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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 -
Innate Immunity Jan 2018The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described... (Review)
Review
The critical role of the CD40/CD40L pathway in B-cell proliferation, immunoglobulin (Ig) isotype switching and germinal center formation has been studied and described extensively in previous literature. Interruption of the CD40/CD40L signal causes hyper-IgM (HIGM) syndrome, which has been classified and recognized as a group of rare inherited immune deficiency disorders. Defects in CD40 and CD40L interactions or in downstream signaling molecules, including activation-induced cytidine deaminase, uracyl-DNA-glycosylase, NF-κB and DNA repair enzymes, result in an increased level of serum IgM and a significantly decreased or absent level of IgA, IgG and IgE that is accompanied by severe recurrent infections and autoimmune diseases. Many genetic defects in HIGM have been identified and, as a result, it is possible for patients to be definitively diagnosed by gene sequencing and to delineate the immunological features of the patients. Modifying the CD40/CD40L signaling pathway may offer the possibility of restoring the normal serum Ab production and curing the immunodeficiency. Hematopoietic stem cell transplantation has achieved a high rate of success using a sibling donor. In addition, successful examples of treating other immunodeficiencies using gene therapy indicated that there was a possibility of eradicating HIGM with this approach. In this review, we summarize the current drugs and a variety of therapeutic approaches for the treatment of the HIGM syndrome by interfering with the defective CD40/CD40L pathway.
Topics: CD40 Antigens; CD40 Ligand; Humans; Hyper-IgM Immunodeficiency Syndrome; Signal Transduction
PubMed: 29132233
DOI: 10.1177/1753425917739681 -
Frontiers in Immunology 2023Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to...
INTRODUCTION
Primary antibody deficiencies (PAD) are inborn defects of the immune system that result in increased susceptibility to infections. Despite the reduced response to vaccination, PAD patients still benefit from it by reducing the risk of severe infections and complications. SARS-CoV-2 vaccines are recommended in PAD patients, but their immune effects are poorly studied. Here, we analyze virus-specific T-cell responses in PAD patients after booster vaccination against SARS-CoV-2.
PATIENTS AND METHODS
The study included 57 adult PAD patients on long-term immunoglobulin replacement therapy (IgRT) diagnosed with X-linked agammaglobulinemia (XLA; n = 4), common variable immunodeficiency (CVID; n = 33), isotype defects or IgG subclass deficiency (n = 6), and unclassified IgG deficiency (n = 14). Of those, 49 patients (86%) received vaccination against SARS-CoV-2 using mRNA vaccine (Pfizer-BioNTech). T-cell responses were assessed at a median of 21 (13 - 30) weeks after the booster dose (mainly the third dose) using commercially available interferon-gamma release assay (IGRA) with recombinant SARS-CoV-2 spike S1 protein.
RESULTS
Vaccinated PAD patients showed an increased (3.8-fold, p = 0.004) release of IFN-γ upon S1 stimulation. In this group, we also documented higher serum levels of anti-SARS-CoV-2 IgG (4.1-fold, p = 0.01), although they were not associated with IGRA results. Further subgroup analysis revealed very similar IGRA responses in CVID and unclassified IgG deficiencies that were 2.4-fold increased compared to XLA and 5.4-fold increased compared to patients with isotype defects or IgG subclass deficiencies (e.g., vs. CVID: p = 0.016). As expected, CVID and XLA patients showed decreased serum titers of anti-SARS-CoV-2 antibodies compared to other studied groups (e.g., CVID vs. unclassified IgG deficiency: 4.4-fold, p = 0.006). The results did not depend directly on IgRT mode or dose, number of vaccine doses and time from the last booster dose, and clinical manifestations of PAD. Interestingly, anti-SARS-CoV-2 titers were positively correlated with serum immunoglobulin levels before IgRT (e.g., for IgA: r = 0.45, p<0.001; for IgG: r = 0.34, p = 0.009) and the percentage of peripheral blood NK cells (r = 0.48, p<0.001).
CONCLUSIONS
Our results documented satisfactory cellular immune response in PAD patients after booster SARS-CoV-2 vaccination. Therefore, even patients with agammaglobulinemia should benefit from vaccination due to the apparent induction of cell-mediated immunity, which, together with IgRT, grants comprehensive protection against the pathogen.
Topics: Adult; Humans; COVID-19 Vaccines; SARS-CoV-2; IgG Deficiency; COVID-19; Immunity, Cellular; Common Variable Immunodeficiency; Antibodies, Viral; Immunoglobulin G; Primary Immunodeficiency Diseases
PubMed: 37901210
DOI: 10.3389/fimmu.2023.1275892 -
Frontiers in Cellular and Infection... 2023Patients with Human Hyper IgM syndromes (HIGM) developed pulmonary and gastrointestinal infections since infancy and most patients have mutations in the CD40 ligand...
Elevated levels of enteric IgA in an unimmunised mouse model of Hyper IgM syndrome derived from gut-associated secondary lymph organs even in the absence of germinal centres.
INTRODUCTION
Patients with Human Hyper IgM syndromes (HIGM) developed pulmonary and gastrointestinal infections since infancy and most patients have mutations in the CD40 ligand (CD40L) gene. Most HIGM patients compared to healthy subjects have higher/similar IgM and lower IgG, and IgA serum concentrations but gut antibody concentrations are unknown. CD40L on activated T-cells interacts with CD40 on B-cells, essential for the formation of germinal centres (GCs) inside secondary lymphoid organs (SLOs), where high-affinity antibodies, long-lived antibody-secreting plasma cells, and memory B-cells, are produced. C57BL6-CD40 ligand deficient mice (C57BL6- ), are a model of HIGM, because serum immunoglobulin concentrations parallel levels observed in HIGM patients and have higher faecal IgA concentrations. In mice, TGFβ and other cytokines induce IgA production.
AIMS
To compare and evaluate B-cell populations and IgA-producing plasma cells in peritoneal lavage, non-gut-associated SLOs, spleen/inguinal lymph nodes (ILN), and gut-associated SLOs, mesenteric lymph nodes (MLN)/Peyer´s patches (PP) of unimmunised C57BL6- and C57BL6-wild-type (WT) mice.
MATERIAL AND METHODS
Peritoneal lavages, spleens, ILN, MLN, and PP from 8-10 weeks old C57BL6- and WT mice, were obtained. Organ cryosections were analysed by immunofluorescence and B-cell populations and IgA-positive plasma cell suspensions by flow cytometry.
RESULTS
In unimmunised WT mice, GCs were only observed in the gut-associated SLOs, but GCs were absent in all C57BL6- SLOs. PP and MLN of C57BL6- mice exhibited a significantly higher number of IgA-producing cells than WT mice. In the spleen and ILN of C57BL6- mice IgA-producing cells significantly decreased, while IgM-positive plasma cells increased. C57BL6- B-1 cells were more abundant in all analysed SLOs, whereas in WT mice most B-1 cells were contained within the peritoneal cavity. C57BL6- B-cells in MLN expressed a higher TGFβ receptor-1 than WT mice. Mouse strains small intestine microvilli (MV), have a similar frequency of IgA-positive cells.
DISCUSSION
Together our results confirm the role of PP and MLN as gut inductive sites, whose characteristic features are to initiate an IgA preferential immune response production in these anatomical sites even in the absence of GCs. IgA antibodies play a pivotal role in neutralising, eliminating, and regulating potential pathogens and microorganisms in the gut.
Topics: Humans; Mice; Animals; CD40 Ligand; Hyper-IgM Immunodeficiency Syndrome; Germinal Center; Intestine, Small; Immunoglobulin A; Immunoglobulin M; Transforming Growth Factor beta
PubMed: 37457961
DOI: 10.3389/fcimb.2023.1172021 -
Clinical Reviews in Allergy & Immunology Aug 2022The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests... (Review)
Review
The field of Immunology is one that has undergone great expansion in recent years. With the advent of new diagnostic modalities including a variety of genetic tests (discussed elsewhere in this journal), the ability to diagnose a patient with a primary immunodeficiency disorder (PIDD) has become a more streamlined process. With increased availability of genetic testing for those with suspected or known PIDD, there has been a significant increase in the number of genes associated with this group of disorders. This is of great importance as a misdiagnosis of these rare diseases can lead to a delay in what can be critical treatment options. At times, those options can include life-saving medications or procedures. Presentation of patients with PIDD can vary greatly based on the specific genetic defect and the part(s) of the immune system that is affected by the variation. PIDD disorders lead to varying levels of increased risk of infection ranging from a mild increase such as with selective IgA deficiency to a profound risk with severe combined immunodeficiency. These diseases can also cause a variety of other clinical findings including autoimmunity and gastrointestinal disease.
Topics: Autoimmunity; Genetic Testing; Humans; IgA Deficiency; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases
PubMed: 35020168
DOI: 10.1007/s12016-021-08881-2 -
Cellular & Molecular Immunology Jun 2018Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand gene. The CD40 ligand has been recently... (Review)
Review
Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand gene. The CD40 ligand has been recently highlighted as playing a key role in the pathogenesis of primary biliary cholangitis. In the present study, we assessed an extensive set of serum autoantibodies in a series of well-defined patients with hyper-immunoglobulin M syndrome. Serum, liver-related and liver-not-related autoantibodies IgG, IgM and IgA were tested by ELISA and standard indirect immunofluorescence in HEp-2 cells in 13 Tunisian patients (8 males and 5 females, aged 1-12 years) with hyper-immunoglobulin M syndrome during 1995-2012 and, as controls, 21 age- and gender-matched blood donors. The level of IgM antibody against MIT3 was significantly higher in patients than in controls (35.8 vs 10.7, P=0.002). Half of the hyperimmunoglobulin M syndrome patients were found to be anti-MIT3 IgM positive vs none of the controls (P<0.0001). Twenty-three percent of patients were found to be anti-sp100 antibody positive vs only 0.05% of controls. By immunofluorescence, 92.3% of patients were MIT3 IgM positive vs none of the controls. In conclusion, the IgM class of anti-MIT3 antibodies was shown to be present by both ELISA and immunofluorescence in most of the patients with hyper-immunoglobulin M syndrome. The presence of the hallmark of primary biliary cholangitis, a disease where the CD40 ligand is a key player, in an immunodeficiency disease caused by mutations in the CD40 ligand gene is very intriguing and opens new scenarios in understanding the immune pathogenesis of primary biliary cholangitis.
Topics: Autoantibodies; Case-Control Studies; Cell Line; Child; Child, Preschool; Female; Humans; Hyper-IgM Immunodeficiency Syndrome; Infant; Liver; Male
PubMed: 29400703
DOI: 10.1038/cmi.2017.140 -
Nature Communications Dec 2023Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few...
Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker.
Topics: Humans; Bacteria; Escherichia coli; IgA Deficiency; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M
PubMed: 38065985
DOI: 10.1038/s41467-023-44007-2 -
Neurology(R) Neuroimmunology &... Jul 2020To investigate the immunologic impact of a single cycle of rituximab (RTX) in children and adolescents with immune-mediated disorders, we evaluated B cells and...
OBJECTIVE
To investigate the immunologic impact of a single cycle of rituximab (RTX) in children and adolescents with immune-mediated disorders, we evaluated B cells and immunoglobulin levels of 20 patients with neuroimmunologic, nephrologic, dermatologic, and rheumatologic disorders treated under recommended guidelines.
METHODS
Retrospective study of immunologic changes in children (aged ≤18 years) diagnosed with immune-mediated disorders in which RTX was prescribed between June 2014 and February 2019. Patients were excluded if they had prior diagnosis of malignant disease or primary immunodeficiency. Patients were clinically and immunologically followed up every 3 months. Only patients having received a single cycle of RTX and with a follow-up greater than 12 months were included in the analysis of persistent dysgammaglobulinemia.
RESULTS
Twenty children were included. Median age at RTX treatment was 12.8 years (interquartile range [IQR] 6.6-15.5 years). Median follow-up was 12.6 months (IQR 10.2-24 months). Of the 14 patients eligible for persistent dysgammaglobulinemia analysis (3 had received RTX retreatment, 2 had <12 months post-RTX follow-up, and in 1 data for this time point was missing), 2/14 (14%) remained with complete B-cell depletion, and 5/14 (36%) had dysgammaglobulinemia. Patients with dysgammaglobulinemia were younger (7.8 vs 15.6 years, = 0.072), had more underlying neuroimmunologic diseases (5/5 vs 0/9, < 0.001), and had received more frequently concentrated doses of RTX (3/5 vs 1/9, = 0.05) than patients without dysgammaglobulinemia. Kinetics of immunoglobulins in the 20 patients revealed a decrease as early as 3 months after RTX in patients with neuroimmunologic disorders.
CONCLUSION
In our cohort, single-cycle RTX-induced dysgammaglobulinemia was enhanced in patients with neuroimmunologic diseases. Further studies are needed to confirm this observation.
Topics: Adolescent; B-Lymphocytes; Child; Child, Preschool; Dysgammaglobulinemia; Female; Follow-Up Studies; Humans; Immune System Diseases; Immunologic Factors; Male; Retrospective Studies; Rituximab
PubMed: 32376706
DOI: 10.1212/NXI.0000000000000724