Recurrent GAS tonsillitis or strep throat is a common pediatric disease. A history of recurrent tonsillitis (RT) prompts a referral for tonsillectomy. It is a long-standing mystery why only some children get strep throat. To answer this question, we developed a cohort of children who had undergone tonsillectomies for either RT due to GAS or non-RT reasons. We have accrued 216 tonsils to determine whether children with RT have an impaired tonsillar germinal center (GC) response to GAS, predisposing them to recurrent infection. Within the tonsillar germinal center are GC T follicular helper (Tfh) cells, specialized CD4+ T cells that provide help to GC B cells to instruct the development of affinity matured, somatically hypermutated memory B cells and antibodies. In our cohort, we observed that RT tonsils have significantly smaller germinal centers with significantly fewer GC Tfh and GC B cells. We identified `At Risk' HLA Class II alleles reminiscent of `At Risk' alleles for toxic shock syndrome and rheumatic heart disease, an adverse sequellae of untreated strep throat. Using our novel live CD4+ T cell assay to identify GAS-specific GC Tfh cells, we discerned that RT tonsils have a bias against GAS-specific GC Tfh cell formation. Intriguingly, as we have paired blood specimens, we observed significantly fewer circulating antibodies against a critical GAS virulence factor streptococcal pyrogenic exotoxin A (SpeA), with a lower titer clinically associated with a predisposition for invasive GAS disease. Finally, we have identified aberrant SpeA-induced granzyme B+ GC Tfh cells endowed with cytolytic activity, which we refer to as `killer Tfh' cells. These `killer Tfh' cells may explain the smaller germinal centers in RT tonsils. We hypothesize that children with RT have an immunosusceptibility to recurrent GAS infections. Herein, we will test specific hypotheses related to this predisposition, focusing on the host response to GAS by evaluating the role of `At Risk' HLA alleles we have identified and GAS's ability to quench an adaptive immune response by inducing `killer Tfh' cells. This K08 proposal, if funded, will support me in my goal to become an independent physician-scientist. During the training period, I will learn advance techniques in human immunology, acquire expertise in bioinformatics and statistical analyses, and apply these skills to translational research projects. La Jolla Institute for Allergy and Immunology (LJI) provides a collaborative environment for the proposed studies. My mentor Shane Crotty and co-mentor Victor Nizet are both world-renowned experts in their respective fields of germinal center and Tfh cell biology and GAS infections. This project will allow me to continue my development as a physician-scientist by applying advanced techniques in human immunology to addressing clinical problems.
Recurrent tonsillitis due to strep throat is a widespread pediatric problem for which a tonsillectomy is often performed. We have developed a pediatric tonsillar cohort to understand why only some children develop recurrent strep throat. We hypothesize that these children are predisposed to recurrent strep throat and thus have an impaired immune response to the bacteria.
| Dan, Jennifer M; Silva Enciso, Jorge; Lund, Lars H et al. (2018) Heart transplantation outcomes for rheumatic heart disease: Analysis of international registry data. Clin Transplant 32:e13439 |
