobulin GABSTRACT
Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which â¼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
Subject(s)
B-Lymphocytes/immunology , Cytidine Deaminase/physiology , DNA Methylation , Hyper-IgM Immunodeficiency Syndrome/genetics , Hyper-IgM Immunodeficiency Syndrome/immunology , Autoimmunity , B-Lymphocytes/metabolism , Cytidine Deaminase/deficiency , Cytidine Deaminase/genetics , Germinal Center/immunology , Humans , Hyper-IgM Immunodeficiency Syndrome/metabolism , Immune Tolerance , Immunologic Memory , Receptors, Antigen, B-Cell/genetics , Transcriptome , Whole Genome SequencingABSTRACT
In 2019, the Public Health Agency of Barcelona, Spain, was notified of a vaccine-derived poliovirus infection. The patient had an underlying common variable immunodeficiency and no signs of acute flaccid paralysis. We describe the ongoing coordinated response to contain the infection, which included compassionate-use treatment with pocapavir.
Subject(s)
Poliomyelitis , Poliovirus , Disease Eradication , Humans , Poliovirus Vaccine, Oral , SpainABSTRACT
Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Gluâ¯∗â¯48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1ß, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.
Subject(s)
B-Lymphocytes/physiology , Common Variable Immunodeficiency/immunology , Gastrointestinal Diseases/immunology , NF-kappa B/genetics , Sequence Deletion/genetics , Th1 Cells/physiology , Adolescent , Adult , Agammaglobulinemia , Cells, Cultured , Common Variable Immunodeficiency/genetics , Cytokines/metabolism , Female , Gastrointestinal Diseases/genetics , Humans , Inflammation Mediators/metabolism , Male , Nod2 Signaling Adaptor Protein/genetics , Respiratory Tract Infections , Young AdultABSTRACT
Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The close relationship between immune-mediated disorders makes it mandatory to perform serological screening periodically in order to avoid delayed diagnosis of additional autoimmune diseases. We studied a patient with type 1 diabetes (T1D) who later developed an autoimmune thyroid disease (ATD) and was referred to our hospital with a serious condition of his clinical status. The patient was suffering from an advance stage of celiac disease (CD), the delay in its diagnosis and in the establishment of a gluten-free dietled the patient to a severe proteincalorie malnutrition. Later, the patient developed an autoimmune hepatitis (AIH). We consider that clinical deterioration in patients with APS should alert physicians about the possible presence of other immune-mediated diseases. Periodic screening for autoantibodies would help to prevent delayed diagnosis and would improve patient's quality of life.
Subject(s)
Celiac Disease/diagnosis , Diabetes Mellitus, Type 1/diagnosis , Hepatitis, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/diagnosis , Protein-Energy Malnutrition/diagnosis , Thyroiditis, Autoimmune/diagnosis , Autoantibodies/immunology , Celiac Disease/complications , Celiac Disease/diet therapy , Celiac Disease/immunology , Delayed Diagnosis , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/immunology , Diet, Gluten-Free , Hepatitis, Autoimmune/complications , Hepatitis, Autoimmune/immunology , Humans , Male , Middle Aged , Polyendocrinopathies, Autoimmune/complications , Polyendocrinopathies, Autoimmune/immunology , Protein-Energy Malnutrition/etiology , Thyroiditis, Autoimmune/complications , Thyroiditis, Autoimmune/immunologyABSTRACT
Celiac disease (CD) is a complex immune-related disease with a very strong genetic component. Multiple genetic findings over the last decade have added to the already known MHC influence numerous genetic variants associated to CD susceptibility. Currently, it is well-established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci. Together, the firmly described genetic variants account for roughly 31% of CD heritability, being 25% explained by the MHC influence. These new variants represent markers of disease risk and turn the identification of the causal genes and the causal variants inside the associated loci, as well as their precise biological role on the disease, into a major challenge in CD research. Numerous studies have been developed with this aim showing the high impact of risk variants on gene expression. These studies also indicate a central role of CD4(+) T cells in CD pathogenesis and point to B cells as important players, which is in accordance with the key steps highlighted by the immunological models of pathogenesis. We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions. These findings are leading to a better understanding of CD pathogenesis and helping in the design of new treatments. The repertoire of potential drug targets for CD has largely broadened last years, bringing us closer to get alternative or complementary treatments to the life-long gluten-free diet, the only effective treatment so far. Epigenetics and microbiota are emerging as potent factors modulating disease risk and putatively affecting disease manifestation, which are also being explored as therapeutic targets.
Subject(s)
Celiac Disease/genetics , Genetic Predisposition to Disease , Animals , Celiac Disease/epidemiology , Celiac Disease/immunology , Celiac Disease/microbiology , Celiac Disease/therapy , Epigenesis, Genetic , Gastrointestinal Microbiome , Genetic Association Studies , Genetic Loci , Genetic Variation , Humans , RiskSubject(s)
Celiac Disease/genetics , Genotype , HLA-DQ Antigens/genetics , Gene Frequency , Humans , SpainABSTRACT
Syndromic immunodeficiencies are a heterogeneous group of inborn errors of immunity that can affect the development of non-immune organs and systems. The genetic basis of these immunodeficiencies is highly diverse, ranging from monogenic defects to large chromosomal aberrations. Antibody deficiency is the most prevalent immunological abnormality in patients with syndromic immunodeficiencies caused by chromosomal rearrangements, and usually manifests as a common variable immunodeficiency (CVID)-like phenotype. Here we describe a patient with a complex phenotype, including neurodevelopmental delay, dysmorphic features, malformations, and CVID (hypogammaglobulinemia, reduced pre-switch and switch memory B cells, and impaired vaccine response). Microarray-based comparative genomic hybridization (aCGH) revealed a 13-Mb deletion on chromosome 4q22.2-q24 involving 53 genes, some of which were related to the developmental manifestations in our patient. Although initially none of the affected genes could be linked to his CVID phenotype, subsequent reanalysis identified NFKB1 haploinsufficiency as the cause. This study underscores the value of periodic reanalysis of unsolved genetic studies performed with high-throughput technologies (eg, next-generation sequencing and aCGH). This is important because of the ongoing incorporation of new data establishing the relationship between genes and diseases. In the present case, NFKB1 had not been associated with human disease at the time aCGH was performed. Eight years later, reanalysis of the genes included in the chromosome 4 deletion enabled us to identify NFKB1 haploinsufficiency as the genetic cause of our patient's CVID. In the future, other genes included in the deletion may be linked to human disease, allowing us to better define the molecular basis of our patient's complex clinical phenotype.
Subject(s)
Agammaglobulinemia , Common Variable Immunodeficiency , Primary Immunodeficiency Diseases , Chromosome Aberrations , Chromosome Deletion , Chromosomes, Human, Pair 4 , Common Variable Immunodeficiency/genetics , Comparative Genomic Hybridization , Humans , NF-kappa B p50 SubunitABSTRACT
Myelin basic protein (MBP) is thought to be one of the key autoantigens in multiple sclerosis (MS) development. A recent study described the association of the single nucleotide polymorphism (SNP) rs12959006, within the MBP gene, with a higher risk of relapse and worse prognosis. We aim at studying potential associations of this SNP to MS in an independent population. Clinical data of the first 5 years of the disease were collected retrospectively from 291 MS confirmed patients. MBP polymorphism rs12959006 was genotyped in all patients. Associations with EDSS, number of relapses and serology for Herpesvirus 6 (HHV-6) and Epstein Barr (EBV) viruses were studied. Lymphocyte activation measured by CD69 expression was also analyzed according to sex and rs12959006 genotype. The rs12959006 polymorphism contributed significantly to a higher number of relapses at 5 years after onset only in male patients (rs12959006∗TT ß = 0.74 [0.36-1.09]; p = 7 × 10-5). Titers of anti-HHV6 IgG antibodies showed also a mild association with relapses, both in male and female patients (ß = 0.01 [0.01-0.02]; p = 3.7 × 10-8). Both the genetic variation in MBP and HHV-6 infection aid in predicting a higher number of relapses during the first years of MS. The association described in MBP rs12959006∗T is exclusive to male patients.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting/genetics , Multiple Sclerosis, Relapsing-Remitting/immunology , Myelin Basic Protein/genetics , Polymorphism, Single Nucleotide , Adult , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , Female , Follow-Up Studies , Genotype , Herpesvirus 4, Human/immunology , Herpesvirus 6, Human/immunology , Humans , Male , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/epidemiology , Prognosis , Recurrence , Retrospective Studies , Roseolovirus Infections/complications , Roseolovirus Infections/immunology , Roseolovirus Infections/virology , Sex Factors , Spain/epidemiology , Young AdultABSTRACT
BACKGROUND AND AIM: To diagnose coeliac disease (CD) in individuals on a gluten free diet (GFD), we aimed to assess the utility of detecting activated γδ and CD8â¯T cells expressing gut-homing receptors after a short gluten challenge. METHODS: We studied 15 CD patients and 35 non-CD controls, all exposed to three days of gluten when following a GFD. Peripheral blood was collected before and six days after starting gluten consumption, and the expression of CD103, ß7 and CD38 in γδ and CD8â¯T cells was assessed by flow cytometry. Determination of IFN-γ and IP-10 was performed by means of ELISPOT and/or Luminex technology. RESULTS: We observed both γδ and CD8â¯T cells coexpressing CD103, ß7hi and CD38 in every patient with CD on day six, but only in one control. The studied CD8â¯T subpopulation was easier to detect than the γδ subpopulation. Increased IFN-γ and IP-10 levels after challenge were observed in patients with CD, but not in controls. CONCLUSION: A short three-day gluten challenge elicits the activation of CD103+ ß7hi CD8+ T cells in CD. These cells can be detected by flow cytometry in peripheral blood, opening new possibilities for CD diagnosis in individuals on a GFD.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Celiac Disease/diagnosis , Celiac Disease/immunology , Glutens/administration & dosage , Adolescent , Adult , Aged , Child , Diet, Gluten-Free , Female , Flow Cytometry , HLA-DQ Antigens/analysis , Humans , Immunophenotyping , Interferon-gamma/immunology , Intestinal Mucosa/immunology , Lymphocyte Activation , Male , Middle Aged , T-Lymphocyte Subsets/immunology , Young AdultABSTRACT
Antibiotics remain the mainstay of treatment for infectious diseases, but the growing frequency of antibiotic resistance represents a major concern for healthcare worldwide. The use of antibiotics in recurrent infections raises other issues, such as their limitations for treating diverse microorganisms, deleterious effects on the microbiota of the patient and potential adverse effects. In recent years, progress has been made towards the development of novel polybacterial vaccines administered via the mucosal route. These drugs target both the innate and adaptive immune systems, at the actual point of entry of most pathogens. In addition to boosting immune responses, mucosal bacterial vaccines have an intriguing immunomodulatory activity that does not compromise their efficacy against infectious agents. We review here the current clinical evidence concerning the efficacy and safety of these mucosal vaccines for the prevention and treatment of recurrent infection. We also provide an overview completing the landscape of the potential clinical uses of these active biological agents.
Subject(s)
Adaptive Immunity/drug effects , Bacterial Vaccines/administration & dosage , Immunity, Innate/drug effects , Administration, Mucosal , Bacterial Infections/prevention & control , Bacterial Infections/therapy , Bacterial Vaccines/adverse effects , Humans , RecurrenceABSTRACT
Recent findings demonstrate the common genetic basis for many immune-mediated diseases, and consequently, the partially shared pathogenesis. We collected these findings and reviewed the extension of these overlaps to other disease characteristics. Two autoimmune diseases were selected that also share the specific target organ, the bowel. The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation, inflammatory bowel disease (IBD) and celiac disease (CeD), are not completely understood. Both are complex diseases with genetics and environment contributing to dysregulation of innate and adaptive immune responses, leading to chronic inflammation and disease. CeD constitutes a particular disease because the main environmental and genetic triggers are largely known. IBD comprises two main clinical forms, Crohn's disease and ulcerative colitis, which most likely involve a complex interplay between some components of the commensal microbiota and other environmental factors in their origin. These multifactorial diseases encompass a broad spectrum of clinical phenotypes and ages of onset, although the clinical presentation often differs depending on childhood or adult onset, with greater heterogeneity commonly observed in adults.