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Anti-Saccharomyces cerevisiae antibodies (ASCA) present in a subgroup of Crohn's disease (CD) patients indicate loss of tolerance against commensal antigens. ASCA can be induced in Candida albicans-infected rabbits, suggesting their potential crossreactive nature. The present study aimed to determine crossreactivities of ASCA with cell wall mannans from other yeasts, including the opportunistic pathogen C. albicans, and to define the requirements for (crossreactive) ASCA in experimental mice.ASCA were determined by enzyme-linked immunosorbent assay (ELISA). ASCA were neutralized by preincubating sera with purified mannans. Binding of ASCA was visualized by Western blot. Mice were immunized with live yeasts and experimental colitis was induced with dextran sodium sulfate (DSS).Seroreactivity of ASCA-positive CD patients against S. cerevisiae mannan significantly correlates with that against mannans from 5 other yeast species, including C. albicans. This correlation is due to crossreactive IgG, demonstrated by the loss of reactivity after preincubation of sera with mannans from the other yeasts. Immunization of mice with S. cerevisiae or C. albicans fails to induce (crossreactive) ASCA IgM or IgG antibodies. Subsequent chronic experimental colitis concomitant with feeding live yeasts promotes ASCA IgM but not IgG generation, while titers remain modest compared to those in ASCA-positive CD patients.Correlations of ASCA reactivities against mannans from different yeasts are due to crossreactive IgGs. The inability of mice to readily generate ASCA is in line with the current opinion that genetic predisposition is a prerequisite for the development of this and other unusual immune reactivities in CD.