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Clinical and Experimental Medicine Oct 2023Studies are scarce regarding IgG anti-tissue transglutaminase 2 (tTG) normalization in selective IgA deficient (SIgAD) celiac disease (CD) patients after beginning a...
Studies are scarce regarding IgG anti-tissue transglutaminase 2 (tTG) normalization in selective IgA deficient (SIgAD) celiac disease (CD) patients after beginning a gluten free diet (GFD). The aim of this study is to analyse the decreasing dynamics of IgG anti-tTG in patients diagnosed with CD who start a GFD. To achieve this objective, IgG and IgA anti-tTG levels at diagnosis and during follow-up in 11 SIgAD CD patients and in 20 IgA competent CD patients were retrospectively evaluated. At diagnosis, statistical differences were not found when comparing IgA anti-tTG levels of IgA competent subjects with IgG anti-tTG levels of SIgAD subjects. Regarding the decreasing dynamics, even though no statistical differences were found (p = 0.06), normalization rates were slower for SIgAD CD patients. After 1 and 2 years on GFD, respectively, only 18.2% and 36.3% of the SIgAD CD patients normalized IgG anti-tTG levels; otherwise, IgA anti-tTG reached values under the reference values in 30% and 80% of the IgA competent patients in the same time-points. Although IgG anti-tTG has demonstrated a high diagnostic efficiency in SIgAD CD pediatric patients, this test does not appear to be as precise for long-term GFD response monitoring as IgA anti-tTG levels in IgA sufficient patients.
Topics: Humans; Autoantibodies; Celiac Disease; Diet, Gluten-Free; IgA Deficiency; Immunity; Immunoglobulin A; Immunoglobulin G; Retrospective Studies; Transglutaminases
PubMed: 36913036
DOI: 10.1007/s10238-023-01040-1 -
Journal of Clinical Immunology Feb 2024B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both...
B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders.
Topics: Humans; Cytidine Deaminase; Hyper-IgM Immunodeficiency Syndrome; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Phenotype; Somatic Hypermutation, Immunoglobulin
PubMed: 38363477
DOI: 10.1007/s10875-024-01665-1 -
Cells Jul 2023CD40L is expressed in activated T cells, and it plays a major role in immune response and is a major therapeutic target for inflammation. High IgM syndrome type 1...
CD40L Activates Platelet Integrin αIIbβ3 by Binding to the Allosteric Site (Site 2) in a KGD-Independent Manner and HIGM1 Mutations Are Clustered in the Integrin-Binding Sites of CD40L.
CD40L is expressed in activated T cells, and it plays a major role in immune response and is a major therapeutic target for inflammation. High IgM syndrome type 1 (HIGM1) is a congenital functional defect in CD40L/CD40 signaling due to defective CD40L. CD40L is also stored in platelet granules and transported to the surface upon platelet activation. Platelet integrin αIIbβ3 is known to bind to fibrinogen and activation of αIIbβ3 is a key event that triggers platelet aggregation. Also, the KGD motif is critical for αIIbβ3 binding and the interaction stabilizes thrombus. Previous studies showed that CD40L binds to and activates integrins αvβ3 and α5β1 and that HIGM1 mutations are clustered in the integrin-binding sites. However, the specifics of CD40L binding to αIIbβ3 were unclear. Here, we show that CD40L binds to αIIbβ3 in a KGD-independent manner using CD40L that lacks the KGD motif. Two HIGM1 mutants, S128E/E129G and L155P, reduced the binding of CD40L to the classical ligand-binding site (site 1) of αIIbβ3, indicating that αIIbβ3 binds to the outer surface of CD40L trimer. Also, CD40L bound to the allosteric site (site 2) of αIIbβ3 and allosterically activated αIIbβ3 without inside-out signaling. Two HIMG1 mutants, K143T and G144E, on the surface of trimeric CD40L suppressed CD40L-induced αIIbβ3 activation. These findings suggest that CD40L binds to αIIbβ3 in a manner different from that of αvβ3 and α5β1 and induces αIIbβ3 activation. HIGM1 mutations are clustered in αIIbβ3 binding sites in CD40L and are predicted to suppress thrombus formation and immune responses through αIIbβ3.
Topics: Humans; Platelet Glycoprotein GPIIb-IIIa Complex; CD40 Ligand; Allosteric Site; Hyper-IgM Immunodeficiency Syndrome, Type 1; Binding Sites; Mutation; Integrin alpha5beta1; Thrombosis
PubMed: 37566056
DOI: 10.3390/cells12151977 -
Immunologic Research Feb 2024Immunoglobulin A Deficiency (IgAD) is the most common primary immunodeficiency and is significantly associated with Celiac Disease (CD), which recognizes a specific...
Immunoglobulin A Deficiency (IgAD) is the most common primary immunodeficiency and is significantly associated with Celiac Disease (CD), which recognizes a specific background of human leukocyte antigens (HLA) predisposition (including HLA-DQB1*02:01 allele). A number of studies investigated the role of HLA in IgAD etiopathogenesis: HLA-DQB1*02 alleles are included in the main haplotypes linked to this primary immunodeficiency. In this preliminary study, we investigated the potential impact of HLA-DQB1*02:01 allelic status on total serum IgA levels: 108 serum samples from the bone marrow donors' registry were analyzed for total IgA concentration with respect to the HLA-DQB1*02:01 status. Although total serum IgA levels between HLA-DQB1*02:01 carriers and HLA-DQB1*02:01 negative donors were not different, we observed a statistically significant difference (p=0.0118) in total serum IgA levels among donors with low IgA concentration (<80mg/dL) in the sub-analysis between HLA-DQB1*02:01 positive group (including both homozygous and heterozygous carriers) compared to HLA-DQB1*02:01 negative donors. Our results might suggest a role of HLA-DQB1*02:01 allelic variant in the determination of total serum IgA levels, at least in patients affected with IgA deficiency and/or otherwise predisposed to it; however, larger and more standardized studies are needed to confirm this speculation.
Topics: Humans; HLA-DQ beta-Chains; Genotype; Haplotypes; IgA Deficiency; Immunoglobulin A; Alleles; Gene Frequency; Genetic Predisposition to Disease
PubMed: 37725324
DOI: 10.1007/s12026-023-09420-1 -
Pediatric Rheumatology Online Journal Oct 2023The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1-7% in various small studies. As a result of the limited number...
BACKGROUND
The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1-7% in various small studies. As a result of the limited number of research and their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers.
METHODS
Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher's exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated.
RESULTS
808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA ≥ 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1-1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1-2.9).
CONCLUSIONS
Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD.
Topics: Humans; Protein Glutamine gamma Glutamyltransferase 2; Arthritis, Juvenile; Case-Control Studies; Transglutaminases; Prevalence; IgA Deficiency; Immunoglobulin A; Autoantibodies; Celiac Disease
PubMed: 37798643
DOI: 10.1186/s12969-023-00890-z -
Transfusion May 2024A life-threatening anaphylactic shock can occur if a patient with undiagnosed immunoglobulin A (IgA) deficiency (i.e., IgA levels <500 ng/mL) receives IgA-containing...
BACKGROUND
A life-threatening anaphylactic shock can occur if a patient with undiagnosed immunoglobulin A (IgA) deficiency (i.e., IgA levels <500 ng/mL) receives IgA-containing blood, hence the need for a rapid, point-of-care (POC) method for IgA deficiency screening. Enzyme-linked immunosorbent assay (ELISA) is routinely used to detect IgA, but this method requires trained specialists and ≥24 h to obtain a result. We developed a surface plasmon resonance (SPR)-based protocol to identify IgA-deficient patients or donors within 1 h.
MATERIALS AND METHODS
The SPR sensor relies on the detection of IgAs captured by primary antibodies adsorbed on the SPR chip and quantified with secondary antibodies. The sensor was calibrated from 0 to 2000 ng/mL in buffer, IgA-depleted human serum, and plasma samples from IgA-deficient individuals. A critical concentration of 500 ng/mL was set for IgA deficiency. The optimized sensor was then tested on eight plasma samples with known IgA status (determined by ELISA), including five with IgA deficiency and three with normal IgA levels.
RESULTS
The limit of detection was estimated at 30 ng/mL in buffer and 400 ng/mL in diluted plasma. The results obtained fully agreed with ELISA among the eight plasma samples tested. The protocol distinguished IgA-deficient from normal samples, even for samples with an IgA concentration closer to critical concentration.
DISCUSSION
In conclusion, we developed a reliable POC assay for the quantification of IgA in plasma. This test may permit POC testing at blood drives and centralized centers to maintain reserves of IgA-deficient blood and in-hospital testing of blood recipients.
Topics: Humans; Surface Plasmon Resonance; Immunoglobulin A; IgA Deficiency; Enzyme-Linked Immunosorbent Assay
PubMed: 38591151
DOI: 10.1111/trf.17818 -
Anesthesia Progress Sep 2023Immunoglobulin A (IgA) deficiency is one of the most common immune disorders characterized by increased susceptibility to infections, especially involving the...
Immunoglobulin A (IgA) deficiency is one of the most common immune disorders characterized by increased susceptibility to infections, especially involving the respiratory tract and mucosal surfaces of the mouth, gingiva, and nasal sinus. Because dental surgery and general anesthesia may pose an increased risk for systemic infections, management of IgA-deficient patients requires caution during dental procedures and intubated general anesthesia. We report a 5-year-old female patient with IgA deficiency who underwent extraction of 18 deciduous teeth under general anesthesia. Antibiotic prophylaxis and antiseptic mouthwash were used perioperatively to reduce bacteremia risks. Nasotracheal intubation was carefully performed after applying topical disinfectants and epinephrine-containing gauze packing into the nasal cavity to minimize trauma. The patient was carefully monitored overnight in the hospital and discharged without any signs or symptoms of infection the next day. Dental anesthesia providers must be aware of the potential implications for safe practice when managing patients with IgA deficiency.
Topics: Female; Humans; Child, Preschool; IgA Deficiency; Intubation, Intratracheal; Dental Care; Anesthesia, General; Immunoglobulin A
PubMed: 37850675
DOI: 10.2344/anpr-70-02-13 -
Journal of Clinical Immunology Feb 2024
Review
Topics: Humans; Hyper-IgM Immunodeficiency Syndrome; Heterozygote
PubMed: 38363450
DOI: 10.1007/s10875-024-01666-0 -
Pediatric Pulmonology Dec 2023
Topics: Humans; Shock, Septic; Pseudomonas aeruginosa; Delayed Diagnosis; Hyper-IgM Immunodeficiency Syndrome; Pneumonia; Community-Acquired Infections; Pseudomonas Infections
PubMed: 37830525
DOI: 10.1002/ppul.26672 -
Journal of Clinical Immunology Oct 2023
Topics: Humans; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome, Type 1; Homozygote; Lymphopenia; Cytidine Deaminase; Immunoglobulin M
PubMed: 37402930
DOI: 10.1007/s10875-023-01546-z