SUMMARY
The MHC class locus has been associated with several diseases. Notably, genome-wide population studies
have identified pivotal polymorphisms within MHC class III (MHC-III) genes that are directly associated with
autoimmune diseases, including type 1 diabetes (T1D), intestinal bowel disease (IBD), systemic lupus
erythematosus (SLE) and rheumatoid arthritis (RA), among others. Although less understood, variations in
expression patterns of MHC-III genes correlate with disease severity, both dependent and independent from
predisposition-related polymorphisms within the MHC class I and II regions. This would suggest that MHC-III
genes can govern immunity vs. tolerance in autoimmune settings, with genetic variations potentially increasing
susceptibility to disease severity. However, much remains unknown regarding the underpinning mechanistic
functions of MHC-III genes in directing autoimmunity. This major gap prevents our understanding of the collective
and interconnective roles of these clustered genes in health and disease. Furthermore, this continues to limit
clinical success in immune-based therapies largely due to our incomplete knowledge of governing factors driving
myeloid cell biology. This is important as failures in the function of antigen presenting myeloid cells, such as
dendritic cells (DC) and macrophages, can cause organ-specific and systemic autoimmune diseases. Therefore,
it is the long-term objective of these studies to determine the underlying mechanistic role of MHC-III genes in
antigen presenting myeloid cells and their contribution to inflammatory diseases. To help resolve the existing
knowledge gap within the field, the proposed set of investigations will determine the functional role of MHC-III
genes in driving pro-inflammatory responses (Aim 1) and their role in priming autoreactive T cell responses (Aim
2). Extensive preliminary investigations have performed an unbiased high-throughput transcriptomic profiling
coupled with RNAi screening to identify key MHC-III genes believed to play key functional roles in macrophages
and DC. In Aim 1, studies will intricately evaluate the role of candidate MHC-III genes in macrophages in vitro
using a novel 3D organoid. The studies will additionally define the mechanisms of key MHC-III genes in initiating
and sustaining inflammation in vivo using both insulitis and colitis autoimmune mouse models. For Aim 2,
investigations will describe the pivotal role of MHC-III genes in governing the priming of T cells in vivo. Studies
will monitor changes in frequency, infiltration and effector responses of autoantigen-specific T cells in absence
of key MHC-III genes within DC subsets to rigorously define their immunoregulatory roles. Collectively,
understanding the determinants of MHC-III genes in regulating macrophage and DC biology under autoimmune
conditions would have broad implications for effective design of novel immunotherapies.
