PMID- 30728285
OWN - NLM
STAT- MEDLINE
DCOM- 20200221
LR  - 20240210
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 11
IP  - 478
DP  - 2019 Feb 6
TI  - Recurrent group A Streptococcus tonsillitis is an immunosusceptibility disease 
      involving antibody deficiency and aberrant T(FH) cells.
LID - 10.1126/scitranslmed.aau3776 [doi]
LID - eaau3776
AB  - "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-T(FH)) 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-T(FH) 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-T(FH) 
      cells, and lower SpeA antibody titers.
CI  - Copyright (c) 2019 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Dan, Jennifer M
AU  - Dan JM
AUID- ORCID: 0000-0002-1672-0657
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
AD  - Department of Medicine, Division of Infectious Diseases, University of 
      California, San Diego (UCSD), La Jolla, CA 92037, USA.
FAU - Havenar-Daughton, Colin
AU  - Havenar-Daughton C
AUID- ORCID: 0000-0002-2880-3927
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
AD  - Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery 
      (CHAVI-ID), La Jolla, CA 92037, USA.
FAU - Kendric, Kayla
AU  - Kendric K
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Al-Kolla, Rita
AU  - Al-Kolla R
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Kaushik, Kirti
AU  - Kaushik K
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Rosales, Sandy L
AU  - Rosales SL
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Anderson, Ericka L
AU  - Anderson EL
AD  - Department of Pediatrics, School of Medicine, UCSD, La Jolla, CA 92037, USA.
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA 92037, 
      USA.
AD  - Human Longevity Inc., San Diego, CA 92121, USA.
FAU - LaRock, Christopher N
AU  - LaRock CN
AUID- ORCID: 0000-0003-3035-5331
AD  - Department of Pediatrics, School of Medicine, UCSD, La Jolla, CA 92037, USA.
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA 92037, 
      USA.
AD  - Department of Microbiology and Immunology, Emory School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Vijayanand, Pandurangan
AU  - Vijayanand P
AUID- ORCID: 0000-0001-7067-9723
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Seumois, Gregory
AU  - Seumois G
AUID- ORCID: 0000-0002-8164-6852
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Layfield, David
AU  - Layfield D
AD  - Cancer Sciences Division, Faculty of Medicine, University of Southampton, UK.
FAU - Cutress, Ramsey I
AU  - Cutress RI
AD  - Cancer Sciences Division, Faculty of Medicine, University of Southampton, UK.
FAU - Ottensmeier, Christian H
AU  - Ottensmeier CH
AUID- ORCID: 0000-0003-3619-1657
AD  - Cancer Sciences Division, Faculty of Medicine, University of Southampton, UK.
FAU - Lindestam Arlehamn, Cecilia S
AU  - Lindestam Arlehamn CS
AUID- ORCID: 0000-0001-7302-8002
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
FAU - Sette, Alessandro
AU  - Sette A
AUID- ORCID: 0000-0001-7013-2250
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA.
AD  - Department of Medicine, Division of Infectious Diseases, University of 
      California, San Diego (UCSD), La Jolla, CA 92037, USA.
FAU - Nizet, Victor
AU  - Nizet V
AUID- ORCID: 0000-0003-3847-0422
AD  - Department of Pediatrics, School of Medicine, UCSD, La Jolla, CA 92037, USA.
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, La Jolla, CA 92037, 
      USA.
FAU - Bothwell, Marcella
AU  - Bothwell M
AUID- ORCID: 0000-0001-9771-6221
AD  - Division of Pediatric Otolaryngology, Rady Children's Hospital, San Diego, CA 
      92123, USA.
AD  - Department of Surgery, UCSD, La Jolla, CA 92037, USA.
AD  - Department of Otolaryngology, Head and Neck Surgery, Naval Medical Center San 
      Diego, San Diego, CA 92134, USA.
FAU - Brigger, Matthew
AU  - Brigger M
AUID- ORCID: 0000-0002-3528-1696
AD  - Division of Pediatric Otolaryngology, Rady Children's Hospital, San Diego, CA 
      92123, USA.
AD  - Department of Surgery, UCSD, La Jolla, CA 92037, USA.
AD  - Department of Otolaryngology, Head and Neck Surgery, Naval Medical Center San 
      Diego, San Diego, CA 92134, USA.
FAU - Crotty, Shane
AU  - Crotty S
AUID- ORCID: 0000-0002-6484-6262
AD  - Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, 
      CA 92037, USA. shane@lji.org.
AD  - Department of Medicine, Division of Infectious Diseases, University of 
      California, San Diego (UCSD), La Jolla, CA 92037, USA.
AD  - Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery 
      (CHAVI-ID), La Jolla, CA 92037, USA.
LA  - eng
GR  - S10 OD016262/OD/NIH HHS/United States
GR  - UM1 AI100663/AI/NIAID NIH HHS/United States
GR  - T32 AI007036/AI/NIAID NIH HHS/United States
GR  - S10 RR027366/RR/NCRR NIH HHS/United States
GR  - 15951/CRUK_/Cancer Research UK/United Kingdom
GR  - R01 AI077780/AI/NIAID NIH HHS/United States
GR  - MR/P024351/1/MRC_/Medical Research Council/United Kingdom
GR  - T32 AI007384/AI/NIAID NIH HHS/United States
GR  - R01 AI135193/AI/NIAID NIH HHS/United States
GR  - L40 AI126497/AI/NIAID NIH HHS/United States
GR  - K08 AI135078/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antibodies, Bacterial)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Superantigens)
RN  - EC 3.4.21.- (Granzymes)
SB  - IM
CIN - Trends Immunol. 2019 May;40(5):377-379. PMID: 30956068
MH  - Adolescent
MH  - Alleles
MH  - Antibodies, Bacterial/*immunology
MH  - B-Lymphocytes/immunology
MH  - Cell Differentiation
MH  - Child
MH  - Disease Susceptibility
MH  - Female
MH  - Germinal Center/immunology
MH  - Granzymes/metabolism
MH  - Histocompatibility Antigens Class II/metabolism
MH  - Humans
MH  - Immunoglobulin G/metabolism
MH  - Male
MH  - Recurrence
MH  - Streptococcus/*physiology
MH  - Superantigens/metabolism
MH  - T-Lymphocytes, Helper-Inducer/immunology
MH  - Tonsillitis/*immunology/*microbiology
PMC - PMC6561727
MID - NIHMS1016595
COIS- Competing interests: The authors declare that they have no competing financial 
      interests. S.C. and J.M.D. have an International Patent Application no. 
      PCT/US18/30948, Diagnosis and treatment of infection involving killer T 
      follicular helper cells, methods of preparation, and uses thereof.
EDAT- 2019/02/08 06:00
MHDA- 2020/02/23 06:00
PMCR- 2019/06/12
CRDT- 2019/02/08 06:00
PHST- 2018/06/04 00:00 [received]
PHST- 2018/09/29 00:00 [revised]
PHST- 2019/01/11 00:00 [accepted]
PHST- 2019/02/08 06:00 [entrez]
PHST- 2019/02/08 06:00 [pubmed]
PHST- 2020/02/23 06:00 [medline]
PHST- 2019/06/12 00:00 [pmc-release]
AID - 11/478/eaau3776 [pii]
AID - 10.1126/scitranslmed.aau3776 [doi]
PST - ppublish
SO  - Sci Transl Med. 2019 Feb 6;11(478):eaau3776. doi: 10.1126/scitranslmed.aau3776.