Journal of Allergy and Clinical Immunology最新文献

{"title":"Baseline Epitope-Specific IgE Profiles are Predictive of Sustained Unresponsiveness or High Threshold One-Year Post OIT in the POISED Trial.","authors":"Maria Suprun, Ashley Sang Eun Lee, Robert Getts, Simon Peck, Sayantani B Sindher, Kari C Nadeau, R Sharon Chinthrajah, Stephen J Galli, Hugh Sampson","doi":"10.1016/j.jaci.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.017","url":null,"abstract":"<p><strong>Background: </strong>Results from the POISED trial suggest that discontinuation of peanut oral immunotherapy can increase the risk of regaining clinical reactivity to peanut.</p><p><strong>Objective: </strong>We sought to determine whether those who achieved sustained unresponsiveness (SU) or sustained high threshold (SHT) have different baseline sequential epitope-specific (es-) IgE profiles than those who achieved transient desensitization (TD).</p><p><strong>Methods: </strong>Subjects in the POISED trial (NCT02103270) were randomized to peanut (n=95) or placebo (n=25) for 24 months. OIT-desensitized subjects were then assigned to no peanut (PN-0, n=51) or 300mg (PN-300, n=30) for 12 months. SU and SHT were determined by those in PN-0 and PN-300, respectively, passing 4000mg peanut oral challenge. Specific IgE and IgG4 levels to peanut, Ara h 1-3 proteins and 64 allergenic epitopes were measured. We developed machine learning glmnet models with bootstrap simulations using baseline data to predict SU/SHT.</p><p><strong>Results: </strong>Eighty (84%) subjects were desensitized to peanut. Of those, 13% (n=8) and 37% (n=13) achieved SU/SHT in PN-0 and PN-300. Decreases in epitope-and protein-specific IgE levels and increases in IgG4 levels were observed during 2 years of OIT. At baseline, patients with SU in Peanut-0 but not Peanut-300 had lower es-IgE and protein-sIgE levels compared to the TD group. A machine-learning model with 12 baseline es-IgEs and age could predict SU/SHT with an accuracy of 94%, AUC 0.97, Sensitivity 1.00, Specificity 0.91.</p><p><strong>Conclusions: </strong>Patients who achieved SU/SHT have different baseline protein-and epitope-specific IgE profiles than those with TD. These profiles may help identify patients with an increased likelihood of achieving SU/SHT.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of CD19+-Targeted Chimeric Antigen Receptor (CAR) T-cell Therapy with Hypogammaglobulinemia, Infection and Mortality.","authors":"Natalia M Sutherland, Baijun Zhou, Lingxiao Zhang, Mei-Sing Ong, Joseph S Hong, Andrew Pak, Katherine J Liu, Matthew J Frigault, Marcela V Maus, Joshua A Hill, Kerry Reynolds, Jolan E Walter, Carlos A Camargo, Sara Barmettler","doi":"10.1016/j.jaci.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.021","url":null,"abstract":"<p><strong>Background: </strong>CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19+ receptors on B-cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.</p><p><strong>Objective: </strong>To evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.</p><p><strong>Methods: </strong>We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (immunoglobulin G [IgG]≤600mg/dL), infections pre- and post-CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.</p><p><strong>Results: </strong>Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy (587 to 362 mg/dL; p<0.0001). 37% of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was associated with worsening hypogammaglobulinemia post-CAR-T therapy. Hypogammaglobulinemia post-CAR-T therapy was associated with an increased risk of serious infection post-CAR-T therapy (IRR=2.7; 95% CI=1.5-5.2; p=0.002). Risk factors for mortality included mild hypogammaglobulinemia (400mg/dL<IgG≤600mg/dL), infections ≤100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality.</p><p><strong>Conclusions: </strong>We identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia post-CAR-T therapy, which was associated with an increased risk of serious infection and mortality post-CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-IgE and Food Allergy.","authors":"Jennifer A Dantzer, Robert A Wood","doi":"10.1016/j.jaci.2024.10.020","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.020","url":null,"abstract":"<p><p>Food allergy is a growing problem that can have a significant impact on both the individual, the family, and society. We are entering a new era of food allergy management with the recent Food and Drug Administration approvals of two therapies for food allergy. Immunoglobulin E (IgE) is now known to play a critical role in allergic diseases, including food allergy. Ant-IgE therapy has been under investigation for decades and is now approved for asthma, urticaria, nasal polyps, and most recently, IgE-mediated food allergy. Here, we evaluate what is known about the safety and efficacy of anti-IgE therapy as monotherapy and in combination with oral immunotherapy. In addition, we will highlight important practical considerations and key knowledge gaps.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covid-19 mRNA vaccine allergy.","authors":"Ágnes Csuth, Lene Heise Garvey, Maria C Jenmalm","doi":"10.1016/j.jaci.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.019","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia","authors":"","doi":"10.1016/j.jaci.2024.08.002","DOIUrl":"10.1016/j.jaci.2024.08.002","url":null,"abstract":"<div><h3>Background</h3><div>Agammaglobulinemia due to variants in <em>IGLL1</em> has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in <em>IGLL1</em>.</div></div><div><h3>Objective</h3><div>We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in <em>IGLL1</em>.</div></div><div><h3>Methods</h3><div>NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to <em>IGLL1</em> variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19⁺ counts, and no alternative diagnosis were included.</div></div><div><h3>Results</h3><div>The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19⁺ B cells (&lt; 0.1 × 10⁹/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic <em>IGLL1</em> variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia.</div></div><div><h3>Conclusion</h3><div>B-cell deficiency resulting from <em>IGLL1</em> variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deconstructing inflammatory memory across tissue set points using cell circuit motifs","authors":"","doi":"10.1016/j.jaci.2024.09.014","DOIUrl":"10.1016/j.jaci.2024.09.014","url":null,"abstract":"<div><div>Tissue ecosystems are cellular communities that maintain set points through a network of intercellular interactions. We position health and chronic inflammatory disease as alternative stable set points that are (1) robust to perturbation and (2) capable of adaptation and memory. Inflammatory memory, which is the storage of prior experience to durably influence future responsiveness, is central to how tissue ecosystems may be pushed past tipping points that stabilize disease over health. Here, we develop a reductionist framework of circuit motifs that recur in tissue set points. In type 2 immunity, we distinctly find the emergence of 2-cell positive feedback motifs. In contrast, directional motif relays and 3-cell networks feature more prominently in type 1 and 17 responses. We propose that these differences guide the ecologic networks established after surpassing tipping points and associate closely with therapeutic responsiveness. We highlight opportunities to improve our current knowledge of how circuit motifs interact when building toward tissue-level networks across adaptation and memory. By developing new tools for circuit motif nomination and applying them to temporal profiling of tissue ecosystems, we hope to dissect the stability of the chronic inflammatory set point and open therapeutic avenues for rewriting memory to restore health.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms involved in the transmission of trained immunity to offspring","authors":"","doi":"10.1016/j.jaci.2024.06.006","DOIUrl":"10.1016/j.jaci.2024.06.006","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma","authors":"","doi":"10.1016/j.jaci.2024.07.020","DOIUrl":"10.1016/j.jaci.2024.07.020","url":null,"abstract":"<div><h3>Background</h3><div>Mepolizumab is an anti-IL-5 mAb treatment for severe eosinophilic asthma that reduces asthma exacerbations. Residual airway inflammation with mepolizumab therapy may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations.</div></div><div><h3>Objective</h3><div>Our study aimed to explore the corticosteroid responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway.</div></div><div><h3>Methods</h3><div>The MAPLE trial was a multicenter, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for severe eosinophilic asthma. We analyzed paired sputum (n = 16) and plasma (n = 25) samples from the MAPLE trial using high-throughput Olink proteomics. We analyzed additional sputum proteins using ELISA.</div></div><div><h3>Results</h3><div>In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type 2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type 2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated.</div></div><div><h3>Conclusions</h3><div>At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial intestinal dysbiosis drives long-term allergic susceptibility by sculpting an ILC2–B1 cell–innate IgE axis","authors":"","doi":"10.1016/j.jaci.2024.07.023","DOIUrl":"10.1016/j.jaci.2024.07.023","url":null,"abstract":"<div><h3>Background</h3><div>The abundance and diversity of intestinal commensal bacteria influence systemic immunity with impact on disease susceptibility and severity. For example, loss of short chain fatty acid (SCFA)-fermenting bacteria in early life (humans and mice) is associated with enhanced type 2 immune responses in peripheral tissues including the lung.</div></div><div><h3>Objective</h3><div>Our goal was to reveal the microbiome-dependent cellular and molecular mechanisms driving enhanced susceptibility to type 2 allergic lung disease.</div></div><div><h3>Methods</h3><div>We used low-dose vancomycin to selectively deplete SCFA-fermenting bacteria in wild-type mice. We then examined the frequency and activation status of innate and adaptive immune cell lineages with and without SCFA supplementation. Finally, we used ILC2-deficient and signal transducer and activator of transcription 6 (STAT6)-deficient transgenic mouse strains to delineate the cellular and cytokine pathways leading to enhanced allergic disease susceptibility.</div></div><div><h3>Results</h3><div>Mice with vancomycin-induced dysbiosis exhibited a 2-fold increase in lung ILC2 primed to produce elevated levels of IL-2, -5, and -13. In addition, upon IL-33 inhalation, mouse lung ILC2 displayed a novel ability to produce high levels of IL-4. These expanded and primed ILC2s drove B1 cell expansion and IL-4–dependent production of IgE that in turn led to exacerbated allergic inflammation. Importantly, these enhanced lung inflammatory phenotypes in mice with vancomycin-induced dysbiosis were reversed by administration of dietary SCFA (specifically butyrate).</div></div><div><h3>Conclusion</h3><div>SCFAs regulate an ILC2–B1 cell–IgE axis. Early-life administration of vancomycin, an antibiotic known to deplete SCFA-fermenting gut bacteria, primes and amplifies this axis and leads to lifelong enhanced susceptibility to type 2 allergic lung disease.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"News beyond our pages","authors":"","doi":"10.1016/j.jaci.2024.09.013","DOIUrl":"10.1016/j.jaci.2024.09.013","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142593050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}