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

ABSTRACT: "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.

SUBMITTER: Dan JM

PROVIDER: S-EPMC6561727 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Dan Jennifer M JM Havenar-Daughton Colin C Kendric Kayla K Al-Kolla Rita R Kaushik Kirti K Rosales Sandy L SL Anderson Ericka L EL LaRock Christopher N CN Vijayanand Pandurangan P Seumois Grégory G Layfield David D Cutress Ramsey I RI Ottensmeier Christian H CH Lindestam Arlehamn Cecilia S CS Sette Alessandro A Nizet Victor V Bothwell Marcella M Brigger Matthew M Crotty Shane S

Science translational medicine 20190201 478

"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 ...[more]

PMID: 30728285

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Project description:Group A Streptococcus (GAS) infections account for an estimated 500,000 deaths every year. This bacterial pathogen is responsible for a variety of mild and life-threatening infections and the triggering of chronic autoimmune sequelae. Pharyngitis caused by group A Streptococcus (GAS), but not asymptomatic GAS carriage, is a prerequisite for acute rheumatic fever (ARF). Repeated bouts of ARF may trigger rheumatic heart disease (RHD), a major cause of heart failure and stroke accounting for 275,000 deaths annually. A vaccine that prevents pharyngitis would markedly reduce morbidity and mortality from ARF and RHD. Nonhuman primates (NHPs) have been utilized to model GAS diseases, and experimentally infected rhesus macaques develop pharyngitis. Here we use an NHP model of GAS pharyngitis to evaluate the efficacy of an experimental vaccine, Combo5 (arginine deiminase [ADI], C5a peptidase [SCPA], streptolysin O [SLO], interleukin-8 [IL-8] protease [SpyCEP], and trigger factor [TF]), specifically designed to exclude GAS components potentially linked to autoimmune complications. Antibody responses against all Combo5 antigens were detected in NHP serum, and immunized NHPs showed a reduction in pharyngitis and tonsillitis compared to controls. Our work establishes the NHP model as a gold standard for the assessment of GAS vaccines.IMPORTANCE GAS-related diseases disproportionally affect disadvantaged populations (e.g., indigenous populations), and development of a vaccine has been neglected. A recent strong advocacy campaign driven by the World Health Organization and the International Vaccine Institute has highlighted the urgent need for a GAS vaccine. One significant obstacle in GAS vaccine development is the lack of a widely used animal model to assess vaccine efficacy. Researchers in the field use a wide range of murine models of infection and in vitro assays, sometimes yielding conflicting results. Here we present the nonhuman primate pharyngeal infection model as a tool to assess vaccine-induced protection against colonization and clinical symptoms of pharyngitis and tonsillitis. We have tested the efficacy of an experimental vaccine candidate with promising results. We believe that the utilization of this valuable tool by the GAS vaccine research community could significantly accelerate the realization of a safe and effective GAS vaccine for humans.

Project description:BackgroundThere is an ongoing debate on the indications for tonsil surgery in both children and adults with recurrent acute tonsillitis. The aim is to provide practical recommendations for diagnostics and treatment for recurrent acute tonsillitis including evidence-based decision making for tonsillectomy.MethodsA systematic literature search in PubMed, Embase, Web of Science, and ScienceDirect from 2014 until April 2023 resulted in 68 articles. These were the basis for the review and a comprehensive series of consensus statements on the most important diagnostics and indications for both non-surgical and surgical therapy. A consensus paper was circulated among the authors and members of the International Head and Neck Scientific Group until a final agreement was reached for all recommendations.ResultsThe differentiation between sore throat and tonsillitis patient episodes is mostly not feasible and hence is not relevant for diagnostic decision making. Diagnostics of a tonsillitis/sore throat episode should always include a classification with a scoring system (Centor, McIssac, FeverPAIN score) to estimate the probability of a bacterial tonsillitis, mainly due to group A streptococcus (GAS). In ambiguous cases, a point-of-care test GAS swab test is helpful. Consecutive counting of the tonsillitis/sore throat episodes is important. In addition, a specific quality of life score (Tonsillectomy Outcome Inventory 14 or Tonsil and Adenoid Health Status Instrument) should be used for each episode. Conservative treatment includes a combination of paracetamol and/or non-steroidal anti-inflammatory drugs. In case of high probability of bacterial tonsillitis, and only in such cases, especially in patients at risk, standard antibiotic treatment is initiated directly or by delayed prescription. Tonsillectomy is indicated and is highly effective if the patient has had ≥7 adequately treated episodes in the preceding year, ≥5 such episodes in each of the preceding 2 years, or ≥3 such episodes in each of the preceding 3 years. An essential part of surgery is standardized pain management because severe postoperative pain can be expected in most patients.ConclusionIt is necessary to follow a stringent treatment algorithm for an optimal and evidence-based treatment for patients with recurrent acute tonsillitis. This will help decrease worldwide treatment variability, antibiotic overuse, and avoid ineffective tonsillectomy.

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

Publications

Recurrent group A <i>Streptococcus</i> tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant T<sub>FH</sub> cells.

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

Publications

Recurrent group A &lt;i&gt;Streptococcus&lt;/i&gt; tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant T&lt;sub&gt;FH&lt;/sub&gt; cells.

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OmicsDI is part of the ELIXIR infrastructure

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Recurrent group A <i>Streptococcus</i> tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant T<sub>FH</sub> cells.