Abstract: Common variable immunodeficiency (CVID) is the most frequent clinically relevant primary immunodeficiency in humans. CVID is a mixed group of heterogeneous conditions linked by lack of immunoglobulin production against pathogens. CVID in human patients has challenged the field of clinical immunology in regards to etiology and, consequently, therapeutic intervention;only a minor percentage of the affected patients are known to have genetic mutations that result in dysfunctional adaptive humoral responses. In addition to its heterogeneous nature, a striking aspect of this disorder relates to its manifestation later in life, confounding the study of putative genetic disorders. The goal of this proposal is to introduce and investigate the mechanism of disease in a natural equine model of CVID, for direct application in diagnostics and management of human patients with primary humoral immunodeficiencies. My hypothesis is that B cell differentiation is impaired at pro-B cell stage in equine patients with B cell lymphopenia due to essential gene silencing. Deregulation of mechanisms that control chromatin modification lead to inappropriate expression or silencing of genes involved in cell differentiation and development that could be involved in progressive B cell depletion in equine patients with CVID. My research proposal is uniquely suited to the New Innovator Award program because it offers a natural horse model of disease, and and non- conventional approach and therory for the etiology of primary immunodeficiencies in humans. Although there is accumulating evidence of epigenetic mechanisms involved in many diseases, tradition and well-defined other genetic primary immunodeficiency disorders may have overshadowed this possibility in the study of CVID in human patients to date. Public Health Relevance: Common variable immunodeficiency (CVID) in horses is a primary humoral immunodeficiency characterized by late-onset recurrent bacterial infections, hypo- or agammaglobulinemia, and B cell lymphopenia or depletion. We propose the CVID horse as a model of study for CVID in humans because they share numerous similarities in clinical disease and patient care. Horses with CVID offer a rare opportunity to study abnormal B cell differentiation and development in a natural setting, with direct applications to the understanding of mechanisms of disease and diagnostics in human patients.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD007216-01
Application #
7981894
Study Section
Special Emphasis Panel (ZGM1-NDIA-O (01))
Program Officer
Basavappa, Ravi
Project Start
2010-09-30
Project End
2015-06-30
Budget Start
2010-09-30
Budget End
2015-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$2,310,000
Indirect Cost
Name
Cornell University
Department
Other Clinical Sciences
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Prieto, J M B; Tallmadge, R L; Felippe, M J B (2017) Developmental expression of B cell molecules in equine lymphoid tissues. Vet Immunol Immunopathol 183:60-71
Schwab, Ute E; Tallmadge, Rebecca L; Matychak, Mary Beth et al. (2017) Effects of autologous stromal cells and cytokines on differentiation of equine bone marrow-derived progenitor cells. Am J Vet Res 78:1215-1228
Tallmadge, Rebecca L; Shen, Lishuang; Tseng, Chia T et al. (2015) Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation. Clin Immunol 160:261-76
Tallmadge, Rebecca L; Tseng, Chia T; Felippe, M Julia B (2014) Diversity of immunoglobulin lambda light chain gene usage over developmental stages in the horse. Dev Comp Immunol 46:171-9
Battista, J M; Tallmadge, R L; Stokol, T et al. (2014) Hematopoiesis in the equine fetal liver suggests immune preparedness. Immunogenetics 66:635-49
Tallmadge, Rebecca L; Tseng, Chia T; King, Rebecca A et al. (2013) Developmental progression of equine immunoglobulin heavy chain variable region diversity. Dev Comp Immunol 41:33-43
Tallmadge, R L; Such, K A; Miller, K C et al. (2012) Expression of essential B cell development genes in horses with common variable immunodeficiency. Mol Immunol 51:169-76