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Current professional guidelines enable diagnosing pediatric Celiac Disease (CeD) without a biopsy, when tissue transglutaminase (TTG) IgA antibodies are >  × 10 the upper limit of normal (ULN) and anti-endomysial antibodies (EMA) are positive in a second sample. We compared baseline characteristics and serology normalization in children diagnosed with or without biopsies. A retrospective study of pediatric patients diagnosed with CeD during 2020: group A, no biopsy and group B, biopsy-based diagnosis. Baseline characteristics included demographics, anthropometrics, symptoms, family history, and celiac serology. Follow-up at 6-month intervals, up to 18 months, included dietary compliance, symptoms, and serology. Of 145 children diagnosed with CeD, 42 (29%) and 103 (71%) were from group A and B respectively. Mean age was 7.8 years (range 2.4-17.9 y), 91 (62.8%) females. Baseline symptoms or signs were present in 93 (64.1%) children, without significant difference between the groups. Baseline TTG levels were >  × 10 ULN in all patients in group A and 71 (68.9%) in group B. Among these patients, the rate of TTG decline during follow-up did not differ at any time point between patients diagnosed with and without biopsy, and between patients with and without symptoms. At the last follow-up visit, 24 (57%) children in group A and 46 (65%) in group B had TTG <  × 3 ULN without significant difference between the groups., Conclusion: Rate of TTG decline did not differ between CeD patients diagnosed with and without biopsy, suggesting that, at least in short term, no biopsy approach may not change patients' adherence and families' attitude towards treatment., What Is Known: • Based on current guidelines, there is a rise in the incidence of pediatric celiac disease (CeD) diagnosis without an intestinal biopsy. • There is insufficient data regarding patients' adherence to treatment, including pattern of serology decline, based on the method of CeD diagnosis., What Is New: • Children with CeD have similar baseline characteristics, including presence or absence of symptoms, whether diagnosed with or without biopsies. • During 18-month follow-up, the rate of celiac serology decline, and the reported adherence to treatment, do not differ between patients diagnosed based on biopsy or no biopsy approaches., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aim of this study was to evaluate the cutaneous manifestations of immunoglobulin A vasculitis (IgAV) in terms of skin lesion type, distribution and persistence and to investigate the relationship between cutaneous manifestations and system involvement and treatment needs. This retrospective observational study was conducted with 489 IgAV patients who were followed-up for at least 6 months between 2013 and 2024. Demographic characteristics, detailed cutaneous manifestations, clinical findings and treatments were retrieved from electronic medical records. IgAV patients were divided into subgroups according to the presence or absence of vesicles/bullae, necrosis/ulcer, rash spreading above the buttocks and persistence. The groups were analyzed statistically for demographic findings, systemic involvement and treatments. Of 489 patients, 36 (7.4%) had vesicles/bullae and 22 (4.5%) had necrosis/ulcers. 345 (70.6%) patients had cutaneous manifestations limited to the lower extremities and buttocks, 144 (29.4%) had cutaneous manifestations spreading from the lower extremities to the trunk, upper extremities or face. 36 (7.4%) patients had persistent rash for more than 1 month. Patients with necrosis/ulcer had more genital tract involvement (p = 0.04). Patients with rash spreading above the buttocks had more gastrointestinal tract and genital tract involvement (p = 0.014, p = 0.003). Patients with persistent rash had more renal involvement (p = 0.05). Patients with vesicles/bullae, necrosis/ulcer, rash spreading above the buttocks and persistent rash required more steroid treatment (p = 0.003, p = 0.001, p < 0.001, p = 0.03)., Conclusions: The characteristics of cutaneous manifestations in IgAV patients may be helpful in predicting the course of the disease. The skin lesion type, distribution and persistence of cutaneous manifestations in IgAV are associated with system involvement. In addition, the need for intensive therapy increases in the presence of vesicles/bullae, necrosis/ulcer, rash spreading over the buttocks and persistent rash in IgAV., What Is Known: • Palpable purpura localized to the lower extremities is the expected cutaneous manifestation of immunoglobulin A vasculitis., What Is New: • The type, distribution and duration of rash in IgAV have effects on the immunoglobulin A vasculitis disease course. • Genital tract involvement is more common in patients with necrosis/ulcers. • Gastrointestinal tract involvement and genital tract involvement are more common in patients with rash spreading above the buttocks. • Renal involvement is more common in patients with persistent rash., Competing Interests: Declarations Disclosures None Ethics approval The study was approved by the Ankara Bilkent City Hospital, ethics committee before the study (Date: 17.07.2024, No: TABED 1-24-406). Due to the retrospective design of the study, no patient consent was obtained. Conflict of interests The authors have no conflicts of interest to declare., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Antibodies to select Epstein-Barr virus proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against Epstein-Barr virus nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years before diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay., Experimental Design: Mammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A, which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using prediagnostic NPC sera from two independent cohorts in Singapore and Shanghai, the People's Republic of China., Results: At 95% sensitivity, 487V yielded a 94.9% specificity compared with 86.1% for 487A. EBNA1 deleted for the conserved glycine-alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390-641) showed lower specificity (84.8%) than the EBNA1 GAr-deleted construct (92.4%) at 95% sensitivity., Conclusions: Although EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr, but with residues consistently detected in Southeast Asian NPC tumors, is optimized for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection., (©2024 American Association for Cancer Research.)

Background: Although polioviruses (PVs) replicate in lymphoid tissue of both the pharynx and ileum, research on polio vaccine-induced mucosal immunity has predominantly focused on intestinal neutralizing and binding antibody levels measured in stool., Methods: To investigate the extent to which routine immunization with intramuscularly injected inactivated polio vaccine (IPV) may induce nasal and pharyngeal mucosal immunity, we measured PV type-specific neutralization and immunoglobulin (Ig) G, IgA, and IgM levels in nasal secretions, adenoid cell supernatants, and sera collected from 12 children, aged 2-5 years, undergoing planned adenoidectomies. All participants were routinely immunized with IPV and had no known contact with live PVs., Results: PV-specific mucosal neutralization was detected in nasal and adenoid samples, mostly from children who had previously received 4 IPV doses. Across the 3 PV serotypes, both nasal (Spearman ρ ≥ 0.87, P ≤ .0003 for all) and adenoid (Spearman ρ ≥ 0.57, P ≤ .05 for all) neutralization titers correlated with serum neutralization titers. In this small study sample, there was insufficient evidence to determine which Ig isotype(s) was correlated with neutralization., Conclusions: Our findings provide policy-relevant evidence that routine immunization with IPV may induce nasal and pharyngeal mucosal immunity. The observed correlations of nasal and pharyngeal mucosal neutralization with serum neutralization contrast with previous observations of distinct intestinal and serum responses to PV vaccines. Further research is warranted to determine which antibody isotype(s) correlate with polio vaccine-induced nasal and pharyngeal mucosal neutralizing activity and to understand the differences from intestinal mucosal immunity., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression., (© 2024 UICC.)

Objectives: To measure and evaluate the impact of receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in pregnancy on immunoglobulin G (IgG) and immunoglobulin A (IgA) titres in maternal and infant samples., Design: Prospective cohort study., Setting: Tertiary obstetric centre., Population or Sample: 52 pregnant women who received one or more SARS-CoV-2 vaccine doses during pregnancy and their neonates., Methods: IgG and IgA concentrations against SARS-CoV-2 antigens were measured from samples collected at delivery and 4-6 weeks postpartum and compared using Spearman correlations., Main Outcome Measures: Maternal and infant IgG and IgA titres in response to vaccination and infection in pregnancy., Results: In maternal serum collected at delivery, participants without evidence of prior infection who received 3 + doses of a SARS-CoV-2 vaccine had higher Anti-Spike (S) IgG geometric mean concentrations (log 10 AU/mL)(GMC) than those who received 2 doses (3 + Doses = 5.00, 2 Doses = 4.60, p = 0.08). The differences in IgG Anti-S GMC were statistically significant in cord serum, and in postpartum samples of maternal serum, infant serum and breast milk (Cord GMCs: 3 + Doses = 5.32, 2 Doses = 4.98, p < 0.05; Postpartum maternal serum GMCs: 3 + Doses = 5.25, 2 Doses = 4.57, p < 0.001; Postpartum infant serum GMCs: 3 + Doses = 5.10, 2 Doses = 4.72, p = 0.03; Postpartum breast milk GMCs: 3 + Doses = 2.61, 2 Doses = 1.94, p < 0.0001). Among participants with 3 + Doses, those with evidence of SARS-CoV-2 infection had statistically significant higher anti-S IgG GMCs than those without prior infection (Maternal serum at delivery: SARS-CoV-2+=5.65, SARS-CoV-2-=5.00, p = 0.004; Cord: SARS-CoV-2+=5.68, SARS-CoV-2-=5.32, p = 0.02; Postpartum maternal serum: SARS-CoV-2+=5.66, SARS-CoV-2-=5.25, p < 0.001; postpartum infant serum: SARS-CoV-2+=5.50, SARS-CoV-2-=5.10, p = 0.003; Postpartum breast milk: SARS-COV-2+=3.25, SARS-COV-2-=2.61, p = 0.009). Significant positive correlations were found for anti-S IgG titres between paired maternal and infant samples at delivery and postpartum (Delivery: R = 0.91, p < 0.001; postpartum: R = 0.86, p < 0.001)., Conclusions: Receipt of a SARS-CoV-2 vaccine and SARS-CoV-2 infection elicit strong IgG and IgA antibody responses in pregnant women with evidence of transplacental transfer to the fetus., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: IK, CM, EM, GA, JA, CE, AJ, MK, MM, GT, IS and DM have no conflicts to disclose. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines, with funds paid to his institute. MS is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Pediatric cow milk allergies (CMA) can occur in immunoglobulin (Ig) E and non-IgE-mediated forms. Unlike IgE-mediated allergies, the mechanisms of disease pathogenesis in non-IgE-mediated food allergy and an association with microbiome has not been well established. Previous studies have identified the presence of altered humoral responses to gut bacteria in IgE mediated allergies. Here, we analyzed IgA, IgE and IgG responses to gut bacteria in subjects with either IgE or non-IgE mediated CMA to identify relative proportions of Ig-coated bacteria and characterize unique disease specific microbial signatures., Methods: Multi-parametric flow cytometry analysis was used to identify IgA, IgE and IgG responses to gut bacteria in CMA patients. Cell sorting of Ig coated gut bacteria was subsequently performed followed by high throughput 16S rRNA gene sequencing and specific patterns of humoral responses to gut bacteria assessed in each study group., Results: We identified significant alterations in IgA and IgG gut bacterial coating patterns in CMA subjects. Proportions of IgA-coated bacteria were decreased in IgE mediated CMA subjects without atopic dermatitis (ALL) and non-IgE mediated CMA subjects (ENP), compared to healthy controls (CON). In comparison, IgG-coated bacteria was significantly elevated in CMA subjects with atopic dermatitis (AD). Alpha and beta diversities displayed significant differences in IgA-, IgE-, and IgG-coated bacteria in AD and ENP groups. Significant differences in bacteria coated by IgA, IgE and IgG were detected at Phyla, Genus and Species levels and associated bacterial dysbiosis in IgE and non-IgE mediated allergies were identified. Linear discriminant analysis (LDA) effect size (LEFse) revealed unique disease associated bacterial signatures, including several pathogenic bacteria namely Bacteroides fragilis, Ruminococcus gnavus, Eubacterium dolichum, Fusobacterium, Clostridium neonatale and Robinsoniella peoriensis. Receiver operating characteristic curve analysis confirmed the efficiency of using the bacterial signatures identified as biomarkers for disease., Conclusions: Altered IgA and IgG responses to gut bacteria were identified in CMA subjects. The disease-specific responses were associated with alterations in bacterial diversity and concomitant dysbiosis of Ig-coated bacteria in IgE-mediated and non-IgE-mediated CMA pediatric subjects. The identification of pathogenic bacteria uniquely associated with different classes of allergic disease indicates a role of these bacteria in driving disease-specific pathological phenotypes., Competing Interests: Declarations Ethics approval and consent to participate The study obtained written parental consent from all participants before enrollment. The study protocol (1500751) was approved by the Institutional Review Board (IRB) at Sidra Medicine, Doha, Qatar Consent for publication Not applicable. Competing interests The authors declare no competing financial or non-financial interests., (© 2024. The Author(s).)

Clinical manifestations, as distinct from thrombotic and obstetric morbidity, were recently included in the update of classification criteria of the antiphospholipid syndrome (APS). However, the existence of several patients with clinical manifestations suggestive of APS, but negative for criteria antiphospholipid antibodies (aPLs) [anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI), and lupus anticoagulant] may suggest an update of diagnostic criteria. In this study, we analysed the prevalence of six non-criteria aPLs in a large monocentric cohort of patients with seronegative APS (SN-APS), to investigate their possible diagnostic role. aCL IgA, aβ2-GPI IgA, and aβ2-GPI Domain 1 antibodies were detected by chemiluminescence, anti-phosphatidylserine/prothrombin (aPS/PT) IgG, anti-vimentin/cardiolipin (aVim/CL) IgG, and anti-carbamylated-β2-glycoprotein I (aCarb-β2-GPI) IgG by ELISA in sera from 144 SN-APS patients. In SN-APS patients, aCL IgA was detected in 4/144 (2.77%), aβ2-GPI IgA in 2/144 (1.39%), aβ2-GPI-Domain 1 in 1/144 (0.69%), aPS/PT in 16/144 (11.11%), aVim/CL in 37/144 (25.69%), and aCarb-β2-GPI in 43/144 patients (29.86%). Patients negative for all non-criteria aPL assays were 77/144 (53.47%). Notably, the Venn diagram showed that aCarb-β2-GPI together with aVim/CL represented the prevalent combination of positive antibodies. In SN-APS patients, aCL IgA were associated with recurrent thrombosis (OR 11.48; P = 0.03); in obstetric SN-APS patients, aPS/PT were significantly associated with foetal deaths (OR 4.84; P = 0.01), aVim/CL with spontaneous abortions (OR 2.71; P = 0.016). This study indicates that aPS/PT, aVim/CL and aCarb-β2-GPI antibodies may represent useful tools to identify 'seronegative' APS patients, who are negative for criteria aPLs, supporting the need to make testing for non-criteria aPLs more accessible in patients with SN-APS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Preexisting anti-interferon-α (anti-IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti-IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti-IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti-IFN-α response. In contrast, systemic IgG1 anti-IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti-IFN-α in the immunopathology of COVID-19 and suggest that anti-IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa.

It remains unclear how previous infections and vaccinations influenced and shaped heterogeneous immune responses against Omicron and its variants in diverse populations in China. After the national wave of Omicron in early 2023, we evaluated serum levels of neutralizing antibodies (nAbs) against Omicron (B.1.1.529) and its variants (BA.5, BF.7, and CH1.1) in 33 COVID-19 convalescents and 40 uninfected vaccinees, using vesicular stomatitis virus-based pseudovirus neutralizing assay. In addition, we followed 34 Delta convalescent patients to compare their immune responses against Omicron before (late 2021) and after the Omicron wave (early 2023). NAbs at the acute phase of the disease were investigated in 50 Omicron inpatients, including 24 vaccinated and 26 unvaccinated patients. Among them, nasal mucosal IgA levels were measured in 42 subjects. Compared to vaccination, breakthrough infections significantly increased the breadth and magnitude of serum nAbs and mucosal IgA levels against Omicron variants. Exposure to Omicron but not Delta elicited stronger pan-Omicron responses. In Omicron inpatients, nAbs continued to rise as vaccination doses increased. However, in both vaccinees and convalescents, a fourth dose vaccination did not elicit higher nAbs against Omicron. Furthermore, nAbs against Omicron variants lasted longer than nAbs against WT SARS-CoV-2. Breakthrough infections of Omicron variants elicited specific immune responses against Omicron compared to vaccination and Delta infection. Although repeated vaccination revealed limited impacts on serum nAbs, populations at high risk of hospitalization may still benefit from continued vaccination.IMPORTANCEThe study described the specific humoral immunity against Omicron and its variants (BA.5, BF.7, and CH1.1) in diverse populations, including Delta-positive convalescent patients, Omicron-infected patients with a previous or current confirmed Delta infection, Omicron-positive patients, and healthy controls. In addition, we followed Delta convalescents for 1 year to evaluate the effect of a booster vaccine, breakthrough infection, and reinfection. Nasal mucosal IgA levels against SARS-CoV-2 were also examined. The findings of this study demonstrated the varied responses of individuals in different states following the outbreak of Omicron, highlighting the potential advantages of ongoing immunization for groups that are more vulnerable and have a greater likelihood of being hospitalized., Competing Interests: The authors declare no conflict of interest.

Background: Around 1.6 billion people worldwide are affected by nutritional anemia. A small percentage of nutritional anemia cases are attributed to celiac disease (CeD). However, data on the prevalence of CeD among individuals with nutritional anemia in the Western part of India is scarce. Patients and methods: Individuals with nutritional anemia were prospectively investigated for the presence of CeD through the detection of immunoglobulin A (IgA) antitissue transglutaminase antibodies (anti-tTG Ab). Those who had a positive antibody result proceeded to have an upper gastrointestinal endoscopy, accompanied by a duodenal biopsy. The diagnosis of CeD was confirmed following Indian guidelines. Results: A total of 116 patients, including 96 females, were screened, with a mean age of 37 ± 17.8 years. Among them, 19 patients (16.3%) were positive for IgA anti-tTG antibodies. Fifteen of these antibody-positive patients agreed to undergo a duodenal biopsy, which showed villous abnormalities of modified Marsh grade 2 or higher in 11 cases. The overall seroprevalence of CeD was 16.3%, while the biopsy-confirmed prevalence stood at 9.3%. Moreover, an additional four patients (3.4%) were identified as having potential CeD. Chronic diarrhea and short stature emerged as significant predictors of CeD among patients with nutritional anemia. Conclusion: Even in the Western part of India, approximately one in 10 patients with nutritional anemia have CeD, reflecting similar findings across the country. Consequently, we should screen all patients with nutritional anemia for CeD through antitissue transglutaminase antibody testing. This is especially crucial for those with unexplained, persistent nutritional anemia that does not respond to oral iron therapy., (© Journal of the Association of Physicians of India 2024.)

This prospective cohort study assessed the SARS-CoV-2 IgG and IgA Ab profiles at delivery and 42 d postpartum in unvaccinated SARS-CoV-2-positive pregnant women and determined the association with the timing and the clinical course of the infection. A total of 387 vaccine-naive women with confirmed SARS-CoV-2 infection during pregnancy were included. IgG and IgA Abs were detected in maternal blood at delivery and 42 d postpartum using ELISA kits. The relationships between Ab detection and value and clinical features, including the timing of the infection, were analyzed using univariate and multivariate logistic and linear regression models. The mean gestational age at infection was 31 4/7 wk of pregnancy. Symptoms of SARS-CoV-2 infection were present in 88.1% of women. IgG and IgA Abs were detected in 45.7 and 58.9% at delivery, respectively, increasing to 72.7 and 76.8% at 42 d postpartum. Detection of IgG and IgA Abs in maternal blood at delivery was independently associated with symptomatic infection (adjusted odds ratio [OR] 3.13, 95% confidence interval (CI): 1.47-6.69 and adjusted OR 3.62, 95% CI: 1.8-7.26, respectively), but not with the time from positive swab to delivery or gestational age at positive swab. Detection of Abs at 42 d postpartum was also strongly associated with the detection of Abs at delivery (OR 29.97, 95% CI: 10.11-88.82 for IgG and OR 13.09, 95% CI: 6.37-26.9 for IgA). Vaccine-naive pregnant women exhibit a significant and durable immune response to SARS-CoV-2, which is more pronounced in symptomatic women but independent of gestational age at diagnosis or the diagnosis-to-delivery interval., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 18 variants, increasing the number of known SIgAD-associated variants to 27 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD., Competing Interests: Declaration of competing Interest C.W. receives funding from GSK and MSD and is a part time employee of GSK. These companies had no input into this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by chronic urticarial rash and monoclonal immunoglobulin M (IgM) or IgG gammopathy. Viruses, including COVID-19, activate the innate immune system, therefore SchS, in which the innate immune system is improperly activated, is hypothesized to be exacerbated by viral infection. However, there were no reported SchS cases exacerbated by any viral infection. Here, we report a SchS case with an unusual IgA gammopathy manifested and exacerbated by COVID-19 infection. This report advocates the need for recognizing unusual cases of SchS with monoclonal IgA, and following up on paraprotein like IgA even when it is initially undetectable in cases with SchS symptoms. We also hypothesize that existing autoinflammatory diseases may be exacerbated by COVID-19 infection in the case of a combination of these diseases., (© 2024 Japanese Dermatological Association.)

Context.—: Galactose-deficient immunoglobulin A1 (Gd-IgA1) deposition in the renal mesangium plays a role in the pathogenesis of IgA nephropathy., Objective.—: To assess the serum Gd-IgA1 level in biopsy-proven IgA nephropathy cases at diagnosis and 3 months post treatment and its relation with histologic Oxford classification., Design.—: In this hospital-based prospective cohort study, 40 cases and 20 controls were enrolled. Serum samples of biopsy-proven IgA nephropathy cases collected on the day of biopsy and 3 months post treatment were evaluated. Solid-phase ELISA (enzyme-linked immunosorbent assay) was performed for assessment of Gd-IgA1 level. All renal biopsies were scored by using the Oxford classification (C-MEST score). The association of serum Gd-IgA1 levels with other established prognostic parameters was assessed. To estimate the prognostic value of markers, logistic regression analysis and Kruskal-Wallis ANOVA (analysis of variance) were used., Results.—: A significant difference was observed in the serum Gd-IgA1 level values in the IgA nephropathy cases and healthy controls (P = .001) at baseline. However, no significant correlation between serum Gd-IgA1 levels at baseline and 3 months of follow-up (P = .31) or between baseline levels and age, proteinuria, hematuria, or estimated glomerular filtration rate was noted. There was no significant correlation between C-MEST score and serum Gd-IgA1 levels at baseline (P > .05); however, the distribution of Gd-IgA1 at 3 months was found to differ significantly between different grades of S score (P = .008)., Conclusions.—: Serum Gd-IgA1 levels may be of utility in predicting disease progression in IgA nephropathy cases. Measurement of serum Gd-IgA1 levels for the diagnosis and prognosis of IgA nephropathy may preclude the need for invasive renal biopsies., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

IgA nephropathy (IgAN) is a genetically complex multifactorial trait. Over the past decade, population-based genome-wide association studies (GWAS) have identified more than 30 IgAN risk loci, providing novel perspectives on both the epidemiology of the disease and its underlying molecular mechanisms. In addition, the association between IgAN and galactose-deficient IgA1 (Gd-IgA1) presented another avenue for genetic exploration due to the heritability of the elevated serum Gd-IgA1 levels. These endeavors also yielded and enabled refinement of polygenic risk scores, which may help identify specific groups of individuals at significantly increased risks, leading to stratifications of medical treatments. In this review, we aim to explore the existing evidence for genetic causation in IgAN. We summarize the state of genetic research in IgAN and how it has led to the reformulation of the new pathogenesis model and novel therapeutic targets., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

The objectives of this study were to evaluate mucosal immune responses in peripartum Holstein cows, to assess the impact of intranasal modified live viral (MLV) vaccination on mucosal immunity, and to explore the relationship between genotype and peripartum immune responses. Eighty multiparous Holstein cows were randomized to receive either: 1) intranasal MLV tri-valent viral vaccine 18-24 days prior to expected calving (DC); 2) the same vaccine within twelve hours after parturition (F); 3) vaccine at both time points (DCF), or 4) no vaccine (CON). Nasal secretions and sera were collected from all cattle pre-vaccination and on multiple days before and after calving to determine concentrations of interferon beta (IFN-beta) and IFN-gamma and bovine herpesvirus-1 (BHV-1-) and bovine respiratory syncytial virus (BRSV-) specific IgA in nasal secretions, and BHV-1 and BRSV serum neutralizing (SN) titers. Cows were genotyped by bead-based microarray, genotypes were used to categorize previously established health traits, and relationships between immune responses and genotype were evaluated. There was no significant effect of vaccination on immune responses, although all vaccinated groups demonstrated numerically increased IFN-gamma within four days post vaccination. There was a significant (P <0.0001) time effect on nasal IgA in CON, F, and DCF groups, with the highest nasal IgA titers measured post calving. There was a significant (P <0.0001) time effect on nasal IFN-beta in all groups. Significant relationships between genotype and immune response were not detected. Contrary to previous reports of systemic immunosuppression, bovine mucosal responses appear to be intact in the peripartum period., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Victor Cortese reports financial support was provided by Zoetis INC US. Victor Cortese reports a relationship with Zoetis US that includes: employment and equity or stocks., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Thromboembolic complications are common in severe COVID-19 and are thought to result from excessive neutrophil-extracellular-trap (NET)-driven immunothrombosis. Glycosylation plays a vital role in the efficiency of immunoglobulin A (IgA) effector functions, with significant implications for NET formation in infectious diseases. This study represents the first comprehensive analysis of plasma IgA glycosylation during severe SARS-CoV-2 or Influenza A infection, revealing lower sialylation and higher galactosylation of IgA1 O-glycans in acute respiratory distress syndrome (ARDS), regardless of the underlying cause of the disease. Importantly, N-glycans displayed an infection-specific pattern, with N47 of IgA2 showing diminished sialylation and bisection, and N340/N327 of IgA1/2 demonstrating lower fucosylation and antennarity along with higher non-complex glycans in COVID-19 compared to Influenza. Notably, COVID-19 IgA possessed strong ability to induce NET formation and its glycosylation patterns correlated with extracellular DNA levels in plasma of critically ill COVID-19 patients. Our data underscores the necessity of further research on the role of IgA glycosylation in the modulation of pathogen-specific immune responses in COVID-19 and other infectious diseases., Competing Interests: Author DP is employee of Bioscientia MVZ Labor Mittelhessen GmbH, Giessen, Germany. DP employment at Bioscientia MVZ Labor Mittelhessen is not related to and has not affected in any way the content of this article. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Potaczek, van Tol, Falck, Krolczik, Zlatina, Bertrams, Wilhelm, Schmeck, Seeliger, David, Skevaki, Mack, Seeger, Schaefer, Galuska, Wuhrer and Wygrecka.)

Old World Orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS) characterized by increased vascular permeability and acute kidney injury (AKI). Despite the systemic nature of the disease, the virus enters humans through inhalation and therefore initially encounters the immunoglobulin class A (IgA) dominated mucosal immune system. Herein, we characterized systemic IgA responses and their potential relationship to the mucosal immune activation by examining blood samples obtained from patients hospitalized due to acute Puumala orthohantavirus infection. Our findings reveal increased frequencies of putative IgA-expressing circulating mucosal-associated B1 cells and plasmablasts, as well as elevated levels of polyreactive, polymeric, virus-specific and secretory IgA in the acute stage of the disease. Importantly, the levels of circulating virus-specific and secretory IgA, as well as the putative IgA+ B1 cells, increased with the severity of AKI. Furthermore, circulating polymeric IgA displayed enhanced effector functions by forming stable complexes with the IgA receptor CD89 and induced pro-inflammatory neutrophil responses. These results suggest that excessive levels of circulating mucosal-like IgA might serve as a biomarker for HFRS disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cabrera, Buckner, Then, Mäki, Vapalahti, Vaheri, Hepojoki, Tietäväinen, Mäkelä, Mustonen and Strandin.)

Current COVID-19 vaccines provide robust protection against severe disease but minimal protection against acquisition of infection. Intramuscularly administered COVID-19 vaccines induce robust serum neutralizing antibodies (NAbs), but their ability to boost mucosal immune responses remains to be determined. In this study, we show that the XBB.1.5 messenger RNA (mRNA) boosters result in increased serum neutralization to multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in humans, including the dominant circulating variant JN.1. In contrast, we found that the XBB.1.5 mRNA booster did not augment mucosal NAbs or mucosal IgA responses, although acute SARS-CoV-2 XBB infection substantially increased mucosal antibody responses. These data demonstrate that current XBB.1.5 mRNA boosters substantially enhance peripheral antibody responses but do not robustly increase mucosal antibody responses. Our data highlight a separation between the peripheral and mucosal immune systems in humans and emphasize the importance of developing next-generation vaccines to augment mucosal immunity to protect against respiratory virus infections.

To prevent infection by respiratory viruses and consequently limit virus circulation, vaccines need to promote mucosal immunity. The extent to which the currently used messenger RNA (mRNA)-based COVID-19 vaccines induce mucosal immunity remains poorly characterized. We evaluated mucosal neutralizing antibody responses in a cohort of 183 individuals. Participants were sampled at several time points after primary adenovirus vector-based or mRNA-based COVID-19 vaccination and after mRNA-based booster vaccinations. Our findings revealed that repeated vaccination with mRNA boosters promoted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies in nasal secretions. Nasal and serum neutralizing antibody titers of both IgG and IgA isotypes correlated to one another. We investigated the source of these mucosal antibodies in a mouse model wherein mice received repeated mRNA vaccines for SARS-CoV-2. These experiments indicated that neutralizing antibody-producing cells reside in the spleen and bone marrow, whereas no proof of tissue homing to the respiratory mucosa was observed, despite the detection of mucosal antibodies. Serum transfer experiments confirmed that circulating antibodies were able to migrate to the respiratory mucosa. Collectively, these results demonstrate that, especially upon repeated vaccination, the currently used COVID-19 mRNA vaccines can elicit mucosal neutralizing antibodies and that vaccination might also stimulate mucosal immunity induced by previous SARS-CoV-2 infection. Moreover, migration of circulating antibodies to the respiratory mucosa might be a main mechanism. These findings advance our understanding of mRNA vaccine-induced immunity and have implications for the design of vaccine strategies to combat respiratory infections.

Introduction: Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) and reinfects adults throughout life, posing a risk for hospitalization in older adults (>60 years) with frailty and comorbidities., Methods: To investigate serum and mucosal antibodies for protection against RSV infections, baseline serum samples were compared for RSV-pre- and -post-fusion (F) binding, and RSV-A2 neutralizing IgG antibodies between symptomatic RSV-ARTI ( N = 30), non-RSV (RSV negative) ARTI ( N = 386), and no ARTI ( N = 338). Mucosal RSV-pre-F IgA and IgG levels, as well as serum RSV-G IgG antibodies, were analyzed to determine their association with protection from symptomatic RSV-ARTI in a subset study., Results: Using a receiver operating characteristic (ROC) analysis, we established thresholds of 1.4- to 1.6-fold change (FC) for RSV-pre-F and -post-F, and RSV-A2 neutralizing IgG antibodies, respectively, enabling the identification of asymptomatic RSV cases with high sensitivity and specificity (>80% and >90%, respectively). As a result, serum RSV-pre-F, RSV-G IgG, and mucosal pre-F binding IgA antibodies showed correlations with protection against symptomatic RSV infection. RSV-pre-F IgG antibodies were correlated with protection from RSV infections irrespective of the symptoms., Discussion: This study provides insights into antibody-mediated protection for symptomatic RSV infection in a community-dwelling older-adult population and establishes a threshold to identify asymptomatic RSV infection using a data-driven approach., Competing Interests: DÖ, SB-J, MC, AB, KT, SO, and JA were employed at the time the work was performed by Janssen Pharmaceuticals, a Johnson & Johnson company, and may be Johnson & Johnson stockholders. CV and AM were employed by Sanofi at the time the work was performed and may be Sanofi stockholder. CV is now employed by Vaccines Europe, Brussels, Belgium. BS and JD are employed by GlaxoSmithKline and may be GlaxoSmithKline stockholders. CB has participated in two virtual Advisory Boards for Moderna relevant to RSV vaccination on 30 March 2023 and 18 May 2023 and received payments. TV has received grant from Innovative Medicines Initiative European Commission, in which Biomerieux, Abbott, BD, BioRad, Janssen contributed ValueDx project, NIHR for project on cellulitis, and NHS UK regional funding for project on respiratory tract infections. He have been on the Advisory Board of a US study on lower respiratory tract infections in primary care EAST-PC funded by the Agency for Healthcare Research and Quality. He is a member of the Dutch Health Council. SD has provided consultancy and/or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Moderna, Valneva, MSD, iLiAD and Sanofi with fees paid to St George’s, University of London. SD has been on the RSV advisory board Sanofi Pasteur and received fees. SD also received support for travel for chairing a conference session, fees paid to his institution SGUL. SD is a member of the UK Department of Health and Social Care’s DHSC Joint Committee on Vaccination and Immunisation JCVI RSV subcommittee and Medicines and Healthcare products Regulatory Agency’s MHRA Paediatric Medicine Expert Advisory Group PMEAG. JW is investigator for clinical trials funded by pharmaceutical companies including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen and investigator for clinical trials funded by IMI/Horizon2020 and ZonMw, with payments paid to her institution. She was a speaker at Sanofi sponsored symposium ESPID, payments paid to her institution. JW participated in the advisory board of Janssen RSV older adults and Sanofi advisory board with fees paid to UMCU. AP is part of EC IMI Programme RESCEU, payments paid to his institution. He has received grants from Gates, Wellcome, CEPI, MRC, NIHR, Serum Institute of India, AstraZeneca, and EC, with payments paid to his institution. Oxford University has entered into a partnership with AZ for development of COVID-19 vaccines. AP is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. AP is chair of the UK Department of Health and Social Care’s DHSC Joint Committee on Vaccination and Immunisation JCVI, NIHR Senior Investigator, member of the Academy of Medical Sciences AMS and was a member of WHO’s SAGE until January 2022. AP’s institution received funding from the European Commission’s IMI programme for the conduct of this study. Oxford University has entered a partnership with AstraZeneca for the development of COVID-19 vaccines. PO received honoraria GSK, Pfizer Inc, Sanofi Pasteur, Seqirus, Moderna and Janssen for participation in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. PO is also a principal investigator in the INFLAMMAGE trial co-funded by the Medical Research Council UK and GSK as part of the EMINENT consortium to promote inflammation research. He received grants from UKRI-MRC/DHSC NIHR Grant award MR/V027859/1, and UKRI-BEIS for human infection challenge with SARS-CoV-2 and had roles as school governor Sidcot, Somerset. LB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding >€100,000 per industrial partner for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill and Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received major funding from Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding €1,000-25,000 per industrial partner for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, Janssen. LB is the founding chairman of the ReSViNET Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Öner, Vernhes, Balla-Jhagjhoorsingh, Moureau, Crabbe, Salaun, Bastian, Thys, De Smedt, Ooft, Korsten, Adriaenssens, Coenen, Butler, Verheij, Drysdale, Wildenbeest, Pollard, Openshaw, Bont and Aerssens.)

There is a clear medical need for an accurate diagnostic test for typhoid that can be performed at point of care. Two antigens (lipopolysaccharide [LPS] and hemolysin E [HlyE]) have recently been identified that can distinguish typhoid from other bacterial infections. Here, we present the results of a diagnostic accuracy study of the Dual Path Platform (DPP) Typhoid assay (Chembio) that detects IgA to both LPS and HlyE using blood culture as the reference standard. This was a retrospective, observational, laboratory study conducted at the Aga Khan University research laboratory, Pakistan, to evaluate the sensitivity and specificity of the DPP Typhoid assay, using archived frozen serum samples collected during a previous typhoid diagnostic accuracy study (NCT04801602). The sensitivity, specificity, and accuracy (area under the receptor operating characteristics curve [AUC]) were then assessed using the manufacturer's and Youden's optimal thresholds. In total, 385 samples were included in the analysis. Using the manufacturer's thresholds, the sensitivity, specificity, and AUC were 97.8% (95% confidence interval [CI] 94.6-99.2), 65.3% (95% CI 58.5-71.6), and 81.5% (95% CI 75.5-85.3), respectively. At Youden's optimal threshold, the overall sensitivity of the DPP Typhoid assay was 89.7% and the specificity was 82.2%. In latent class modeling compared with other nine rapid diagnostic tests evaluated from the same cohort sample, the DPP Typhoid assay demonstrated the highest balanced accuracy (89.2%). The DPP Typhoid assay demonstrated a high diagnostic accuracy for typhoid fever. However, further adjustment to new thresholds is recommended to enhance its performance capabilities., Importance: Currently available diagnostic tests for typhoid have several limitations, including low sensitivity and specificity. Dual Path Platform Typhoid assay is a multiplex rapid test that detects IgA antibodies to lipopolysaccharide and hemolysin E antigen. It is considered to have high sensitivity and specificity, and its results were found to be highly correlated with ELISA results. However, very few studies have been conducted to evaluate this test and limited information about the accuracy of this test is present. Hence, this study evaluated the new typhoid test., Competing Interests: The authors declare no conflict of interest.

There is an urgent need for vaccines against Neisseria gonorrhoeae, the causative agent of gonorrhea. Vaccination with an outer membrane vesicle-based Neisseria meningitidis vaccine provides some protection from N. gonorrhoeae; however, the mechanisms underlying this cross-protection are unknown. To address this need, we developed multiplexed bead-based assays for the relative quantification of human and mouse IgG and IgA against N gonorrhoeae antigens. The assays were evaluated for analyte independence, dilutional linearity, specificity, sensitivity, intra- and interassay variability, and robustness to sample storage conditions. The assay was then used to test samples from mice and humans immunized with an N meningitidis outer membrane vesicle vaccine., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We aimed to model binding of donor antibodies to virus that infects COVID-19 patients following transfusion of convalescent plasma (CCP). An immunosorbent assay was developed to determine apparent affinity (K d, app ). Antibody binding to virus was modelled using antibody concentration and estimations of viral load. Assay and model were validated using reference antibodies and clinical data of monoclonal antibody therapy. A single K d, app or two resolvable K d, app were found for IgG in 11% or 89% of CCP donations, respectively. For IgA this was 50%-50%. Median IgG K d, app was 0.8nM and 3.6nM for IgA, ranging from 0.1-14.7nM and 0.2-156.0nM respectively. The median concentration of IgG was 44.0nM (range 8.4-269.0nM) and significantly higher than IgA at 2.0nM (range 0.4-11.4nM). The model suggested that a double CCP transfusion (i.e. 500 mL) allows for > 80% binding of antibody to virus provided K d, app was < 1nM and concentration > 150nM. In our cohort from the pre-vaccination era, 4% of donations fulfilled these criteria. Low and mid-range viral loads are found early post exposure, suggesting that convalescent plasma will be most effective then. This study provides a biochemical rationale for selecting high affinity and high antibody concentration CCP transfused early in the disease course., (© 2024. The Author(s).)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), led to a global pandemic from 2020. In Thailand, five waves of outbreaks were recorded, with the fourth and fifth waves driven by the Delta and Omicron variants, resulting in over 20,000 new confirmed cases daily at their peaks., Methods: This cross-sectional study investigated the associations between clinical symptoms, vaccination status, antibody responses, and post-COVID-19 sequelae in COVID-19 patients. Plasma samples and clinical data were collected from participants admitted to hospitals in Thailand between July 2021 and August 2022, with follow-ups conducted for one year. The study included 110 participants infected with either the Delta (n = 46) or Omicron (n = 64) variants. Virus genotypes were confirmed by RT-PCR of nasal swab RNA and partial nucleotide sequencing of the S gene. IgG and IgA antibody levels against the receptor-binding domain (RBD) of SARS-CoV-2 Delta and Omicron variants were measured in plasma samples using ELISA., Results: Pneumonia was found to be associated with Delta variant infections, while sore throat, congestion or runny nose, and headache were linked to Omicron infections. Vaccination with fewer than two doses and diabetes mellitus were significantly associated with higher disease severity. Specific IgG and IgA antibodies against the RBD of the Delta variant generally rose by day 14 and were maintained for up to two months, whereas the pattern of antibody response to the Omicron variant was less clear. Antibody risings were found to be positively associated with pneumonia, certain underlying conditions (obesity, hypertension, dyslipidemia, and diabetes mellitus), and age ≥ 60 years. Delta variant infections were associated with forgetfulness, hair loss, and headache during the 1-year post-infection period. Females were more likely to experience hair loss, forgetfulness, and joint pain, while older age was associated with joint pain., Conclusions: This study enhances our understanding of SARS-CoV-2 infections in Thais, particularly concerning the Delta and Omicron variants. The findings can inform public health planning and response strategies for future outbreaks of SARS-CoV-2 or other emerging viral diseases., (© 2024. The Author(s).)

The gut microbiota is a key and primary stimulus for the development of a host's immune system. The early establishment of the gut microbiota is affected by several perinatal factors but little is known about their influence on shaping normal immune development and, consequently, on the programming of future health. The analysis of different immune compounds is well-documented in serum samples; however, their presence in faecal samples has not been studied, and this information could be valuable in early life. In this context, the authors of this study aimed to both describe the immunological faecal profile of a cohort of one-month-old infants and describe the impact of different perinatal factors, exploring possible associations between immune compounds and gut microbiota in faecal samples. Clear differences in immune profile were observed between full-term and premature infants. Breastfeeding increases IgG2, IgG4, and IgA; in addition, male babies showed some increased Igs, among other observations. Overall, the findings of this study reinforce the hypothesis that microorganisms and immune compounds interact with each other in the early neonatal gut and that understanding these interactions in depth will help us comprehend the influence of the gut microbiota on short- and long-term infant health outcomes.

Background: Celiac disease (CeD) has an estimated prevalence of 1%-3%. The classical clinical presentation is malabsorption, but now patients may present with more subtle symptoms such as constipation, osteoporosis, or iron deficiency anemia. Children may also present with poor growth.CeD has a strong genetic component, and high-risk groups include first-degree relatives with CeD, patients with co-existing autoimmune diseases, and patients with chromosomal aberrations., Content: Diagnostic tests for CeD include duodenal histology, serology, and genetic testing. Duodenal histology has traditionally been the gold standard of diagnosis. However, serological tests, especially IgA tissue transglutaminase antibodies (TTG-IgA), are widely used and diagnostic algorithms are based primarily on TTG-IgA as a starting point. Human leukocyte antigen typing may also be incorporated to determine genetic risk for CeD. Guidelines for children endorse biopsy avoidance provided high levels of TTG-IgA, with diagnostic accuracy being comparable to duodenal biopsy. Confirmation may be achieved by identifying IgA endomysial antibodies in a separate blood sample. Subjects with low positive TTG-IgA levels and subjects with IgA deficiency need a biopsy to establish a diagnosis of CeD. The clinical follow-up of CeD usually includes a repeat TTG-IgA examination. In adults, healing may be delayed or incomplete, and a rare consequence of refractory celiac disease is transformation to enteric T-cell lymphoma., Summary: Laboratory testing, in particular TTG-IgA, plays a central role in the diagnosis and has an accuracy comparable to histology. Diagnostic algorithms utilizing laboratory testing are critical for the development of novel strategies to improve diagnosis., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The reported number of pertussis cases declined after the implementation of COVID-19 prevention and control measures, however, the burden of pertussis among adults in China remains largely unknown. Additionally, the waning of natural antibody level has also rarely been assessed., Methods: A total of 762 healthcare workers (HCWs) who had underwent the health examinations in 2021 and 2022 were included. Serum anti-PT IgG and IgA levels were determined by ELISA. Recent B. pertussis infection was defined as anti-PT IgG ≥100 IU/ml and/or anti-PT IgA ≥10 IU/ml., Results: In 2021, the seroprevalence of recent B. pertussis infection was 10.1 %, and those HCWs in outpatient department had a higher percentage (18.6 %), and geometric mean concentration (GMC) (6.3 IU/ml) than those in other departments. This seroprevalence decreased to 2.4 % in 2022, although the difference remained significant. In the 77 subjects with recent B. pertussis infection in 2021, anti-PT IgG was undetectable in 18 cases the following year. Majority (68/76) of the subjects with anti-PT IgA ≥10 IU/ml in 2021 no longer had detected this antibody in 2022. Among 95 pertussis cases, approximately 60.0 % of cases reported no history of cough. Among those with a documented cough history, 36 cases with suspected pertussis courses who had never been diagnosed. Prolonged cough with nocturnal exacerbation (29/38) was the most commonly reported clinical symptom, and whoop was confirmed in six cases. Uroclepsia and syncopes during the cough attacks were reported by three and one subjects, respectively. One case presented with subconjunctival hemorrhage and tensionic purpura during the course., Conclusions: The results suggested a high prevalence of B. pertussis infection among HCWs. The presence of unrecognized adult pertussis cases and the rapid waning of antibody indicate the need to improve clinical management for suspected pertussis in adults, and to updated immunization schedule after childhood program., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Recurrent respiratory tract infections (rRTIs) are a common reason for immunodiagnostic testing in children, which relies on serum antibody level measurements. However, because RTIs predominantly affect the respiratory mucosa, serum antibodies may inaccurately reflect local immune defences. We investigated antibody responses in saliva and their interplay with the respiratory microbiota in relation to RTI severity and burden in young children with rRTIs., Methods: We conducted a prospective cohort study including 100 children aged <10 years with rRTIs, their family members and healthy healthcare professionals. Total and polyreactive antibody concentrations were determined in serum and saliva (ELISA); respiratory microbiota composition (16S rRNA sequencing) and respiratory viruses (quantitative PCR) were characterised in nasopharyngeal swabs. Proteomic analysis (Olink) was performed on saliva and serum samples. RTI symptoms were monitored with a daily mobile phone application and assessed using latent class analysis and negative binomial mixed models., Results: Serum antibody levels were not associated with RTI severity. Strikingly, 28% of salivary antibodies and only 2% of serum antibodies displayed polyreactivity (p<0.001). Salivary polyreactive IgA was negatively associated with recurrent lower RTIs (adjusted OR 0.80, 95% CI 0.67-0.94) and detection of multiple respiratory viruses (adjusted OR 0.76, 95% CI 0.61-0.96). Haemophilus influenzae abundance was positively associated with RTI symptom burden (regression coefficient 0.05, 95% CI 0.02-0.08)., Conclusion: These results highlight the importance of mucosal immunity in RTI severity and burden, and suggest that the level of salivary polyreactive IgA and H. influenzae abundance may serve as indicators of infection severity and burden in young children with rRTIs., Competing Interests: Conflict of interest: D. Bogaert reports grants from GSK and OM Pharma, speaker fees from MedImmune, and a leadership role as Treasurer of the International Society of Pneumonia and Pneumococcal Diseases, all outside the submitted work. The authors have no other conflicts of interest to disclose., (Copyright ©The authors 2024.)

This study was designed to investigate the risk factors for renal involvement in children with immunoglobulin A (IgA) vasculitis. It is a hospital-based retrospective cohort study with a sample size of 117 children aged ≤16 years with primary IgA vasculitis. Out of 117 patients, 49 (41.9%) developed renal injury. Univariate analysis revealed that age, gastrointestinal bleeding (GIB), time of duration, white blood cell count, D-dimer, and platelet count were all associated with renal injury in the patients with HSP. These variables were included in the multivariate logistic regression analysis. Results showed that elevated D-dimer level, older age, and GIB were independent risk factors for renal damage in patients with IgA vasculitis. Key Words: Henoch-schonlein purpura, Immunoglobulin A vasculitis, Nephritis, D-dimer, Risk factors.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in transient antibody response against the spike protein. The individual immune status at the time of vaccination influences the response. Using mathematical models of antibody decay, we determined the dynamics of serum immunoglobulin G (IgG) and serum immunoglobulin A (IgA) over time. Data fitting to longitudinal IgG and IgA titers was used to quantify differences in antibody magnitude and antibody duration among infection-naïve and infection-positive vaccinees. We found that prior infections result in more durable serum IgG and serum IgA responses, with prior symptomatic infections resulting in the most durable serum IgG response and prior asymptomatic infections resulting in the most durable serum IgA response. These findings can guide vaccine boosting schedules., Competing Interests: Declaration of competing interest We declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Malondialdehyde-acetaldehyde (MAA) adducts lead to generation of anti-MAA autoantibodies and have been independently identified in inflamed periodontal and rheumatoid arthritis (RA) tissues. This study evaluates serum samples from RA cases and osteoarthritis (OA) controls to quantify associations between periodontal clinical measures, alveolar bone loss (ABL), and anti-Porphyromonas gingivalis, anti-Prevotella intermedia, and anti-Fusobacterium nucleatum antibody concentrations with anti-MAA antibody concentrations., Methods: Participants (n = 284 RA cases, n = 330 OA controls) underwent periodontal clinical assessments and ABL measurements. Serum immunoglobulin (Ig) A, IgG, and IgM anti-MAA and serum IgG antibacterial antibody concentrations were quantified by enzyme-linked immunosorbent assay (ELISA). Analyses utilized simple linear regression and multivariable adjusted models., Results: No significant associations of periodontal clinical measures with serum anti-MAA were found. Moderate (p = 0.038 and p = 0.036, respectively) and high ABL (p = 0.012 and p = 0.014, respectively) in RA cases (but not in OA) were positively associated with IgG and IgM anti-MAA. Anti-P. gingivalis and anti-P. intermedia antibody concentrations were positively associated with IgA (p = 0.001 for both), IgG (p = 0.007 and p = 0.034, respectively), and IgM anti-MAA antibody concentrations (p < 0.001 and p = 0.020, respectively), while anti-F. nucleatum was positively associated with IgG anti-MAA (p = 0.042), findings that were similar across groups., Conclusions: A positive association was demonstrated between ABL and serum IgG and IgM anti-MAA antibody concentrations that was unique to RA and not observed in OA. Serum anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations displayed significant associations with anti-MAA antibody in both groups. These findings suggest MAA may play a role in the interrelationship between the periodontium and RA., (© 2024 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (< 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in 'quick-attained and persistent remission' rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice., Competing Interests: Declarations Ethics approval and consent to participate The tREACH was approved by the local medical ethics committee of the Erasmus Medical Centre, Rotterdam, The Netherlands (MEC-2006–252). All patients gave written informed consent before inclusion. Consent for publication Not applicable. Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Objective: High serum IgA and low serum C3 levels resulting from lectin and alternative pathway activation might be related to IgA nephropathy (IgAN) progression and exacerbation. This study examined whether the serum IgA/C3 ratio can serve as an IgAN progression marker., Methods: (1) This nationwide multicenter retrospective study in Japan included 718 patients with biopsy-confirmed IgAN. The patients whose serum creatinine levels at the time of renal biopsy had doubled were defined as having disease progression. (2) Furthermore, to investigate the pathological significance of a reduction in serum IgA/C3 ratio, we reviewed 63 patients whose serum IgA and C3 data at the end of the observation period were obtained., Results: (1) A Kaplan-Meier analysis of the patients with IgAN revealed that the group with a high serum IgA/C3 (≥ 3.3) had a significantly worse renal outcome. In a multivariate analysis of eGFR ≥ 60 mL/min per 1.73m 2 at the time of biopsy, poor renal outcome was significantly predicted by a serum IgA/C3 ratio of ≥ 3.3. (2) A 15% reduction in the change of serum IgA/C3 ratio was associated with a significantly higher percentage of complete remission of proteinuria. Among the four groups divided by treatment, both the serum IgA/C3 ratio and proteinuria were reduced only in the tonsillectomy and steroid pulse group., Conclusion: The serum IgA/C3 level might reflect the disease activity and be a potent surrogate marker of therapeutic efficacy in patients with IgAN., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Competing Interests: Conflicts of interest Dr Min is on the advisory boards of Horizon and BMS and is an investigator for Amgen, Priovant, and BMS. Authors Elghazzawy, Nassir, and Arora have no conflicts of interest to declare.

Orally dissolving films (ODF) are designed to be dissolved on the tongue and absorbed in the mouth. It offers multiple advantages over the commonly used needle-based vaccines, especially in terms of convenience allowing safe, painless, and easy self-administration. As the efficacy of ODF-encapsulated influenza vaccines has not been demonstrated, we assessed the protection elicited by inactivated influenza virus (A/PR/8/34, H1N1) vaccine delivered using ODFs in mice. Trehalose and pullulan components of the ODF ensured that the HA antigens of the inactivated PR8 virus retained their stability while ensuring the rapid release of the vaccines upon exposure to murine saliva. Mice were immunized thrice by placing the PR8-ODF on the tongues of mice at 4-week intervals, and vaccine-induced protection was evaluated upon lethal homologous challenge infection. The PR8-ODF vaccination elicited virus-specific serum IgG and IgA antibody responses, hemagglutinin inhibition (HAI), and viral neutralization. Upon challenge infection, ODF vaccination showed higher levels of IgG and IgA antibody responses in the lungs and antibody-secreting cell (ASC) responses in both lung and spleen compared to unimmunized controls. These results corresponded with the enhanced T cell and germinal center B cell responses in the lungs and spleens. Importantly, ODF vaccination significantly reduced lung virus titers and inflammatory cytokines (IFN-γ, IL-6) production compared to unvaccinated control. ODF vaccination ensured 100% survival and prevented weight loss in mice. These findings suggest that influenza vaccine delivery through ODFs could be a promising approach for oral vaccine development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Celiac disease (CD) may be frequently undiagnosed due to the absence of characteristic gastroenterologic symptoms in many CD patients. Our objective was to diagnose CD by utilizing documented oral manifestations such as Recurrent Aphthous Stomatitis (RAS) and Molar-Incisor Hypomineralization (MIH)., Methods: The study comprised sixty children who presented with complaints of RAS lesions. The MIH group consisted of 40 children, while the control group comprised 20 children without MIH lesions, ranging in age from 7 to 13 years. After the dental examination, all children were given a questionnaire to assess whether they had any previous history of general symptoms related to CD. Following that, diagnostic testing for celiac disease were conducted, including serological tests such as Tissue transglutaminase IgA (tTG-IgA), Endomysium Antibody (EMA), and Total IgA, as well as genetic tests for HLA-DQ2 and HLA-DQ8., Results: The statistical analysis, conducted using Fisher's Exact, Yates' Continuity Correction, Fisher Freeman Halton, and Student's t tests, revealed no significant differences between the groups (p < 0.05). Within the MIH group, 3 children exhibited border tTG-IgA values, while another 3 had positive tTG-IgA results. Two of these 6 children had also positive EMA and HLA results. Following a biopsy procedure, these two children were ultimately diagnosed with celiac disease (CD)., Conclusions: In this study, while children initially presented to the clinic with complaints of recurrent aphthous stomatitis (RAS), 2 children (5% of the MIH group) were diagnosed with CD shortly after the onset of MIH lesions. CD enhanced the likelihood of observing some oral manifestations particularly recurrent aphtous stomatitis and developmental enamel defects. We recommend that dentists be cautious about diagnosing CD when RAS lesions and DEDs and/or MIH lesions are present, whether or not other indications of this systemic disease exist., (© 2024. The Author(s).)

Background: Rotavirus is a leading cause of severe pediatric gastroenteritis; 2 highly effective vaccines are used in the United States (US). We aimed to identify correlates of immune response to rotavirus vaccination in a US cohort., Methods: Pediatric Respiratory and Enteric Virus Acquisition and Immunogenesis Longitudinal (PREVAIL) is a birth cohort of 245 mother-child pairs enrolled in 2017-2018 and followed for 2 years. Infant stool samples and symptom information were collected weekly. Shedding was defined as reverse-transcription polymerase chain reaction detection of rotavirus vaccine virus in stools collected 4-28 days after dose 1. Seroconversion was defined as a 3-fold rise in immunoglobulin A between the 6-week and 6-month blood draws. Correlates were analyzed using generalized estimating equations and logistic regression., Results: Prevaccination immunoglobulin G (IgG) (odds ratio [OR], 0.84 [95% confidence interval {CI}, .75-.94] per 100-unit increase) was negatively associated with shedding. Shedding was also less likely among infants with a single-nucleotide polymorphism inactivating FUT2 antigen secretion ("nonsecretors") with nonsecretor mothers, versus all other combinations (OR, 0.37 [95% CI, .16-.83]). Of 141 infants with data, 105 (74%) seroconverted; 78 (77%) had shed vaccine virus following dose 1. Prevaccination IgG and secretor status were significantly associated with seroconversion. Neither shedding nor seroconversion significantly differed by vaccine product., Conclusions: In this US cohort, prevaccination IgG and maternal and infant secretor status were associated with rotavirus vaccine response., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Objective: In the current debate surrounding the biopsy-free diagnosis of CeD, it is crucial to identify factors influencing the accuracy of results. This study investigated the impact of total IgA on the non-invasive diagnosis of celiac disease (CeD)., Methods: We retrospectively assessed total IgA titers' influence on the diagnostic accuracy of different tTG-IgA thresholds compared to the upper reference value (UNL)., Results: Of 165 included patients, tTG-IgA values at 10× UNL and 6× UNL showed specificity of 82.6% and 73.9% and sensitivity of 49.3% and 69.0%, respectively, in predicting intestinal villous atrophy (Marsh 3). In 130 patients, total IgA levels were known at baseline. These patients were divided into three tertiles according to total IgA, i.e., patients with lower, intermediate, or higher total IgA within the population. For patients with total IgA ≥ 245 mg/dL, using a tTG-IgA cutoff of 6× UNL instead of 10× UNL resulted in decreased specificity from 71.4% to 42.8% and increased sensitivity from 67.6% to 81.1%. For patients with total IgA < 174 mg/dL and between 174 mg/dL and 245 mg/dL, using a tTG-IgA cutoff of 6× UNL instead of 10× UNL maintained specificity (75.0% and 85.7%, respectively) with increased sensitivity (from 46.2% to 64.1% and from 36.1% to 52.8%, respectively)., Conclusions: In conclusion, total IgA influences the diagnostic accuracy of a predetermined tTG-IgA cutoff. Greater consideration should be given to total IgA, beyond its deficiency, in evaluating the applicability and accuracy of non-invasive CeD diagnosis.

High titres of rotavirus-specific maternal antibodies may contribute to lower rotavirus vaccine efficacy in low- and middle-income countries (LMICs). RV3-BB vaccine (G3P[6]) is based on a neonatal rotavirus strain that replicates well in the newborn gut in the presence of breast milk. This study investigated the association between maternal serum antibodies and vaccine response in infants administered the RV3-BB vaccine. Serum was collected antenatally from mothers of 561 infants enrolled in the RV3-BB Phase II study conducted in Blantyre, Malawi, and analysed for rotavirus-specific serum IgA and IgG antibodies using enzyme-linked immunosorbent assay. Infant vaccine take was defined as cumulative IgA seroconversion (≥3 fold increase) and/or stool vaccine shedding. Maternal IgA or IgG antibody titres did not have a negative impact on vaccine-like stool shedding at any timepoint. Maternal IgG (but not IgA) titres were associated with reduced take post dose 1 ( p < 0.005) and 3 ( p < 0.05) in the neonatal vaccine schedule group but not at study completion (week 18). In LMICs where high maternal antibodies are associated with low rotavirus vaccine efficacy, RV3-BB in a neonatal or infant vaccine schedule has the potential to provide protection against severe rotavirus disease.

Using a modified proximity extension assay, total and immunoglobulin (Ig) class-specific anti-SARS-CoV-2 antibodies were sensitively and conveniently detected directly from ø1.2 mm discs cut from dried blood and saliva spots (DBS and DSS) without the need for elution. For total Ig detection, antigen probes were prepared by conjugating recombinant spike protein subunit 1 (S1-RBD) to a pair of oligonucleotides. To detect isotype-specific antibody reactivity, one antigen probe was replaced with oligonucleotide-conjugated antibodies specific for antibody isotypes. Binding of pairs of oligonucleotide-conjugated probes to antibodies in patient samples brings oligonucleotides in proximity. An added DNA polymerase uses a transient hybridization between the oligonucleotides to prime synthesis of a DNA strand, which serves as a DNA amplicon that is quantified by real-time PCR. The S1-RBD-specific IgG, IgM, and IgA antibodies in DBS samples collected over the course of a first and second vaccination exhibited kinetics consistent with previous reports. Both DBS and DSS collected from 42 individuals in the autumn of 2023 showed significant level of total S1-RBD antibodies with a correlation of R = 0.70. However, levels in DSS were generally 10 to 100-fold lower than in DBS. Anti-S1-RBD IgG and IgA in DSS demonstrated a correlation of R = 0.6., (© 2024. The Author(s).)

Background: Intranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry. Immunogenicity of intranasal vaccination can be improved through the use of adjuvants. Bacteria-like particles derived fromLactococcus lactishave the potential to serve as a vaccine adjuvant.This clinical study investigated the safety, reactogenicity and immunogenicity of intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix particles (FluGEM®)., Methods: This was a first-in-human, randomized, double-blind, controlled, dose-escalation study performed at the Centre for Human Drug Research (CHDR), the Netherlands. Participants aged 18-49 were randomized in a 3:1 ratio to receive FluGem® in ascending doses (two-dose regimens) together with a standard trivalent inactivated influenza vaccine or unadjuvanted TIV only. Primary outcomes were safety and tolerability. Secondary outcomes were serum hemagglutination inhibition (HI) antibody titers and mucosal IgA. The most immunogenic dose was used in an additionalelderly cohort (>65 years)., Results: Ninty participants were included. Intranasal FluGem®was safe and well tolerated. The majority of adverse events were mild (97.4 %) with (un)solicited adverse events comparable across all dose levels and control groups. All groups showed geometric mean increases ≥ 2.5-fold. Seroconversion (≥40 % participants) was achieved at both day 21 (single-dose) and 42 (two-dose) for the 1.25 mg dose and on day 42 (two-dose only) for the 2.5 mg dose. Highest geometric mean IgA increases were observed in the 1.25 mg group on day 21. Immunogenicity was less pronounced in elderly., Conclusions: Intranasal vaccination of FluGEM®was safe and tolerable in healthy adult volunteers aged 18-49 years and 65 and older. Highest immunogenicity was observed for 1.25 mg and 2.5 mg doses (compared to 5 mg) suggesting a potential non-linear dose-response relationship.More research is needed to further investigate the capabilities of bacteria-like peptides as adjuvants., Competing Interests: Declaration of competing interest Kees Leenhouts and Bert-Jan Haijema were former employees of Mucosis BV. The study was sponsored by Mucosis BV. For the other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: PPE 59, which is absent from bacillus Calmette Guérin (BCG) strains, seems to induce a humoral immune response in patients with tuberculosis (TB). Additional studies are needed to better evaluate this protein in immune response to tuberculosis., Objectives: To evaluate the response of antibodies to PPE59 in TB individuals, its combination with IgG response to other, previously tested mycobacterial antigens (Ag) and with sputum smear microbiology (SM) results., Methods: We have cloned and expressed the rv3429 gene that encodes PPE59, then IgG, IgM, and IgA against PPE59 antigens measured by enzyme-linked immunosorbent assay (ELISA) in 212 sera samples obtained from the following subject cohorts: TB residents from Italy (79) and in Brazil (52); and an all-Brazilian cohort of 55 patients with other respiratory disorders; 10 patients infected with non-tuberculous mycobacteria, and 16 asymptomatic subjects. Drawing on results from a previous study(17) of serum samples from Brazilian subjects tested for IgG by ELISA against mycobacterial antigens ESAT-6, 16kDa, MT10.3, MPT-64 and 38kDa, the results were analysed in combination with those of the PPE59 and SM tests., Findings: Keeping the specificity rate at 97%, the overall PPE59 IgA sensitivity was 42.7%, while IgG and IgM showed lower performance (p < 0.0001). Combining PPE59 IgA/16kDa IgG results increased sensitivity to 71%, and even higher rates when the results were combined with SM results (86.5%, p = 0.001), at 88.9% specificity. Positive IgA was associated with pulmonary image alterations of high TB probability (p < 0.05)., Main Conclusions: Tests with TB patients found a moderate frequency of positivity for PPE59 IgA. However, the higher level of sensitivity attained in combination with PPE59 IgA/16kDa IgG/SM results unheard of before, although imperfect, suggests that this may be a potential additional tool for rapid detection of TB in low-resource areas.

Background: The immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and immunisation is variable., Objectives: To describe the humoral immune response by correlating IgA and IgG antibodies with NAbs titration following CoronaVac® immunisation and an mRNA (Comirnaty®) booster among healthcare workers (HCWs) and to compare the cytokine and interleukin profiles between HCWs vaccinated with CoronaVac and coronavirus disease 2019 (COVID-19) infected patients., Methods: Samples from 133 HCWs collected at 20 (T1) and 90 (T2) days after CoronaVac immunisation and 15 (T3) days after a booster dose with the Comirnaty vaccine were analysed for IgA and IgG EIA and neutralisation assay. Cytokine levels from vaccinated individuals at T1 day and COVID-19 patients were compared., Findings: Neutralising antibodies (NAbs) were observed in 81.7% of participants at T1, but only 49.2% maintained detectable NAbs after 90 days. The booster dose increased NAbs response in all participants. The cytokines with the highest levels post-vaccination were IL-6 and MCP-1. The MCP-1, IL-18, and IFN- γ levels were higher in COVID-19 patients than in vaccinated HCWs, while IL-22 levels increased in the vaccinated HCWs group., Main Conclusions: The neutralisation titres in the T2 samples decreased, and antibody levels detected at T2 showed a more significant reduction than the neutralisation. The higher IL-22 expression in immunised individuals compared to those with COVID-19 suggests that IL-22 may be beneficial in protecting against severe disease.

Background: The prevalence of microsporidiosis in the general population, or within specific groups of individuals/patients, is largely underestimated. The absence of specific seroprevalence tools limits knowledge of the epidemiology of these opportunistic pathogens, although known since the 1980s. Since microsporidia hijack the machinery of its host cell and certain species multiply within intestinal cells, a potential link between the parasite and colorectal cancer (CRC) has been suggested., Methodology/principal Findings: To explore a potential epidemiological link between microsporidia and CRC, we evaluated the seroprevalence of Encephalitozoon intestinalis among CRC patients and healthy subjects using ELISA assays based on two recombinant proteins, namely rEiPTP1 and rEiSWP1, targeting polar tube and spore wall proteins. ELISA were performed in 141 CRC patients and 135 healthy controls. Patients with CRC had significantly higher anti-rEiPTP1 IgG levels than subjects in the control group. Anti-rEiPTP1 IgG, anti-rEiSWP1 IgG and anti-rEiPTP1 IgA levels were significantly increased among men with CRC compared to healthy men. Women with CRC who had died had higher rEiSWP1 IgG levels than those who were still alive., Conclusions/significance: These higher antibody levels against microsporidia in patients with CRC suggest a relationship between microsporidia and pathophysiology of CRC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nourrisson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Nasopharyngeal carcinoma (NPC) is diagnosed relatively late and has a poor prognosis, requiring early detection to reduce the disease burden. This diagnostic test accuracy meta-analysis evaluated the serological diagnostic value of nine EBV-related IgA antibody panels (EBNA1-IgA, VCA-IgA, EA-IgA, Zta-IgA, EBNA1-IgA + VCA-IgA, VCA-IgA + EA-IgA, VCA-IgA + Rta-IgG, EBNA1-IgA + VCA-IgA + Zta-IgA and VCA-IgA + EA-IgA + Rta-IgG), aiming to identify suitable serological detection biomarkers for NPC screening., Methods: PubMed, Embase, China National Knowledge Infrastructure and Chinese BioMedical Literature Database were searched from January 1st, 2000 to September 30th, 2023, with keywords nasopharyngeal carcinoma, IgA, screening, early detection, early diagnosis, sensitivity and specificity. Articles on the diagnostic value of serum EBV-related IgA antibody panels for NPC were included. Study selection, data extraction, and quality assessment were performed independently by two researchers, and a third researcher was consulted in the case of disagreement. Bivariate models were used for statistical analysis. The quality of included studies was evaluated through Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2)., Results: A total of 70 articles were included, involving 11 863 NPC cases and 34 995 controls. Among the nine EBV-related IgA antibody panels, EBNA1-IgA + VCA-IgA [0.928 (0.898, 0.950)], VCA-IgA + Rta-IgG [0.925 (0.890, 0.949)], EBNA1-IgA + VCA-IgA + Zta-IgA [0.962 (0.909, 0.985)] and VCA-IgA + EA-IgA + Rta-IgG [0.945 (0.918, 0.964)] demonstrated higher pooled sensitivity (95%CI). In terms of diagnostic odds ratio (DOR) (95%CI), EBNA1-IgA + VCA-IgA [107.647 (61.173, 189.430)], VCA-IgA + Rta-IgG [105.988 (60.118, 186.857)] and EBNA1-IgA + VCA-IgA + Zta-IgA [344.450 (136.351, 870.153)] showed superior performance. Additionally, the SROC curves for EBNA1-IgA + VCA-IgA and VCA-IgA + Rta-IgG were more favorable. However, publication bias was detected for VCA-IgA (P = 0.005) and EBNA1-IgA + VCA-IgA (P = 0.042)., Conclusions: In general, parallel detection of serum EBNA1-IgA, VCA-IgA and Zta-IgA antibodies using ELISA demonstrates better pooled sensitivity and DOR among the studied panels. In the cases where fewer indicators are used, serum VCA-IgA and EBNA1-IgA/Rta-IgG antibody panel exhibits a comparable performance., Trial Registration: The International Prospective Register of Systematic Reviews registration number: CRD42023426984, registered on May 28, 2023., (© 2024. The Author(s).)

Objective: To explore the distribution of different biomarkers for Behcet's syndrome (BS) and their correlation with distinct clinical phenotypes of BS patients in real-world studies. Methods: This study was a retrospective cross-sectional study. A total of 483 patients diagnosed with BS in the Department of Rheumatology and Immunology, Peking University People's Hospital from 2019 to 2022 were enrolled. The baseline information and clinical features of the patients were recorded at their first diagnosis and tested the level of HLA-B51, several auto-antibodies, antistreptolysin-O(ASO), immune globulin, complement in blood serum and interleukin-6 (IL-6). Logistic regression was used to analyze the correlation of biomarkers and phenotypes. Results: Among BS patients, the number of positive cases for HLA-B51, anti-endothelial cell antibody (AECA), antinuclear antibodies (ANA) and ASO was 129, 115, 79 and 54, respectively. The positive rate of other biomarkers was less than 5.0%. About 12.6% of patients with BS had an increased level of IgA ( n =61), and 10.8% of patients had an increased level of IgG ( n =52). About 41.0% of patients had increased levels of IL-6 ( n =198), and 6.4% of patients had decreased levels of IgM ( n =31). About 11.2% of patients had decreased levels of C3 ( n =54), and 6.0% of patients had decreased levels of C4 ( n =29). Elevated IgA was a risk factor for the articular phenotype of BS ( OR =2.652, P =0.011). Decreased complement C4 was a risk factor for the neurological phenotype of BS ( OR =3.594, P =0.039). Positive ASO was a risk factor for the gastrointestinal phenotype of BS ( OR =2.578, P =0.041). Elevated IL-6 was a risk factor for the ocular phenotype of BS ( OR =7.560, P =0.016). Conclusion: HLA-B51 and AECA are common biomarkers in BS. Elevated IgA, decreased complement C4, positive ASO, and elevated IL-6 are risk factors for different phenotypes of BS.

The monoclonal antibody rituximab improves clinical outcome in the treatment of CD20-positive lymphomatous neoplasms, and it is an established drug for treatment of these cancers. Successful mRNA COVID-19 (SARS-CoV-2) vaccination is extremely important for lymphoma patients because they tend to be elderly with comorbidities which leaves them at increased risk of poor outcomes once infected by Coronavirus. Anti-CD20 therapies such as rituximab, deplete B-cell populations and can affect vaccine efficacy. Therefore, a knowledge of the effect of COVID-19 vaccination in this group is critical. We followed a cohort of 28 patients with CD20-positive lymphomatous malignancies treated with rituximab that started prior to their course of COVID-19 vaccination, including boosters. We assayed for vaccine "take" in the humoral (IgG and IgA) and cellular compartment. Here, we show that short-term and long-term development of IgG and IgA antibodies directed toward COVID-19 spike protein are reduced in these patients compared to healthy controls. Conversely, the robustness and breath of underlying T-cell response is equal to healthy controls. This response is not limited to specific parts of the spike protein but spans the spike region, including response to the conserved Receptor Binding Domain (RBD). Our data informs on rational vaccine design and bodes well for future vaccination strategies that require strong induction of T-cell responses in these patients., Competing Interests: MH: Advisory Board: Servier, Novartis, AnHeart, Bayer; Steering Committee: Novartis; Honoraria for educational talks: Pfizer (educational talk for Pfizer staff in 2021), Novartis; Data Safety Monitoring Board: Advarra, Parexel. MR: Patent applications have been filed and are currently pending in US, US-2023-0372469, and Europe, EP 4228686 for a T cell vaccine for SARS virus. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Komlodi-Pasztor, Escarra-Senmarti, Bazer, Bhatnagar, Perez Heydrich, Messmer, Ambinder, Gladstone, Clayton, Goodrich, Schoch, Wagner-Johnston, VandenBussche, Huang, Holdhoff and Rosario.)

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and obstetric morbidity, with accurate laboratory examination of antiphospholipid antibodies (aPLs) being crucial for diagnosis. This study focused on anti-β2 glycoprotein I (aβ2GPI) antibodies and aimed to establish the first population-based cutoff values for aβ2GPI IgA/IgM/IgG antibodies in non-pregnant women of reproductive age in Southwest China. The study cohort comprised 181 healthy women of reproductive age for study. Blood samples were collected on an early morning fast. Anti-β2GPI antibodies including IgA, IgM and IgG were measured in serum using the HOB ® BioCLIA kit. According to the Clinical and Laboratory Standards Institute (CLSI) guidelines, the study used non-parametric percentile methods to calculate the 95th, 97.5th, and 99th percentiles cutoff values for aβ2GPI IgA/IgM/IgG antibodies, along with corresponding 90% confidence intervals (CI), while excluding outliers. A total of 168 independent samples were collected for verification, including 85 samples from healthy subjects and 83 samples from APS patients, in order to evaluate the analytical performance of the obtained cutoff values. The 99th percentile cutoff values were 3.36 RU/mL for aβ2GPI IgA, 27.54 RU/mL for aβ2GPI IgM and 1.81 RU/mL for aβ2GPI IgG, which indicated that the levels of aβ2GPI IgM antibodies were generally higher compared to those of IgA and IgG antibodies. Our established reference range was confirmed to be successful in validating the detected values of aβ2GPI antibodies in all healthy controls. With the 99th percentile cutoff value, the sensitivity was 14.46% for aβ2GPI IgA, 22.89% for aβ2GPI IgG, and 9.64% for aβ2GPI IgM in APS patients. This study established population-based cutoff values that are applicable to the local population for the accurate laboratory examination of aβ2GPI antibodies in non-pregnant women of reproductive age. The study also recommends paying more attention to IgM positivity in women of reproductive age., (© 2024. The Author(s).)