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Cleveland Clinic Journal of Medicine Feb 2006If a patient has frequent or recurrent bronchopulmonary or sinus infections, they may be due to low levels of immunoglobulins. This article describes common primary... (Review)
Review
If a patient has frequent or recurrent bronchopulmonary or sinus infections, they may be due to low levels of immunoglobulins. This article describes common primary (idiopathic) and secondary forms of hypogammaglobulinemia and how to evaluate and manage them.
Topics: Agammaglobulinemia; Diagnosis, Differential; Humans; Immunoglobulins, Intravenous
PubMed: 16478038
DOI: 10.3949/ccjm.73.2.133 -
International Archives of Allergy and... 2016Primary antibody deficiencies (PADs) are the most common inherited primary immunodeficiencies in humans, characterized by hypogammaglobulinemia, an inability to produce... (Review)
Review
Primary antibody deficiencies (PADs) are the most common inherited primary immunodeficiencies in humans, characterized by hypogammaglobulinemia, an inability to produce specific antibodies, and recurrent infections mainly caused by encapsulated bacteria. However, it has been shown that inflammatory disorders, granulomatous lesions, lymphoproliferative diseases, cancer, and autoimmunity are associated with the various types of PAD. Both systemic and organ-specific autoimmune diseases could be attributed to B-cell defects in PAD patients. Immune thrombocytopenic purpura and autoimmune hemolytic anemia are the most common autoimmune disorders in this group of patients. The aim of this review is to describe the proposed mechanisms for autoimmunity and to review the literature with respect to the reported autoimmune disorders in each type of PAD.
Topics: Agammaglobulinemia; Antibodies; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance
PubMed: 28013299
DOI: 10.1159/000453263 -
Blood Reviews Nov 2019The development and regulatory approval of chimeric antigen receptor T cell (CAR-T) therapies targeting the B-lineage surface antigen CD19 represents a major milestone... (Review)
Review
The development and regulatory approval of chimeric antigen receptor T cell (CAR-T) therapies targeting the B-lineage surface antigen CD19 represents a major milestone in cancer immunotherapy. This treatment also results in depletion of normal CD19+ B cells and is associated with hypogammaglobulinemia. These on-target, off-tumor toxicities may result in an increased risk for infection, particularly for encapsulated bacteria. Data regarding the efficacy and cost-effectiveness of prophylactic IgG replacement in CD19-targeted CAR-T cell therapy recipients is lacking, and current expert recommendations are extrapolated from the data for individuals with primary immune deficiencies. This article reviews CAR-T cell therapies targeting B-lineage lymphocytes, associated side effects, and considerations for the approach to management of hypogamaglobulinemia in this patient population. Studies are needed to establish evidence-based approaches to prophylactic immunoglobulin administration in this context, and strategies may differ by patient and CAR-T cell product characteristics.
Topics: Agammaglobulinemia; Antigens, CD19; B-Lymphocytes; Disease Management; Humans; Immunoglobulin G; Immunotherapy, Adoptive; Neoplasms
PubMed: 31416717
DOI: 10.1016/j.blre.2019.100596 -
Frontiers in Immunology 2022Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo... (Review)
Review
Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo reticularis. The clinical phenotype of DADA2 is, however, very broad and may involve several organ systems. Apart from vasculitis, children may present with i) Hematological manifestations (ii) Lymphoproliferation and iii) Immunodeficiencies. Patients with DADA2 can have variable patterns of cytopenias and bone marrow failure syndromes. Patients with DADA2 who have predominant haematological manifestations are associated with ADA2 gene variants that result in minimal or no residual ADA2 activity. Lymphoproliferation in patients with DADA2 may range from benign lymphoid hyperplasia to lymphoreticular malignancies. Patients may present with generalized lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome (ALPS) like phenotype, Hodgkin lymphoma, T-cell large granular lymphocytic infiltration of bone marrow and multicentric Castleman disease. Immunodeficiencies associated with DADA are usually mild. Affected patients have variable hypogammaglobulinemia, decrease in B cells, low natural killer cells, common variable immunodeficiency and rarely T cell immunodeficiency. To conclude, DADA2 has an extremely variable phenotype and needs to be considered as a differential diagnosis in diverse clinical conditions. In this review, we describe the evolving clinical phenotypes of DADA2 with a special focus on haematological and immunological manifestations.
Topics: Adenosine Deaminase; Agammaglobulinemia; Humans; Immunologic Deficiency Syndromes; Intercellular Signaling Peptides and Proteins; Polyarteritis Nodosa; Severe Combined Immunodeficiency
PubMed: 35592317
DOI: 10.3389/fimmu.2022.869570 -
The Journal of Allergy and Clinical... Jan 2022Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary...
BACKGROUND
Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited.
OBJECTIVES
This study sought to describe NRH prevalence, associated features, and impact in patients with XLA.
METHODS
Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons.
RESULTS
Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002).
CONCLUSIONS
NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
Topics: Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Genetic Diseases, X-Linked; Humans; Hyperplasia; Liver; Male; Mutation; Platelet Count; Retrospective Studies; Young Adult
PubMed: 34087243
DOI: 10.1016/j.jaci.2021.05.028 -
Scandinavian Journal of Immunology Aug 2013BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and... (Review)
Review
BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.
Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Antineoplastic Agents; Autoimmunity; B-Lymphocytes; Epstein-Barr Virus Infections; Gene Expression Regulation, Neoplastic; Genetic Diseases, X-Linked; Humans; Inflammation; Lymphoma; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Small Molecule Libraries; T-Lymphocytes
PubMed: 23672610
DOI: 10.1111/sji.12069 -
The Journal of Allergy and Clinical... Jan 2020Primary antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies. More severe forms of PADs-common variable immunodeficiency (CVID) and X-linked...
BACKGROUND
Primary antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies. More severe forms of PADs-common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA)-require immunoglobulin replacement therapy (IRT) and may have serious complications. Differentiating severe PAD from milder hypogammaglobulinemia not requiring IRT can involve prolonged evaluations and treatment discontinuation. Severe PAD is defined by plasma cell deficiency, but this requires a biopsy to establish. Serum B-cell maturation antigen (sBCMA) is elevated in multiple myeloma, but levels are reduced among patients with myeloma in remission who have hypogammaglobulinemia.
OBJECTIVE
To measure the sBCMA level in 165 subjects to determine whether it differentiates severe PAD-CVID and XLA-from less severe forms not requiring IRT and those without PAD.
METHODS
sBCMA, B cells, and tissue plasma cells were measured among subjects with and without PAD, and correlated to clinical and laboratory data.
RESULTS
Subjects with an IgG level of less than 600 mg/dL had reduced sBCMA levels compared with subjects with PAD with IgG levels of greater than or equal to 600 mg/dL and controls without PAD. sBCMA level was lower in patients with CVID and XLA compared with patients with IgA or IgG deficiency and controls. sBCMA level correlated with gastrointestinal plasma cells. sBCMA level of less than 15 ng/mL had 97% positive predictive value for CVID or XLA, whereas 25 ng/mL or more had an 88% negative predictive value.
CONCLUSIONS
sBCMA level is profoundly reduced in patients with severe PAD, including those with CVID and XLA and those with IgG levels of less than 600 mg/dL. sBCMA level measurement has potential to augment clinical evaluation of PAD. Prospective studies are needed to evaluate sBCMA for new PAD diagnosis and determine the necessity of IRT.
Topics: Agammaglobulinemia; B-Cell Maturation Antigen; Common Variable Immunodeficiency; Humans; Primary Immunodeficiency Diseases; Prospective Studies
PubMed: 31430592
DOI: 10.1016/j.jaip.2019.08.012 -
Frontiers in Immunology 2020X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase () gene and is the most common genetic mutation in patients with congenital...
X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase () gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for expression and genetic analysis. Nineteen (from 16 families) out of 29 patients had mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with mutations had obviously decreased expressions. sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.
Topics: Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Diseases, X-Linked; Humans; Infant; Male; Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mutation; Pedigree; Phenotype; Pseudomonas; Respiratory Tract Infections; Sepsis; Taiwan; Young Adult
PubMed: 33013854
DOI: 10.3389/fimmu.2020.02001 -
The Journal of Investigative Dermatology Sep 1976
Review
Topics: Agammaglobulinemia; Ataxia Telangiectasia; Dysgammaglobulinemia; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Skin Manifestations; Thymus Gland; Wiskott-Aldrich Syndrome
PubMed: 787434
DOI: 10.1111/1523-1747.ep12514714 -
Scandinavian Journal of Immunology Nov 2010Congenital agammaglobulinemia is a humoral primary immunodeficiency and affected patients have extremely low levels of peripheral B cells and profound deficiency of all...
Congenital agammaglobulinemia is a humoral primary immunodeficiency and affected patients have extremely low levels of peripheral B cells and profound deficiency of all immunoglobulin isotypes. Mutations of the Bruton's tyrosine kinase (BTK) gene are responsible for most of the congenital agammaglobulinemia. In this study, the phenotypes of congenital agammaglobulinemia were investigated in 21 male children from 21 unrelated Chinese families. Sixteen different mutations of BTK gene were identified in 18 patients, and three patients did not have BTK gene mutations. Nine mutations had been reported previously including one gross deletion (c.722_2041del), one missense mutation (c.1764G>T), three non-sense mutations (c.194C>A, c.895C>T and c.1821G>A) and four invariant splice-site mutations (c.971+2T>C, c.1481+2T>A, c.1482-2A>G, c.1699-2A>G). Seven novel mutations were identified (c.373_441del, c. 504delG, c.537delC, c.851delA, c.1637G>A, c.1879T>C and c. 1482_1882 del). Ten of the eighteen mutations of BTK gene were located in the TK domain, four in the PH domain, three in the SH3 domain and one spanned the TH, SH3, SH2 and TK domain. Candidate genes of autosomal-recessive agammaglobulinemia, including IGHM, CD79a, CD79b and IGLL1, were screened in three patients without mutations in the BTK gene. A compound heterozygosity mutation in the IGHM gene (c.1956G>A, c.175_176insC) was identified in one patient. The results of our study further support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Asian People; Binding Sites; CD79 Antigens; Child; Child, Preschool; China; Codon, Nonsense; DNA Mutational Analysis; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains, Surrogate; Immunoglobulin M; Male; Mutation; Mutation, Missense; Protein-Tyrosine Kinases; RNA Splice Sites; Sequence Deletion
PubMed: 21039741
DOI: 10.1111/j.1365-3083.2010.02457.x