Selective IgA Deficiency and Allergy: A Fresh Look to an Old Story

Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.

STXBP6 and B3GNT6 Genes are Associated With Selective IgA Deficiency

Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies (GWAS) have identified five non-HLA risk loci (IFIH1, PVT1, ATG13-AMBRA1, AHI1 and CLEC16A). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes (N = 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele (HLA-B*08:01-DRB1*03:01-DQB1*02:01 or HLA-DRB1*07:01-DQB1*02:02 or HLA-DRB1*01-DQB1*05:01) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in STXBP6 (rs4097492; p = 7.63 × 10−9) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for B3GNT6 (PGene = 2.1 × 10–6) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.

Proteomics Profiling to Distinguish DOCK8 Deficiency From Atopic Dermatitis

Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.

An Update on Pediatric Immune Thrombocytopenia (ITP): Differentiating Primary ITP, IPD, and PID

Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia in children and is caused by both immune-mediated decreased platelet production and increased platelet destruction. In the absence of a diagnostic test, ITP must be differentiated from other thrombocytopenic disorders, including inherited platelet disorders (IPD). In addition, a diagnosis of secondary ITP due to a primary immune deficiency (PID) with immune dysregulation may not be apparent at diagnosis but can alter management and should be considered in an expanding number of clinical scenarios. The diagnostic evaluation of children with thrombocytopenia will vary based on the clinical history and laboratory features. Access to genotyping has broadened the ability to specify the etiology of thrombocytopenia, while increasing access to immunophenotyping, functional immunologic and platelet assays, and biochemical markers has allowed for more in-depth evaluation of patients. With this greater availability of testing, diagnostic algorithms in patients with thrombocytopenia have become complex. In this article, we highlight the diagnostic evaluation of thrombocytopenia in children with a focus on ITP, including consideration of underlying genetic and immune disorders, and utilize hypothetical patient cases to describe disease manifestations and strategies for treatment of pediatric ITP.

Inborn Errors of Immunity on the Island of Ireland – A Cross-Jurisdictional UKPID/ESID Registry Report

The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland respectively, and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. We identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population (1:11,299).

Patients with Chromosome 11q-abberations are Characterized by a Combined Primary Immunodeficiency Involving Both B- and T-lymphocytes

Disorders of the long arm of chromosome 11 (11q) are rare and involve various chromosomal regions. Patients with 11q-disorders, including Jacobsen syndrome, often present with a susceptibility for bacterial, prolonged viral and fungal infections partially explained by hypogammaglobulinemia. Additional T-lymphocyte or granular neutrophil dysfunction may also be present. In order to evaluate infectious burden and immunological function in patients with 11q-disorders, we prospectively studied a cohort of 14 patients with various 11q aberrations. Clinically, 12 patients exhibited prolonged and repetitive respiratory tract infections, frequently requiring (prophylactic) antibiotic treatment (n=7), ear-tube placement (n=9) or use of inhalers (n=5). Complicated varicella infections (n=5), chronic eczema (n=6), warts and chronic fungal infections (n=4) were reported. Six patients were on immunoglobulin replacement therapy. We observed a high prevalence of low B-lymphocyte counts (n=8), decreased T-lymphocyte counts (n=5) and abnormal T-lymphocyte function (n=12). Granulocyte function was abnormal in 29% without an aberrant clinical phenotype. Immunodeficiency was found in patients with terminal and interstitial 11q-deletions and in one patient with 11q trisomy. Genetically, FLI1 and ETS1 are seen as causative for the immunodeficiency, but these genes were deleted nor duplicated in 5 of our 14 patients. Alternative candidate genes on 11q such as ATM, CD3-cluster, CBL and THYN1 may have a role in immune dysregulation in our patients. In conclusion, we present evidence that a combined primary immune deficiency may be present in patients with 11q-disorders leading to clinically relevant infections. Therefore, broad immunological screening and necessary treatment is of importance in this patient group.

Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells

Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases.

Poliovirus excretion among children with primary immune deficiency in Pakistan: a pilot surveillance study protocol

IntroductionChildren with primary immunodeficiency disorders (PID) are more susceptible to developing viral infections and are at a substantially increased risk of developing paralytic poliomyelitis. Such children, if given oral polio vaccines tend to excrete poliovirus chronically that may lead to the propagation of highly divergent vaccine-derived poliovirus (VDPV). Consequently, they may act as a reservoir for the community by introducing an altered virus potentially imposing a risk to global polio eradication. However, the risks of chronic and prolonged excretion are not well characterised in the study context. This study seeks to establish a pilot surveillance system for successful identification and monitoring of VDPV excretion among children with PID. It will assess whether the Jeffrey Modell warning signs of PID can be used as an appropriate screening tool for PID in Pakistan.Methods and analysisIn this pilot surveillance, recruitment of PID cases is currently done at participating hospitals in Pakistan. Potential children are screened and tested against the Jeffrey Modell Foundation (JMF) warning signs for immunodeficiency and their stool is collected to test for poliovirus excretion. Cases excreting poliovirus are followed until the two consecutive negative stool samples are obtained over a period of 6 months. The data will be analysed to calculate hospital-based proportions of total Immunodeficiency-related vaccine-derived poliovirus (iVDPV) cases over a 2-year period and to determine the sensitivity and specificity of the JMF signs.Ethics and disseminationThis protocol was reviewed and approved by the WHO (WHO Reference-2018/811124-0), Aga Khan University (AKU ERC-2018-0380-1029) and National Bioethics Committee (Ref No. 4-87 NBC-308-Y2). The results will be published in an open access peer-reviewed scientific journal and presented to the iVDPV Working Group members, policy-makers, paediatric consultants and fellow researchers with the same domain interest. It may be presented in scientific conferences and seminars in the form of oral or poster presentations.