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Frontiers in Pediatrics 2021Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by mutations in PI3Kδ catalytic p110δ () or regulatory p85α () subunits, is a primary...
Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by mutations in PI3Kδ catalytic p110δ () or regulatory p85α () subunits, is a primary immunodeficiency affecting both humoral and cellular immunity, which shares some phenotypic similarities with hyper-IgM syndromes and common variable immunodeficiency (CVID). Since its first description in 2013, over 200 patients have been reported worldwide. Unsurprisingly, many of the newly diagnosed patients were recruited later in life from previously long-standing unclassified immunodeficiencies and the early course of the disease is, therefore, often less well-described. In this study, we report clinical and laboratory features of eight patients followed for APDS, with particular focus on early warning signs, longitudinal development of their symptoms, individual variations, and response to therapy. The main clinical features shared by our patients included recurrent bacterial and viral respiratory tract infections, gastrointestinal disease, non-malignant lymphoproliferation, autoimmune thyroiditis, and susceptibility to EBV. All patients tolerated vaccination with both attenuated live and subunit vaccines with no adverse effects, although some failed to mount adequate antibody response. Laboratory findings were characterized by dysgammaglobulinaemia, elevated serum IgM, block in B-cell maturation with high transitional B cells, and low naïve T cells with CD8 T-cell activation. All patients benefited from immunoglobulin replacement therapy, whereas immunosuppression with mTOR pathway inhibitors was only partially successful. Therapy with specific PI3K inhibitor leniolisib was beneficial in all patients in the clinical trial. These vignettes, summary data, and particular tell-tale signs should serve to facilitate early recognition, referral, and initiation of outcome-improving therapy.
PubMed: 34350147
DOI: 10.3389/fped.2021.697706 -
Frontiers in Immunology 2021The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it... (Review)
Review
The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.
Topics: Adrenal Cortex Hormones; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1; Male; Meningitis, Cryptococcal; Systemic Inflammatory Response Syndrome; Young Adult
PubMed: 34335625
DOI: 10.3389/fimmu.2021.708837 -
Frontiers in Immunology 2021Patients with primary humoral immunodeficiency are more prone to invasive as well as recurrent pneumococcal infections. Therefore, anti-pneumococcal vaccination...
BACKGROUND
Patients with primary humoral immunodeficiency are more prone to invasive as well as recurrent pneumococcal infections. Therefore, anti-pneumococcal vaccination including the 13-valent conjugate vaccine is recommended. Nevertheless, to date, no data is available on immunogenicity of this vaccine in this population.
OBJECTIVE
To assess the immunogenicity and the persistence of protection up to one year after a 13-valent pneumococcal conjugate vaccine in patients with primary humoral immunodeficiency.
METHODS
Twenty-nine patients with common variable immunodeficiency or IgG subclass deficiency were vaccinated. Immune response and immune protection at baseline as well as at one, six and twelve months after vaccination were evaluated by measuring specific IgG serum concentrations (ELISA), and opsonophagocytic activities directed against selected pneumococcal (MOPA).
RESULTS
By ELISA, half of the patients had protective IgG concentrations before vaccination, 35.7% showed an immune response one month after vaccination, 71.4%, 66.7% and 56.0% of the patients were protected at one, six and twelve months respectively. Conversely, by MOPA, 3.4% of the patients were protected at baseline, 10.7% showed an immune response and 28.6%, 48.2% and 33.3% were protected at one, six and twelve months respectively. IgG subclass deficiency, Ig replacement therapy and higher IgG2 concentrations at diagnosis were associated with long-term protection.
CONCLUSION
Pneumococcal conjugate vaccine improves immune protection and antibodies' functionality in a subset of patients with primary immunodeficiency. Prime-boost vaccine strategy needs to be better and individually adapted.
Topics: Adult; Aged; Antibodies, Bacterial; Antibody Specificity; Common Variable Immunodeficiency; Female; Humans; IgG Deficiency; Immunoglobulin G; Male; Middle Aged; Phagocytosis; Pneumococcal Infections; Pneumococcal Vaccines; Serogroup; Streptococcus pneumoniae; Time Factors; Vaccines, Conjugate; Young Adult
PubMed: 34290713
DOI: 10.3389/fimmu.2021.697128 -
Scientific Reports Jul 2021Immunoglobulin A (IgA) is the dominant antibody found in our mucosal secretions and has long been recognized to play an important role in protecting our epithelium from...
Immunoglobulin A (IgA) is the dominant antibody found in our mucosal secretions and has long been recognized to play an important role in protecting our epithelium from pathogens. Recently, IgA has been shown to be involved in gut homeostatic regulation by 'recognizing' and shaping our commensal microbes. Paradoxically, yet selective IgA-deficiency is often described as asymptomatic and there is a paucity of studies only focused on the mice and human gut microbiome context fully ignoring other niches of our body and our commensal viruses. Here, we used as a model the human oral cavity and employed a holistic view and studied the impact of IgA deficiency and also common variable IgA and IgM immunodeficiencies (CVID), on both the human virome and microbiome. Unexpectedly, metagenomic and experimental data in human IgA deficiency and CVID indicate minimal-moderate changes in microbiome and virome composition compared to healthy control group and point out to a rather functional, resilient oral commensal viruses and microbes. However, a significant depletion (two fold) of bacterial cells (p-value < 0.01) and viruses was observed in IgA-deficiency. Our results demonstrate that, within the limits of our cohort, IgA role is not critical for maintaining a rather functional salivary microbiome and suggest that IgA is not a major influence on the composition of abundant commensal microbes.
Topics: Adolescent; Adult; Aged; Child; Female; Humans; IgA Deficiency; Immunoglobulin A; Immunoglobulin M; Male; Metagenomics; Microbiota; Middle Aged; Mouth; Saliva; Virome; Young Adult
PubMed: 34290346
DOI: 10.1038/s41598-021-94507-8 -
Frontiers in Pediatrics 2021Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered...
Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-deficient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic etiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favor of genetic defects. We describe a school-age male patient with a clinical picture suggestive of DOCK8 deficiency, except for high serum IgE or a family history: early onset, failure to thrive, eczema, warts, condyloma, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leukocytosis, eosinophilia, high IgA, low IgG, and low CD4+ T cells. We were able to confirm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-deficient patients; at least 4 other patients have had no elevated IgE, and about 40% do not have Hyper-IgE (above 1,000 IU/mL). Despite this, the constellation of signs, symptoms, and findings allow the suspicion of DOCK8 deficiency and other actinopathies.
PubMed: 34195158
DOI: 10.3389/fped.2021.635322 -
Wiadomosci Lekarskie (Warsaw, Poland :... 2021The aim: To present data on the possibility of occurrence and active progression of generalized periodontitis in persons with secretory immunoglobulin A deficiency and... (Review)
Review
OBJECTIVE
The aim: To present data on the possibility of occurrence and active progression of generalized periodontitis in persons with secretory immunoglobulin A deficiency and possible methods of its correction.
PATIENTS AND METHODS
Мaterials and methods: Analytical elaboration of scientific and medical literature based on the immunological aspect of generalized periodontitis.
CONCLUSION
Conclusions: The deficiency of secretory immunoglobulin A may occur in cases of primary or secondary insufficiency of the immune system. Selective IgA deficiency is an example of primary insufficiency of the immune system. Secondary immunodeficiency disorders is a clinical and immunological syndrome that develops against the background of a previously normally functioning immune system, characterized by a steady decrease in quantitative or functional indicators of specific or(and) nonspecific factors of immunoresistance. Insufficient awareness of dentists about certain aspects of the etiology and pathogenesis of generalized periodontitis leads to deterioration of treatment results.
Topics: Humans; IgA Deficiency; Immunoglobulin A; Immunoglobulin A, Secretory; Periodontitis
PubMed: 34159947
DOI: No ID Found -
Molecular Genetics & Genomic Medicine Aug 2021X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects.
BACKGROUND
X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects.
METHODS
We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole-exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features.
RESULTS
Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti-phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non-frameshift deletion c.436_438delTAC, stop-gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis.
CONCLUSION
This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.
Topics: Adolescent; Adult; Antiphospholipid Syndrome; CD40 Ligand; Child; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1; Male; Mutation; Phenotype
PubMed: 34114358
DOI: 10.1002/mgg3.1732 -
Clinical and Experimental Immunology Sep 2021Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the...
Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the mainstay therapy to improve clinical outcomes. IRT is, however, expensive and, in minor PAD, clear recommendations concerning IRT are lacking. We conducted a retrospective real-life study to assess the effectiveness of low-dose IRT in minor PAD on 143 patients fulfilling European Society for Immunodeficiencies (ESID) diagnostic criteria for immunoglobulin (Ig)G subclass deficiency (IgGSD) or unclassified antibody deficiency (UAD). All patients were treated with intravenous low-dose IRT (0.14 ± 0.06 g/kg/month). Immunoglobulin (Ig) classes and IgG subclasses were measured at baseline and after 1 year of IRT. The annual rate of total infections, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI) and hospitalizations was measured at baseline and after 1 and 2 years of IRT. After 1 year of IRT significant improvement was demonstrated in: (a) serum IgG (787.9 ± 229.3 versus 929.1 ± 206.7 mg/dl; p < 0.0001); (b) serum IgG subclasses (IgG1 = 351.4 ± 109.9 versus 464.3 ± 124.1, p < 0.0001; IgG2 = 259.1 ± 140 versus 330.6 ± 124.9, p < 0.0001; IgG3 = 50.2 ± 26.7 versus 55.6 ± 28.9 mg/dl, p < 0.002); (c) annual rate of total infections (5.75 ± 3.87 versus 2.13 ± 1.74, p < 0.0001), URTI (1.48 ± 3.15 versus 0.69 ± 1.27; p < 0.005), LRTI (3.89 ± 3.52 versus 1.29 ± 1.37; p < 0.0001) and hospitalizations (0.37 ± 0.77 versus 0.15 ± 0.5; p < 0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low-dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.
Topics: Aged; Bronchiectasis; Female; Hospitalization; Humans; IgG Deficiency; Immunoglobulin G; Immunoglobulins, Intravenous; Male; Middle Aged; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Retrospective Studies
PubMed: 34061980
DOI: 10.1111/cei.13629 -
Frontiers in Immunology 2021Selective 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... (Review)
Review
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.
Topics: Epigenesis, Genetic; Gastrointestinal Microbiome; Humans; IgA Deficiency; Immunity, Innate; Immunoglobulin A; Infant; Infant, Newborn; T-Lymphocytes; Transmembrane Activator and CAML Interactor Protein
PubMed: 33981304
DOI: 10.3389/fimmu.2021.649112 -
QJM : Monthly Journal of the... May 2022Immunoglobulin G (IgG) subclass 2 deficiency is the most frequent IgG subclass deficiency identified in patients with bronchiectasis, but its clinical significance is...
BACKGROUND
Immunoglobulin G (IgG) subclass 2 deficiency is the most frequent IgG subclass deficiency identified in patients with bronchiectasis, but its clinical significance is not known.
AIM
To analyse if bronchiectasis patients with isolated IgG2 deficiency at risk of recurrent exacerbations and/or hospitalization? Do patients with IgG2 deficiency have worse disease progression?
DESIGN AND METHODS
This is a retrospective study (2015-20) exploring independent risk factors for recurrent exacerbations (3 or more per year) and/or hospitalization with bronchiectasis exacerbations using multivariable models using binary logistic regression. There was no patient with IgG deficiency, IgG 1, 3 or 4 deficiency, or IgA or IgM deficiency included. In this model, the authors included: serum IgG2 level; lung function; body mass index; MRC breathlessness scale; age; sex; number of bronchiectatic lobes; bacterial colonization; comorbidities; and the use of long-term immunosuppressant drugs or antibiotics for more than 28 days. Analysing 2-year longitudinal data, one-way ANOVA and Mann-Whitney U-test were used to compare bronchiectasis severity between patients with different IgG2 levels.
RESULTS
Serum IgG2 levels (<2.68 g/l, 2.68-3.53 g/l and 3.54-4.45 g/l); hospital admission in the preceding 2 years; bacterial colonization with potentially pathogenic organisms and asthma were independent predictors for three or more bronchiectasis exacerbations. Those with low IgG2 levels (<2.68 g/l and 2.68-3.53 g/l), had worsening progression of their bronchiectasis, using the Bronchiectasis Severity Index, over 1 year compared with those who were IgG2 replete (>4.45 g/l) (P = 0.003, 0.013).
CONCLUSION
Reduced IgG2 levels were an independent predictor for bronchiectasis exacerbations and have increased disease progression.
Topics: Bronchiectasis; Disease Progression; Humans; IgG Deficiency; Immunoglobulin G; Retrospective Studies; Risk Factors
PubMed: 33970283
DOI: 10.1093/qjmed/hcab129