Author ORCID Identifier

Defense Date


Document Type


Degree Name

Master of Science


Microbiology & Immunology

First Advisor

Masoud H Manjili


Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of taking reductionist approaches and missing the collective function of the hepatic immune system by focusing on specific immune cell types. To this end, we propose that focusing on the dominant-subdominant patterns of the immune cells would allow understanding of the mechanism by which a collective immune function emerges. To identify the collective immune function through a systems immunology perspective, we performed high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. Assessment of the immune and non-immune cell patterns throughout disease progression, along with the expression of molecules involved in intercellular signaling provides insight to pattern-specific functions of the hepatic immune system. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Changes in the position of immune cell types from subdominant to dominant resulted in changes in their function by producing new ligands or targeting different cells by the same ligands, in which innate immune cells play a major role in promoting fibrosis and the development of HCC. These data suggest that discovery of the immune pattern not only explains dynamic changes in immune cells during the course of disease, but also offers immune modulatory interventions for the treatment of NAFLD and HCC.


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