Mapping adaptive immune responses toward fungal antigens in inflammatory bowel disease using T cell repertoire sequencing and phage-immunoprecipitation sequencing

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BACKGROUND AND AIMS: Immune reactivity to the gut mycobiome has been implicated in inflammatory bowel disease (IBD), particularly Crohn's disease (CD), but the systemic adaptive immune repertoire targeting the gut mycobiome remains incompletely defined. We aimed to map systemic T cell and antibody responses to fungal antigens in IBD. METHODS: We quantified expansion of fungal-specific T cell receptor β (TRB) clonotypes in the SPARC IBD cohort (CD, n = 1890; ulcerative colitis [UC], n = 914). In participants with paired data (n = 637), we analyzed the gut mycobiome by ITS2 sequencing and linked prevalent amplicon sequence variants (ASVs) to TRB clonotypes using a co-occurrence framework. For humoral immune profiling, we built a Saccharomyces cerevisiae-focused PhIP-Seq library and screened sera from CD (n = 100) and healthy controls (n = 60), including anti-S. cerevisiae antibody+ (ASCA+) and ASCA- individuals. RESULTS: Fungal-specific TRB clonotypes showed greater expansion in CD than UC, including increased responses toward S. cerevisiae and enrichment in more aggressive CD phenotypes. Co-occurrence analysis identified a limited number of TRB-mycobiota associations, consistent with the largely private nature of the gut mycobiome at the ASV level. Antibody reactivity to S. cerevisiae peptides was low relative to common viral and bacterial antigen classes, and no single S. cerevisiae peptide was associated with anti-S. cerevisiae antibody serostatus. CONCLUSIONS: CD is associated with expansion of fungal-specific T cell clonotypes, but S. cerevisiae peptide-based PhIP-Seq reveals limited shared IgG reactivity. Broader antigen libraries and complementary assays capturing glycosylated and virulence-associated fungal epitopes will be needed to comprehensively define antifungal humoral immunity in IBD.

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