Instructor Washington University School of Medicine, St. Louis Saint Louis, Missouri, United States
Introduction/Rationale: Growth failure and sarcopenia affect approximately 30–40% of patients with Crohn’s disease (CD), particularly in pediatric disease, yet the immune mechanisms driving systemic growth impairment beyond intestinal inflammation remain poorly defined. Our prior work in a bone marrow chimeric TNFΔARE model showed unexpected sarcopenic wasting in the absence of B cells and B-cell-derived lymphotoxin alpha (LTα), suggesting a protective role for B cells. Whether this phenotype persists in a germline B-cell-deficient TNF-driven ileitis model is unknown. We therefore examined the role of B cells in early-life growth failure using a germline TNF-driven model.
Methods: TNFΔ69Au mice were crossed with μMT mice to generate B-cell-deficient animals. Heterozygous TNFΔ69Au/+ mice have minimal ileitis, whereas homozygous TNFΔ69Au/Δ69Au mice develop severe disease. Body weight was tracked from weaning through 8–10 weeks. Ileal inflammation was assessed by ADAPT-3D confocal imaging, and peripheral blood leukocytes were analyzed by flow cytometry at week 12.
Results: μMT mice displayed normal growth comparable to wild-type controls. B-cell deficiency did not affect growth in TNFΔ69Au/+ mice. In contrast, μMT/TNFΔ69Au/Δ69Au mice developed profound post-weaning growth failure compared with B-cell-sufficient TNFΔ69Au/Δ69Au littermates, with significantly reduced weight gain by week 8 (p < 0.05). While both groups exhibited similar mucosal neutrophilic inflammation, B-cell-deficient mice showed increased myeloid accumulation within the ileal muscularis. Peripheral immunophenotyping revealed monocytosis with reduced CD4 and CD8 T cells, along with extensive CD115+ myeloid aggregates in the ileum and mesentery.
Conclusion: These data demonstrate that B-cell deficiency unmasks a severe growth-stunting phenotype in chronic TNF-driven ileitis, associated with aberrant myeloid infiltration. This model provides a platform to dissect immune mechanisms underlying growth failure in Crohn’s disease.
