1. Novel IL-12Rβ1 deficiency-mediates recurrent cutaneous leishmaniasis
- Author
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Noor Ul Akbar, Maira Riaz, Shahid Niaz Khan, Mubashir Hussain, Khalid Rehman, Farhad Ali Khattak, and Taj Ali Khan
- Subjects
Microbiology (medical) ,Nonsense mutation ,Leishmaniasis, Cutaneous ,Infectious and parasitic diseases ,RC109-216 ,Biology ,IL-12/IFN-γ axis ,Peripheral blood mononuclear cell ,Interferon-gamma ,cutaneous leishmaniasis ,Cutaneous leishmaniasis ,Recurrence ,medicine ,Missense mutation ,Humans ,Mutation Spectra ,Receptors, Interleukin-12 ,Leishmaniasis ,General Medicine ,deficiency ,medicine.disease ,Leishmania ,biology.organism_classification ,Interleukin-12 ,Infectious Diseases ,Immunology ,Interleukin 12 ,Leukocytes, Mononuclear ,recurrent infection ,IL-12Rβ1 - Abstract
Background The IL-12/IFN-γ axis has a vital role to regulate and control intramacrophagic pathogens (e.g., Leishmania spp and mycobacteria spp). The predisposition of mycobacteria and other intramacrphagic pathogens usually cause defects in this pathway, known as Mendelian susceptibility to mycobacterial diseases(MSMD).. However, Leishmania infections are rarely documented in those individuals having defective IL-12/IFN-γ axis. Objective To investigate the genetic defects of IL-12/IFN-γ axis in recurrent Cutaneous leishmaniasis (CL) patients using immunologic and genetic evaluation. Enzyme linked immunosorbent assay (ELISA) had assessed quantification of IFN-γ and IL-12p40 while flow cytometry identified surface IL-12Rβ1/ IL-12Rβ2 expressions and phosphorylation of STAT-4. . DNA Sequencing was carried out for genetic analysis.. Result The Peripheral blood mononuclear cells (PBMCs) from the two patients (P1 and P2) demonstrated impaired production of IFN-γ in response to IL-12+BCG stimulation. Furthermore, abolishment of the surface expression of Il-12Rβ1, impairment in the signal transducer and activator of transcription 4(STAT-4) phosphorylation in lymphocytes in both P1 and P2 were also observed. We identified the two patients (P1 and P2) with cutaneous leishmaniasis who had autosomal recessive IL-12Rβ1. deficiency due to a novel missense mutation (c.485>T/p.P162L) in exon 5 and a novel nonsense mutation (v.805G>T/P.E269*) in exon 9 of IL-12Rβ1 respectively. In silico analyses predicted that both these novel mutations (c.485>T/p.P162L and c.805G>T/P.E269*) are pathogenic and causing truncated proteins with inactivating effects. Conclusion Our data expand the phenotype and mutation spectra associated with deficiency of IL-12Rβ1. In addition toour findings highlighted that the laboratory methods are required for identifying the defects of IL12/IFN- γ axis in the recurrent CL areas to improve treatment modalities and quality of life for an epidemic leishmaniasis.
- Published
- 2021