ABSTRACT
PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients.
Subject(s)
Cytomegalovirus Infections , Lymphadenitis , Microcephaly , Phosphatidylinositol 3-Kinases , Respiratory Tract Infections , Adolescent , Class Ia Phosphatidylinositol 3-Kinase , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/immunology , Humans , Lymphadenitis/complications , Lymphadenitis/genetics , Lymphadenitis/immunology , Male , Microcephaly/complications , Microcephaly/genetics , Paranasal Sinuses/physiopathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/immunology , Recurrence , Respiratory Tract Infections/complications , Respiratory Tract Infections/genetics , Th17 Cells/immunologyABSTRACT
Chronic cytomegalovirus (CMV) infection may contribute significantly to T-cell immunosenescence, chronic inflammation, and adverse health outcomes in older adults. Recent studies suggest detectable CMV DNA in peripheral monocytes as a better indicator for this persistent viral infection than anti-CMV IgG serology. Here, we conducted longitudinal comparisons of anti-CMV IgG titers, CMV DNA in the peripheral monocytes, serum IL-6 levels, and CMV pp65 (NLV)-specific CD8(+) T-cell frequencies in fifteen community-dwelling older women with twelve year follow-up. The results showed that anti-CMV IgG titers did not change over twelve years. Women with detectable CMV DNA had significantly higher IL-6 levels than those without, both at baseline (3.06±0.58 vs 1.19±0.37pg/ml, respectively, p<.001) and at the follow-up (3.23±0.66 versus 0.98±0.37pg/ml, respectively, p<.001). In addition, CMV pp65 (NLV)-specific CD8(+) T cells were detected only in women who had CMV DNA with similar frequencies at both time points. These findings indicate that anti-CMV IgG serology is neither sensitive to change nor useful for monitoring chronic CMV infection over time. They also provide a basis for further investigation into chronic CMV infection as defined by detectable CMV DNA in the peripheral monocytes and its impact on immunity and health in the elderly.