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JCI Insight. 2019 Mar 7;4(5). pii: 122728. doi: 10.1172/jci.insight.122728. eCollection 2019 Mar 7.

BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency.

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Division of Clinical Immunology, Department of Medicine.
Department of Pathology.
Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Experimental Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain.



Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and is frequently complicated by interstitial lung disease (ILD) for which etiology is unknown and therapy inadequate.


Medical record review implicated B cell dysregulation in CVID ILD progression. This was further studied in blood and lung samples using culture, cytometry, ELISA, and histology. Eleven CVID ILD patients were treated with rituximab and followed for 18 months.


Serum IgM increased in conjunction with ILD progression, a finding that reflected the extent of IgM production within B cell follicles in lung parenchyma. Targeting these pulmonary B cell follicles with rituximab ameliorated CVID ILD, but disease recurred in association with IgM elevation. Searching for a stimulus of this pulmonary B cell hyperplasia, we found B cell-activating factor (BAFF) increased in blood and lungs of progressive and post-rituximab CVID ILD patients and detected elevation of BAFF-producing monocytes in progressive ILD. This elevated BAFF interacts with naive B cells, as they are the predominant subset in progressive CVID ILD, expressing BAFF receptor (BAFF-R) within pulmonary B cell follicles and blood to promote Bcl-2 expression. Antiapoptotic Bcl-2 was linked with exclusion of apoptosis from B cell follicles in CVID ILD and increased survival of naive CVID B cells cultured with BAFF.


CVID ILD is driven by pulmonary B cell hyperplasia that is reflected by serum IgM elevation, ameliorated by rituximab, and bolstered by elevated BAFF-mediated apoptosis resistance via BAFF-R.


NIH, Primary Immune Deficiency Treatment Consortium, and Rare Disease Foundation.


B cells; Cellular immune response; Immunology

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