Journal of Allergy and Clinical Immunology最新文献

Background: Pivotal studies with dupilumab demonstrated clinically relevant improvements in nasal polyp score (NPS), symptom and quality of life scores in patients with chronic rhinosinusitis with nasal polyps (CRSwNP).

Objective: We evaluated the effectiveness of dupilumab in a large-scale CRSwNP cohort from 6 European tertiary care centres.

Methodology: NPS, SinoNasal Outcome Test (SNOT)-22 score, visual analogue scale (VAS) for total sinus symptoms, loss of smell (LoS) and nasal blockage (NB), and Asthma Control Test (ACT) score were collected from hospital records and assessed at baseline, 24 and 52 weeks of treatment of dupilumab in CRSwNP patients. Treatment effectiveness was evaluated in relation to demographic and lifestyle factors, sinus surgery history, presence of comorbidities and blood eosinophil counts (BEC). Treatment response was evaluated according to EUFOREA 2021 criteria.

Results: All patient outcomes improved at 24 and 52 weeks of treatment compared to baseline. Dupilumab showed effectiveness independent of age, sex, body mass index, smoking status, prior sinus surgery, presence of asthma, NSAID exacerbated respiratory disease (NERD), allergy or baseline BEC. 92.5% and 94.4% showed an improvement in at least 1 EUFOREA criterion at 24 and 52 weeks respectively. 54.4% and 68.2% reached all 4 of the more stringent EUFOREA criteria at 24 and 52 weeks respectively.

Conclusions: Real-world evaluation of dupilumab effectiveness demonstrates a robust and sustained response in at least two thirds of patients at 52 weeks of treatment. Favourable treatment response was independent of the number of sinus surgery procedures, major comorbidities or baseline systemic levels of type 2 inflammation.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions often triggered by medications. While the involvement of CD8⁺ T cells causing keratinocyte death is well recognized, the contribution of neural elements to the persistent skin inflammation has been largely overlooked.

Objective: We investigated the potential neuroimmune regulation in SJS/TEN.

Methods: Unbiased single-cell RNA sequencing and flow cytometry were performed using circulating CD8⁺ T cells from healthy controls and patients with SJS/TEN. ELISA and LEGENDplex assays were respectively used to detect neuropeptides and inflammatory mediators. Skin tissues were examined by immunofluorescence staining for neuropeptide-associated nerves and cytokine receptors. Calcium imaging, Smart-seq, and a 3-D skin model were used for cultured human CD8⁺ T cells.

Results: Unbiased RNA sequencing revealed an upregulation of the receptor for neuropeptide calcitonin gene-related peptide (CGRP), known as RAMP1, in effector CD8⁺ T cells in SJS/TEN. Increased CGRP⁺ nerve fibers and CGRP levels, along with upregulated IL-15R and IL-18R on CD8⁺ T cells, were displayed in the affected skin of SJS/TEN. The CGRP-RAMP1 axis was necessary and sufficient to enhance receptors for IL-15 and IL-18 and cytotoxic activities in CD8⁺ T cells, ultimately resulting in keratinocyte apoptosis. Calcium influx was detected in CGRP-stimulated CD8⁺ T cells. HCN2, a hyperpolarization-activated cation channel, was required for this process and the subsequent cytotoxic effects.

Conclusions: Our study highlights the role of neural elements in regulating CD8⁺ T-cell-mediated inflammatory responses and provides new potential translational targets to improve the outcomes of severe cutaneous drug reactions.

Background: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by the presence of pathogenic autoantibodies and a substantial influx of immune cells into skin lesions. However, the role of eosinophils in BP remains inadequately elucidated.

Objective: We sought to determine the pathologic involvement of eosinophils and eosinophil extracellular traps (EETs) in BP.

Methods: Human samples collected from BP patients and healthy controls were utilized to explore the potential role of eosinophils and their EETs in BP patients through serologic detection, flow cytometry, and immunofluorescence. Naive CD4⁺ T cells isolated from healthy donors were stimulated and subjected to further analysis via RNA sequencing. We additionally evaluated the potential of targeting EETs in BP180-immunized BP-like mice and in in vitro settings.

Results: We found that elevated levels of eosinophils and EETs in BP patients correlated with disease severity. The DNA components within EETs played a crucial role in driving the differentiation of naive CD4⁺ T cells into follicular helper T (Tfh) cells by activating coil domains containing 25 (CCDC25). Treatment with DNase I, which disrupts the structural integrity of EETs, or neutralizing antibody against CCDC25 reduced the expansion of Tfh cells and suppressed the production of autoantibodies in BP180-immunized BP-like mouse models. Additionally, we discovered that EETs induced the N⁶-methyladenosine methylation of the transcription factor musculoaponeurotic fibrosarcoma (MAF) via the DNA-CCDC25-VIRMA pathway, thereby enhancing its mRNA stability and promoting Tfh cell differentiation.

Conclusion: Our study revealed a previously unrecognized mechanism by which EETs trigger abnormal Tfh cell differentiation through CCDC25, followed by Vir-like m⁶A methyltransferase-associated protein (VIRMA)-mediated N⁶-methyladenosine modification of MAF. These insights provide promising avenues for the development of targeted therapeutic interventions in the field of BP and potentially other autoimmune diseases.