DESCRIPTION (provided by applicant): Common variable immunodeficiency is a well described primary immunodeficiency characterized by low serum immunoglobulin concentrations, defective specific antibody production and increased susceptibility to bacterial infections. Only approximately 5-10% of cases are due to genetically identifiable defects in ICOS or TACI, leaving the majority of cases as a heterogeneous group of unknown etiology. Theoretically, the pathogenesis of CVID could involve defects in B cell maturation, T cell help, and/or antigen presentation. While several defects in T cell function have been described in CVID, the only specific co-stimulation defect known is deficiency of ICOS1, a T cell co-stimulatory molecule whose function is important for B cell immunoglobulin class switching1,2. Given that ICOS is important for the elaboration of T cell help, and that CVID is likely a polygenic disease, other defects of T cell co-stimulation probably exist, whether manifested by genetic defects in the co-stimulatory molecules themselves, or in the pathways that they promote. There are many co-stimulatory molecules, (members of the Immunoglobulin or TNFR superfamilies), that are temporally expressed after initial stimulation via CD3/CD28, which promote T cell memory responses and longevity, both important for the elaboration of T cell help. This project will explore the pathogenesis of Common Variable Immunodeficiency Disease from a T cell help perspective, specifically investigating defects of T cell co-stimulation. Several other findings in CVID also suggest a possible defect in T cell help including: the presence in some patients of a relatively expanded population of CD28-/CD8+ T cells ("exhausted" effector cells, also seen in chronic HIV infection), decreased serum IL7, a T cell survival factor, and low numbers of class switched memory B cells3-10. The central hypothesis of this project is: Defects in T cell co-stimulation result in faulty T cell help, and contribute to the pathogenesis of CVID. This will be explored using functional assays with an artificial antigen presenting cell (aAPC) system for analysis of effects on T cell proliferation and function including downstream effects of co-stimulation (Aim #1), genome wide SNP analysis from CVID samples and microarray gene expression analysis of T cells stimulated using the aAPC system (Aim #2),. Preliminary data from this project will be used to develop a research program exploring T cell co-stimulation defects in primary immunodeficiency diseases. PUBLIC HEALTH RELEVANCE: This study aims to discover contributing factors to the pathogenesis of CVID from a T cell help perspective. The T cell co-stimulatory molecules of the Tumor Necrosis Factor Superfamily (TNFSF) have been avidly studied in mouse models, yet characterization in humans is not yet completely understood. The population to be studied is a group of patients with common variable immunodeficiency (CVID) who presented in the first two decades of life, rather than the traditional population of CVID that presents later. Studying this population will lead to important discoveries regarding the pathogenesis of CVID in a younger age group and to the development of therapeutics targeting TNFSF members which holds promise for manipulating immune responses for the treatment of immunodeficiency diseases.
|Effective start/end date||9/29/09 → 8/31/12|
- National Institutes of Health: $72,765.00
- National Institutes of Health: $73,500.00
- Immunology and Microbiology(all)