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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 -
Journal of Pediatric Hematology/oncology Mar 2024Three-year-old boy who presented with colicky abdominal pain, diarrhoea and vomiting was investigated with computed tomography which revealed a mass in the...
Three-year-old boy who presented with colicky abdominal pain, diarrhoea and vomiting was investigated with computed tomography which revealed a mass in the peripancreatic region. An imaging possibility of duodenal intramural hematoma was considered after reassessment with ultrasound which was subsequently confirmed by magnetic resonance imaging. The development of a spontaneous duodenal hematoma lead to further evaluation of the patient and revealed X linked hyper IgM syndrome.
Topics: Male; Humans; Hyper-IgM Immunodeficiency Syndrome, Type 1; Hyper-IgM Immunodeficiency Syndrome; Duodenal Diseases; Duodenum; Gastrointestinal Hemorrhage; Hematoma
PubMed: 37867238
DOI: 10.1097/MPH.0000000000002773 -
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 -
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 -
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 -
Kyobu Geka. the Japanese Journal of... Sep 2023Immunoglobulin A (IgA) deficiency is the most common type of primary immunodeficiency. When a patient receives a blood product transfusion, anti-IgA antibodies are...
Immunoglobulin A (IgA) deficiency is the most common type of primary immunodeficiency. When a patient receives a blood product transfusion, anti-IgA antibodies are formed. Second transfusion may sometimes cause an anaphylactic reaction, thus caution is necessary. Reported here is a case of Stanford type A acute aortic dissection performed in the patient with IgA deficiency with a history of blood transfusion. Red blood cells and platelet were washed and prepared, and flesh frozen plasma from IgA deficient donors was obtained. Thereafter, the surgery was safely performed.
Topics: Humans; IgA Deficiency; Aortic Dissection; Anaphylaxis; Antibodies; Tissue Donors
PubMed: 37735726
DOI: No ID Found -
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 -
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 -
Allergy and Asthma Proceedings Sep 2023There are no published epidemiologic studies with regard to the prevalence of neurologic diseases among subjects with selective immunoglobulin A (IgA) deficiency...
There are no published epidemiologic studies with regard to the prevalence of neurologic diseases among subjects with selective immunoglobulin A (IgA) deficiency (sIgAD). To investigate the prevalence of neurologic diseases among the Israeli population with sIgAD. A population-based case-control study among members of a large nationwide health maintenance organization in Israel providing services to > 700,000 members. The sIgAD group included individuals ≥4 years of age with a serum IgA level of <0.07 g/L and with a diagnosis of sIgAD. The control group was randomly sampled from the entire study population with a case-control ratio of five controls for each case (1:5), with exact matching for age, gender, ethnic group, and socioeconomic status category. A total of 796 subjects ages 20.58 ± 15.46 years; 391 female subjects (49.1%) were identified as having sIgAD. The control group was constituted of 3980 matched subjects. The sIgAD group was characterized by a higher prevalence of autism spectrum disorder and tic disorders. Migraine was less prevalent in the sIgAD group (19 [2.39%]) than in the control group (168 [4.22%]), odds ratio (OR) 0.55 (95% confidence interval {CI}, 0.34-0.90); p = 0.016]. More cases of subjects with epilepsy were observed in the sIgAD group (14 [1.76%]) than in the control group (31 [0.80%]), OR 2.28 (95% CI, 1.12 - 4.44; p = 0.015). Our observation raises the question of the role of IgA in noninfectious diseases of the central nervous system. Further basic studies are needed to explain our observation.
Topics: Humans; Female; IgA Deficiency; Prevalence; Autism Spectrum Disorder; Case-Control Studies; Immunoglobulin A
PubMed: 37641224
DOI: 10.2500/aap.2023.44.230036 -
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