Abstract
Interferon-γ receptor 1 (IFNγR1) deficiency is one of the inborn errors of IFN-γ immunity underlying Mendelian Susceptibility to Mycobacterial Disease (MSMD). This molecular circuit plays a crucial role in regulating the interaction between dendritic cells (DCs) and T lymphocytes, thus affecting DCs activation, maturation, and priming of T cells involved in the immune response against intracellular pathogens. We studied a girl who developed at the age of 2.5 years a Mycobacterium avium infection characterized by disseminated necrotizing granulomatous lymphadenitis, and we compared her findings with other patients with the same genetic condition. The patient carried a heterozygous 818del4 mutation in the IFNGR1 gene responsible of autosomal dominant (AD) partial IFNγR1 deficiency. During the acute infection blood cells immunophenotyping showed a marked reduction in DCs counts, including both myeloid (mDCs) and plasmacytoid (pDCs) subsets, that reversed after successful prolonged antimicrobial therapy. Histology of her abdomen lymph node revealed a profound depletion of tissue pDCs, as compared to other age-matched granulomatous lymphadenitis of mycobacterial origin. Circulating DCs depletion was also observed in another patient with AD partial IFNγR1 deficiency during mycobacterial infection. To conclude, AD partial IFNγR1 deficiency can be associated with a transient decrease in both circulating and tissular DCs during acute mycobacterial infection, suggesting that DCs counts monitoring might constitute a useful marker of treatment response.
Highlights
Interferon-γ receptor 1 (IFNγR1) deficiency was discovered in 1996 as the first genetic etiology of the Mendelian Susceptibility to Mycobacterial Disease (MSMD) [1, 2]
We report the immunological study of a pediatric patient with autosomal dominant (AD) partial IFNγR1 deficiency who onset with disseminated mycobacterial disease that associated with defective dendritic cells (DCs) counts
DCs deficiency has been reported in patients with heterozygous germline GATA2 mutations, a heterogeneous disorder characterized by familial myelodysplasia/acute myeloid leukemia (MSD/AML), the MonoMac syndrome, and/or the Emberger syndrome [17]
Summary
Interferon-γ receptor 1 (IFNγR1) deficiency was discovered in 1996 as the first genetic etiology of the Mendelian Susceptibility to Mycobacterial Disease (MSMD) [1, 2]. Patients with autosomal recessive (AR) complete IFNγR1 deficiency display the most severe clinical phenotype with life-threatening disseminated infections starting in early childhood [3] In this form, the majority are null mutations that prevent the production of the receptor; alternatively, in-frame deletions and missense mutations are reported to cause the production of IFNγR1 that, altered in its extracellular domain, in unable to bind the ligand [3]. The autosomal dominant (AD) form of partial IFNγR1 deficiency includes heterozygous mutations in the cytoplasmic domain of the receptor leading to truncated molecule that accumulates at the cell surface, binds IFNγ, but cannot transduce the signal These patients manifest mycobacterial disease at an older age (late childhood/adulthood) and are successfully treated with prolonged antimicrobial treatment [6, 7]. We report the immunological study of a pediatric patient with AD partial IFNγR1 deficiency who onset with disseminated mycobacterial disease that associated with defective dendritic cells (DCs) counts
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