Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton’s tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.

WITHDRAWN: Causal relationship between immune cells and idiopathic pulmonary fibrosis based on Mendelian randomization analysis

“…According to the literature, B cells are closely related to the pathogenesis of IPF, especially the naive CD38dim B-cell population, which increases Bruton's tyrosine kinase (BTK) levels and promotes substrate level phosphorylation, which provides the basis for B-cell proliferation and promotes the development of IPF. CD25 expression on CD4 Tregs is a subpopulation of CD25 in the CD4 of natural regulatory T cells distributed in normal human and mouse peripheral blood and splenic tissues, which can inhibit T-cell proliferation and induce autoimmune diseases through antigenic nonspeci c mechanisms [13]. CD4 and CD25 proteins can increase the expression of the transcription factor Foxp3 [14].…”

Identification of key immune-related genes in dilated cardiomyopathy using bioinformatics analysis

“…In DCM, the cardiac fibrosis, an important pathological characteristic, could be activated by multiple humoral and cellular factors, leading to the increased cardiac rigidity, decreased myocardial performance, and enhanced sudden death risk. Accumulated studies had revealed various immune cells (e.g., macrophages, CD8(+) T cells, and activated B cells) were involved in the development of cardiac fibrosis via directly activating cardiac fibroblasts or/and indirectly releasing pro-fibrotic cytokine 13 , 25 . COL3A1 , also named collagen type III alpha 1 chain, plays a significant role in encoding fibrillar collagen, contributing to the progression of fibrosis in extensible connective tissues such as lung, skin and the vascular system.…”

Identification of key immune-related genes in dilated cardiomyopathy using bioinformatics analysis

“…In DCM, the cardiac brosis, an important pathological characteristic, could be activated by multiple humoral and cellular factors, leading to the increased cardiac rigidity, decreased myocardial performance, and enhanced sudden death risk. Accumulated studies had revealed various immune cells (e.g., macrophages, CD8(+) T cells, and activated B cells) were involved in the development of cardiac brosis via directly activating cardiac broblasts or/and indirectly releasing pro-brotic cytokine [13,25] . COL3A1, also named collagen type III alpha 1 chain, plays a signi cant role in encoding brillar collagen, contributing to the progression of brosis in extensible connective tissues such as lung, skin and the vascular system.…”