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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

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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 4

Correlation of X-skewing results with in vitro immunoglobulin production.

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Correlation of X-skewing results with in vitro immunoglobulin production...
(A) Baseline (before immunoglobulin replacement therapy) serum IgM, IgA, and IgG of X-skewed (S: ≥80% X-skewing, black, n = 10) and non–X-skewed patients with CVID (NS: <80% X-skewing, white, n = 11) are shown. (B) LLPCs: CD20–CD27+CD38+CD138+) were generated from isolated naive or memory B cells from X-skewed and non–X-skewed patients with CVID as previously described. LLPC counts within the naive and memory B cell cultures on day 13, day 27, and day 41. Median and interquartile ranges are depicted. Statistically significant differences are highlighted as *P < 0.05 (2-tailed Mann-Whitney U test).

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