iHALT unlocks liver functionality as a surrogate secondary lymphoid organ

Area of Science:

• Immunology
• Virology
• Hepatology

Background:

• The established model of humoral immunity involves germinal center reactions in secondary lymphoid organs (SLOs) to generate plasma cells.
• The role of viral tissue tropism in shaping immune response dynamics remains unclear.

Purpose of the Study:

• To investigate how viral tropism influences the generation and localization of virus-specific plasma cells.
• To explore the mechanisms of immune responses against hepatotropic viruses.

Main Methods:

• Comparative analysis of immune responses to systemic viruses versus hepatotropic hepaciviruses in mice.
• Characterization of inducible hepatic-associated lymphoid tissue (iHALT) structures.
• Investigation of cellular composition, cell-cell interactions, and microarchitecture within iHALT.
• Analysis of signaling pathways (e.g., CD40L) and receptor specificities involved in plasma cell maintenance.

Main Results:

• Hepatotropic hepaciviral infection induces local plasma cell generation in the liver, independent of SLOs.
• Inducible hepatic-associated lymphoid tissue (iHALT) structures, containing T follicular helper cells, myeloid cells, and B cells, support local germinal center-like reactions.
• These iHALT structures in mice closely resemble those observed in humans during hepaciviral infection.
• Locally generated plasma cells are anchored to periportal fibroblast tracts via specific molecular interactions, ensuring their maintenance within the liver.

Conclusions:

• Humoral immunity can be generated and maintained exclusively within an extralymphoid site of viral infection, such as the liver.
• Inducible hepatic-associated lymphoid tissue (iHALT) compensates for SLO evasion strategies by hepatotropic viruses.
• This localized immune response is critical for preventing persistent infection by strictly hepatotropic viruses.