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Principal Investigator: Joyce Blossom Kang
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2024
Award: $51,226
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary:
Autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are debilitating
and highly prevalent chronic conditions that result from pathogenic inflammatory responses. The major
histocompatibility (MHC) region on chromosome 6, which contains the human leukocyte antigen (HLA) and
other immune-related genes, has the strongest genetic association with autoimmune diseases, but the exact
molecular mechanisms behind MHC disease risk are yet unsolved. Previous research has primarily explored
how coding variants affect HLA protein structure and antigen binding, but recent studies highlight the potential
role of noncoding variants in regulating HLA expression. Increased HLA expression could play a causal role in
disease through higher levels of antigen presentation to autoreactive T cells. There is a critical need to better
understand how a cell’s biological state impacts genetic control of HLA expression.
The proposed research will test the hypothesis that genetic variation in the MHC region modulates HLA
expression in a cell-state-dependent and disease-relevant manner. The applicant will develop innovative
computational methods to integrate both genetic and single-cell transcriptomic data sampled from inflamed
tissues and controls across multiple human immune-mediated disease contexts, comprising >1,088,000 cells
from 384 individuals. Specifically, the study aims to (1) quantify the effect of genetic variation on HLA
expression in key immune and stromal cell states (T, B, fibroblast, and myeloid cells), (2) identify expression
programs and transcriptional regulators that modulate the effect of HLA regulatory variants, and (3) link HLA
regulatory variation to autoimmune disease risk loci. This work will generate a resource detailing HLA
expression across diverse cell states and identify the specific contexts in which genetic variants regulate HLA
expression. This will deepen our fundamental understanding of mechanisms underlying autoimmune disease
risk and may pave the way for better informed therapeutic strategies.
The proposed training plan will enable the applicant to: (A) strengthen an understanding of the genetic
and immune basis of human diseases, (B) cultivate strong skills in computational genomics methods
development, (C) develop data science skills in statistical genetics and computational immunology, (D)
improve understanding of the clinical aspects of autoimmune diseases, and (E) develop professional scientific
communication skills. An enriching and supportive training environment and close mentorship by experts in
complex trait genetics, immunology, and single-cell methods development will equip the applicant with
knowledge and skills to become an effective physician-scientist who can contribute to the field of disease-
focused computational immunogenomics.
Terms: <Acceleration><Affect><Alleles><Allelomorphs><Antigen Presentation><Atrophic Arthritis><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Binding Sites><Biological><Body Tissues><Cell Body><Cells><Chromosome 6><Chronic><Class I Antigens><Class I Major Histocompatibility Antigens><Class II Antigens><Class II Genes><Class II Major Histocompatibility Antigens><Clinical><Code><Coding System><Combining Site><Communication><Complex Class 1><Complex Genetic Trait><Computing Methodologies><Data><Data Science><Data Set><Dendritic Cells><Disease><Disorder><Environment><Fibroblasts><Functional RNA><Funding><Gene Expression><Gene Transcription><Gene variant><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Diversity><Genetic Transcription><Genetic Variation><Genome><Genomics><Genotype><Grain><HL-A Antigens><HLA Antigens><HLA Class II Genes><Histocompatibility><Histocompatibility Antigens Class I><Histocompatibility Antigens Class II><Human><Human Genetics><Human Leukocyte Antigens><I-A Antigen><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Ia Antigens><Ia-Like Antigens><Immune><Immune Interferon><Immune Response Antigens><Immune system><Immune-Response-Associated Antigens><Immunes><Immunogenomics><Immunology><Individual><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Response><Interferon Gamma><Interferon Type II><Knowledge><Label><Lead><Leukocyte Antigens><Link><Lupus Erythematosus Disseminatus><MHC Class I Molecule><MHC Class I Protein><MHC Class II><MHC Class II Genes><MHC Class II Molecule><MHC Class II Protein><MHC class I antigen><MHC class II antigen><Macrophage><Major Histocompatibility Complex Class 1><Major Histocompatibility Complex Class II><Maps><Mediating><Medicine><Mentorship><Methods><Modeling><Modern Man><Molecular><Myelogenous><Myeloid><Myeloid Cells><Mφ><NIAID><National Institute of Allergy and Infectious Disease><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Pathogenicity><Patients><Pb element><Peptides><Personalized medical approach><Physicians><Play><Population><Probabilistic Models><Probability Models><Process><Publishing><QTL><Quantitative Trait Loci><RNA Expression><Reactive Site><Regulation><Research><Research Resources><Resolution><Resources><Rheumatoid Arthritis><Risk><Risk-associated variant><Role><SLE><Sampling><Scientist><Single Base Polymorphism><Single Nucleotide Polymorphism><Statistical Models><Stromal Cells><Surface><Synovitis><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><T-Cell Activation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><Testing><Therapeutic><Tissue Compatibility><Tissues><Training><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Untranslated RNA><Variant><Variation><Veiled Cells><Work><activate T cells><allele variant><allelic variant><antigen binding><antigen bound><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive T cell><biologic><cell type><cohort><compare to control><comparison control><computational methodology><computational methods><computer based method><computer methods><computing method><disease risk><disorder risk><disseminated lupus erythematosus><driving><genetic association><genetic variant><genomic data><genomic data-set><genomic dataset><genomic variant><heavy metal Pb><heavy metal lead><high dimensionality><human disease><human model><human tissue><improved><individualized approach><inflamed synovial tissue><inflamed synovium><inflammatory disease of the intestine><inflammatory disorder of the intestine><innovate><innovation><innovative><intestinal autoinflammation><lFN-Gamma><method development><model of human><multimodal modeling><multiple data sets><multiple datasets><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><noncoding><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><personalized approach><precision approach><programs><protein structure><protein structures><proteins structure><reference assembly><reference genome><resolutions><response><rheumatic arthritis><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><self-reactive T cell><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleotide variant><single-cell RNA sequencing><skills><social role><statistical linear mixed models><statistical linear models><synovial inflammation><systemic lupus erythematosis><tailored approach><thymus derived lymphocyte><transcription co-activator><transcription factor><transcriptional co-activator><transcriptomics><translational immunology>