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

被引：56

作者：

Maglione, Paul J. ^{[1
]}

Gyimesi, Gavin ^{[1
]}

Cols, Montserrat ^{[1
,7
]}

Radigan, Lin ^{[1
]}

Ko, Huaibin M. ^{[2
]}

Weinberger, Tamar ^{[1
]}

Lee, Brian H. ^{[3
]}

Grasset, Emilie K. ^{[1
,4
]}

Rahman, Adeeb H. ^{[3
]}

Cerutti, Andrea ^{[1
,5
,6
]}

Cunningham-Rundles, Charlotte ^{[1
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Med, Div Clin Immunol, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Human Immune Monitoring Ctr, New York, NY 10029 USA

[4] Karolinska Univ Hosp, Ctr Mol Med, Expt Cardiovasc Med, Dept Med,Karolinska Inst, Stockholm, Sweden

[5] Inst Hosp Mar Invest Med IMIM, Program Inflammatory & Cardiovasc Disorders, Barcelona, Spain

[6] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain

[7] Mem Sloan Kettering Canc Ctr, Immunol Program, 1275 York Ave, New York, NY 10021 USA

来源：

JCI INSIGHT | 2019年 / 4卷 / 05期

基金：

瑞典研究理事会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; PRIMARY SJOGRENS-SYNDROME; GENE-EXPRESSION; TRANSMEMBRANE ACTIVATOR; IMMUNE DYSREGULATION; T-CELLS; PULMONARY; TACI; DISORDERS; MUTATIONS;

D O I：

10.1172/jci.insight.122728

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

BACKGROUND. 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. METHODS. 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. RESULTS. 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. CONCLUSION. 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.

引用

页数：18