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Clinical Immunology (Orlando, Fla.) Aug 2023X-Linked Hyper-IgM Syndrome is caused by pathogenic variants in CD40LG. Three patients with atypical clinical and immunological features were identified with variants in...
X-Linked Hyper-IgM Syndrome is caused by pathogenic variants in CD40LG. Three patients with atypical clinical and immunological features were identified with variants in CD40LG requiring further characterization. Flow cytometry was used to evaluate CD40L protein expression and binding capacity to a surrogate receptor, CD40-muIg. Though functional anomalies were observed, there was still a lack of clarity regarding the underlying mechanism. We developed structural models for wild-type and the three variants of CD40L protein observed in these patients (p. Lys143Asn, Leu225Ser and Met36Arg) to evaluate structural alterations by molecular mechanic calculations, and assess protein movement by molecular dynamic simulations. These studies demonstrate that functional analysis of variants of unknown significance in CD40LG can be supplemented by advanced computational analysis in atypical clinical contexts. These studies in combination identify the deleterious effects of these variants and potential mechanisms for protein dysfunction.
Topics: Humans; CD40 Antigens; CD40 Ligand; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome, Type 1; Immunoglobulin M; Mutation
PubMed: 37433422
DOI: 10.1016/j.clim.2023.109692 -
Journal of Clinical Immunology Dec 2023Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have...
PURPOSE
Inherited deficiencies of CD40 and CD40 ligand (CD40L) reflect the crucial immunological functions of CD40-CD40L interaction/signaling. Although numerous studies have provided a detailed description of CD40L deficiency, reports of CD40 deficiency are scarce. Herein, we describe the characteristics of all reported patients with CD40 deficiency.
METHODS
The PubMed, Embase and Web of Science databases were searched for relevant literature published till 7th August 2023. Study deduplication and identification of relevant reports was performed using the online PICO Portal. The data were extracted using a pre-designed data extraction form and the SPSS software was used for analysis.
RESULTS
Systematic literature review revealed 40 unique patients with CD40 deficiency. Respiratory tract and gastrointestinal infections were the predominant clinical manifestations (observed in 93% and 57% patients, respectively). Sclerosing cholangitis has been reported in nearly one-third of patients. Cryptosporidium sp. (29%) and Pneumocystis jirovecii (21%) were the most common microbes identified. Very low to undetectable IgG levels and severely reduced/absent switch memory B cells were observed in all patients tested/reported. Elevated IgM levels were observed in 69% patients. Overall, splice-site and missense variants were the most common (36% and 32%, respectively) molecular defects identified. All patients were managed with immunoglobulin replacement therapy and antimicrobial prophylaxis was utilized in a subset. Hematopoietic stem cell transplantation (HSCT) has been performed in 45% patients (curative outcome observed in 73% of these patients). Overall, a fatal outcome was reported in 21% patients.
CONCLUSIONS
We provide a comprehensive description of all important aspects of CD40 deficiency. HSCT is a promising curative treatment option for CD40 deficiency.
Topics: Humans; CD40 Ligand; Cryptosporidiosis; Cryptosporidium; Hyper-IgM Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; CD40 Antigens; Immunoglobulin M; Lymphopenia
PubMed: 38129705
DOI: 10.1007/s10875-023-01633-1 -
The Lancet. Gastroenterology &... Nov 2023Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA...
Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study.
BACKGROUND
Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease.
METHODS
In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data.
FINDINGS
We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet.
INTERPRETATION
Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA.
FUNDING
None.
Topics: Adolescent; Adult; Female; Humans; Male; Atrophy; Autoantibodies; Celiac Disease; IgA Deficiency; Immunoglobulin A; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; Transglutaminases
PubMed: 37696284
DOI: 10.1016/S2468-1253(23)00205-4 -
The Journal of Allergy and Clinical... 2017
Topics: Adult; Arthralgia; Autoimmunity; Expert Testimony; Female; Humans; IgA Deficiency; Immunoglobulin A; Immunoglobulin E; Up-Regulation
PubMed: 28941669
DOI: 10.1016/j.jaip.2017.07.013 -
Frontiers in Immunology 2018Antibody production and function represent an essential part of the immune response, particularly in fighting bacterial and viral infections. Multiple immunological... (Review)
Review
Antibody production and function represent an essential part of the immune response, particularly in fighting bacterial and viral infections. Multiple immunological phenotypes can result in dysregulation of the immune system humoral compartment, including class-switch recombination (CSR) defects associated with hyper-IgM (HIGM) syndromes. The CSR/HIGM syndromes are defined by the presence of normal or elevated plasma IgM levels in the context of low levels of switched IgG, IgA, and IgE isotypes. Recently described autosomal dominant gain-of-function (GOF) mutations in and cause combined immunodeficiencies that can also present as CSR/HIGM defects. These defects, their pathophysiology and derived clinical manifestations are described in depth. Previously reported forms of CSR/HIGM syndromes are briefly reviewed and compared to the phosphoinositide 3-kinase (PI3K) pathway defects. Diseases involving the PI3K pathway represent a distinctive subset of CSR/HIGM syndromes, presenting with their own characteristic clinical and laboratory attributes as well as individual therapeutic approaches.
Topics: Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Humans; Hyper-IgM Immunodeficiency Syndrome; Immunity, Humoral; Immunoglobulin Class Switching; Immunoglobulin Isotypes; Mutation; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 30319630
DOI: 10.3389/fimmu.2018.02172 -
Medicina (Kaunas, Lithuania) Jul 2019Celiac disease (CD) is a systemic autoimmune disease driven by gluten-ingestion in genetically predisposed individuals. Although it primarily affects the small bowel, CD... (Review)
Review
Celiac disease (CD) is a systemic autoimmune disease driven by gluten-ingestion in genetically predisposed individuals. Although it primarily affects the small bowel, CD can also involve other organs and manifest as an extraintestinal disease. Among the extraintestinal features of CD, hematologic ones are rather frequent and consist of anemia, thrombocytosis (thrombocytopenia also, but rare), thrombotic or hemorrhagic events, IgA deficiency, hyposplenism, and lymphoma. These hematologic alterations can be the sole manifestation of the disease and should prompt for CD testing in a suggestive clinical scenario. Recognition of these atypical, extraintestinal presentations, including hematologic ones, could represent a great opportunity to increase the diagnostic rate of CD, which is currently one of the most underdiagnosed chronic digestive disorders worldwide. In this review, we summarize recent evidence regarding the hematological manifestations of CD, with focus on practical recommendations for clinicians.
Topics: Anemia; Celiac Disease; Hematologic Diseases; Humans; IgA Deficiency; Lymphoma
PubMed: 31311098
DOI: 10.3390/medicina55070373 -
Expert Review of Clinical Immunology Dec 2016For twenty years, two paradigms have been considered as the main genetic contributors to immunoglobulin A deficiency, including cytogenetic defects involving large... (Review)
Review
For twenty years, two paradigms have been considered as the main genetic contributors to immunoglobulin A deficiency, including cytogenetic defects involving large chromosomal aberrations and an association with the human major histocompatibility complex (MHC) locus. However, an overview of recent studies suggests a role for several monogenic disorders in the development of this disease. Areas covered: This review examines the concept of monogenic disorders for patients with IgA deficiency in order to identify the underlying pathogenic mechanism(s). Expert commentary: A clinical/immunologic workup followed by targeted gene mutation analysis has been proposed for an approach to IgA deficient patients.
Topics: Animals; Chromosome Aberrations; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Genotype; HLA Antigens; Humans; IgA Deficiency; Immunoglobulin A; Mutation; Pedigree; Polymorphism, Genetic
PubMed: 27266541
DOI: 10.1080/1744666X.2016.1198696 -
Frontiers in Immunology 2022
Topics: Humans; IgA Deficiency; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases
PubMed: 36052063
DOI: 10.3389/fimmu.2022.959720 -
Clinical Immunology (Orlando, Fla.) May 2017Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and...
Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.
Topics: Adolescent; Adult; Agammaglobulinemia; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cause of Death; Child; Cohort Studies; Female; Humans; Hyper-IgM Immunodeficiency Syndrome; IgA Deficiency; Immunoglobulin G; Immunologic Deficiency Syndromes; Life Expectancy; Male; Middle Aged; Mutation; Neoplasms; Odds Ratio; Phenotype; Proportional Hazards Models; Retrospective Studies; Survival Rate; Young Adult
PubMed: 28126470
DOI: 10.1016/j.clim.2017.01.009 -
The Journal of Allergy and Clinical... Jun 2023
Topics: Humans; IgA Deficiency; COVID-19; Immunoglobulin A
PubMed: 36858279
DOI: 10.1016/j.jaip.2023.02.016