Irie M, Kabata H, Kamatani T
… +21 more, Yamagishi M, Nakamura R, Masaki K, Homma R, Suzukawa M, Sasano H, Harada N, Miyazaki Y, Katsura H, Tagaya E, Terada J, Hojo M, Sugimoto N, Nagase H, Kono Y, Hiranuma H, Gon Y, Miyata J, Uemura S, Shirasaki Y, Fukunaga K
BACKGROUND: Severe asthma is a heterogeneous disease with variable treatment responses to biologic therapy. Conventional biomarkers, including blood eosinophil counts and fractional exhaled nitric oxide, only partially c...BACKGROUND: Severe asthma is a heterogeneous disease with variable treatment responses to biologic therapy. Conventional biomarkers, including blood eosinophil counts and fractional exhaled nitric oxide, only partially capture response heterogeneity. OBJECTIVE: We evaluated the cytokine secretion profiles of group 2 innate lymphoid cells (ILC2s) and T2 cells and examined their associations with clinical outcomes after benralizumab therapy. METHODS: We analyzed 70 patients with severe type 2-high asthma enrolled onto the multicenter Tokyo Asthma Study. Cytokine secretion by ILC2s and T2 cells was evaluated by live cell imaging of secretion activity, which enables real-time visualization of cytokine secretion from individual lymphocytes. The frequencies of IL-4-, IL-5-, and IL-13-producing cells were quantified at baseline and after 24 weeks of benralizumab treatment. Clinical responses were primarily assessed by the Asthma Control Questionnaire 5, and patients were classified as experiencing response or not. STUDY REGISTRATION: Japan Registry of Clinical Trials (jRCTs031190237). RESULTS: In type 2-high asthma, ILC2s and T2 cells exhibited distinct cytokine secretion profiles with no significant correlation between the two cell populations. Benralizumab selectively suppressed IL-5- and IL-13-producing ILC2s but had little effect on T2 cells. Patients with higher baseline frequencies of IL-4-producing T2 cells showed limited clinical improvement after benralizumab therapy. In multivariable logistic regression analysis, baseline IL-4-producing T2 cell frequency was associated with Asthma Control Questionnaire-defined nonresponse after adjustment for blood eosinophil counts and fractional exhaled nitric oxide. CONCLUSIONS: Single-cell functional lymphocyte profiling identifies distinct innate and adaptive type 2 responses to benralizumab and provides complementary information associated with response heterogeneity in severe asthma.
BACKGROUND: Psoriasis is a common chronic inflammatory skin disease characterized by recurrent flares at previously affected locations. Although biologics targeting IL-17 or IL-23 effectively suppress active disease, the...BACKGROUND: Psoriasis is a common chronic inflammatory skin disease characterized by recurrent flares at previously affected locations. Although biologics targeting IL-17 or IL-23 effectively suppress active disease, they rarely result in long-term remission, suggesting that clinically resolved skin retains molecular changes predisposing to relapse. OBJECTIVE: The STEPIn main study indicated that early intervention with secukinumab, an anti-IL-17A monoclonal antibody, may modify the course of psoriasis. This mechanistic substudy sought to define cellular and molecular changes in psoriatic skin lesions during treatment. METHODS: Psoriatic skin was sampled at baseline and at up to 52 weeks of secukinumab treatment in new-onset (≤1 year) and long-standing (≥5 years) cohorts. Biopsy samples were evaluated histologically by immune profiling, global gene expression, and genome-wide DNA CpG methylation analyses. RESULTS: Treatment with secukinumab resulted in marked molecular differences between new-onset and long-standing psoriasis despite similar clinical improvement. Gene expression normalized faster in new-onset disease but ultimately resolved in both cohorts. In contrast, disease-associated CpG methylation detected at baseline persisted despite treatment, but only in long-standing psoriasis. Baseline methylation differences were enriched for AP-1 transcription factor binding sites in long-standing disease and persistent methylation changes mapped to genes enriched for small GTPase pathways. Notably, AP-1 components were found to amplify IL-17A and TNF-α responses in keratinocytes, and a subset of these persistent methylation sites overlapped with accessible chromatin regions in psoriatic keratinocytes. CONCLUSIONS: Early secukinumab intervention may prevent formation of an epigenetic scar that persists in long-standing psoriasis even after clinical resolution. CLINICAL TRIAL REGISTRATION: NCT03020199.
Dantzer JA, Virkud YV, Cox AL
… +17 more, Sindher SB, Mudd K, Anania N, Kim EH, Kulis M, Hamilton D, Penumarti A, Kesselring J, Sampson HA, Scurlock AM, Perry TT, Pesek RD, Kost L, Bogetic D, Chinthrajah RS, Jones SM, Wood RA
BACKGROUND: The IMPACT trial (NCT01867671) demonstrated strong desensitization and the potential for remission with peanut oral immunotherapy (pnOIT) in 1- to 3-year-olds. Data on long-term outcomes of early intervention...BACKGROUND: The IMPACT trial (NCT01867671) demonstrated strong desensitization and the potential for remission with peanut oral immunotherapy (pnOIT) in 1- to 3-year-olds. Data on long-term outcomes of early intervention oral immunotherapy (OIT) are limited. OBJECTIVE: IMPACT-PLuS sought to assess the long-term efficacy, safety, and mechanistic changes related to early-life pnOIT. METHODS: Participants randomized in IMPACT (n = 146) were recruited. The primary outcome was long-term efficacy, defined as ongoing peanut consumption. Secondary outcomes included safety, peanut serology, and skin prick tests. Participants were categorized according to IMPACT treatment (pnOIT, placebo) and participation in any additional peanut allergy intervention apart from guidance given at the end of the IMPACT trial. Patients were grouped as follows: group A, pnOIT with no subsequent intervention; group B, pnOIT with subsequent intervention; group C, placebo OIT with no subsequent intervention; and group D, placebo OIT with subsequent intervention. RESULTS: Follow-up data were available for 78 of the 146 IMPACT participants (aged 9-14 years; 8-11 years after IMPACT enrollment). Fifty-eight received pnOIT in IMPACT. Overall, 80% (32/40) of group A were eating peanut at follow-up (48/58, 83%, of the entire IMPACT follow-up pnOIT group), with 35% (14/40) eating ≥1000 mg peanut. All 15 subjects from the IMPACT remission group were eating peanut at follow-up. Peanut reactions were reported by 35% (14/40) in group A, with epinephrine therapy received by 5. Compared with group C (placebo), group A had significantly lower levels of peanut and Ara h 2 IgE, and higher peanut and Ara h 2 IgG. CONCLUSIONS: pnOIT initiated early in life can have long-term, sustainable impact, both clinically and immunologically.
Kan-O K, Watanabe H, Chibana K
… +47 more, Suzukawa M, Tanaka A, Masaki K, Ohta S, Kabata H, Asano K, Ito R, Inoue H, Nakano T, Kanda H, Yamashita T, Obase Y, Kobayashi K, Sugimoto N, Ito Y, Ogata H, Takagi K, Ohshima N, Kinoshita T, Tashiro H, Takahashi K, Oishi K, Hirano T, Sakakibara H, Sennari K, Sugimoto Y, Shiroyama T, Fukahori S, Oguma T, Tomomatsu K, Shimada S, Kondo M, Akaba T, Yoshimi M, Moriuchi Y, Ujike M, Mitsui M, Shimizu K, Shindo Y, Takasawa S, Wakahara K, Uno T, Miyata J, Ishida A, Tsuji M, Shimada A, Okamoto I
BACKGROUND: Clinical remission has emerged as an ambitious therapeutic goal in severe asthma, shifting emphasis from symptomatic relief to long-term disease modification. Tezepelumab, a monoclonal antibody targeting thym...BACKGROUND: Clinical remission has emerged as an ambitious therapeutic goal in severe asthma, shifting emphasis from symptomatic relief to long-term disease modification. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin, has demonstrated broad-spectrum anti-inflammatory activity. However, prospective data assessing clinical remission with tezepelumab, especially in biologic-experienced patients, remain limited. OBJECTIVE: The Tezepelumab-induced Clinical Remission in Severe Asthma (TERESA) study is a multicenter, prospective, single-arm, investigator-initiated phase 4 study evaluating clinical remission at week 52 in patients with uncontrolled severe asthma receiving tezepelumab every 4 weeks. METHODS: Clinical remission was defined as the absence of asthma exacerbations, discontinuation of maintenance oral corticosteroids, an Asthma Control Questionnaire 6 score of ≤1.5, and stabilized lung function. Secondary end points included complete remission (clinical remission plus type 2 biomarker negativity). RESULTS: Among 107 patients enrolled (including 50 biologic-experienced patients), 34.6% (95% confidence interval, 26.2, 44.0) obtained clinical remission at week 52. Complete remission was observed in 9.3%. Biologic-naive patients demonstrated higher remission rates than biologic-experienced patients (47.4% vs 20.0%, respectively). Multivariable logistic regression identified absence of previous biologic receipt (adjusted odds ratio, 3.61; 95% confidence interval, 1.29, 10.15) and baseline blood eosinophil count ≥ 300 cells/μL (adjusted odds ratio, 5.10; 95% confidence interval, 1.23, 21.18) as independent predictors of clinical remission. CONCLUSION: In this single-arm study with 1 year's follow-up, tezepelumab resulted in clinical remission in approximately one third of patients with severe asthma, with a favorable safety profile. Higher baseline eosinophil count and biologic-naive status were key predictors of remission, underscoring tezepelumab's potential to obtain comprehensive disease control in appropriately selected patients. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071230026).
Yildirim TC, Ozsurekci Y, Yildirim M
… +11 more, Yazar V, Evcili I, Gungor B, Yilmaz IC, Ozen S, Aykac K, Cengiz AB, Guler U, Salih B, Gursel M, Gursel I
BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a post-SARS-CoV-2 hyperinflammatory condition with multiorgan involvement. The contribution of circulating extracellular vesicles (EVs) to MIS-C immuno...BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a post-SARS-CoV-2 hyperinflammatory condition with multiorgan involvement. The contribution of circulating extracellular vesicles (EVs) to MIS-C immunopathology remains incompletely defined. OBJECTIVE: To compare humoral and cytokine responses and EV-associated viral/inflammatory signatures in MIS-C versus pediatric COVID-19 across the clinical spectrum. METHODS: In a prospective cohort, children with PCR-confirmed SARS-CoV-2 infection were classified as asymptomatic, mild/moderate, or severe COVID-19, or MIS-C, with healthy controls. Serum anti-Spike, anti-RBD, and anti-nucleocapsid IgG/IgA/IgM were quantified by ELISA and followed longitudinally. Nineteen cytokines were measured using multiplex bead assays. Plasma EVs were isolated by size-exclusion chromatography, characterized by TRPS/flow cytometry, assessed for Spike/RBD by immunoblot, tested for NF-κB/IRF activation in THP-1 reporter cells, and profiled by LC-MS/MS proteomics. RESULTS: MIS-C patients had higher anti-Spike/RBD IgG (and broader isotype responses) at admission and sustained titers over follow-up, consistent with prolonged antigenic exposure. MIS-C showed a distinct inflammatory profile with prominent IL-17A (and IL-22) elevation relative to severe COVID-19. Spike and RBD were detectable in EVs from severe COVID-19 and MIS-C. Functionally, severe COVID-19 EVs activated both NF-κB and IRF pathways, whereas MIS-C EVs preferentially activated IRF with minimal NF-κB signaling. Proteomics identified a MIS-C-specific EV cargo enriched for innate immune pathways, neutrophil degranulation, and adhesion/integrin-associated proteins. CONCLUSION: MIS-C is characterized by sustained humoral responses, Th17-skewed cytokines, and antigen-bearing EVs with distinct, IRF-biased immunostimulatory and proteomic signatures. EV profiling and implicated pathways (e.g., IL-17 and adhesion/integrin networks) may inform biomarker development and targeted immunomodulatory strategies in MIS-C.
Pérez-Díez A, Liu X, Bennett A
… +6 more, Barrios M, Anderson M, Wolfarth AA, Choi D, Lisco A, Sereti I
J Allergy Clin Immunol
· 2026 May · PMID 42155681
·
Full text
BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome characterized by low CD4 T-cell counts (<300 cells/μL), occasionally accompanied by CD8 lymphopenia. ICL, which is associated with serious opportuni...BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome characterized by low CD4 T-cell counts (<300 cells/μL), occasionally accompanied by CD8 lymphopenia. ICL, which is associated with serious opportunistic infections, cancers, and autoimmune diseases, has no established treatment. OBJECTIVE: We tested NT-I7 (efineptakin alfa), a long-acting form of recombinant human (rh) IL-7, as a potential immunotherapy for ICL in a preclinical mouse model. METHODS: Mice received peripheral blood mononuclear cells from 15 individuals: 5 healthy donors and 10 persons with ICL. Mice receiving ICL cells were either untreated or treated with a single NT-I7 dose. Blood was sampled at different times, and spleens were collected on day 28 to compare lymphocyte reconstitution, IL-7Rα expression, and TCR clonality, while weight was monitored to detect potential graft-versus-host disease. In a single patient study, NT-I7 was administered, and blood lymphocytes were enumerated up to 98 days. RESULTS: In mice that phenocopied their donors' lymphopenia, NT-I7 treatment restored CD4 T-cell counts to the levels observed in mice receiving lymphocytes from healthy donors. A single NT-I7 dose downregulated IL-7Rα on CD4-T cells for 2 to 3 weeks and increased T-cell counts with preserved polyclonality in 3 of 4 patients tested, without causing graft-versus-host disease. The lymphopenic NT-I7-treated patient experienced a 2- and 3-fold rise in CD4 and CD8-T cell numbers, respectively, 2 months after a single dose of NT-I7. CONCLUSION: A single dose of NT-I7 restored T-cell numbers in a mouse model of ICL and improved lymphocyte counts in a single-patient study.
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease of the esophagus with substantial clinical manifestations including dysphagia, odynophagia, food impaction and failure to thrive in children. New evide...Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease of the esophagus with substantial clinical manifestations including dysphagia, odynophagia, food impaction and failure to thrive in children. New evidence is emerging regarding phenotypic and symptom variations in diverse EoE populations. EoE pathogenesis involves impaired epithelial barrier function, antigen-driven Type 2 inflammation, and eosinophilic infiltration, yet eosinophil and mast cell depletion does not improve patient symptoms. Recent research has unveiled new potential mechanisms of epithelial dysfunction, including the role of epithelial alarmins in inducing downstream inflammatory cascades. New clinical scoring tools are emerging to improve diagnosis and monitor disease severity. Therapeutic approaches for EoE are rapidly evolving with a wider range of therapies becoming available. Dietary elimination, topical corticosteroids, proton pump inhibitors (PPIs), and anti-type 2 biological agents aim to provide histologic and symptomatic relief. Overall, this review aims to present recent advances in the epidemiology, pathophysiology, diagnosis, and treatment of EoE, while also extending this information to the broader field of eosinophilic gastrointestinal diseases (EGIDs).
BACKGROUND: The role of the nasal microbiome in allergic rhinitis (AR), particularly following direct allergen exposure using a controlled model, is incompletely understood. Understanding microbiome dynamics after allerg...BACKGROUND: The role of the nasal microbiome in allergic rhinitis (AR), particularly following direct allergen exposure using a controlled model, is incompletely understood. Understanding microbiome dynamics after allergen challenge could provide insights into AR pathophysiology. OBJECTIVE: We sought to evaluate nasal microbiome changes following nasal allergen challenge (NAC) with ragweed pollen extract in participants with ragweed-induced AR compared with control participants without allergy. METHODS: An out-of-season NAC was completed by 19 participants with ragweed allergy and 12 control participants without allergy. Middle meatus and adjacent nasal cavity secretions were collected at baseline and 6, 24, and 48 hours after challenge. Microbial composition was characterized using 16S ribosomal RNA sequencing. Alpha diversity was assessed using the Shannon and Chao1 indices, and beta diversity was assessed using Bray-Curtis dissimilarity with principal coordinate analysis. Ragweed pollen-specific IgE (sIgE), total IgE, and Staphylococcus aureus nasal carriage were also evaluated. RESULTS: Nasal microbial community composition differed according to biological sex (beta diversity P = .001) and S aureus carriage (P = .015). However, allergic status and NAC exposure had no significant effect on alpha or beta diversity over time. Genus-level differences between participants with AR and control participants emerged at 24 and 48 hours after challenge (P = .028 and P = .0062), with greater relative abundance of Streptococcus and Veillonella observed in control participants. Stratification by sIgE demonstrated significant differences in microbial community structure (P = .001), with higher sIgE levels associated with increased relative abundance of Streptococcus, Rothia, Staphylococcus, Neisseria, and Delftia. Higher total IgE levels were also associated with distinct microbial community profiles. CONCLUSIONS: The nasal microbiome remained stable following acute allergen exposure despite clinical responses, whereas host factors including IgE levels, sex, and S aureus carriage were associated with differences in microbial community composition.
Advances in clinical immunology have led to substantial developments in the diagnosis and treatment of patients with inborn errors of immunity. Still, publications between 2023 and 2025 reveal several persistent needs. F...Advances in clinical immunology have led to substantial developments in the diagnosis and treatment of patients with inborn errors of immunity. Still, publications between 2023 and 2025 reveal several persistent needs. First, ongoing reports from the International Union of Immunological Societies demonstrate the need for continued gene discoveries. Second, growing data illustrate the important need for phenotype improvement in not only new diseases but also established ones. Third, recognition of the potentially pleiomorphic nature of heterozygous variants exposes the critical need to challenge prior hypotheses about accepted disease models of inborn errors of immunity. Next, continued pursuit of genetic etiologies for inborn errors of immunity in unsolved cases portends the need to embrace new disease mechanisms, such as somatic mosaicism and monoallelic expression. Furthermore, the rising number of variants of uncertain significance underscores the vital need to investigate multiple variant pathogenicity at scale. Also, recent studies reflect avid realization of the constant need for biomarkers and enhanced detection, such as through bioassays, specific clinically available tests, or even artificial intelligence. Last, key reports support the further need to study innovative treatment approaches and disease outcomes. Overall, the field of clinical immunology must continue to push forward to address these needs.
BACKGROUND: The C-X-C motif chemokine receptor CXCR6 is considered a marker of some tissue-resident memory T (Trm) cells, but its importance in controlling lung CD4 Trm cells in asthma remains unclear. OBJECTIVE: We expl...BACKGROUND: The C-X-C motif chemokine receptor CXCR6 is considered a marker of some tissue-resident memory T (Trm) cells, but its importance in controlling lung CD4 Trm cells in asthma remains unclear. OBJECTIVE: We explored the involvement of CXCL16-CXCR6 interactions in the activity and accumulation of CD4 Trm cells relevant to lung inflammatory disease. METHODS: Human and murine asthmatic lung CD4 T cells were analyzed by single-cell transcriptomics to assess CXCR6 expression, and the effects of blocking the CXCL16-CXCR6 pathway were then evaluated using a disease model. RESULTS: Single-cell RNA sequencing of human and murine asthmatic lung cells revealed elevated CXCR6 mRNA expression in CD4 T cells. Confirming a role for CXCR6, short-term blockade of its ligand, CXCL16, during repeated intranasal allergen challenges in the mouse reduced the accumulation of lung CD4 memory effector T cells by 50% to 70%, coincident with decreased tissue inflammation. This protective effect persisted, with reduced numbers of lung CD4 Trm cells being visualized over time, and was evident during subsequent asthma exacerbations shown by a tolerogenic effect with continued marked reduction in lung inflammation. Late blockade of CXCL16 after allergen exposure also resulted in fewer Trm cells, an effect reproduced by blocking antigen presentation but not by inhibiting T-cell trafficking into the lung. This implies a role of the chemokine in sustaining local antigen presentation and correlates with CXCL16 expression being found in human asthmatic lung macrophages, monocytes, and dendritic cells. CONCLUSION: CXCL16 blockade may regulate allergen-induced CD4 Trm cell accumulation and persistence in the lungs, suggesting a potential therapeutic approach for asthma.
The current paradigm regarding the pathogenesis of chronic spontaneous urticaria (CSU) involves two separate mechanisms by which cutaneous mast cells and basophils are activated. Type Ia has higher IgE levels, rapidly re...The current paradigm regarding the pathogenesis of chronic spontaneous urticaria (CSU) involves two separate mechanisms by which cutaneous mast cells and basophils are activated. Type Ia has higher IgE levels, rapidly responds to omalizumab, and possesses IgE antibody to either thyroperoxidase, IL-24, or both. Type IIb has IgG antibody to IgE receptor, activates complement, has augmented mast cell secretion via C5a, and takes longer to respond to omalizumab. Reports are mixed regarding the incidence of IgE autoantibodies in controls versus patients with CSU. Because 25% of the total population have allergic disorders associated with elevated IgE (allergic rhinitis, extrinsic asthma, atopic dermatitis), as well as a personal and often family history of atopy, any type Ia mechanism for production of urticaria has to separate out those with CSU who have atopic disease and not assume that these parameters or their IgE levels have anything to do with hive formation. The type IIb mechanism depends not only on a stimulus through an IgE receptor but also on C5a acting through the C5a receptor, together accounting for close to 40% of patients. It has been reproduced by multiple laboratories world-wide with an incidence of 25-45%. In fact, our proof-of-concept study regarding the efficacy of omalizumab to treat CSU were all based on type IIb disease with the presence of IgG antibody to the IgE receptor. We conclude that the evidence for type Ia allergy being an endotype of CSU is sparse; data are conflicting, and it's a large jump to infer a molecular mechanism or endotype. The data for a type IIb mechanism are substantial but are demonstrable in less than half the patients.
Chen P, Le KM, Li W
… +20 more, Hinrichsen F, Liu X, Braathen RS, Mamia N, Szymanska M, Li Z, Trotta L, Almusa H, Mamia K, Glumoff V, Holland P, Anders S, Kalinichenko A, Kaustio M, Seppänen MRJ, Haapaniemi EM, Varjosalo M, Martelius T, Grönholm J, Saarela J
BACKGROUND: The transmembrane adaptor protein SIT1 (signaling threshold-regulating transmembrane adaptor 1) is a negative regulator of T-cell receptor (TCR) signaling, but its role in human immunity remains poorly charac...BACKGROUND: The transmembrane adaptor protein SIT1 (signaling threshold-regulating transmembrane adaptor 1) is a negative regulator of T-cell receptor (TCR) signaling, but its role in human immunity remains poorly characterized. OBJECTIVE: We sought to investigate the molecular consequences of a biallelic loss-of-function SIT1 variant in a patient with combined immune deficiency and recurrent lymphoma. METHODS: Exome sequencing identified the putative disease-causing variant. Immunophenotyping and functional assays were performed on patient-derived lymphocytes and CRISPR-Cas9-mediated SIT1 knockout (KO) T cells from healthy donors. Transcriptomics, proteomics, and super-resolution imaging were used to characterize SIT1 deficiency. RESULTS: The c.236+2T>G variant caused exon 2 skipping and complete SIT1 loss. Patient/KO T cells revealed skewed T-cell subsets, increased activation and proliferation, and impaired CD8 cytotoxicity. Transcriptomic analysis demonstrated that SIT1 KO upregulated cytokine signaling, metabolic reprogramming, and cell cycle hallmarks. Proteomic analysis confirmed SIT1's association with Src and receptor tyrosine kinases and suggested a novel role for SIT1 in intracellular vesicle trafficking. Imaging revealed SIT1 localized to plasma membrane and TCR microclusters, colocalizing with endolysosomal compartments and linker for activation of T cells. Patient T cells exhibited impaired immune synapse maturation and vesicle accumulation on TCR stimulation. Population data link this rare SIT1 variant to lymphoid malignancy and reduced risk of autoimmunity. CONCLUSIONS: We report the first patient with biallelic loss-of-function SIT1 variant, establishing SIT1 as a critical regulator of T-cell activation, proliferation, and synapse organization, implicating SIT1 deficiency as a novel cause of combined immunodeficiency, predisposing to lymphoid malignancy.
BACKGROUND: Hereditary angioedema with C1 esterase inhibitor (C1INH) deficiency is caused by variants in the SERPING1 gene. A decrease in C1INH function results in overproduction of bradykinin, causing enhanced vascular...BACKGROUND: Hereditary angioedema with C1 esterase inhibitor (C1INH) deficiency is caused by variants in the SERPING1 gene. A decrease in C1INH function results in overproduction of bradykinin, causing enhanced vascular permeability and swelling. Signal peptide (SP) is essential for C1INH secretion. While SP variants in the SERPING1 gene have been reported, their genotype-phenotype correlations have not been well characterized. OBJECTIVE: To investigate the impact of SP variants, we systematically evaluated 33 SP variants of C1INH by examining their expression, function, and intracellular location. METHODS: The SP variants were transiently transfected into 293T cells. Their concentration was compared to wild-type C1INH. Functional analyses were performed by assessing their binding with activated C1s, kallikrein, and factor XIIa. Transfected HeLa cells were used to assess the intracellular localization of C1INH variants. RESULTS: Of 33 SP variants, 6 were poorly synthesized. Among these, 3 are in the H region (L10R, L12R, L13-L15del) and 3 are in the C-terminal region (G17R, A20D, S22L). Compared to wild type, the remaining variants demonstrated normal recombinant protein expression and intact binding activity to their substrates. Protein aggregates were observed in the endoplasmic reticulum of L10R-, G17R-, and S22L-transfected cells. CONCLUSIONS: The H- and C-terminal regions of SP are critical for C1INH production. Shortening or introducing positive charges into the hydrophobic core of the H-terminal region can lead to pathogenic consequences. Disrupting the SP cleavage site in the C-terminal region impairs protein production. This study provides new insights into the impact of SP variants on C1INH expression leading to hereditary angioedema.
BACKGROUND: Pemphigus is an autoimmune bullous disease primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the disease pathogenesis beyond anti-Dsg autoantibodies remains unclear. OBJECTIVE: We sought to e...BACKGROUND: Pemphigus is an autoimmune bullous disease primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the disease pathogenesis beyond anti-Dsg autoantibodies remains unclear. OBJECTIVE: We sought to explore the pathogenic role of IFN-γ in pemphigus and to evaluate the therapeutic potential of targeting the IFN-γ-JAK pathway. METHODS: The pathogenetic effects of IFN-γ signaling in pemphigus were investigated by integrated single cell analysis, ex vivo human skin explants, and cocultures. Therapeutic efficacy of the JAK1 inhibitor abrocitinib was evaluated in a murine pemphigus model and in refractory pemphigus patients. RESULTS: IFN-γ-expressing T cells largely infiltrate pemphigus lesions and drive IFN-γ-dominant inflammation. IFN-γ-activated keratinocytes secrete C-X-C motif chemokines CXCL9/10/11 to recruit more CD8 T cells. Notably, IFN-γ primes keratinocytes to become more susceptible to CD8 T-cell-mediated cytotoxicity. Moreover, IFN-γ synergizes with anti-Dsg autoantibodies to induce keratinocyte dissociation through p38 activation and augments anti-Dsg autoantibody production. Oral JAK1 inhibitor abrocitinib effectively attenuated IFN-γ-dominant inflammation and improved skin lesions in a murine pemphigus model and in patients with refractory disease. CONCLUSION: A self-amplifying inflammatory circuit between IFN-γCD8 T cells and keratinocytes acts as a key driver of pemphigus pathogenesis and provides a mechanistic rationale for targeting the IFN-γ-JAK pathway in its treatment.
Wang CW, Chen WT, Chen CB
… +28 more, Chu CY, Chung-Yee Hui R, Lu CW, Chiu TM, Hung SI, Huei HY, Tassaneeyakul W, Choon SE, Nakkam N, Sukasem C, Jan Wu YJ, Chung HY, Lung JH, Chang JS, Lee YS, Chang YC, Yu KH, Teng YC, Lin SH, Lai KC, Hou HH, Wu J, Chi MH, Lee HE, Yu-Wei Lin Y, Lin YJ, Chung WH, Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium
BACKGROUND: Sulfasalazine is a disease-modifying antirheumatic drug used to treat arthritis and ankylosing spondylitis. However, it may cause life-threatening severe cutaneous adverse reactions (SCARs), including Stevens...BACKGROUND: Sulfasalazine is a disease-modifying antirheumatic drug used to treat arthritis and ankylosing spondylitis. However, it may cause life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. OBJECTIVE: Genetic predisposition to sulfasalazine-induced SCARs was assessed. METHODS: This multicountry genetic study involved discovery, replication, and meta-analysis cohorts. The discovery cohort comprised 62 cases of sulfasalazine-induced SCARs and 75 sulfasalazine-tolerant subjects as well as 657 population controls from China and Taiwan who underwent whole-exome sequencing. The replication cohort comprised additional 17 cases and 2038 population controls from Taiwan who underwent HLA genotyping. The meta-analysis cohort comprised a total of 105 cases from Japan, Thailand, Malaysia, Taiwan, and China, together with 23,743 country-matched population controls. Functional immune mechanisms were explored with ex vivo lymphocyte activation assays. RESULTS: In the discovery cohort, rs9266217 in HLA-B exhibited the strongest association. HLA genotyping in replication cohort and phenotype stratification found 4 HLA-B alleles that jointly yielded 84.8% sensitivity (P = 2.3 × 10) in predicting sulfasalazine-induced SCARs in the Chinese population. Meta-analysis across 4 Asian countries confirmed significant associations for 3 alleles. Functional assays showed that sulfasalazine or its active metabolite, sulfapyridine, markedly increased granulysin release from CD8 T cells of affected patients, supporting an HLA-restricted reaction. CONCLUSION: Multiple HLA-B alleles (B∗39:01, B∗13:01, and B∗38:02) are strongly associated with sulfasalazine-induced SCARs in Asians.