Journal of Allergy and Clinical Immunology最新文献

Modern pulmonary imaging can reveal underlying pathological and pathophysiological changes in the lungs of people with asthma, with important clinical implications. A multitude of imaging modalities are now used to examine underlying structure/function relationships including computed tomography, magnetic resonance imaging, optical coherence tomography, and endobronchial ultrasound. Imaging-based biomarkers from these techniques, including airway dimensions, blood vessel volumes, mucus scores, ventilation defect extent and air trapping extent, often have increased sensitivity compared to traditional lung function measurements, and are increasingly used as endpoints in clinical trials. Imaging has been crucial to recent improvements in our understanding of relationships between T2-inflammation, eosinophilia, and mucus extent. With the advent of effective anti-T2 biologic therapies, computed tomography and magnetic resonance imaging techniques can identify not just which patients benefit from therapy, but why they benefit. Clinical trials have begun to assess the utility of imaging to prospectively plan airway therapy targets in bronchial thermoplasty and have potential to direct future bronchoscopic therapies. Together, imaging techniques provide a diverse set of tools to investigate how spatially-distributed airway, blood, and parenchymal abnormalities shape disease heterogeneity in patients with asthma.

Background: Chronic erythroderma is a potentially life-threatening condition that can be caused by various diseases, but approximately 30% of cases remain idiopathic, often with insufficient treatment options.

Objective: We sought to establish a molecular disease map of chronic idiopathic erythroderma (CIE).

Methods: We performed single-cell RNA sequencing combined with T-cell receptor sequencing of blood and skin from 5 patients with CIE and compared results with 8 cases of erythrodermic cutaneous T-cell lymphoma (eCTCL), 15 cases of moderate to severe atopic dermatitis, 10 cases of psoriasis, and 20 healthy control individuals.

Results: In eCTCL, we found strong expansion of CD4⁺ malignant clones with a CCR7⁺SELL⁺ central memory phenotype. In contrast, CIE exhibited a pattern of low-level, but consistent, expansion of CD8A⁺KLRK1⁺ T-cell clones, both in blood and in skin. KLRK1 was also expressed by CCR10⁺FUT7⁺ skin-homing CIE blood T cells that had increased proliferation rates and were absent in all other conditions. While patients with CIE and eCTCL lacked the strong type 2 or type 17 immune skewing typically found in atopic dermatitis or psoriasis, respectively, they were characterized by upregulation of MHC II genes (HLA-DRB1, HLA-DRA, and CD74) in keratinocytes and fibroblasts, most likely in an IFN-γ-dependent fashion. Overall, we found the strongest upregulation of type 1 immune mediators in CIE samples, both in the expanded CD8A⁺ clones and in the tissue microenvironment.

Conclusions: Despite the notion that CIE might be a mere bundle of various yet uncharacterized disease processes, we found specific pathogenic signatures in these patients, which were different from other forms of erythroderma. These data might help to improve our pathogenic understanding of the blood and skin compartments of CIE, aiding in discovery of future treatment targets.

Background: Approximately 85% of hereditary angioedema (HAE) attacks are associated with prodromal symptoms.

Objective: We investigated the clinical effect of treating HAE C1-esterase inhibitor (HAE-C1-INH) type 1 patients with recombinant human C1-INH (rhC1-INH) during their prodrome versus an active swelling episode and associated changes in blood transcriptomic genes and pathways before and after treatment.

Methods: A 2-center, unblinded, case-crossover study randomly assigned 5 HAE-C1-INH type 1 patients to prodrome or attack treatment groups; after a patient was treated for either 2 prodromes or 2 HAE attacks, they were crossed over to be treated for 2 HAE attacks or 2 prodromes. All patients were treated during the prodrome or acute attack with rhC1-INH; (conestat alfa, 50 IU/kg body weight, maximum 4200 IU for body weight ≥85 kg). Blood samples for analysis by RNA sequencing were obtained (1) at baseline, (2) during the prodrome before and after treatment, and (3) during an attack before and after treatment. Differentially expressed genes and pathways were elucidated by Ingenuity Pathway Analysis (IPA; Qiagen).

Results: Treatment during the HAE prodrome with rhC1-INH was as effective at preventing progression to a swelling episode as treatment of an acute attack. HAE prodromes were associated with upregulation of multiple inflammatory extracellular matrix genes, neuropeptide, and inflammasome member genes (eg, SPARCL1, AGRP, NLRP9; log₂ fold change = 4.1, 3.9, and 3.0, respectively). TNF-α and IL-10 were 2 major hub genes in prodrome-associated enriched gene networks. rhC1-INH treatment resulted in reversal of the disease signature in HAE-associated dysregulated pathways. Approximately 42% of prodrome-associated differentially expressed genes were also associated with HAE attacks. The enriched gene networks with hub genes for prodrome (ERK and VEGF) and for acute attack (insulin and SERPINA1) stages of HAE were identified. The major enriched pathways shared between HAE prodrome and attack were associated with neutrophil function and prostaglandin metabolism.

Conclusion: Treatment of HAE-C1-INH type 1 patients who have a well-defined prodrome that historically results in an acute attack may be justified clinically and mechanistically. This approach would represent a paradigm shift for management of HAE on-demand treatment.

Chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has revolutionized the treatment of hematologic malignancies, demonstrating significant clinical efficacy and leading to US Food and Drug Administration approval of several CAR T-cell-based products. This success has prompted exploration of CAR-T in other disease areas, including autoimmune diseases (AIDs). CAR-T targeting B cells has been shown to provide clinical and biological improvements in patients with refractory AIDs. The aim of this review is to discuss promising strategies involving CAR-T in AIDs, such as those targeting B cells and T cells, and to explore new approaches targeting fibroblasts or plasmacytoid dendritic cells. Despite these advances, the application of CAR-T in AIDs faces several unique challenges. The quality and functionality of T cells in patients with AIDs may be compromised as a result of previous treatments and the underlying inflammatory state, affecting the generation and efficacy of CAR-T. In addition, achieving adequate tissue biodistribution and persistence of CAR T cells in affected tissues remains a major challenge. Finally, the high costs associated with T-cell production pose economic problems, particularly in the context of chronic diseases, which are far more numerous than the hematologic diseases for which CAR-Ts have been granted marketing authorization to date. If the indications for CAR-T increase significantly, production costs will have to drop drastically in order to obtain reliable economic models.

Background: Chronic spontaneous urticaria (CSU), a common and debilitating disease, is widely held not to be life limiting, but the mortality of CSU has not been investigated.

Objective: We sought to assess all-cause mortality in patients with CSU, risk for comorbidities that are leading causes of death, and impact of guideline-recommended urticaria treatments on mortality rates.

Methods: This was a retrospective population-based cohort study of electronic health records of 272,190 adult patients with CSU and 12,728,913 controls without urticaria from the US collaborative network TriNetX.

Results: The study included 264,680 propensity score-matched patients with CSU (mean [SD] age = 47.5 [19.8] years; 71.5% female) and a corresponding number of controls without urticaria. Patients with CSU had higher 3-month (hazard ratio [HR] 2.10, 95% CI 1.97-2.22), 1-year (HR 1.77, 95% CI 1.71-1.83), and 5-year (HR 1.69, 95% CI 1.65-1.73) all-cause mortality (all P < .0001). Compared with controls, patients with CSU exhibited higher risk and rates of the leading causes of death in the United States, including suicidal ideations/suicide attempts (HR 3.14, 95% CI 3.00-3.28) and malignant neoplasms (HR 2.09, 95% CI 2.02-2.16). The risk of mortality appeared to be more pronounced in White and younger patients with CSU. All-cause mortality rates at 5 years were significantly lower in patients treated with second-generation H₁ antihistamines versus untreated patients (1.0% vs 2.3%; HR 1.84, P < .0001) and omalizumab-treated patients versus antihistamine-treated patients (0.7% vs 2.6%; HR 3.99, P = .0003).

Conclusions: CSU is associated with increased mortality likely due to comorbidities, especially suicide, and effective CSU treatment may reduce mortality. These findings should be investigated in additional studies and in other populations.

Background: Phospholipase Cγ2 (PLCγ2) is an important signaling molecule that receives and transmits signals from various cell surface receptors in most hematopoietic lineages. Variants of PLCG2 cause PLCγ2-associated immune dysregulation (PLAID), a family of conditions classified by mutational effect. PLAID with cold urticaria (PLAID-CU) is caused by in-frame deletions of PLCG2 that are dominant negative at physiologic temperatures but become spontaneously active at subphysiologic temperatures.

Objective: We identified genetic lesions that cause PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing.

Methods: We studied 9 probands with antibody deficiency and a positive evaporative cooling test, along with 2 known PLAID-CU patients and 3 healthy subjects. Illumina sequencing was performed on full-length PLCG2 cDNA synthesized from peripheral blood mononuclear cell RNA, and whole genome sequencing was used to identify genetic lesions. Novel alternate transcripts were overexpressed in the Plcg2-deficient DT40 cell overexpression system. Extracellular signal-regulated kinase (ERK) phosphorylation was quantified by flow cytometry with and without B-cell receptor crosslinking.

Results: Two probands expressed novel alternative transcripts of PLCG2 with in-frame deletions. Proband 1, expressing PLCG2 without exons 18-19, carried a splice site mutation in intron 19. Proband 2, expressing PLCG2 without exons 19-22, carried a 14 kb de novo deletion of PLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to B-cell receptor crosslinking.

Conclusion: In addition to autosomal dominant genomic deletions, de novo deletions and splice site mutations of PLCG2 can also cause PLAID-CU. All of these can be identified by cDNA-based sequencing.

Background: Food sensitization (FS) develops in early infancy and is a risk factor for subsequent food allergy (FA). Recent evidence suggests relationships of gut microbiota with FS and FA. However, little is known about the role of neonatal gut microbiota in the pathobiology of these manifestations.

Objectives: We sought to characterize gut microbiota in children using an enterotyping approach and determine the association of gut microbiota and the enterotypes with the development of FS and FA.

Methods: We combined gut microbiome and fecal short-chain fatty acid data from 2 longitudinal birth-cohort studies in Japan, clustered the microbiome data from children who were 1 week to 7 years old and their mothers and identified enterotypes. We also determined the associations of gut microbiota and enterotypes with risks of developing FS and FA across the 2 studies using multivariable regression models.

Results: Data from the 2563 microbiomes identified 6 enterotypes. More gut bacteria (eg, Bifidobacterium) in 1-month-old children showed significant relationships with the development of FS and FA than in 1-week-old children. Enterotypes at 1 month old consisted of Bacteroides-dominant, Klebsiella-dominant, and Bifidobacterium-dominant enterotypes. Bifidobacterium-dominant enterotypes with the highest fecal propionate concentration had the lowest risks of developing FS and FA, especially of hen egg white sensitization. Bifidobacterium-dominant enterotypes had lower risks at 2 years old in one study (vs Bacteroides-dominant enterotype, adjusted odds ratio [adjOR]: 0.10, 95% CI: 0.01-0.78; vs Klebsiella-dominant enterotype, adjOR: 0.10, 95% CI: 0.01-0.77) and at 9 months old in the other study (vs Bacteroides-dominant enterotype, adjOR: 0.33, 95% CI: 0.11-0.91).

Conclusions: In these birth-cohort studies, gut microbiome clustering identified distinct neonatal enterotypes with differential risks of developing FS and FA.

Background: Allergic diseases are major causes of morbidity in both developed and developing countries and represent a global burden on health care systems. Allergic sensitization is defined as the production of IgE specific to common environmental allergens and is an important indicator in the assessment of allergic diseases.

Objective: We sought to clarify the genetic basis of allergic sensitization.

Methods: We performed a genome-wide association study (GWAS) of allergic sensitization in the Japanese population followed by a cross-ancestry meta-analysis with a European population including 20,492 cases and 23,342 controls for Japanese and 8,246 cases and 16,786 controls for Europeans. We also performed a polysensitization GWAS of a Japanese population including 4,923 cases and 17,009 controls.

Results: Allergic sensitization GWAS identified 18 susceptibility loci for Japanese only and 23 loci for the cross-ancestry population, among which 4 loci were novel. Polysensitization GWAS identified 8 significant loci. Expression quantitative trait locus colocalization analysis revealed polysensitization GWAS significant variants affecting both the phenotype and the expression of the CD28, LPP, and LRCC32 genes. Cross-population genetic correlation analysis of allergic sensitization suggested that heterogeneity exists in allergic sensitization between Europeans and Japanese, indicating that more genetic heterogeneity may exist in allergic sensitization than allergic diseases.

Conclusions: Our investigation provides new insights into the molecular mechanism of allergic sensitization that could enhance current understanding of allergy and allergic diseases.