Dataset Information

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

ABSTRACT:

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.

Funding

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

SUBMITTER: Maglione PJ

PROVIDER: S-EPMC6483510 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Maglione Paul J PJ Gyimesi Gavin G Cols Montserrat M Radigan Lin L Ko Huaibin M HM Weinberger Tamar T Lee Brian H BH Grasset Emilie K EK Rahman Adeeb H AH Cerutti Andrea A Cunningham-Rundles Charlotte C

JCI insight 20190307 5

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 30843876

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Project description:Common variable immunodeficiency (CVID) is the most frequently diagnosed primary antibody deficiency. About half of CVID patients develop chronic non-infectious complications thought to be due to intrinsic immune dysregulation, including autoimmunity, gastrointestinal disease, and interstitial lung disease (ILD). Multiple studies have found ILD to be a significant cause of morbidity and mortality in CVID. Yet, the precise mechanisms underlying this complication in CVID are poorly understood. CVID ILD is marked by profound pulmonary infiltration of both T and B cells as well as granulomatous inflammation in many cases. B cell depletive therapy, whether done as a monotherapy or in combination with another immunosuppressive agent, has become a standard of therapy for CVID ILD. However, CVID is a heterogeneous disorder, as is its lung pathology, and the precise patients that would benefit from B cell depletive therapy, when it should administered, and how long it should be repeated all remain gaps in our knowledge. Moreover, some have ILD recurrence after B cell depletive therapy and the relative importance of B cell biology remains incompletely defined. Developmental and functional abnormalities of B cell compartments observed in CVID ILD and related conditions suggest that imbalance of B cell signaling networks may promote lung disease. Included within these potential mechanisms of disease is B cell activating factor (BAFF), a cytokine that is upregulated by the interferon gamma (IFN-γ):STAT1 signaling axis to potently influence B cell activation and survival. B cell responses to BAFF are shaped by the divergent effects and expression patterns of its three receptors: BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA). Moreover, soluble forms of BAFF-R, TACI, and BCMA exist and may further influence the pathogenesis of ILD. Continued efforts to understand how dysregulated B cell biology promotes ILD development and progression will help close the gap in our understanding of how to best diagnose, define, and manage ILD in CVID.

Project description:BackgroundCommon variable immunodeficiency (CVID) is one of the most common primary immunodeficiency syndromes, affecting one in 25,000-50,000 people. Renal insufficiency occurs in approximately 2% of patients with CVID. To date, there are no case series of renal biopsies from patients with CVID, making it difficult to determine whether individual cases of renal disease in CVID represent sporadic events or are related to the underlying pathophysiology. We performed a retrospective analysis of renal biopsy specimens in our database from patients with a clinical history of CVID (n=22 patients, 27 biopsies).MethodsLight, immunofluorescence, and electron microscopy were reviewed. IgG subclasses, PLA2R immunohistochemistry, and THSD7A, EXT1, and NELL1 immunofluorescence were performed on all membranous glomerulopathy cases. CD3, CD4, CD8, and CD20 immunohistochemistry was performed on cases of tubulointerstitial nephritis.ResultsAKI and proteinuria were the leading indications for renal biopsy in patients with CVID. Immune-complex glomerulopathy was present in 12 of 22 (54.5%) cases, including nine cases with membranous glomerulopathy, one case with a C3 glomerulopathy, and one case with membranoproliferative GN with IgG3κ deposits. All membranous glomerulopathy cases were PLA2R, THSD7A, EXT1, and NELL1 negative. The second most common renal biopsy diagnosis was chronic tubulointerstitial nephritis, affecting 33% of patients. All tubulointerstitial nephritis cases showed tubulitis and a lymphocytic infiltrate with >90% CD3+ T cells. Other renal biopsy diagnoses within our cohort included acute tubular injury (n=1), amyloid light-chain amyloidosis (n=1), diabetic glomerulosclerosis (n=1), thin basement membranes (n=1), pauci-immune GN (n=1), and arterionephrosclerosis (n=1).ConclusionsMembranous glomerulopathy and tubulointerstitial nephritis were the predominant pathologic findings in patients with CVID. Membranous glomerulopathy cases in patients with CVID were IgG1 subclass dominant and showed mesangial immune deposits. Four of the membranous glomerulopathy cases had associated proliferation, with mesangial and/or endocapillary hypercellularity, with or without crescent formation. CVID should be considered as a potential cause when membranous glomerulopathy or chronic tubulointerstitial nephritis is seen in a young patient with a history of recurrent infections.

Dataset Information

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

Background

Methods

Results

Conclusion

Funding

Publications

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

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