Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis

Background: The IL-12/IFN-γ axis plays a vital role in the control of intramacrophagic pathogens including Leishmania infections.Objective: The aim of this study was to investigate genetic defects in the IL-12/IFN-γ axis in cutaneous leishmaniasis patients, using immunological and genetic evaluation...

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Autores principales:	Farhad Ali Khattak, Noor ul Akbar, Maira Riaz, Mubashir Hussain, Khalid Rehman, Shahid Niaz Khan, Taj Ali Khan
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	IL-12Rβ1 IL-12/IFN-γ axis cutaneous leishmaniasis deficiency recurrent infection Infectious and parasitic diseases RC109-216
Acceso en línea:	https://doaj.org/article/a3e0a25a0a6c4067913ffb154265f871
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spelling	oai:doaj.org-article:a3e0a25a0a6c4067913ffb154265f8712021-11-30T04:14:00ZNovel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis1201-971210.1016/j.ijid.2021.08.049https://doaj.org/article/a3e0a25a0a6c4067913ffb154265f8712021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1201971221006822https://doaj.org/toc/1201-9712Background: The IL-12/IFN-γ axis plays a vital role in the control of intramacrophagic pathogens including Leishmania infections.Objective: The aim of this study was to investigate genetic defects in the IL-12/IFN-γ axis in cutaneous leishmaniasis patients, using immunological and genetic evaluation.Methods: Enzyme-linked immunosorbent assay was used to quantify IFN-γ , while flow cytometry was performed to analyze surface IL-12Rβ1/IL-12Rβ2 expression and phosphorylation of signal transducers as well as the activator of transcription 4 (pSTAT4). Sequencing was carried out for genetic analysis.Results: The peripheral blood mononuclear cells from the two patients (P1 and P2) demonstrated impaired production of IFN-γ. Furthermore, abolishment of the surface expression of Il-12Rβ1 was observed in lymphocytes, with consequent impairment of STAT4 phosphorylation in the lymphocytes of P1 and P2. IL-12Rβ1 deficiency was identified, which was caused by a novel homozygous missense mutation (c.485>T/p.P162L) and a novel homozygous nonsense mutation (c.805G>T/P.E269*) in the IL-12Rβ2 gene of P1 and P2, respectively. In silico analyses predicted these novel mutations as being pathogenic, causing truncated proteins, with consequent inactivation.Conclusion: Our data have expanded the phenotype and mutation spectra associated with IL-12Rβ1 deficiency, and suggest that patients with CL should be screened for mutations in genes of the IL-12/IFN-γ axis.Farhad Ali KhattakNoor ul AkbarMaira RiazMubashir HussainKhalid RehmanShahid Niaz KhanTaj Ali KhanElsevierarticleIL-12Rβ1IL-12/IFN-γ axiscutaneous leishmaniasisdeficiencyrecurrent infectionInfectious and parasitic diseasesRC109-216ENInternational Journal of Infectious Diseases, Vol 112, Iss , Pp 338-345 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IL-12Rβ1 IL-12/IFN-γ axis cutaneous leishmaniasis deficiency recurrent infection Infectious and parasitic diseases RC109-216
spellingShingle	IL-12Rβ1 IL-12/IFN-γ axis cutaneous leishmaniasis deficiency recurrent infection Infectious and parasitic diseases RC109-216 Farhad Ali Khattak Noor ul Akbar Maira Riaz Mubashir Hussain Khalid Rehman Shahid Niaz Khan Taj Ali Khan Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
description	Background: The IL-12/IFN-γ axis plays a vital role in the control of intramacrophagic pathogens including Leishmania infections.Objective: The aim of this study was to investigate genetic defects in the IL-12/IFN-γ axis in cutaneous leishmaniasis patients, using immunological and genetic evaluation.Methods: Enzyme-linked immunosorbent assay was used to quantify IFN-γ , while flow cytometry was performed to analyze surface IL-12Rβ1/IL-12Rβ2 expression and phosphorylation of signal transducers as well as the activator of transcription 4 (pSTAT4). Sequencing was carried out for genetic analysis.Results: The peripheral blood mononuclear cells from the two patients (P1 and P2) demonstrated impaired production of IFN-γ. Furthermore, abolishment of the surface expression of Il-12Rβ1 was observed in lymphocytes, with consequent impairment of STAT4 phosphorylation in the lymphocytes of P1 and P2. IL-12Rβ1 deficiency was identified, which was caused by a novel homozygous missense mutation (c.485>T/p.P162L) and a novel homozygous nonsense mutation (c.805G>T/P.E269*) in the IL-12Rβ2 gene of P1 and P2, respectively. In silico analyses predicted these novel mutations as being pathogenic, causing truncated proteins, with consequent inactivation.Conclusion: Our data have expanded the phenotype and mutation spectra associated with IL-12Rβ1 deficiency, and suggest that patients with CL should be screened for mutations in genes of the IL-12/IFN-γ axis.
format	article
author	Farhad Ali Khattak Noor ul Akbar Maira Riaz Mubashir Hussain Khalid Rehman Shahid Niaz Khan Taj Ali Khan
author_facet	Farhad Ali Khattak Noor ul Akbar Maira Riaz Mubashir Hussain Khalid Rehman Shahid Niaz Khan Taj Ali Khan
author_sort	Farhad Ali Khattak
title	Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
title_short	Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
title_full	Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
title_fullStr	Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
title_full_unstemmed	Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
title_sort	novel il-12rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a3e0a25a0a6c4067913ffb154265f871
work_keys_str_mv	AT farhadalikhattak novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis AT noorulakbar novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis AT mairariaz novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis AT mubashirhussain novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis AT khalidrehman novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis AT shahidniazkhan novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis AT tajalikhan novelil12rb1deficiencymediatesrecurrentcutaneousleishmaniasis
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Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis

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