Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications

被引:12
作者
Abyazi, Miranda L. [1 ,2 ]
Bell, Kayla A. [1 ,2 ]
Gyimesi, Gavin [3 ]
Baker, Turner S. [4 ]
Byun, Minji [4 ]
Ko, Huaibin M. [6 ]
Cunningham-Rundles, Charlotte [4 ]
Feng, Feng [5 ]
Maglione, Paul J. [1 ,2 ]
机构
[1] Boston Univ, Sch Med, Pulm Ctr, 72 East Concord St,R304, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Dept Med, Sect Pulm Allergy Sleep & Crit Care, Boston, MA 02118 USA
[3] Fordham Univ, Dept Biol Sci, Bronx, NY 10458 USA
[4] Icahn Sch Med Mt Sinai, Dept Med, Div Clin Immunol, New York, NY 10029 USA
[5] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA
[6] Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USA
基金
美国国家卫生研究院;
关键词
Common variable immunodeficiency; CVID; lipopolysaccharide; LPS; noninfectious complications; IL-12; IFN-gamma; TNF; monocytes; T cells; DIFFERENTIAL EXPRESSION ANALYSIS; MICROBIAL TRANSLOCATION; T-CELLS; ACTIVATION; DISEASE; PATHOGENESIS; RESPONSES; IL-12;
D O I
10.1016/j.jaci.2021.06.008
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Noninfectious complications are the greatest cause of morbidity and mortality in common variable immunodeficiency (CVID), but their pathogenesis remains poorly defined. Objective: Using high-throughput approaches, we aimed to identify, correlate, and determine the significance of immunologic features of CVID with noninfectious complications (CVIDc). Methods: We simultaneously applied proteomics, RNA sequencing, and mass cytometry to a large cohort with primary antibody deficiency. Results: CVIDc is differentiated from uncomplicated CVID, other forms of primary antibody deficiency, and healthy controls by a distinct plasma proteomic profile. In addition to confirming previously reported elevations of 4-1BB, IL-6, IL-18, and IFN-gamma, we found elevations of colony-stimulating factor 1, IL-12p40, IL-18R, oncostatin M, TNF, and vascular endothelial growth factor A to differentiate CVIDc. This cytokine dysregulation correlated with deficiency of LPS-specific antibodies and increased soluble CD14, suggesting microbial translocation. Indicating potential significance of reduced LPS-specific antibodies and resultant microbial-induced inflammation, CVIDc had altered LPS-induced gene expression matching plasma proteomics and corresponding with increased CD14(+)CD16(-) monocytes, memory T cells, and tissue inflammation ameliorated by T-cell-targeted therapy. Unsupervised machine learning accurately differentiated subjects with CVIDc and supported cytokine dysregulation, antibody deficit, and T-cell activation as defining and convergent features. Conclusions: Our data expand understanding of CVIDc proteomics, establish its link with deficiency of IgA and LPS-specific antibodies, and implicate altered LPS-induced gene expression and elevated monocytes and T cells in this cytokine dysregulation. This work indicates that CVIDc results when insufficient antibody neutralization of pathogen-associated molecular patterns, like LPS, occurs in those with a heightened response to these inflammatory mediators, suggesting a 2-hit model of pathogenesis requiring further exploration.
引用
收藏
页码:315 / +
页数:21
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