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Introduction: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) is the most frequent non-infectious cause of high fever observed among the European child population. While its cause is still not yet fully identified, PFAPA patients were previously shown to have altered tonsillar microbiome composition. Our study hypothesized that this is associated with a change in antimicrobial peptide (AMP) expression levels, as in the case of Crohn's disease which is another autoinflammatory disorder., Methods and Materials: The tonsil specimens were isolated from seven patients with PFAPA syndrome, and six patients with group A beta-hemolytic streptococcal (GAβHS) recurrent tonsillitis. Tonsillar expression levels of human beta-defensin 1-2, cathelicidin, ribonuclease-7, and liver expressed antimicrobial peptide-1 were monitored by immunohistochemistry (IHC). Expression levels were scored using semi-quantitative analysis method and were statistically analyzed by Two-Way Repeated Measures Analysis of Variance test., Results: Our results showed no significant difference in AMP expression levels between PFAPA and GAβHS patients. Immunolocalization of human beta-defensin 1 was different between the two groups; expressed at higher levels on tonsil surface epithelium (SE) than lymphoid interior (LI) in PFAPA patient group, while this was not evident in GAβHS patients group., Conclusions: Our results suggest that, PFAPA patients may be associated with altered AMP expression as in other autoinflammatory diseases. Future studies with subjects without any inflammatory condition are required for more precise conclusions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Recurrent tonsillitis might reduce the immunological capability of fighting against the infection of tonsil tissue. Polypodium leucotomos (Anapsos) immunomodulating effect has been subject of research in the last years. The aim of this research is to test the in vitro immunomodulating capacity of Anapsos in a child palatine tonsil explants model., Methods: Palatine tonsils explants of children undergoing amigdalectomy were stimulated with mononuclear cells obtained from their own blood by density gradient centrifugation. Some were then treated with Anapsos while others rest untreated. Cytokines were measured by ELISA, immune cells activation was measured by flow cytometry and activation of immunoglobulins was appreciated by indirect immunofluorescence in tonsils tissue., Results: Anapsos activates Natural Killers cells. It increases IL-2 and IFN-γ levels by the activation of Th2 lymphocytes, and IL-10, by the Th1 lymphocytes. Anapsos also increases immunoglobulins IgM, IgD and IgG4 by B-lymphocyte activation in tonsils tissue., Conclusion: Anapsos has an immunomodulating effect, both in humoral and cellular responses, which might benefit children suffering of recurrent tonsillitis as it could enhance their immune system. This effect might reduce the number of episodes suffered and therefore the number of children undergoing surgery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To analyze soluble and membrane-bound peptidase activities in the tonsils and adenoids removed from patients with adenoid hyperplasia, tonsillar hyperplasia and chronic tonsillitis., Methods: A total of 48 tissue samples from patients undergoing adenoidectomy and tonsillectomy for adenoid hyperplasia, tonsillar hyperplasia or chronic tonsillitis were analyzed. The catalytic activity of a pool of peptidases in the soluble (dipeptidyl peptidase IV, aminopeptidase A, aminopeptidase N and cystinyl aminopeptidase) and membrane-bound (prolyl endopeptidase, aspartyl aminopeptidase, aminopeptidase B and pyroglutamyl peptidase I) fractions was measured fluorometrically., Results: The activity of membrane-bound aminopeptidase B was higher in cases of chronic tonsillitis and adenoid hyperplasia than in tonsillar hyperplasia, p=0.004. Soluble dipeptidyl peptidase IV and membrane-bound pyroglutamyl peptidase I were found to be more active in tissues from male chronic tonsillitis tissues, p<0.05, while membrane-bound aminopeptidase B activity was higher in tissues of females with tonsillar hyperplasia, p<0.001. In the case of chronic tonsillitis, soluble aminopeptidase A was found to have a higher level of activity in tissues from children than those from adults, p=0.005., Conclusions: Our results suggest a potential role of soluble aminopeptidase A, soluble dipeptidyl peptidase IV, membrane-bound aminopeptidase B and membrane-bound pyroglutamyl peptidase I in the pathobiology of adenoid hyperplasia, tonsillar hyperplasia and chronic tonsillitis that is differently regulated as a function of gender. These finfings may modify in the future the clinical approach to these diseases., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: To analyse peptidase activities in the removed tonsils and adenoids from patients with chronic tonsillitis, tonsillar hyperplasia and adenoid hyperplasia., Methods: We have analyzed 48 tissue samples from patients undergoing tonsillectomy and adenoidectomy for chronic tonsillitis, tonsillar hyperplasia or adenoid hyperplasia. Tonsillectomy and adenoidectomy samples were collected and frozen for later enzyme analysis. The catalytic activity of a pool of peptidases (dipeptidyl peptidase IV, prolyl endopeptidase, aminopeptidase A, aminopeptidase N, aspartyl aminopeptidase, aminopeptidase B, neutral endopeptidase, pyroglutamyl peptidase I, puromycin-sensitive aminopeptidase and cystinyl aminopeptidase) was measured fluorometrically., Results: The activity of prolyl endopeptidase was higher in tonsillar hyperplasia and adenoid hyperplasia than in chronic tonsillitis. On the contrary, dipeptidyl peptidase IV activity was higher in chronic tonsillitis than in hypertrophic tissues. When data were stratified by age and gender, dipeptidyl peptidase IV was also found to be more active in adult and male chronic tonsillitis tissues. Inversely, dipeptidyl peptidase IV activity was higher in tissues of females with tonsillar hyperplasia., Conclusions: These data indicate the involvement of dipeptidyl peptidase IV and prolyl endopeptidase in the mechanisms underlying chronic tonsillitis, tonsillar hyperplasia and adenoid hyperplasia., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: Tonsillectomy is the most common surgery performed in the pediatric and young adult populations. Although recent guidelines based on meta-analysis suggest that perioperative chemoprophylaxis plays a role in reducing bacteraemia-related post-tonsillectomy complications, there is no evidence or agreement upon which specific antibiotic, dosage or administration route should be preferred. Since few previous studies have assessed the effectiveness of prophylaxis by direct measurement of antibiotic levels both in plasma and tissue, we designed an experimental study to quantitatively evaluate amoxicillin concentrations in children ready for tonsillectomy and compare these plasma and tissue levels with the Minimal Inhibitory Concentrations (MIC) of the bacteria more commonly involved in the upper airway infections., Methods: Thirty-three pediatric patients under 14 years of age (median 5.0, IQR 4-7, range 3-11; M:F 18:15) with recurrent tonsillitis were treated with 3 doses (established on patient's weight) of amoxicillin-clavulanic acid given orally the day before plus a further dose 2h before tonsillectomy. Amoxicillin concentrations on both homogenated tonsillar cores and plasma were measured by HPLC-UV. Bacterial epidemiology and susceptibility were derived respectively from survey data collected by Microbiology Unit and MIC according to the National Committee for Clinical Laboratory Standards (NCCLS)., Results: Median plasma and tissue amoxicillin concentrations were respectively 4.7 microg/ml (IQR 2.1-8.0; min-max 0.4-14.3) and 1.1 microg/g (IQR 0.4-2.1; min-max 0.4-12.9), considerably below the selected target MIC of pathogens involved in the upper respiratory tract infections (S. aureus, H. influenzae, M. catarrhalis). 20 Children showed undetectable amoxicillin levels in one or both tonsils. Interestingly, 7 out of these patients (35%) had plasma concentrations higher than the target MIC (8 microg/ml). No patient displayed plasma concentrations under the limit of sensitivity of the method. Poor core-plasma and left-right core correlation was observed among patients, suggesting that fibrosis developed after recurrent tonsillitis may hamper antibiotic penetration., Conclusions: Based upon direct measurement of antibiotic levels in plasma and tissue, this study suggests that a revision of the oral prophylaxis in children is required in order to reduce microbial charge in the operative field and accordingly improve the recovery after tonsillectomy., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Evaluation of lymphocyte homeostasis within the chronically inflamed adenoid, closely related to the functioning of the immune system, may have a role in qualifying children for adenoidectomy. Apoptosis is a major process maintaining balance between tonsillar lymphocytes. The Fas receptor and Bcl-2 protein family which show pro-apoptotic and anti-apoptotic actions are of particular significance in apoptosis induction. Adenoid excised due to hypertrophy with or without chronic otitis media with effusion was used as study material. Flow cytometry was used to assess the percentages of apoptotic lymphocytes and CD4(+), CD8(+), CD19(+) cells with CD95(+) antigen and Bcl-2 protein in the group of children who underwent adenoidectomy due to adenoid hypertrophy and accompanying otitis media with effusion. The percentages of CD4(+)Bcl-2(+), CD8(+)Bcl-2(+) and CD19(+)Bcl-2(+) lymphocytes in the group of children with adenoid hypertrophy and acute otitis media were lower as compared to the reference group. However, the percentages of CD4(+), CD8(+) and CD19(+) cells with CD95(+) antigen were higher in the study group comparing to the reference group. The tendency of reduced percentages of T and B lymphocytes with Bcl-2 expression and elevated percentages of these cells with CD95(+) expression within the adenoid may reflect local immunity disorders., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We aimed to determine serum IGF-1 levels and plasma ghrelin levels in male children with adenoid and tonsillar hypertrophy and compare with healthy controls., Methods: Forty-four male children with obstructive adenotonsillar hypertrophy between the ages of 8 and 11.9 years (mean 9.98+/-0.98 years) and age matched 40 healthy male children (between 8 and 12 years old, mean 9.83+/-0.85 years) as control group were enrolled in this study. In both the groups plasma ghrelin and serum IGF-1 levels were measured at 08.30, in the morning., Results: Male children with adenotonsillar hypertrophy had significantly depressed serum IGF-1 levels (227.29+/-83.11 ng/ml) and plasma ghrelin levels (389.67+/-170.94 pg/ml) compared to control group (389.67+/-170.94 ng/ml and 629.76+/-263.62 pg/ml respectively, p<0.05). Body mass indexes of children with adenotonsillar hypertrophy were significantly lower than those of their healthy peers (15.72+/-2.08 kg/m(2) and 19.12+/-2.79 kg/m(2) respectively, p<0.05)., Conclusions: Delayed growth in male children with adenotonsillar hypertrophy may be related to the lower serum IGF-1 and plasma ghrelin levels compared to that of normal male controls. Since ghrelin increases hunger and food intake and its levels increase before the meals, lower levels lead to decreased appetite and also swallowing difficulties in children with adenotonsillar hypertrophy may lead to suboptimal nutrition. Lower serum levels of IGF-1 in children with adenoid and tonsillar hypertrophy may be secondary to deficient growth hormone stimulation by ghrelin., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: We aimed to evaluate the ghrelin levels in the children with adenoid or tonsil hyperthrophies., Methods: The study included 27 children (17 boys and 10 girls). Mean age was 6.9+/-3.5 years, ranging from 3 to 16. Ghrelin levels in the patients and their weight and height measurements were evaluated before surgery and after 3 months later of the operation., Results: While 18 (67%) children were operated for adenoid hypertrophy, 9 (33%) children were operated for adenoid and tonsil hypertrophy. It was found that postoperative ghrelin levels were significantly decreased whereas weight and BMI scores were significantly increased (p<0.01). A weak correlation was observed between preoperative ghrelin and weight (r=-0.29). This negative correlation became more profound at the postoperative 3rd month examination (r=0.85) (p<0.01)., Conclusions: The present study showed that the surgical treatment provides positive contributions on the growing of children with adenoid and tonsil hypertrophies. The ghrelin levels were significantly decreased at the postoperative period in the children, and a negative relationship was observed between the ghrelin levels and the weight. These findings suggest that blood ghrelin levels may be useful as a parameter for following the development of the children.

Objective: The Waldeyer's ring, comprised of the nasopharyngeal tonsil, the paired tubal tonsils, the paired palatine tonsils, and the lingual tonsil, is arranged in a circular orientation around the wall of the throat. The location of the palatine tonsils, specifically, enables these structures to come in direct contact with potentially harmful inhaled and ingested material that exist in their native form since digestive enzymes are not present in the oral cavity. Thus, the tonsillar epithelium must not only serve a protective role but it must also function in an antigen-sampling role. Previous studies involving the tissues of the Waldeyer's ring have been focused on the adaptive immune system, with little consideration toward the innate immune system. Studies have demonstrated that the tonsils are capable of producing proinflammatory and antiviral cytokines and chemokines. In addition, other studies have highlighted the importance of epithelial cells in this response. Therefore, we postulate that toll-like receptors (TLRs), which recognize components of pathogenic organisms, may play a key role in the innate immune response in tonsillar epithelial cells. TLRs are innate pattern recognition receptors, which produce proinflammatory cytokines and chemokines upon ligation. In this study, we examine the expression and function of TLRs in the tonsillar epithelial cell lines, UT-SCC-60A and UT-SCC-60B. Additionally, we demonstrate successful isolation of primary tonsillar epithelial cells and examine TLR expression in these cells., Methods: We utilized endpoint RT-PCR, real time RT-PCR, and flow cytometric analysis to determine TLR expression. To assess TLR function, cells were stimulated with TLR ligands and supernatants were assayed for secretion of cytokines., Results: UT-SCC-60A and UTSCC-60B express TLR mRNA and TLR protein, and the observed responses to the TLR ligands, Pam3Cys and Poly I:C suggest that TLR2 and TLR3 are functional in these cells. Additionally, primary tonsillar epithelial cells express TLRs., Conclusions: TLRs are expressed in human tonsillar epithelial cells and may play a vital role in the immunological outcomes in this tissue.

Background: Epithelial cells can be called the first line of a defense barrier to microorganisms by the innate immune system. The antimicrobial peptides are the major participants of this system. Cathelicidins are a family of peptides thought to provide an innate defensive barrier against a variety of potential microbial pathogens., Objectives: To evaluate the expression of the cathelicidin in recurrent throat infection., Patients and Methods: Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical staining were performed for 10 palatine tonsil tissues with hypertrophy and 10 palatine tonsil tissues with recurrent throat infection., Results: Cathelicidin mRNA transcripts were detected in recurrent throat infection. The expression levels of cathelicidin mRNA in recurrent throat infection was significantly higher compared with those in hypertrophic tonsils. Cathelicidin protein was localized on the tonsillar surface epithelium and inflammatory cells in the tonsillar crypt of recurrent throat infection patients., Conclusion: These results suggest that cathelicidin is one of antimicrobial peptides in the human palatine tonsils, and that cathelicidin may also play an important role in innate host defense of human tonsils.

Objective: The aim of the study is to determine the possible role of oxidants and antioxidants in the pathogenesis of chronic adenotonsillitis and adenotonsillar hypertrophy in children., Patients and Methods: The children were divided into infection and hypertrophy groups, which were comparable according to age and gender distribution. The infection group was consisted of 20 children with the diagnosis of chronic adenotonsillitis and the hypertrophy group was made up of 19 children with adenotonsillar hypertrophy to whom adenotonsillectomy was performed. Preoperative blood levels of erythrocyte MDA, serum MDA, erythrocyte catalase and serum catalase, and adenoidal and tonsillar tissue levels of MDA and catalase were studied., Results: There were significant increase in tonsil MDA, adenoid MDA, tonsil catalase and adenoid catalase levels in infection group (p<0.05)., Conclusion: Oxidants and antioxidants are found to have an important role in the pathogenesis of adenotonsillar hypertrophy and chronic adenotonsillitis. These findings strengthen the hypothesis that indicates adenotonsillar hypertrophy and chronic adenotonsillitis are different diseases of the same tissues.

Objective: Human palatine tonsils and the nasopharyngheal tonsil are the largest components of the Waldeyer's ring. Subepithelial and intraepithelial lymphocytes of human adenoids and tonsils are responsible for the local and the systemic immune response. We studied the cytokine production by lymphoid cells isolated from 16 nasopharyngeal tonsils (adenoid) and 9 palatine tonsils surgically removed by from 25 children (aged from 4 to 15 years) suffering from tonsil hypertrophy., Methods: We evaluated (by the cytometry method, using BD Bioscience kits, San Diego, CA) the concentration of IL-2, IL-4, IL-5, IL-10, TNF(alpha) and IFN(gamma) released from human peripheral blood mononuclear cells (MC) (activated or not activated by phytohaemagglutinin (PHA)) cultured in vitro during 72 h. The fluorescence-activated cell sorter (FACS) analysis was also performed and the percentage of mononuclear cells (unstimulated or activated by phorbol acetate during 24 h) stained with the monoclonal antibodies anti-CD3 containing the intracellular cytokines was calculated., Results: The increased secretion of IL-2, IL-4, IL-5, TNF(alpha) and IFN(gamma) from PHA activated palatine origin immune cell cultures, as compared to adenoids, was revealed. The higher mobilization (Delta%) of CD3+ T-lymphocytes containing IL-12 in palatine cell cultures (798.5+/-276.29%), in comparison with to the adenoids (298.5+/-49.16%; p< or =0.05), was also noted., Conclusion: In palatine tonsils, as compared to adenoids, the cellular immune (Th1) response dominates over humoral immune (Th2) reaction.

The lymphoid tissue of Waldeyer's ring, and particularly the nasopharyngeal tonsil (adenoids), appears to be functionally comparable to nasal-associated lymphoid tissue in rodents. Antigen-stimulated lymphoid follicles give rise to: (a) clonal B-cell expansion; (b) B-cell receptor affinity maturation; (c) positive selection of B cells according to receptor affinity for antigen; (d) differentiation to B memory cells and plasma cells; and (e) variable induction of the joining (J)-chain gene. B-cell differentiation is also important to promote downstream isotype switching of the immunoglobulin (Ig) heavy chain constant genes. For tonsillar B cells, this process gives mainly rise to IgG and IgA plasma cells, partially associated with J-chain expression. Because the J chain is a key peptide in the polymer structure of secretory IgA, tonsils and adenoids may provide B cells for mucosal effector sites. Thus, several observations suggest that these lymphoid organs generate polymeric IgA (pIgA)-expressing B cells that migrate to the upper airway mucosa, lacrimal glands and salivary glands. Accordingly, the nasal route of vaccination induces secretory IgA-dependent regional mucosal immunity and will also enhance systemic immunity. Although the pIgA-producing capacity of tonsillar B cells is considerably decreased in children with recurrent tonsillitis, a conservative attitude towards adenotonsillectomy appears immunologically desirable, particularly in the young age group.

Forty-four adenoids and 52 palatine tonsils from 71 children and adolescents (age 3-21 years) undergoing surgery because of adenoidal hypertrophy or recurrent tonsillitis were examined for the presence of immunoglobulin-secreting cells (ISC) employing an enzyme-linked immunospot assay (ELISPOT). ISC constituted less than 2% of the mononuclear cell population. Adenoids contained IgG, IgA, and IgM ISC in significantly lower numbers than palatine tonsils. The predominant isotype of the ISC was IgG, in adenoids accounting for 62% of the ISC and in palatine tonsils for 73%. The relative numbers for IgA and IgM ISC were similar. A significant correlation existed between autologous adenoids and palatine tonsils for the numbers of IgA and IgM ISC, but not for the numbers of IgG cells. These observations suggest that, adenoid and palatine tonsils display similar immunoglobulin distribution patterns within a single individual. However, individuals with hypertrophied adenoids exhibited a numeric decrease in IgG ISC with increasing age (P less than 0.01). Both lymphoid tissues may be involved in mucosal immune defense.

The treatment of infections in the ring of Waldeyer in children is an ever present problem. Most infections are caused by group A streptococci, and various antibiotics are routinely used for their treatment. In many cases, however, this treatment is ineffective as demonstrated by prolonged disease duration and recurrences. This may be due to the resistance of the pathogens to the used antibiotic, too low dose, or inadequate penetration of the drug into the focus of infection. To explain this problem the reported investigation was undertaken carrying out bacteriological investigations of the removed tonsils and determining antibiotic concentrations in tonsil homogenates and in the serum after cloxacillin and erythromycin treatment of 45 children aged 4-14 years subjected to tonsillectomy or adenotomy . It was found that the most frequent aetiological factors in angina and adenoiditis were group A streptococci. Cloxacillin and erythromycin are the antibiotics penetrating well into the lymphoid tissue and reaching high concentrations in the focus of infection but the courses of treatment should not be shorter than 10 days.