In a major advance for autoimmune research, an international team has mapped the three-dimensional genomic architecture of rare immune cells to reveal unexpected genetic drivers of Crohn’s disease. The team was led by scientists at Cincinnati Children’s Hospital in Cincinnati, Ohio, United States, the VIB-UAntwerp Center for Molecular Neurology in Edegem, Belgium, and the MRC Laboratory of Medical Sciences in London, England, United Kingdom.

has mapped the three-dimensional genomic architecture of rare immune cells to reveal unexpected genetic drivers of Crohn’s disease. The team was led by scientists at Cincinnati Children’s Hospital in Cincinnati, Ohio, United States, the VIB-UAntwerp Center for Molecular Neurology in Edegem, Belgium, and the MRC Laboratory of Medical Sciences in London, England, United Kingdom.

Published in Nature Genetics on August 4, 2026, the study overcomes a long-standing technological bottleneck in studying sparse cell populations to explain how non-coding genetic variants influence autoimmune risk.

The research focuses on type 3 innate lymphoid cells (ILC3s), a specialized population of tissue-resident immune cells concentrated in barrier tissues such as the gut. Although ILC3s play a vital role in maintaining mucosal integrity and regulating inflammation, their extreme scarcity in human tissue has historically prevented researchers from mapping their regulatory DNA. Most genome-wide association studies identify disease-linked variants in “non-coding” regions far from active genes, making it difficult to pinpoint which genes are actually being regulated without spatial genomic data.

To bridge this gap, the team utilized a miniaturized Promoter Capture Hi-C approach. This specialized 3D genome mapping technique allows researchers to examine physical, long-range contacts between distant regulatory elements and gene promoters using a fraction of the cell input required by traditional methods.

By constructing high-resolution 3D promoter interaction maps for human ILC3s, the researchers connected known Crohn’s disease risk variants to more than 100 candidate target genes. While roughly half of these targets were established immune factors, the analysis revealed dozens of novel candidates previously unlinked to inflammatory bowel disease.

The most striking finding was the unexpected implication of CLN3, a gene primary known for causing Batten disease—a severe neurodegenerative disorder. Follow-up experiments demonstrated that Cln3 expression decreases when ILC3 cells are activated, whereas artificially increasing Cln3 levels suppressed inflammatory gene activity and reduced cytokine secretion. These results suggest that CLN3 acts as a direct regulator of immune responses in the gut, highlighting a novel cross-system link between neurodevelopmental pathways and mucosal inflammation.

Beyond Crohn’s disease, the authors extended their regulatory catalog to prioritize risk genes across five additional autoimmune conditions. By demonstrating how 3D genome architecture connects distant genetic variants to functional target genes in rare cell types, the study provides a powerful new biological roadmap for identifying therapeutic targets in complex immune disorders.