Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome

Dytrych Petra; Krol Petra; Kotrova Michaela; Kuzilkova Daniela; Hubacek Petr; Krol Ladislav; Katra Rami; Hrusak Ondrej; Kabelka Zdenek; Dolezalova Pavla; Kalina Tomas; Fronkova Eva

doi:10.1016/j.molimm.2015.01.004

Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome

Dytrych Petra, Krol Petra, Kotrova Michaela, Kuzilkova Daniela, Hubacek Petr, Krol Ladislav, Katra Rami, Hrusak Ondrej, Kabelka Zdenek, Dolezalova Pavla, Kalina Tomas, Fronkova Eva

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: PFAPA syndrome is a benign, recurrent inflammatory disease of childhood. Tonsillectomy is one of the therapeutic options with a yet unexplained biological mechanism. We tested whether specific lymphocyte subsets recruited from blood to human tonsils participate in PFAPA pathogenesis. Methods: Paired tonsils/peripheral blood (PB) samples were investigated (a) from children with PFAPA that successfully resolved after tonsillectomy (n= 10) (b) from children with obstructive sleep apnoea syndrome as controls (n= 10). The lymphocyte profiles were analysed using 8-colour flow cytometry, immunoglobulin (IGH) and T-cell receptor (TCR) gene rearrangements via PCR and next generation sequencing; a TREC/KREC analysis was performed using qPCR. Results: The PFAPA tonsils in the asymptomatic phase had a lower percentage of B-lymphocytes than controls; T-lymphocyte counts were significantly higher in PB. The percentages of cytotoxic CD8pos T-lymphocytes were approximately 2-fold higher in PFAPA tonsils; the transitional B cells and naïve stages of both the CD4pos and CD8pos T-lymphocytes with a low expression of PD-1 molecule and high numbers of TREC were also increased. With the exception of elevated plasmablasts, no other differences were significant in PB. The expression levels of CXCL10, CXCL9 and CCL19 genes were significantly higher in PFAPA tonsils. The IGH/TCR pattern showed no clonal/oligoclonal expansion. DNA from the Epstein-Barr virus, Human Herpervirus-6 or adenovirus was detected in 7 of 10 PFAPA tonsils but also in 7 of 9 controls. Conclusions: Our findings suggest that the uninhibited, polyclonal response of newly derived lymphocytes participate in the pathogenesis of PFAPA. Because most of the observed changes were restricted to tonsils and were not present in PB, they partly explain the therapeutic success of tonsillectomy in PFAPA syndrome.

Original language	English
Pages (from-to)	139-147
Journal	Molecular Immunology
Volume	65
Issue number	1
DOIs	https://doi.org/10.1016/j.molimm.2015.01.004
Publication status	Published - 2015 May
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by GAUK 266411. T.K. and J.T. were supported by the GAČR Centre of Excellence P302/12/G101. E.F. received the ĹOreal for Women in Science Fellowship in 2013. M.K. was supported by IGA NT/14343-3. We thank Jan Stuchly for help with the data analysis. The authors are most grateful to doc. Zdeněk Kabelka, Ph. D. (passed away on 24 March 2014) for his expertise and invaluable help with all aspects of the study. The authors wish to dedicate this paper to his memory.

Publisher Copyright:
© 2015 Elsevier Ltd.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Subject classification (UKÄ)

Immunology in the medical area
Cancer and Oncology

Free keywords

Autoinflammatory disease
Chemokine
Flow cytometry
KREC
PD-1
PFAPA
T lymphocyte
T-cell receptor gene rearrangement
Tonsillectomy
TREC

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Petra, D., Petra, K., Michaela, K., Daniela, K., Petr, H., Ladislav, K., Rami, K., Ondrej, H., Zdenek, K., Pavla, D., Tomas, K., & Eva, F. (2015). Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome. Molecular Immunology, 65(1), 139-147. https://doi.org/10.1016/j.molimm.2015.01.004

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title = "Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome",

abstract = "Purpose: PFAPA syndrome is a benign, recurrent inflammatory disease of childhood. Tonsillectomy is one of the therapeutic options with a yet unexplained biological mechanism. We tested whether specific lymphocyte subsets recruited from blood to human tonsils participate in PFAPA pathogenesis. Methods: Paired tonsils/peripheral blood (PB) samples were investigated (a) from children with PFAPA that successfully resolved after tonsillectomy (n= 10) (b) from children with obstructive sleep apnoea syndrome as controls (n= 10). The lymphocyte profiles were analysed using 8-colour flow cytometry, immunoglobulin (IGH) and T-cell receptor (TCR) gene rearrangements via PCR and next generation sequencing; a TREC/KREC analysis was performed using qPCR. Results: The PFAPA tonsils in the asymptomatic phase had a lower percentage of B-lymphocytes than controls; T-lymphocyte counts were significantly higher in PB. The percentages of cytotoxic CD8pos T-lymphocytes were approximately 2-fold higher in PFAPA tonsils; the transitional B cells and na{\"i}ve stages of both the CD4pos and CD8pos T-lymphocytes with a low expression of PD-1 molecule and high numbers of TREC were also increased. With the exception of elevated plasmablasts, no other differences were significant in PB. The expression levels of CXCL10, CXCL9 and CCL19 genes were significantly higher in PFAPA tonsils. The IGH/TCR pattern showed no clonal/oligoclonal expansion. DNA from the Epstein-Barr virus, Human Herpervirus-6 or adenovirus was detected in 7 of 10 PFAPA tonsils but also in 7 of 9 controls. Conclusions: Our findings suggest that the uninhibited, polyclonal response of newly derived lymphocytes participate in the pathogenesis of PFAPA. Because most of the observed changes were restricted to tonsils and were not present in PB, they partly explain the therapeutic success of tonsillectomy in PFAPA syndrome.",

keywords = "Autoinflammatory disease, Chemokine, Flow cytometry, KREC, PD-1, PFAPA, T lymphocyte, T-cell receptor gene rearrangement, Tonsillectomy, TREC",

author = "Dytrych Petra and Krol Petra and Kotrova Michaela and Kuzilkova Daniela and Hubacek Petr and Krol Ladislav and Katra Rami and Hrusak Ondrej and Kabelka Zdenek and Dolezalova Pavla and Kalina Tomas and Fronkova Eva",

note = "Funding Information: This work was supported by GAUK 266411. T.K. and J.T. were supported by the GA{\v C}R Centre of Excellence P302/12/G101. E.F. received the {\'L}Oreal for Women in Science Fellowship in 2013. M.K. was supported by IGA NT/14343-3. We thank Jan Stuchly for help with the data analysis. The authors are most grateful to doc. Zden{\v e}k Kabelka, Ph. D. (passed away on 24 March 2014) for his expertise and invaluable help with all aspects of the study. The authors wish to dedicate this paper to his memory. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2015",

month = may,

doi = "10.1016/j.molimm.2015.01.004",

language = "English",

volume = "65",

pages = "139--147",

journal = "Molecular Immunology",

issn = "0161-5890",

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Petra, D, Petra, K, Michaela, K, Daniela, K, Petr, H, Ladislav, K, Rami, K, Ondrej, H, Zdenek, K, Pavla, D, Tomas, K & Eva, F 2015, 'Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome', Molecular Immunology, vol. 65, no. 1, pp. 139-147. https://doi.org/10.1016/j.molimm.2015.01.004

Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome. / Petra, Dytrych; Petra, Krol; Michaela, Kotrova et al.
In: Molecular Immunology, Vol. 65, No. 1, 05.2015, p. 139-147.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome

AU - Petra, Dytrych

AU - Petra, Krol

AU - Michaela, Kotrova

AU - Daniela, Kuzilkova

AU - Petr, Hubacek

AU - Ladislav, Krol

AU - Rami, Katra

AU - Ondrej, Hrusak

AU - Zdenek, Kabelka

AU - Pavla, Dolezalova

AU - Tomas, Kalina

AU - Eva, Fronkova

N1 - Funding Information: This work was supported by GAUK 266411. T.K. and J.T. were supported by the GAČR Centre of Excellence P302/12/G101. E.F. received the ĹOreal for Women in Science Fellowship in 2013. M.K. was supported by IGA NT/14343-3. We thank Jan Stuchly for help with the data analysis. The authors are most grateful to doc. Zdeněk Kabelka, Ph. D. (passed away on 24 March 2014) for his expertise and invaluable help with all aspects of the study. The authors wish to dedicate this paper to his memory. Publisher Copyright: © 2015 Elsevier Ltd. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2015/5

Y1 - 2015/5

N2 - Purpose: PFAPA syndrome is a benign, recurrent inflammatory disease of childhood. Tonsillectomy is one of the therapeutic options with a yet unexplained biological mechanism. We tested whether specific lymphocyte subsets recruited from blood to human tonsils participate in PFAPA pathogenesis. Methods: Paired tonsils/peripheral blood (PB) samples were investigated (a) from children with PFAPA that successfully resolved after tonsillectomy (n= 10) (b) from children with obstructive sleep apnoea syndrome as controls (n= 10). The lymphocyte profiles were analysed using 8-colour flow cytometry, immunoglobulin (IGH) and T-cell receptor (TCR) gene rearrangements via PCR and next generation sequencing; a TREC/KREC analysis was performed using qPCR. Results: The PFAPA tonsils in the asymptomatic phase had a lower percentage of B-lymphocytes than controls; T-lymphocyte counts were significantly higher in PB. The percentages of cytotoxic CD8pos T-lymphocytes were approximately 2-fold higher in PFAPA tonsils; the transitional B cells and naïve stages of both the CD4pos and CD8pos T-lymphocytes with a low expression of PD-1 molecule and high numbers of TREC were also increased. With the exception of elevated plasmablasts, no other differences were significant in PB. The expression levels of CXCL10, CXCL9 and CCL19 genes were significantly higher in PFAPA tonsils. The IGH/TCR pattern showed no clonal/oligoclonal expansion. DNA from the Epstein-Barr virus, Human Herpervirus-6 or adenovirus was detected in 7 of 10 PFAPA tonsils but also in 7 of 9 controls. Conclusions: Our findings suggest that the uninhibited, polyclonal response of newly derived lymphocytes participate in the pathogenesis of PFAPA. Because most of the observed changes were restricted to tonsils and were not present in PB, they partly explain the therapeutic success of tonsillectomy in PFAPA syndrome.

AB - Purpose: PFAPA syndrome is a benign, recurrent inflammatory disease of childhood. Tonsillectomy is one of the therapeutic options with a yet unexplained biological mechanism. We tested whether specific lymphocyte subsets recruited from blood to human tonsils participate in PFAPA pathogenesis. Methods: Paired tonsils/peripheral blood (PB) samples were investigated (a) from children with PFAPA that successfully resolved after tonsillectomy (n= 10) (b) from children with obstructive sleep apnoea syndrome as controls (n= 10). The lymphocyte profiles were analysed using 8-colour flow cytometry, immunoglobulin (IGH) and T-cell receptor (TCR) gene rearrangements via PCR and next generation sequencing; a TREC/KREC analysis was performed using qPCR. Results: The PFAPA tonsils in the asymptomatic phase had a lower percentage of B-lymphocytes than controls; T-lymphocyte counts were significantly higher in PB. The percentages of cytotoxic CD8pos T-lymphocytes were approximately 2-fold higher in PFAPA tonsils; the transitional B cells and naïve stages of both the CD4pos and CD8pos T-lymphocytes with a low expression of PD-1 molecule and high numbers of TREC were also increased. With the exception of elevated plasmablasts, no other differences were significant in PB. The expression levels of CXCL10, CXCL9 and CCL19 genes were significantly higher in PFAPA tonsils. The IGH/TCR pattern showed no clonal/oligoclonal expansion. DNA from the Epstein-Barr virus, Human Herpervirus-6 or adenovirus was detected in 7 of 10 PFAPA tonsils but also in 7 of 9 controls. Conclusions: Our findings suggest that the uninhibited, polyclonal response of newly derived lymphocytes participate in the pathogenesis of PFAPA. Because most of the observed changes were restricted to tonsils and were not present in PB, they partly explain the therapeutic success of tonsillectomy in PFAPA syndrome.

KW - Autoinflammatory disease

KW - Chemokine

KW - Flow cytometry

KW - KREC

KW - PD-1

KW - PFAPA

KW - T lymphocyte

KW - T-cell receptor gene rearrangement

KW - Tonsillectomy

KW - TREC

U2 - 10.1016/j.molimm.2015.01.004

DO - 10.1016/j.molimm.2015.01.004

M3 - Article

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AN - SCOPUS:84921951883

SN - 0161-5890

VL - 65

SP - 139

EP - 147

JO - Molecular Immunology

JF - Molecular Immunology

IS - 1

ER -

Petra D, Petra K, Michaela K, Daniela K, Petr H, Ladislav K et al. Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome. Molecular Immunology. 2015 May;65(1):139-147. doi: 10.1016/j.molimm.2015.01.004