Aberrant X chromosome skewing and acquired clonal hematopoiesis in adult-onset common variable immunodeficiency
Gabriel K. Wong, … , Alex Richter, Mark Cobbold
Gabriel K. Wong, … , Alex Richter, Mark Cobbold
Published July 25, 2019
Citation Information: JCI Insight. 2019;4(14):e127614. https://doi.org/10.1172/jci.insight.127614.
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Research Article Hematology Immunology

Aberrant X chromosome skewing and acquired clonal hematopoiesis in adult-onset common variable immunodeficiency

Abstract

Advances in genomic medicine have elucidated an increasing number of genetic etiologies for patients with common variable immunodeficiency (CVID). However, there is heterogeneity in clinical and immunophenotypic presentations and a limited understanding of the underlying pathophysiology of many cases. The primary defects in CVID may extend beyond the adaptive immune system, and the combined defect in both the myeloid and lymphoid compartments suggests the mechanism may involve bone marrow output and earlier progenitors. Using the methylation profile of the human androgen receptor (AR) gene as a surrogate epigenetic marker for bone marrow clonality, we examined the hematopoietic compartments of patients with CVID. Our data show that clonal hematopoiesis is common among patients with adult-onset CVID who do not have associated noninfectious complications. Nonblood tissues did not show a skewed AR methylation status, supporting a model of an acquired clonal hematopoietic event. Attenuation of memory B cell differentiation into long-lived plasma cells (CD20–CD27+CD38+CD138+) was associated with marked changes in the postdifferentiation methylation profile, demonstrating the functional consequence of clonal hematopoiesis on humoral immunity in these patients. This study sheds light on a potential etiology of a subset of patients with CVID, and the findings suggest that it is a stage of an acquired lymphocyte maturation disorder.

Authors

Gabriel K. Wong, Sara Barmettler, James M. Heather, David Millar, Sarah A. Penny, Aarnoud Huissoon, Alex Richter, Mark Cobbold

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Figure 1

Exaggerated X chromosome skewing demonstrated in CVID group 1 patients (patients with infectious complications only) by HUMARA assay.

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Exaggerated X chromosome skewing demonstrated in CVID group 1 patients (...
X chromosome skewing of whole-blood DNA was determined using the HUMARA assay. X-skewing was corrected by the matching undigested control. (A) Results of female healthy controls (HCs) (n = 22), CVID patients (n = 23), group 1 patients (n = 12), and group 2 patients (n = 11) are shown. The horizontal lines represent the median, and statistical differences are highlighted (Mann-Whitney U test). (B) The frequencies of X-skewing of HCs and patients with CVID are shown, demonstrating a right shift within the CVID cohort. Comparison of buccal and blood X-skewing suggested acquired clonal hematopoiesis in patients with CVID but primary X-skewing in healthy donors. (C) X-skewing by the HUMARA assay was compared between matching blood and buccal samples of healthy donors (n = 5, light blue circles) and patients with CVID (n = 10, red circles) who had previously demonstrated high levels of X-skewing in their whole-blood analysis. The dotted blue line represents a theoretical 1:1 ratio. Dots in the white zone are considered to have primary X-skewing, while dots in the pink zone are considered to have clonal hematopoiesis. (D) The X-skewing ratios in the blood were adjusted to the expected ratios observed in the buccal sample and depicted as a bar chart (HCs, white; CVID, red). The highest HC blood/buccal ratio (1.6) is marked by the green dotted line.