RESUMEN
Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker.
Asunto(s)
Deficiencia de IgA , Humanos , Bacterias , Escherichia coli , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunoglobulina A , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Polyautoimmunity or multiple autoimmune syndrome (MAIS) is increasingly being recognized in pediatric clinical practice, often in conjunction with systemic lupus erythematosus (SLE). Besides multi-organ autoimmunity, children with SLE are often at a higher risk of developing infections including tuberculosis. The tendency to develop infections and multiple autoimmune diseases in childhood SLE often occurs in the absence of monogenic primary immunodeficiency disease. Conversely, children with inborn errors of immunity, of which selective IgA deficiency (sIgAD) is the most common, may develop recurrent infections and autoimmune disorders including SLE. Herein, we report a child with MAIS (including SLE) and sIgAD who developed drug-resistant tuberculosis, which was managed successfully with second-line anti-tubercular drug therapy. To the best of our knowledge, this combination of rare findings has not been reported previously in the pediatric literature. Although a majority of patients with sIgAD are either asymptomatic or have mild infections/autoimmunity, the index child had a myriad of infectious illnesses and multi-organ autoimmunity. Our case highlights the prudence of thoroughly evaluating children with SLE for other autoimmune diseases and vice versa. Given the higher probability of inherited disorders, including early complement deficiencies and monogenic interferonopathies, in childhood SLE compared with adult SLE, it may be prudent to perform a basic immunological workup (for example, immunoglobulin levels, 50% hemolytic complement) in such patients. A more extensive immunological and genetic evaluation (including next-generation sequencing) may also be required in the presence of unusual clinical or laboratory features, a positive family history, or a complicated clinical course.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Autoinmunidad , Deficiencia de IgA/complicaciones , Tuberculosis Resistente a Múltiples Medicamentos/complicaciones , Enfermedades Autoinmunes/inmunología , Niño , Femenino , Humanos , Deficiencia de IgA/inmunología , Síndrome , Tuberculosis Resistente a Múltiples Medicamentos/inmunologíaRESUMEN
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).
Asunto(s)
Ataxia Telangiectasia/inmunología , Ataxia Telangiectasia/mortalidad , Linfocitos B/inmunología , Deficiencia de IgA/inmunología , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Deficiencia de IgA/mortalidad , Deficiencia de IgG/inmunología , Deficiencia de IgG/mortalidad , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lactante , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Selective IgA deficiency (SIgAD), characterized by a serum IgA level below 0.07 mg/ml, while displaying normal serum levels of IgM and IgG antibodies, is the most frequently occurring primary immunodeficiency that reveals itself after the first four years after birth. These individuals with SIgAD are for the majority healthy and even when they are identified they are usually not investigated further or followed up. However, recent studies show that newborns and young infants already display clinical manifestations of this condition due to aberrancies in their immune defense. Interestingly, there is a huge heterogeneity in the clinical symptoms of the affected individuals. More than 50% of the affected individuals do not have clinical symptoms, while the individuals that do show clinical symptoms can suffer from mild to severe infections, allergies and autoimmune diseases. However, the reason for this heterogeneity in the manifestation of clinical symptoms of the individuals with SIgAD is unknown. Therefore, this review focusses on the characteristics of innate immune system driving T-cell independent IgA production and providing a mechanism underlying the development of SIgAD. Thereby, we focus on some important genes, including TNFRSF13B (encoding TACI), associated with SIgAD and the involvement of epigenetics, which will cover the methylation degree of TNFRSF13B, and environmental factors, including the gut microbiota, in the development of SIgAD. Currently, no specific treatment for SIgAD exists and novel therapeutic strategies could be developed based on the discussed information.
Asunto(s)
Deficiencia de IgA/inmunología , Inmunidad Innata/inmunología , Inmunoglobulina A/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/inmunología , Epigénesis Genética/genética , Epigénesis Genética/inmunología , Microbioma Gastrointestinal/inmunología , Humanos , Deficiencia de IgA/genética , Deficiencia de IgA/metabolismo , Inmunidad Innata/genética , Inmunoglobulina A/sangre , Lactante , Recién Nacido , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
IgA is the most abundant Ab in the human body. However, most patients with selective IgA deficiency (SIgAD) are asymptomatic. IgM, and to lesser extent IgG Abs, are generally presumed to compensate for the lack of IgA in SIgAD by multiplying and adopting functions of IgA. We used data from the Northern Finland Birth Cohort 1966 to investigate whether SIgAD patients have differences in levels of natural Abs to oxidized epitopes compared with 20 randomly selected healthy controls. First, we screened the saliva and serum samples from the Northern Finland Birth Cohort 1966 cohort (n = 1610) for IgA concentration. We detected five IgA-deficient subjects, yielding a prevalence of 0.3%, which is consistent with the general prevalence of 0.25% in the Finnish population. To detect natural Abs, we used malondialdehyde acetaldehyde-low-density lipoprotein (MAA-LDL), an Ag known to bind natural Abs. In this study, we show that natural secretory IgM and IgG Abs to MAA-DL were significantly increased in subjects with SIgAD. Given that secretory IgA is an important part of mucosal immune defense and that, in the gut microbiota, dysbiosis with SIgAD patients has been observed, we characterized the oral bacterial microbiota of the subjects with and without SIgAD using high-throughput 16S rRNA gene sequencing. We found no significant alterations in diversity and composition of the oral microbiota in subjects with SIgAD. Our data suggest that increased levels of secretory natural Abs in patients with SIgAD could be a compensatory mechanism, providing alternative first-line defense against infections and adjusting mucosal milieu to maintain a healthy oral microbiota.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Deficiencia de IgA/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Bacterias/genética , Cohorte de Nacimiento , Estudios de Casos y Controles , Femenino , Finlandia , Humanos , Inmunoglobulina G/inmunología , Lipoproteínas LDL/inmunología , Masculino , Malondialdehído/inmunología , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Saliva/inmunologíaRESUMEN
BACKGROUND & AIMS: IgA exerts its primary function at mucosal surfaces, where it binds microbial antigens to regulate bacterial growth and epithelial attachment. One third of individuals with IgA deficiency (IgAD) suffers from recurrent mucosal infections, possibly related to an altered microbiota. We aimed to delineate the impact of IgAD and the IgA-autoantibody status on the composition and functional capacity of the gut microbiota. METHODS: We performed a paired, lifestyle-balanced analysis of the effect of IgA on the gut microbiota composition and functionality based on fecal samples from individuals with IgAD and IgA-sufficient household members (n = 100), involving quantitative shotgun metagenomics, species-centric functional annotation of gut bacteria, and strain-level analyses. We supplemented the data set with 32 individuals with IgAD and examined the influence of IgA-autoantibody status on the composition and functionality of the gut microbiota. RESULTS: The gut microbiota of individuals with IgAD exhibited decreased richness and diversity and was enriched for bacterial species encoding pathogen-related functions including multidrug and antimicrobial peptide resistance, virulence factors, and type III and VI secretion systems. These functional changes were largely attributed to Escherichia coli but were independent of E coli strain variations and most prominent in individuals with IgAD with IgA-specific autoreactive antibodies. CONCLUSIONS: The microbiota of individuals with IgAD is enriched for species holding increased proinflammatory potential, thereby potentially decreasing the resistance to gut barrier-perturbing events. This phenotype is especially pronounced in individuals with IgAD with IgA-specific autoreactive antibodies, thus warranting a screening for IgA-specific autoreactive antibodies in IgAD to identify patients with IgAD with increased risk for gastrointestinal implications.
Asunto(s)
Autoanticuerpos/metabolismo , Microbioma Gastrointestinal/inmunología , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunoglobulina A/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
B cell differentiation and memory are controlled by the transmembrane activator and CAML interactor (TACI), a receptor encoded by TNFRSF13B. TNFRSF13B mutations are frequently found in common variable immunodeficiency (CVID) and in IgA -deficiency; yet, ~98% of those with mutant TNFRSF13B are healthy. Indeed, TNFRSF13B is among the 5% most polymorphic genes in man. Other mammals evidence polymorphism at comparable loci. We hypothesize that TNFRSF13B diversity might promote rather than detract from well-being by controlling key elements of innate immunity. We shall discuss how extraordinary diversity of TNFRSF13B could have evolved and persisted across diverse species of mammals by controlling innate and adaptive B cell responses in apparently paradoxical ways.
Asunto(s)
Inmunidad Adaptativa/genética , Linfocitos B/inmunología , Inmunodeficiencia Variable Común/genética , Evolución Molecular , Deficiencia de IgA/genética , Inmunidad Innata/genética , Mutación , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Animales , Anticuerpos/metabolismo , Linfocitos B/metabolismo , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Deficiencia de IgA/inmunología , Deficiencia de IgA/metabolismo , Fenotipo , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismoRESUMEN
Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often diagnosed during the diagnostic work up of several and different autoimmune disorders, which are associated with this primary immune defect. The genetic background of SIgAD is complex and three HLA haplotypes resulted to be more frequently associated with it; in detail, two of them include HLA-DQB1∗02 allelic variants, which are essential predisposing factors to develop Celiac Disease (CD). Here, we discuss the evidence regarding the role of HLA in the etiopathogenesis of SIgAD and its association with CD. Actually, the HLA region seems to play a modest role in the genetic predisposition to SIgAD and we may speculate that the association with the HLA-DQB1∗02 alleles (or haplotypes including them) could derive from its link with CD. Indeed, SIgAD and some related immunological alterations are likely to predispose to several autoimmune diseases (with and despite different HLA backgrounds), including CD, which is relatively common and directly associated with the HLA-DQB1∗02 allelic variants coding the DQ2 heterodimer. Further and specific studies are needed to make final conclusions in this regard.
Asunto(s)
Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Cadenas beta de HLA-DQ/genética , Deficiencia de IgA/genética , Deficiencia de IgA/inmunología , Enfermedad Celíaca/complicaciones , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Cadenas beta de HLA-DQ/inmunología , Haplotipos , Humanos , Deficiencia de IgA/complicacionesRESUMEN
OBJECTIVES: Autoimmune inner ear disease (AIED) is a distinct clinical entity from sudden sensorineural hearing loss. The purpose of this study was to investigate the clinical characteristics of AIED in patients with selective IgA deficiency (sIgAD). MATERIALS AND METHODS: This retrospective observational study was based on data from the Leumit Healthcare Services database in Israel. We searched all subjects aged ≥12 years who had undergone serum total IgA measurements during 2004-2014 for any reason. The sIgAD patients included all subjects with serum IgA of ≤7 mg/dL (0.07 g/L). A control group was randomly sampled from the full study population (n ≈ 730,000) with a case-control ratio of 10 controls for each case (1:10). RESULTS: Among 347 subjects with sIgAD, we identified 9 patients with concomitant AIED (sIgAD + AIED group). This group was characterized by a higher prevalence of allergic diseases (8 patients; 88.9%) than sIgAD patients without AEID (sIgAD + AIED group; 153 patients; 45.2%; p = 0.014). Both systemic diseases (3 patients; 33.3%) and organ-specific autoimmune diseases (7 patients; 77.8%) were more prevalent in the sIgAD + AIED group (sIgAD + AIED group: 19 patients 5.5%, p = 0.015; sIgAD - AEID group: 76 patients, 21.9%, p < 0.001), with an OR of 8.39 (1.94-36.19; p = 0.004). sIgAD patients with and without AIED were characterized by a higher prevalence of documented episodes of acute otitis media, allergic diseases, and autoimmune diseases than the control group. CONCLUSION: The study exposes a significant association between AIED and sIgAD. We believe that sIgAD has to be excluded in AIED patients.
Asunto(s)
Enfermedades Autoinmunes/epidemiología , Enfermedades del Oído/epidemiología , Deficiencia de IgA/epidemiología , Adolescente , Adulto , Enfermedades Autoinmunes/inmunología , Estudios de Casos y Controles , Comorbilidad , Enfermedades del Oído/inmunología , Femenino , Humanos , Deficiencia de IgA/inmunología , Masculino , Prevalencia , Estudios Retrospectivos , Adulto JovenAsunto(s)
Autoinmunidad/fisiología , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Deficiencia de IgA/etiología , Deficiencia de IgA/inmunología , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Adulto , COVID-19 , Infecciones por Coronavirus/diagnóstico por imagen , Femenino , Humanos , Deficiencia de IgA/diagnóstico por imagen , Pandemias , Intercambio Plasmático/métodos , Neumonía Viral/diagnóstico por imagen , SARS-CoV-2RESUMEN
In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is well established that primary immunodeficiencies (PIDs) exhibit gastrointestinal manifestations and mimic other diseases, including CeD and IBD. PIDs are often considered pediatric ailments, whereas between 25 and 45% of PIDs are diagnosed in adults. The most common PIDs in adults are the selective immunoglobulin A deficiency (SIgAD) and the common variable immunodeficiency (CVID). A trend to autoimmunity occurs, while gastrointestinal disorders are common in both diseases. Besides, the occurrence of CeD and IBD in SIgAD/CVID patients is significantly higher than in the general population. However, some differences concerning diagnostics and management between enteropathy/colitis in PIDs, as compared to idiopathic forms of CeD/IBD, have been described. There is an ongoing discussion whether CeD and IBD in CVID patients should be considered a true CeD and IBD or just CeD-like and IBD-like diseases. This review addresses the current state of the art of the most common primary immunodeficiencies in adults and co-occurring CeD and IBD.
Asunto(s)
Enfermedad Celíaca/diagnóstico , Inmunodeficiencia Variable Común/diagnóstico , Deficiencia de IgA/diagnóstico , Enfermedades Inflamatorias del Intestino/diagnóstico , Adulto , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/inmunología , Niño , Inmunodeficiencia Variable Común/epidemiología , Inmunodeficiencia Variable Común/inmunología , Diagnóstico Diferencial , Tracto Gastrointestinal/inmunología , Humanos , Deficiencia de IgA/epidemiología , Deficiencia de IgA/inmunología , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/inmunologíaRESUMEN
Common variable immunodeficiency (CVID) and selective immunoglobulin A deficiency (IgAD) often cause chronic lung disease, but the pulmonary pathologic features of these systemic diseases are poorly recognized by pathologists. It has been claimed that CVID cases show a characteristic combination of noncaseating granulomas-lymphoid proliferations termed granulomatous-lymphocytic interstitial lung disease (GLILD). We present 34 surgical lung biopsy cases of CVID and 4 of IgAD. Noncaseating granulomas were seen in 23/34 (68%) CVID and 2/4 (50%) IgAD cases. A statistically identical pattern of benign lymphoid proliferation was found in CVID and IgAD whether or not granulomas were present. Organizing pneumonia, sometimes considered a part of GLILD, was seen in 25/34 (74%) CVID and 2/4 (50%) IgAD cases and did not correlate with the presence of granulomas. On follow-up, 3 CVID patients died (only 1 of pulmonary disease), while 21 others are alive at 1 to 300 months with no difference by presence or absence of granulomas. Three IgAD patients with follow-up are alive. We conclude that CVID and IgAD are indistinguishable in surgical lung biopsies and a subset of both show patterns that would qualify as GLILD, while other cases lack granulomas but have identical patterns of lymphoid infiltration and organizing pneumonia. We suggest that GLILD is neither a specific nor a useful entity, and biopsies from CVID and IgAD patients should be diagnosed simply by microscopic pattern(s) observed. The prognosis of CVID with lymphoid infiltrates with or without granulomas in this series was good, contrary to claims in the literature about GLILD.
Asunto(s)
Inmunodeficiencia Variable Común/patología , Granuloma del Sistema Respiratorio/patología , Deficiencia de IgA/patología , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Linfocitos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Proliferación Celular , Niño , Preescolar , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/mortalidad , Inmunodeficiencia Variable Común/terapia , Femenino , Granuloma del Sistema Respiratorio/inmunología , Granuloma del Sistema Respiratorio/mortalidad , Granuloma del Sistema Respiratorio/terapia , Humanos , Deficiencia de IgA/inmunología , Deficiencia de IgA/mortalidad , Deficiencia de IgA/terapia , Pulmón/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/terapia , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , América del Norte , Valor Predictivo de las Pruebas , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.
Asunto(s)
Anomalías Múltiples/inmunología , Anomalías Múltiples/patología , Linfocitos B/patología , Cara/anomalías , Enfermedades Hematológicas/inmunología , Enfermedades Hematológicas/patología , Ganglios Linfáticos Agregados/patología , Enfermedades Vestibulares/inmunología , Enfermedades Vestibulares/patología , Animales , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Proteínas de Unión al ADN/genética , Cara/patología , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Deficiencia de IgA/genética , Deficiencia de IgA/inmunología , Cadenas beta de Integrinas/metabolismo , Intestinos/inmunología , Ratones , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Ganglios Linfáticos Agregados/inmunologíaRESUMEN
Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of defense against invasion of pathogenic micro-organisms. The reported prevalence rate of complete IgA deficiency in healthy children ranges from 1:170 to 1:400, and as a solitary condition, it is often considered of limited clinical importance. However, patients with IgA deficiency can develop recurrent respiratory and gastrointestinal infections, as well as allergic and autoimmune diseases. In children referred for recurrent respiratory tract infections, the observed prevalence rate increases more than tenfold. This review discusses several aspects of IgA deficiency in children, including immunologic and microbiome changes in early childhood and the potential consequences of this condition in later life. It illustrates the importance of early identification of children with impaired IgA production who deserve appropriate clinical care and follow-up.
Asunto(s)
Deficiencia de IgA/inmunología , Inmunoglobulina A/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Niño , Humanos , Prevalencia , Infecciones del Sistema Respiratorio/inmunologíaRESUMEN
BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
Asunto(s)
Linfocitos B/inmunología , Diferenciación Celular/inmunología , Inmunodeficiencia Variable Común/inmunología , Endotoxemia/inmunología , Deficiencia de IgA/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Linfocitos B/patología , Niño , Preescolar , Inmunodeficiencia Variable Común/patología , Endotoxemia/patología , Femenino , Humanos , Deficiencia de IgA/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/patologíaRESUMEN
Transient hypogammaglobulinaemia of infancy (THI) is a relatively rare disorder where there is an exaggeration of the physiological nadir of immunoglobulin (Ig)G between loss of transplacentally acquired maternal IgG and production by the infant. Patients may be vulnerable to infections during the period of hypogammaglobulinaemia. The precise time to recovery in all infants is currently unknown. We sought to determine the clinical features and time-course of recovery for patients with THI. We reviewed our experience with THI over the last three decades in order to describe clinical and laboratory features, as well as the time-course of recovery. Forty-seven patients were identified with THI. Only thirty-seven per cent remitted by 4 years of age, while some patients did not recover until the third or fourth decade. In keeping with previous studies, the majority (25 of 47) presented with recurrent infections, nine had a family history of immunodeficiency and 13 had adverse reactions to food as their dominant clinical manifestation. Chronic tonsillitis developed in 10 patients and symptoms improved following surgery. The group with food allergies recovered sooner than those presenting with infections or with a family history immunodeficiency. Eight patients failed to respond to at least one routine childhood vaccine. Two have IgA deficiency and four individuals recovering in adolescence and adulthood continue to have borderline/low IgG levels. None have progressed to common variable immunodeficiency disorders (CVID). THI is a misnomer, as the majority do not recover in infancy. Recovery from THI can extend into adulthood. THI must be considered in the differential diagnosis of adolescents or young adults presenting with primary hypogammaglobulinemia.
Asunto(s)
Agammaglobulinemia/inmunología , Deficiencia de IgA/inmunología , Adolescente , Adulto , Agammaglobulinemia/patología , Agammaglobulinemia/terapia , Preescolar , Femenino , Humanos , Deficiencia de IgA/patología , Deficiencia de IgA/terapia , Lactante , MasculinoRESUMEN
Primary immunodeficiencies and immune dysregulatory disorders (PIDDs; now referred to as inborn errors in immunity) are rare disorders with a prevalence of 41. 4 or 50.5 per 100,000 persons (1). The incidence of malignancy in PIDD patents is the second-highest cause of death in children as well as adults, after infection, and is higher in certain PIDDs compared to others. We performed a systematic review of the literature to identify reports of B cell and T cell neoplasias in PIDDs and clustered them based on their classification in the IUIS schema. As would be expected, higher susceptibility to malignancies are typically reported in patients with Common Variable Immunodeficiency (CVID), combined immunodeficiencies affecting cellular immunity, in particular, DNA repair defects, or in the context of impaired immune regulatory control. There is not much evidence of increased risk for cancer in patients with innate immune defects, indicating that not all types of infection or genetic susceptibility predispose equally to cancer risk. Viral infections, in particular EBV, HHV and HPV, have been shown to increase susceptibility to developing cancer, but also patients with defects in immune regulation, such as Autoimmune Lymphoproliferative Syndrome (ALPS), activated p110delta syndrome (APDS type 1) and IL-10 receptor deficiency among others have a higher incidence of neoplastic disease, particularly lymphomas. In fact, lymphomas account for two-thirds of all malignancies reported in PIDD patients (2), with either a combined immunodeficiency or DNA repair defect predominating as the underlying immune defect in one registry, or antibody deficiencies in another (3). The vast majority of lymphomas reported in the context of PIDDs are B cell lymphomas, though T cell lymphomas have been reported in a few studies, and tend to largely be associated with chromosomal breakage disorders (4) or Cartilage Hair Hypoplasia (5). There appears to be a much higher prevalence of T cell lymphomas in patients with secondary immunodeficiencies (6), though this could reflect treatment bias. We reviewed the literature and summarized the reports of B and T cell lymphoma in PIDD patients to survey the current state of knowledge in this area.
Asunto(s)
Enfermedades del Sistema Inmune/complicaciones , Linfoma de Células B/etiología , Linfoma de Células T/etiología , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Predisposición Genética a la Enfermedad , Humanos , Deficiencia de IgA/inmunología , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Linfoma de Células T/terapia , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunologíaRESUMEN
Objectives: It has recently been shown that individuals with selective IgA deficiency (sIgAD) have defective B cell responses both to T cell dependent and independent mimicking stimulations. The complex intracellular signaling pathways from different stimuli leading to IgA isotype switching have not been fully elucidated. Thus, the main objective of this study was to delineate these pathways and their potential role in the immunopathology linked to sIgAD. Materials and Methods: PBMCs from 10 individuals with sIgAD and 10 healthy controls (HC) were activated in vitro via either a T cell dependent or independent mimicking stimulation. Intracellular phosphorylation of pSTAT3, pSTAT5, pSTAT6, and as pERK1/2 was evaluated in T and B cells using phosphoflow cytometry. Results: By evaluating T cell dependent cytokine driven pathways linked to IgA isotype induction we identified a defect involving an IL-21 driven STAT3 activation isolated to B cells in sIgAD individuals. However, all other signaling pathways studied were found to be normal compared to HC. In T cell dependent cytokine driven stimulations linked to IgA isotype induction the following patterns emerged: (i) IL-10 led to significant STAT3 activation in both T- and B cells; (ii) IL-4 stimulation was predominantly confined to STAT6 activation in both T- and B cells, with some effects on STAT3 activation in T-cells; (iii) as expected, of tested stimuli, IL-2 alone activated STAT5 and some STAT3 activation though in both cases only in T-cells; (iv) IL-21 induced significant activation of STAT3 in both T- and B cells, with some effects on STAT5 activation in T-cells; and finally (v) synergistic effects were noted of IL-4+IL-10 on STAT5 activation in T-cells, and possibly STAT6 in both T- and B cells. On the other hand, CPG induced T cell independent activation was confined to ERK1/2 activation in B cells. Conclusion: Our results indicate a diminished STAT3 phosphorylation following IL-21 stimulation solely in B cells from sIgAD individuals. This can represent aberrant germinal center reactions or developmental halt. Thus, our work provides further insight into the unraveling of the previously hypothesized role of IL-21 to reconstitute immunoglobulin production in primary antibody deficiencies.
Asunto(s)
Linfocitos B/inmunología , Deficiencia de IgA/inmunología , Interleucinas/inmunología , Activación de Linfocitos/inmunología , Factor de Transcripción STAT3/inmunología , Linfocitos B/metabolismo , Humanos , Deficiencia de IgA/metabolismo , Fosforilación , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut. OBJECTIVE: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA. METHODS: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera. RESULTS: Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota. CONCLUSION: Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Inmunoglobulina A Secretora/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Anticuerpos Antibacterianos/inmunología , Inmunodeficiencia Variable Común/inmunología , Heces/química , Humanos , Deficiencia de IgA/inmunologíaRESUMEN
In a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our study underlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of this condition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own study.