Gastroenterology | Immunodominant B Cell Epitopes in the Flagellin Hinge Region of Lachnospiraceae Induce IgG Antibody Responses in Crohn’s Patients and Healthy Infants

This study, for the first time, identifies the immunodominant B cell epitopes targeting the flagellin hinge region of Lachnospiraceae in both Crohn’s disease (CD) patients and healthy infants, and links this antibody response to the progression of disease complications. The findings highlight the potential role of early intestinal immune homeostasis disruption in later disease pathogenesis.

Literature Overview
The article, titled 'Crohn’s patients and healthy infants share immunodominant B cell response to commensal flagellin peptide epitopes', published in the journal Gastroenterology, reviews and summarizes the IgG response characteristics against the flagellin hinge region of the commensal bacterial family Lachnospiraceae in Crohn’s disease (CD) patients and healthy infants, and their association with disease progression and immune homeostasis. The study systematically evaluated antibody response patterns across different populations using a novel flagellin peptide microarray and cytometric bead array technology.

Background Knowledge
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders driven by abnormal host immune responses to the intestinal microbiota, with Crohn’s disease (CD) and ulcerative colitis (UC) as the main subtypes. Previous studies have shown that approximately 50% of CD patients exhibit IgG responses to Lachnospiraceae flagellins, though the epitope specificity of this response has remained unclear. Lachnospiraceae is a highly abundant family of commensal bacteria in the gut, and their flagellins possess highly conserved D0 and D1 domains, with immunogenic properties localized in the hinge region. Earlier research has suggested a potential link between immune responses to this region and disease complications. This study aimed to fill this knowledge gap and assess the physiological relevance of early IgG responses in infants.

Research Methods and Experiments
The study enrolled multiple independent cohorts, including adult CD patients, newly diagnosed pediatric CD patients, and healthy infants along with their mothers from Uganda, Sweden, and the United States. A flagellin peptide microarray containing 1512 15-mer peptides covering 19 Lachnospiraceae flagellins, combined with a cytometric bead array, was used to assess serum IgG, IgA, and IgM responses to various flagellin-derived peptides. Immunodominant epitopes were identified through bioinformatics analysis and cross-validation, and their associations with disease phenotypes and progression were evaluated.

Key Conclusions and Perspectives

• The immunodominant B cell epitopes in CD patients are located in the hinge region (D0–1N p25–59) of Lachnospiraceae flagellin, a region that is highly conserved across species
• IgG antibody responses to this hinge epitope in pediatric CD patients are significantly associated with disease complications (e.g., strictures, penetrating lesions) within the next 5 years
• Healthy infants also exhibit IgG responses to the hinge region at age 1 year, but these responses decline rapidly thereafter, suggesting a transient homeostatic immune response
• The antibody response is broadly present in infants from Uganda, Sweden, and the U.S., but its magnitude and temporal kinetics are influenced by environmental factors
• In both adult and pediatric CD patients, hinge peptide-specific IgG strongly correlates with multi-flagellin reactivity and does not cross-react with flagellins from other bacterial families (e.g., Enterobacteriaceae)

Conclusion
Through multi-cohort analysis, this study identified strong IgG responses against the flagellin hinge region of Lachnospiraceae in both CD patients and healthy infants. This finding suggests that immune responses targeting this region may play a role in early intestinal homeostasis, and their persistence or dysregulation may be linked to later disease progression. The results provide a theoretical basis for early serological screening and personalized immunotherapy in CD, and underscore the importance of monitoring immune responses to gut microbiota starting in infancy.

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HDOCK uses a global search method based on Fast Fourier Transform (FFT) for sampling by a modified shape complementarity scoring method. During docking, one molecule (e.g. receptor) is fixed and the other molecule (e.g. ligand) is rotated uniformly in 3D Eulerian space. For each rotation of the ligand, the receptor and ligand are mapped onto a mesh and possible binding modes are exhaustively sampled in 3D translational space using the FFT method. The general case is rigid-body docking, although the flexibility problem can be handled indirectly by providing the residue information of the binding sites as constraints.