Modeling development of tertiary lymphoid structures in pulmonary tuberculosis by 3D profiling and trajectory...

Area of Science:

• Immunology
• Pathology
• Computational Biology

Background:

• Tertiary lymphoid structures (TLSs) are crucial for immune responses in chronic inflammation, infection, and cancer.
• Understanding TLS formation mechanisms is vital but remains incomplete.
• Current 2D methods struggle to accurately assess TLS development and organization.

Purpose of the Study:

• To investigate the 3D architecture and developmental trajectories of TLSs in human lungs during Mycobacterium tuberculosis infection.
• To compare the limitations of 2D histopathology with advanced 3D modeling techniques for TLS analysis.
• To elucidate the spatiotemporal dynamics of immune cell organization within TLSs.

Main Methods:

• High-plex imaging and serial-section 3D reconstruction of human lung tissues.
• Optimal transport trajectory modeling to analyze cellular organization and development.
• Comparative analysis of 2D versus 3D assessment of TLS morphology and developmental stage.

Main Results:

• The irregular 3D shape of TLSs is inadequately represented by 2D histopathology and spatial profiling.
• 2D methods lead to errors in assessing TLS developmental stages (early, primary, secondary).
• 3D optimal transport modeling identified two distinct developmental trajectories for TLSs, differing in immune cell coordination and tissue positioning.

Conclusions:

• Volumetric analysis is essential for accurately understanding immune organization within TLSs.
• New insights into TLS biology and development during tuberculosis infection have been uncovered.
• Advanced 3D modeling provides a more robust framework for studying TLS formation and function.