Examination of HLA-DRB1*15-linked Candidate Antigens in Still Disease With and Without Lung Disease and Drug-Associated Immune Reactions.

Abstract

Lung disease (LD) in systemic juvenile idiopathic arthritis and adult-onset Still disease (Still-LD) is a severe manifestation strongly associated with HLA-DRB1*15 alleles and drug-associated immune reactions (DAIR), including eosinophilia, non-Still disease rashes, and elevated liver function tests. Despite the high morbidity and mortality of these phenomena, pathogenesis remains poorly understood. This study investigates whether Still-LD and DAIR are associated with pathogenic antigens through hypersensitivity reactions to <i>Aspergillus fumigatus</i>, for which HLA-DRB1*15 is a known risk allele, or drug reaction with eosinophilia and systemic symptoms (DRESS), which is frequently associated with human herpesvirus (HHV) reactivation. Pediatric and adult subjects were drawn from the National Institutes of Health Still disease cohort. Subjects with Still-LD and/or DAIR were identified by chart review. Serum samples were analyzed for anti-<i>A. fumigatus</i> IgE using ImmunoCap assay, and Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HHV 6 (HHV-6) antibodies were analyzed by luciferase immunoprecipitation systems. Subjects were screened for EBV, CMV, and HHV-6 by nucleic acid amplification tests and/or Viral Transcript Usage Sensor (VIRTUS) analysis of whole-blood RNA sequencing data. Fifty-four subjects were included in the study, 11 had LD and DAIR, and 8 had DAIR alone. Thirty-three subjects were tested for anti-<i>A. fumigatus</i> antibodies and all were negative. Forty-nine subjects were tested for CMV, EBV, and HHV-6; 2 were positive for EBV, both of whom did not have Still-LD or DAIR. The absence of anti-<i>A. fumigatus</i> IgE antibodies and detectable herpesvirus nucleic acids in subjects with Still-LD and DAIR does not support a mechanistic association with hypersensitivity to <i>A. fumigatus</i> or with HHV reactivation.