Dataset Information

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

ABSTRACT: Common variable immunodeficiency (CVID) is a late-onset humoral deficiency characterized by B lymphocyte dysfunction or loss, decreased immunoglobulin production, and recurrent bacterial infections. CVID is the most frequent human primary immunodeficiency but still presents challenges in the understanding of its etiology and treatment. CVID in equine patients manifests with a natural impairment of B lymphocyte differentiation, and is a unique model to identify genetic and epigenetic mechanisms of disease. Bone marrow transcriptome analyses revealed decreased expression of genes indicative of the pro-B cell differentiation stage, importantly PAX5 (p?0.023). We hypothesized that aberrant epigenetic regulation caused PAX5 gene silencing, resulting in the late-onset and non-familial manifestation of CVID. A significant increase in PAX5 enhancer region methylation was identified in equine CVID patients by genome-wide reduced-representation bisulfite sequencing and bisulfite PCR sequencing (p=0.000). Thus, we demonstrate that integrating transcriptomics and epigenetics in CVID enlightens potential mechanisms of dysfunctional B lymphopoiesis or function.

SUBMITTER: Tallmadge RL

PROVIDER: S-EPMC4581901 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

Tallmadge Rebecca L RL Shen Lishuang L Tseng Chia T CT Miller Steven C SC Barry Jay J Felippe M Julia B MJ

Clinical immunology (Orlando, Fla.) 20150516 2

Common variable immunodeficiency (CVID) is a late-onset humoral deficiency characterized by B lymphocyte dysfunction or loss, decreased immunoglobulin production, and recurrent bacterial infections. CVID is the most frequent human primary immunodeficiency but still presents challenges in the understanding of its etiology and treatment. CVID in equine patients manifests with a natural impairment of B lymphocyte differentiation, and is a unique model to identify genetic and epigenetic mechanisms o ...[more]

PMID: 25988861

Similar Datasets

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

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

Publications

Bone marrow transcriptome and epigenome profiles of equine common variable immunodeficiency patients unveil block of B lymphocyte differentiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets