Background/Purpose: Still’s disease is a rare and severe autoinflammatory disorder characterized by daily spiking fevers, arthritis, an evanescent rash, and prominent systemic features, including lymphadenopathy, hepatosplenomegaly, serositis, and systemic inflammation mediated primarily by IL-1, IL-6, and IL-18. Still’s disease can lead to severe and often fatal complications, such as Still’s disease-associated lung disease (Still’s-LD). Still’s-LD is a chronic and severe pulmonary disorder, particularly observed in patients treated with modern biologic therapies. It is characterized by interstitial lung disease (ILD), pulmonary alveolar proteinosis (PAP), pulmonary arterial hypertension, and chronic respiratory failure. Although extensive innate immune dysregulation, T cell activation, and an IFN-𝛾-driven inflammatory milieu have been implicated in the pathogenesis of Still’s-LD, the immunopathologic basis of the disease remains poorly understood. CD21low T-bet+ atypical or Age-Associated B cells (ABCs) are known to expand under conditions of chronic antigen exposure and inflammation, such as chronic infections (e.g., malaria, HIV) and autoimmune diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis). We aimed to investigate the potential role of ABCs in Still’s disease and related clinical complications.

Methods: Single-cell RNA sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) of Still’s disease patients (n = 21) and healthy individuals (n = 5) were studied in silico to assess B cell composition and characterize ABCs. In parallel, 36-color spectral flow cytometry immunophenotyping was performed on a separate cohort of Still’s disease patients (n = 61) and healthy individuals (n = 27) to further evaluate B cell subset distribution, class-switching, activation status, and ABC phenotype.

Results: scRNA-seq analysis revealed an expansion of ABCs in Still’s disease patients compared to healthy controls (7.46 +/- 5.58% vs. 3.69 +/- 1.3%), that was more prominent in active vs inactive patients (8.19 +/- 6.09% vs. 5.13 +/- 2.72%). Notably, ABCs were more abundant in patients with Still’s disease-associated lung disease (Still’s-LD) than in those with active or inactive Still’s disease without pulmonary involvement (9.86 +/- 8.45% vs. 5.54 +/- 2.82%). Flow cytometry analysis revealed widespread B cell activation, confirmed the expansion of ABCs across the patient cohort (p = 0.0049), and identified a significant correlation between ABC frequency and the presence of lung disease (p = 0.0066).

Conclusion: These findings suggest that ABC expansion is associated with Still’s disease and correlates with both disease severity and the presence of lung complications. This previously unrecognized association implicates ABCs in the pathogenesis of Still’s-LD and indicates that their abundance may serve as a potential biomarker for disease progression and clinical status.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/expansion-of-t-bet%e2%81%ba-age-associated-b-cells-is-associated-with-clinical-complications-in-stills-disease/