International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases · 2021
Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis.
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Khattak Farhad Ali, Akbar Noor Ul, Riaz Maira, Hussain Mubashir, Rehman Khalid, Khan Shahid Niaz, Khan Taj Ali
Аннотация
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.
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.