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

One Sentence Summary Recurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to Group A Streptococcus. ABSTRACT Recurrent 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.

[1]  Jun Huang,et al.  The receptor repertoire and functional profile of follicular T cells in HIV-infected lymph nodes , 2018, Science Immunology.

[2]  Susan M. Corley,et al.  STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles , 2018, Scientific Reports.

[3]  A. Schilder,et al.  Addressing the Challenges in Tonsillectomy Research to Inform Health Care Policy: A Review , 2017, JAMA otolaryngology-- head & neck surgery.

[4]  S. Haeryfar,et al.  Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells , 2017, Proceedings of the National Academy of Sciences.

[5]  R. Ahmed,et al.  Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection , 2017, Proceedings of the National Academy of Sciences.

[6]  Michael Y. Gerner,et al.  Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies , 2017, Science Translational Medicine.

[7]  S. Mallal,et al.  Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity , 2016, Journal of Virology.

[8]  S. Tangye,et al.  Immunology: Cytotoxic T cells that escape exhaustion , 2016, Nature.

[9]  Di Wu,et al.  CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles , 2016, Nature Immunology.

[10]  Matheus C. Bürger,et al.  Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy , 2016, Nature.

[11]  Alessandro Sette,et al.  A Cytokine-Independent Approach To Identify Antigen-Specific Human Germinal Center T Follicular Helper Cells and Rare Antigen-Specific CD4+ T Cells in Blood , 2016, The Journal of Immunology.

[12]  S. Crotty,et al.  Activin A programs the differentiation of human TFH cells , 2016, Nature Immunology.

[13]  R. D. Di Francesco,et al.  Asymptomatic Group A Streptococcus carriage in children with recurrent tonsillitis and tonsillar hypertrophy. , 2016, International journal of pediatric otorhinolaryngology.

[14]  Bali Pulendran,et al.  Cytokine-Independent Detection of Antigen-Specific Germinal Center T Follicular Helper Cells in Immunized Nonhuman Primates Using a Live Cell Activation-Induced Marker Technique , 2016, The Journal of Immunology.

[15]  I. Maclennan,et al.  Follicular Helper T Cells. , 2016, Annual review of immunology.

[16]  M. Pichichero,et al.  A Reappraisal of the Minimum Duration of Antibiotic Treatment Before Approval of Return to School for Children With Streptococcal Pharyngitis , 2015, The Pediatric infectious disease journal.

[17]  V. Nizet,et al.  Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing. , 2015, Cell host & microbe.

[18]  Weiqun Peng,et al.  LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6 , 2015, Nature Immunology.

[19]  Ravi V. Kolla,et al.  Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity , 2015, Proceedings of the National Academy of Sciences.

[20]  L. Picker,et al.  A B cell follicle sanctuary permits persistent productive SIV infection in elite controllers , 2014, Nature Medicine.

[21]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[22]  S. Crotty.  T follicular helper cell differentiation, function, and roles in disease. , 2014, Immunity.

[23]  Paul Theodor Pyl,et al.  HTSeq—a Python framework to work with high-throughput sequencing data , 2014, bioRxiv.

[24]  Daan Van Brusselen,et al.  Streptococcal pharyngitis in children: to treat or not to treat? , 2014, European Journal of Pediatrics.

[25]  Bjoern Peters,et al.  Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility , 2014, Nature Immunology.

[26]  S. Haeryfar,et al.  Bacterial Superantigens Promote Acute Nasopharyngeal Infection by Streptococcus pyogenes in a Human MHC Class II-Dependent Manner , 2014, PLoS pathogens.

[27]  Timothy C. Barnett,et al.  Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus , 2014, Clinical Microbiology Reviews.

[28]  Åsa K. Björklund,et al.  Full-length RNA-seq from single cells using Smart-seq2 , 2014, Nature Protocols.

[29]  Bjoern Peters,et al.  A strategy to determine HLA class II restriction broadly covering the DR, DP, and DQ allelic variants most commonly expressed in the general population , 2013, Immunogenetics.

[30]  A. Bisno,et al.  Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  Ravi V. Kolla,et al.  T Cell Responses to Known Allergen Proteins Are Differently Polarized and Account for a Variable Fraction of Total Response to Allergen Extracts , 2012, The Journal of Immunology.

[32]  J. Wilson,et al.  Streptococcus pyogenes infection of tonsil explants is associated with a human β-defensin 1 response from control but not recurrent acute tonsillitis patients. , 2012, Molecular oral microbiology.

[33]  É. Marijon,et al.  Rheumatic heart disease , 2012, The Lancet.

[34]  M. Bonneville,et al.  Ex vivo measurement of the cytotoxic capacity of human primary antigen-specific CD8 T cells. , 2012, Journal of immunological methods.

[35]  T. R. Peters,et al.  Detection of group A Streptococcus in tonsils from pediatric patients reveals high rate of asymptomatic streptococcal carriage , 2012, BMC Pediatrics.

[36]  J. Musser,et al.  Group A Streptococcus emm Gene Types in Pharyngeal Isolates, Ontario, Canada, 2002–2010 , 2011, Emerging infectious diseases.

[37]  S. Crotty,et al.  Follicular helper CD4 T cells (TFH). , 2011, Annual review of immunology.

[38]  Robert A. Edwards,et al.  Quality control and preprocessing of metagenomic datasets , 2011, Bioinform..

[39]  P. Wilkins,et al.  Public Health Implications of Cysticercosis Acquired in the United States , 2011, Emerging infectious diseases.

[40]  R. Rosenfeld,et al.  Clinical Practice Guideline: Tonsillectomy in Children , 2010, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[41]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[42]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[43]  J. Carlin,et al.  Normal Ranges of Streptococcal Antibody Titers Are Similar Whether Streptococci Are Endemic to the Setting or Not , 2008, Clinical and Vaccine Immunology.

[44]  Ramy K. Aziz,et al.  Rise and Persistence of Global M1T1 Clone of Streptococcus pyogenes , 2008, Emerging infectious diseases.

[45]  M. Singh,et al.  Evaluating the role of HLA-DQ polymorphisms on immune response to bacterial superantigens using transgenic mice. , 2007, Tissue antigens.

[46]  J. Jeong,et al.  Bacteriologic Comparison of Tonsil Core in Recurrent Tonsillitis and Tonsillar Hypertrophy , 2007, The Laryngoscope.

[47]  B. Hirst,et al.  Pili mediate specific adhesion of Streptococcus pyogenes to human tonsil and skin , 2007, Cellular microbiology.

[48]  J. Musser,et al.  New understanding of the group A Streptococcus pathogenesis cycle. , 2007, Trends in microbiology.

[49]  D. Zavadska,et al.  HLA class II DR and DQ genotypes and haplotypes associated with rheumatic fever among a clinically homogeneous patient population of Latvian children , 2007, Arthritis research & therapy.

[50]  F. Oguz,et al.  The role of HLA molecules in susceptibility to chronic rheumatic heart disease , 2006, International journal of immunogenetics.

[51]  J. Carapetis,et al.  The global burden of group A streptococcal diseases. , 2005, The Lancet. Infectious diseases.

[52]  Rita Kansal,et al.  Invasive M1T1 group A Streptococcus undergoes a phase‐shift in vivo to prevent proteolytic degradation of multiple virulence factors by SpeB , 2003, Molecular microbiology.

[53]  D. Zavadska,et al.  HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia , 2003, Arthritis research & therapy.

[54]  Malak Kotb,et al.  An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections , 2002, Nature Medicine.

[55]  A. Norrby-Teglund,et al.  Differential presentation of group A streptococcal superantigens by HLA class II DQ and DR alleles , 2002, European journal of immunology.

[56]  Dwight R. Johnson,et al.  The heterogeneity of endemic community pediatric group a streptococcal pharyngeal isolates and their relationship to invasive isolates. , 2002, The Journal of infectious diseases.

[57]  Dwight R. Johnson,et al.  Dynamic epidemiology of group A streptococcal serotypes associated with pharyngitis , 2001, The Lancet.

[58]  Ramy K. Aziz,et al.  Reciprocal, Temporal Expression of SpeA and SpeB by Invasive M1T1 Group A Streptococcal Isolates In Vivo , 2001, Infection and Immunity.

[59]  Mark H. Ebell,et al.  Does This Patient Have Strep Throat , 2000 .

[60]  M. Cunningham,et al.  Pathogenesis of group A streptococcal infections. , 2000, Clinical microbiology reviews.

[61]  Malak Kotb,et al.  Genetic Relatedness and Superantigen Expression in Group A Streptococcus Serotype M1 Isolates from Patients with Severe and Nonsevere Invasive Diseases , 2000, Infection and Immunity.

[62]  J. Schellekens,et al.  Invasive group A streptococcal disease in the Netherlands: evidence for a protective role of anti-exotoxin A antibodies. , 2000, The Journal of infectious diseases.

[63]  J. Andersson,et al.  Invasive group A streptococcal infections: T1M1 isolates expressing pyrogenic exotoxins A and B in combination with selective lack of toxin-neutralizing antibodies are associated with increased risk of streptococcal toxic shock syndrome. , 1999, The Journal of infectious diseases.

[64]  B. Schwartz,et al.  Risk Factors in the Pathogenesis of Invasive Group A Streptococcal Infections: Role of Protective Humoral Immunity , 1999, Infection and Immunity.

[65]  M. Pichichero,et al.  Recurrent group A streptococcal tonsillopharyngitis. , 1998, The Pediatric infectious disease journal.

[66]  M. Kleerebezem,et al.  Controlled overproduction of proteins by lactic acid bacteria. , 1997, Trends in biotechnology.

[67]  A. Norrby-Teglund,et al.  Relation between low capacity of human sera to inhibit streptococcal mitogens and serious manifestation of disease. , 1994, The Journal of infectious diseases.

[68]  J M Scheller,et al.  The rational clinical examination. , 1992, JAMA.

[69]  A. Jones,et al.  American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc. , 2004 .

[70]  P. Soulié,et al.  RHEUMATIC HEART DISEASE , 1954, La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris.

[71]  M. Nussenzweig,et al.  Dopamine in germinal centers , 2017, Nature Immunology.

[72]  M H Ebell,et al.  The rational clinical examination. Does this patient have strep throat? , 2000, JAMA.

[73]  B. Schwartz,et al.  Risk factors in the pathogenesis of invasive group A streptococcal infections: role of protective humoral immunity. , 1999, Infection and immunity.

[74]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .