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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 -
Critical Reviews in Immunology 2021Selective immunoglobulin A (IgA) deficiency (SIgAD) is the most common primary immunodeficiency disease with a prevalence of about 1:500 individuals. SIgAD is... (Review)
Review
Selective immunoglobulin A (IgA) deficiency (SIgAD) is the most common primary immunodeficiency disease with a prevalence of about 1:500 individuals. SIgAD is heterogeneous, though thought to be due to a defect in the differentiation of IgA-bearing B lymphocytes into IgA-secreting plasma cells which provide a first line of defense against bacterial and viral pathogens. Although SIgAD was for a long time considered asymptomatic, longitudinal studies have revealed that about 80% of patients are symptomatic and can present with a range of phenotypes including allergic disease, recurrent bacterial respiratory tract infections, gastrointestinal disorders, and autoimmune diseases. Secretory IgA has been shown to play a critical role in maintaining immune homeostasis in the gut by determining the composition of and directing the function of gut microbiota. Patients with SIgAD demonstrate gut dysbiosis with enriched proinflammatory phyla that is only partially compensated for by IgM and IgG. In this review, we will discuss what is known about the microbiome of individuals with SIgAD and how this might provide insights into therapeutics and monitoring in these patients.
Topics: Dysbiosis; Humans; IgA Deficiency; Immunoglobulin A; Microbiota
PubMed: 35695643
DOI: 10.1615/CritRevImmunol.2022042293 -
The Journal of Allergy and Clinical... Sep 2023Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is...
BACKGROUND
Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is associated with gut fungal dysbiosis remains unknown.
OBJECTIVES
Our goal was to study the impact of IgA on gut mycobiota ecology.
METHODS
The Fungi-Flow method was used to characterize fecal, systemic, and maternal IgA, IgM, and IgG responses against 14 representative fungal strains (yeast/spores or hyphae forms) in healthy donors (HDs) (n = 34, 31, and 20, respectively) and to also compare gut mycobiota opsonization by secretory antibodies in HDs (n = 28) and patients with selective IgA deficiency (SIgAd) (n = 12). Stool mycobiota composition was determined by internal transcribed spacer gene sequencing in HDs (n = 23) and patients with SIgAd (n = 17). Circulating CD4 T-cell cytokine secretion profiles were determined by intracellular staining. The impact of secretory IgA, purified from breast milk (n = 9), on Candidaalbicans growth and intestinal Caco-2 cell invasion was tested in vitro.
RESULTS
Homeostatic IgA binds commensal fungi with a body fluid-selective pattern of recognition. In patients with SIgAd, fungal gut ecology is preserved by compensatory IgM binding to commensal fungi. Gut Calbicans overgrowth nevertheless occurs in this condition but only in clinically symptomatic patients with decreased T17/T22 T-cell responses. Indeed, secretory IgA can reduce in vitro budding and invasion of intestinal cells by Calbicans and therefore exert control on this pathobiont.
CONCLUSION
IgA has a selective impact on Calbicans ecology to preserve fungal-host mutualism.
Topics: Female; Humans; Candida albicans; Caco-2 Cells; IgA Deficiency; Immunoglobulin A; Immunoglobulin A, Secretory; Immunoglobulin M
PubMed: 37169153
DOI: 10.1016/j.jaci.2023.03.033 -
Immunology and Allergy Clinics of North... Nov 2015Patients with specific antibody deficiency (SAD) have a deficient immunologic response to polysaccharide antigens. Such patients experience sinopulmonary infections with... (Review)
Review
Patients with specific antibody deficiency (SAD) have a deficient immunologic response to polysaccharide antigens. Such patients experience sinopulmonary infections with increased frequency, duration, or severity compared with the general population. SAD is definitively diagnosed by immunologic challenge with a pure polysaccharide vaccine in patients 2 years old and older who have otherwise intact immunity, using the 23-valent pneumococcal polysaccharide vaccine as the current gold standard. Specific antibody deficiencies comprise multiple immunologic phenotypes. Treatment must be tailored based on the severity of symptoms. Most patients have a good prognosis. The deficiency may resolve over time, especially in children.
Topics: Diagnosis, Differential; Disease Management; Dysgammaglobulinemia; Humans; Prognosis
PubMed: 26454312
DOI: 10.1016/j.iac.2015.07.003 -
Paediatric Drugs Sep 2021Targeted therapies have emerged as innovative treatments for patients whose disease does not respond to conventional chemotherapy, and their use has widely expanded in... (Review)
Review
Targeted therapies have emerged as innovative treatments for patients whose disease does not respond to conventional chemotherapy, and their use has widely expanded in the field of pediatric hematologic malignancies in the last decade. While they carry the promise of improved disease control and survival and are currently investigated in first-line treatment protocols for patients with poor prognostic markers, they are associated with a considerable incidence of specific toxicities, including cytokine-release syndrome, neurotoxicity, hepatotoxicity, nephrotoxicity, cardiotoxicity, endocrine adverse events, and infectious complications. Iatrogenic or secondary dysgammaglobulinemia is a main consequence of targeted therapies using monoclonal antibodies and other antibody-derived treatments that target specific antigens on lymphoid cells (blinatumomab, inotuzumab ozogamicin, rituximab), chimeric antigen receptor T cells, tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) and, to a lesser extent, checkpoint inhibitors (pembrolizumab, nivolumab). This review discusses the diagnosis and incidence of secondary or iatrogenic dysgammaglobulinemia in children treated with targeted therapies for leukemias and lymphomas, and options for monitoring and treatment.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Child; Dysgammaglobulinemia; Hematologic Neoplasms; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34292515
DOI: 10.1007/s40272-021-00461-3 -
The Journal of Allergy and Clinical... 2016The primary immunodeficiency (PID) diseases comprise a heterogeneous group of inherited disorders of immune function. Technical advancements in whole-genome,... (Review)
Review
The primary immunodeficiency (PID) diseases comprise a heterogeneous group of inherited disorders of immune function. Technical advancements in whole-genome, whole-exome, and RNA-sequencing have seen the explosion of genetic discoveries in the field of PIDs. The present review aims to focus on a group of immunodeficiency disorders associated with elevated levels of IgM (hyper IgM; HIGM) and provides a clinical differential diagnosis. Most patients present for evaluation of immunodeficiency due to recurrent infections, and laboratory studies show either a clear isolated elevation of serum immunoglobulin M (IgM) with low or absent IgG, IgA, and IgE. Alternatively, IgM levels may be normal or moderately elevated while other serum immunoglobulins are reported below the norms for age but not absent. Mechanistically, these disorders are recognized as defects in immunoglobulin (Ig) class switch recombination (CSR). Importantly, to safeguard genetic stability, CSR utilizes elements of the DNA repair machinery including multi-protein complexes involved in mismatch repair (MMR). Therefore, it is not uncommon for defects in the DNA repair machinery, to present with laboratory findings of HIGM. This review will discuss clinical phenotypes associated with congenital defects associated with HIGM. Clinical manifestations, relevant immunologic testing, inheritance pattern, molecular diagnosis, presumed pathogenesis, and OMIM number, when annotated are compiled. Accepted therapeutic options, when available, are reviewed for each condition discussed.
Topics: Humans; Hyper-IgM Immunodeficiency Syndrome; Immunoglobulin Class Switching; Immunoglobulin G; Phenotype
PubMed: 27836054
DOI: 10.1016/j.jaip.2016.09.013 -
Frontiers in Cellular and Infection... 2021A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce... (Review)
Review
A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2.
Topics: Antibodies, Neutralizing; Antibodies, Viral; COVID-19; Humans; IgA Deficiency; Immunoglobulin A; SARS-CoV-2; Virus Shedding
PubMed: 33889552
DOI: 10.3389/fcimb.2021.655896 -
International Archives of Allergy and... 2019Selective immunoglobulin A deficiency (SIgAD) is the most prevalent type of primary immunodeficiency disorder. The phenotypic feature of SIgAD is related to a defect in... (Review)
Review
Selective immunoglobulin A deficiency (SIgAD) is the most prevalent type of primary immunodeficiency disorder. The phenotypic feature of SIgAD is related to a defect in B lymphocyte differentiation into plasma cell-producing immunoglobulin A (IgA). In this review, we summarize the recent advances in this regard. Genetic (including major histocompatibility complex [MHC] and non-MHC genes), immunologic (including B and T lymphocyte subsets abnormality), cytokines/chemokines and their related receptors, apoptosis and microbiota defects are reviewed. The mechanisms leading to SIgAD are most likely multifactorial and it can be speculated that several pathways controlling B cells functions or regulating epigenetic of the IGHA gene encoding constant region of IgA heavy chain and long-term survival of IgA switched memory B cells and plasma cells may be defective in different SIgAD patients.
Topics: Animals; Apoptosis; Cytokines; Disease Models, Animal; Genetic Predisposition to Disease; Humans; IgA Deficiency; Microbiota; Receptors, Immunologic
PubMed: 31091523
DOI: 10.1159/000499044 -
Clinical Immunology (Orlando, Fla.) Dec 2019Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of... (Review)
Review
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.
Topics: Animals; Autoimmune Diseases; Child; Humans; IgA Deficiency; Immunoglobulin A; Prevalence; Respiratory Tract Infections
PubMed: 31678364
DOI: 10.1016/j.clim.2019.108293 -
Expert Review of Clinical Immunology May 2019CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available... (Review)
Review
CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients' susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.
Topics: Allografts; Animals; CD40 Antigens; CD40 Ligand; Disease-Free Survival; Genetic Therapy; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1; Immunity, Innate; Mutation; Survival Rate
PubMed: 30681380
DOI: 10.1080/1744666X.2019.1573674