CD4+ T Cell Antigen Discovery in Sarcoidosis
Sarcoidosis is an inflammatory granulomatous disease that primarily affects the lung. It has a worldwide distribution and affects individuals of all ages, races and both sexes. Despite the prevalence of the disease and continued investigation, the cause of sarcoidosis remains unknown. Evidence suggests that CD4+ T cells in the bronchoalveolar lavage (BAL) of sarcoidosis patients are instrumental in disease progression. Löfgren’s syndrome (LS) is an acute form of sarcoidosis that is accompanied by a specific set of inflammatory symptoms. In patients with LS, disease susceptibility has been associated with expression of HLA-DR3 and an expansion of BAL CD4+ T cells expressing T cell receptor (TCR) a-chain variable region (TRAV) 12-1. We hypothesize that in HLA-DR3+ LS patients, TRAV12-1 CD4+ T cell clones accumulate and expand in the lung in response to unknown antigens. To address the antigen specificity of these expanded CD4+ T cells, we performed single cell PCR of BAL CD4+ T cells derived from DR3+ LS patients to identify related abTCRs expressing TRAV12-1 and generated T cell hybridomas expressing these disease-relevant abTCRs. Using unbiased decapeptide positional scanning libraries, we have identified several stimulatory mimotopes. We used a biometrical analysis to obtain candidate etiologic peptides derived from human, viral, pollen, and mycobacterial protein databases and have identified several exogenous peptides that stimulate TCRs derived from the BAL of patients with active LS. Once etiologic antigens are validated, we will synthesize HLA-DR3-peptide tetramers to allow for more sophisticated approaches in the diagnosis and prognosis of this disease.
Conference Proceeding Title
Journal of Immunology, Volume 202, Supplement 1
Greaves, Sarah A.; Mitchell, Angela; Falta, Michael; Santos, Radleigh; Pinilla, Clemencia; and Fontenot, Andrew P., "CD4+ T Cell Antigen Discovery in Sarcoidosis" (2019). Mathematics Faculty Proceedings, Presentations, Speeches, Lectures. 408.