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.

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management

“…This observation revealed a novel mechanism responsible for the defective generation of memory cells in CVID patients [17]. Using an equine CVID model, disturbance of methylation in the form of hypermethylation of PAX5 was shown to block B-cell development, reduce B-cell numbers, and lead to the development of late-onset CVID [22]. Other factors implicated in the epigenetic regulation of B cells are ncRNAs [26], which exert their regulatory functions by posttranscriptional changes in mRNA or by influencing DNA transcription [26].…”

“…Several recent studies have highlighted the role of epigenetic factors in the pathogenesis of CVID [16,17,22,23]. Epigenetic mechanisms can influence gene expression without altering the germline DNA gene sequences and play an important role in the normal developmental program of immune cells [16].…”

Heat stress: A risk factor for skin carcinogenesis

“…If melanin is produced and distributed correctly, keratinocytes are protected from the harmful effects of UV, even as the cell is undergoing cell division (Seripa et al, 2015;Tallmadge et al, 2015;Wilken et al, 2015). However, if the melanin production and distribution is significantly reduced, or if alterations in the signalling pathways of the keratinocyte-melanocyte complex arise, leading to diminished melanin production, then it is possible for UV and other environmental stresses to cause the DNA mutations that precede skin cancers .…”

Neuroborreliosis in a horse with common variable immunodeficiency

“…Relatively few cases have been reported, 2,3,6,12,17 though the Equine Immunology Laboratory at Cornell College of Veterinary Medicine (Ithaca, NY) has identified this condition in >50 horses since 2002 and has been actively investigating potential genetic and epigenetic mechanisms of the disease. 16 Age of onset is 2-23 y, with an average of 11.3 y. Like human patients, horses with CVID most often have recurrent infections of the respiratory tract.…”