Poster Tour: Friday

Introduction: IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder classically described as indolent and non-destructive, with pseudotumoral lesions mimicking malignancy, vasculitis, or infection. Sinonasal involvement is not included in the 2019 European League Against Rheumatism classification criteria. We report two cases highlighting a potentially distinct sinonasal phenotype in IgG4-RD. Case description: A 34-year-old woman underwent ethmoidectomy for presumed chronic rhinosinusitis. She later developed left maxillary pain and underwent multiple dental procedures for suspected odontogenic infection. PET-CT revealed a hypermetabolic destructive maxillary sinus mass with bone invasion and hard palate perforation. Biopsy confirmed IgG4-RD. A 42-year-old woman presented with recurrent eyelid swelling and chronic rhinosinusitis, progressing to left maxillary pain and cheek swelling. PET-CT showed salivary and lacrimal gland involvement with destructive maxillary sinus lesions. Lacrimal gland and sinonasal biopsies confirmed IgG4-RD. Serum IgG4 was normal in the first patient and elevated (2.4 g/L) in the second. Anti-neutrophil cytoplasmic antibodies were negative in both cases, and pathology review excluded granulomatosis with polyangiitis and malignancy. The first patient received glucocorticoids and rituximab, and the second rituximab alone, both with clinical improvement. Conclusion: IgG4-RD may rarely present as a locally destructive sinonasal disease. Recognition of this phenotype is important and may support its inclusion in future classification criteria.

Introduction and Aim: Cardiac sarcoidosis (CS) is associated with substantial morbidity and mortality. Treatment remains challenging in patients refractory to corticosteroids, conventional immunosuppressants and tumour necrosis factor inhibitors (TNFi). Janus kinase (JAK) inhibition has emerged as a potential therapeutic strategy in sarcoidosis, but data in CS are limited. We evaluated the efficacy and safety of tofacitinib in refractory CS.

Design and Methods: We retrospectively analysed eight patients with refractory or probable CS treated with tofacitinib at the University Hospital Zurich between 2020 and 2024. Treatment response was assessed using serial 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), left ventricular ejection fraction (LVEF), prednisone dose and serum neopterin levels.

Results: Seven of eight patients (87.5%) achieved inactive or remitting myocardial disease activity on repeat 18F-FDG PET/CT. Mean myocardial SUVmax decreased from 7.96 to 5.06, while cardiac metabolic activity decreased from 397 to 191. LVEF remained stable or improved in all patients. Mean prednisone dose decreased from 5.94 mg/day to 2.5 mg/day. Neopterin levels and extracardiac FDG uptake decreased in most patients. No venous thromboembolic or acute ischaemic cardiac events occurred during follow-up.

Conclusions: Tofacitinib demonstrated promising anti-inflammatory and steroid-sparing effects in therapy-refractory CS and may represent a novel therapeutic option for difficult-to-treat disease.

Chronic wildfire smoke disrupts respiratory epithelial barriers, but the molecular drivers and their links to allergy remain unclear. We applied a dual-omics approach to define targeted inflammatory mediators and systemic proteomic changes in controls (n=17) and wildfire-exposed subjects with (n=25) or without allergies (n=38). Plasma was analyzed by NULISAseq Inflammation Panel 250 for low-abundance mediators and untargeted LC-MS/MS for global profiling. XGBoost with SHAP identified signatures of exposure and allergic status. Targeted profiling revealed a dominant inflammatory phenotype marked by increased tissue remodeling and metabolic markers. MMP3, MMP8, and MMP9 were significantly elevated, consistent with impaired barrier integrity, together with NAMPT and the pro-inflammatory cytokines IL-1β, IL-18, and IL-36A. In contrast, vascular and neural maintenance markers were reduced. GFAP, the strongest discriminator, was suppressed in exposed subjects, suggesting neuroglial effects, while FLT1 (VEGFR1) downregulation indicated impaired endothelial repair. Although linear modeling of the untargeted proteome was constrained by heterogeneity, machine learning resolved distinct allergic signatures. Asthma, eczema, and food allergy were characterized by IFNW1, CCL1, and FGF19, whereas environmental allergy was associated with IL-4 and PD-L2 (PDCD1LG2). Drug hypersensitivity was predicted by BMP7 and IL-5RA. These findings indicate that wildfire smoke drives systemic metabolic reprogramming, matrix remodeling, and vascular dysregulation beyond airway inflammation.

Pig-to-human xenotransplantation has progressed from concept to clinics, yet T cell-mediated rejection remains a major barrier to durable graft acceptance despite extensive immunosuppression. We investigated how genetic modifications in porcine aortic endothelial cells (PAEC) shape human CD8⁺ T cell function. Human PBMC were co-cultured with wild-type (PAEC_WT), transgenic hPD‑L1/hCD47 (PAEC_TG.1), or PAEC_TG.2 lacking MHC-I (B2M-KO/hPD‑L1). Flow cytometry showed that PAEC_WT and PAEC_TG.1 supported balanced T cell expansion (mean CD4/CD8 ratios 2.1 ± 0.9 and 2.1 ± 1.4), whereas PAEC_TG.2 impaired CD8⁺ priming, increasing the ratio (4.5 ± 2.4). Co-culture with PAEC_TG.2 reduced differentiation into effector memory subset (11.6 ± 4.5 % vs 29.8 ± 13.9 % with PAEC_WT, p = 0.004). Specific lysis was preserved against PAEC_TG.1 compared to PAEC_WT (AUC 325.3 ± 174.4 vs 299.7 ± 215.9) but reduced against PAEC_TG.2 (AUC 76.2 ± 50.3) to levels of the 3^rd party control. hPD‑L1 expression selectively inhibited degranulation without reducing granzyme B content, consistent with checkpoint‑mediated suppression of TCR/CD28 signalling. PD‑L1 blockade partially restored cytotoxicity in bulk cultures but failed to rescue the function of purified CD8⁺ T cells, highlighting the need for CD4⁺ help under inhibitory conditions. Donor‑dependent variability in memory differentiation and cytotoxicity further emphasized the heterogeneity of human xenogeneic responses. Overall, MHC-I dependent antigen presentation was determined CTL function, while hPD‑L1 provided secondary modulation.

Atopic dermatitis (AD) is driven by epithelial barrier dysfunction and type 2 immunity, with IL-13 disrupting epidermal differentiation and barrier integrity. Tralokinumab, an anti–IL-13 antibody, is effective in moderate-to-severe AD, yet response biomarkers are lacking.

Adults with moderate-to-severe AD starting tralokinumab (n=20) were followed for 8 weeks. SCORAD and electrical impedance spectroscopy (EIS) were measured at weeks 0, 4, 16. Response was defined as ≥50% SCORAD reduction at week 8 (SCORAD-50). Paired biopsies underwent bulk RNA-seq and imaging mass cytometry; serum was profiled by Olink. Analyses included differential expression, immune deconvolution, and Elastic Net regression.

SCORAD-50 was achieved by 70% of patients (median reduction 58%); SCORAD and EIS correlated inversely (ρ=−0.54, p=3.8×10⁻⁵). RNA-seq showed downregulation of type 2, chemokine, and HDAC-associated programs and upregulation of keratinization and barrier genes. At baseline, responders and non-responders differed in lipid metabolism, epigenetics, and inflammation, with enrichment of myeloid cells (ρ=0.62, p=0.01) and non-classical monocytes (ρ=0.61, p=0.01). Elastic Net identified serum PSIP1 as the top predictor (AUC=0.87); longitudinal CD28 correlated with SCORAD trajectory (ρ=−0.61, p=4×10⁻⁴).

Baseline transcriptomic differences in lipid metabolism, epigenetics, and inflammation, together with myeloid enrichment, serum PSIP1, and treatment CD28 dynamics, stratify tralokinumab responders, while IL-13 blockade resolves type 2 inflammation and restores epidermal barrier programs.

Aim of the study:

Some IEI patients develop lymphomas, suggesting gain-of-survival states in which autoreactive lymphocytes evade negative selection, persist, and occasionally transform. While antigen drives clonal selection, intracellular signaling and antigen receptor configuration are also critical. Many B lymphomas express stereotyped, autoreactive antigen receptors with biased IGHV usage and conserved CDR3 motifs, yet how IGHV identity shapes signaling during selection remains unclear. Germline IEI-causing defects often affect signaling nodes recurrently mutated in lymphoma, providing adjustable models of how these changes reshape lymphocyte fitness. We profiled TCR/BCR repertoires across five monogenic IEIs to test for convergent, lymphoma-like immunogenetic signatures.

Design and methods: Bulk VDJ sequencing was performed on blood from HA20, APLAID, DADA2, IKAROS haploinsufficiency and ALPS patients.

Results: BCR repertoires were more perturbed than TCR. ALPS and IKAROS haploinsufficiency showed oligoclonal BCR architectures, while HA20 and especially APLAID exhibited reduced diversity and SHM. APLAID TCRs were hyperdiverse, clonally skewed in ALPS/IKAROS, and contracted in HA20/DADA2. IEIs affecting NF-κB/BCR signaling converged on enrichment of the autoreactive, lymphoma-associated IGHV4-34 BCRs, alongside other lymphoma-linked biases. These coincided with shared CDR3 hydrophobicity/polarity sifts, consistent with attenuated tolerance checkpoints.

Conclusions: Single mutations in BCR/TCR signaling nodes co-select autoreactive, lymphoma-like receptor architectures.