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Sci Transl Med. 2019 Feb 6;11(478). pii: eaau3776. doi: 10.1126/scitranslmed.aau3776.

Recurrent group A Streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant TFH cells.

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Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.
Department of Medicine, Division of Infectious Diseases, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.
Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA 92037, USA.
Department of Pediatrics, School of Medicine, UCSD, La Jolla, CA 92037, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA 92037, USA.
Human Longevity Inc., San Diego, CA 92121, USA.
Department of Microbiology and Immunology, Emory School of Medicine, Atlanta, GA 30322, USA.
Cancer Sciences Division, Faculty of Medicine, University of Southampton, UK.
Division of Pediatric Otolaryngology, Rady Children's Hospital, San Diego, CA 92123, USA.
Department of Surgery, UCSD, La Jolla, CA 92037, USA.
Department of Otolaryngology, Head and Neck Surgery, Naval Medical Center San Diego, San Diego, CA 92134, USA.
Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA.


"Strep throat" is highly prevalent among children, yet it is unknown why only some children develop recurrent tonsillitis (RT), a common indication for tonsillectomy. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric group A Streptococcus (GAS) RT and non-RT tonsils from two independent cohorts. GAS RT tonsils had smaller germinal centers, with an underrepresentation of GAS-specific CD4+ germinal center T follicular helper (GC-TFH) cells. RT children exhibited reduced antibody responses to an important GAS virulence factor, streptococcal pyrogenic exotoxin A (SpeA). Risk and protective human leukocyte antigen (HLA) class II alleles for RT were identified. Lastly, SpeA induced granzyme B production in GC-TFH cells from RT tonsils with the capacity to kill B cells and the potential to hobble the germinal center response. These observations suggest that RT is a multifactorial disease and that contributors to RT susceptibility include HLA class II differences, aberrant SpeA-activated GC-TFH cells, and lower SpeA antibody titers.

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