Evidence that recurrent Group A streptococcus tonsillitis is animmunosusceptibility disease involving antibody deficiency and aberrant Tfh cells

Dan, J. M.; Havenar-Daughton, C.; Kendric, K.; Kaushik, K.; Rosales, S.; Anderson, E.; LaRock, C.; Vijayanand, P.; Seumois, G.; Layfield, D.; Cutress, R.; Ottensmeier, C.; Lindestam Arlehamn, C.; Sette, A.; Nizet, V.; Bothwell, M.; Brigger, M.; Crotty, S.

doi:10.1101/356741

bioRxiv · 10.1101/356741

Evidence that recurrent Group A streptococcus tonsillitis is animmunosusceptibility disease involving antibody deficiency and aberrant Tfh cells

Dan, J. M.·Havenar-Daughton, C.·Kendric, K.·Kaushik, K.·Rosales, S.·Anderson, E.·LaRock, C.·Vijayanand, P.·Seumois, G.·Layfield, D.·Cutress, R.·Ottensmeier, C.·Lindestam Arlehamn, C.·Sette, A.·Nizet, V.·Bothwell, M.·Brigger, M.·Crotty, S.

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Abstract

One Sentence SummaryRecurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to Group A Streptococcus.\n\nABSTRACTRecurrent Group A Streptococcus (GAS) tonsillitis (RT) is a common indication for pediatric tonsillectomy. Strep throat is highly prevalent among children; yet, it is unknown why some children develop RT. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric GAS RT and non-RT tonsils. We observed significantly smaller germinal centers in GAS RT tonsils, and underrepresentation of GAS-specific germinal center follicular helper (GC Tfh) CD4+ T cells. RT children exhibited reduced antibody responses to GAS virulence factor SpeA. Risk and protective HLA Class II alleles for RT were identified. Finally, SpeA induced granzyme B+ GC Tfh cells in RT tonsils that had capacity to kill B cells. Together, these observations suggest that RT susceptibility can occur due to genetic differences that can result in aberrant GC Tfh cells and poor antibody responses to GAS SpeA.

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Dan, J. M., Havenar-Daughton, C., Kendric, K., Kaushik, K., Rosales, S., Anderson, E., LaRock, C., Vijayanand, P., Seumois, G., Layfield, D., Cutress, R., Ottensmeier, C., Lindestam Arlehamn, C., Sette, A., Nizet, V., Bothwell, M., Brigger, M., Crotty, S.. 2018-06-27. Evidence that recurrent Group A streptococcus tonsillitis is animmunosusceptibility disease involving antibody deficiency and aberrant Tfh cells. https://doi.org/10.1101/356741

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