TY - JOUR

T1 - Deep Proteome Profiling Reveals Common Prevalence of MZB1-positive Plasma B Cells in Human Lung and Skin Fibrosis

AU - Schiller, Herbert B

AU - Mayr, Christoph H

AU - Leuschner, Gabriela

AU - Strunz, Maximilian

AU - Staab-Weijnitz, Claudia

AU - Preisendörfer, Stefan

AU - Eckes, Beate

AU - Moinzadeh, Pia

AU - Krieg, Thomas

AU - Schwartz, David A

AU - Hatz, Rudolf A

AU - Behr, Jürgen

AU - Mann, Matthias

AU - Eickelberg, Oliver

PY - 2017

Y1 - 2017

N2 - RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets.OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across endstage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis.METHODS: We collected samples of ILD tissue (n=45) and healthy donor controls (n=10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n=6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging.MEASUREMENTS AND MAIN RESULTS: We determined the abundance of >7900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteome comparison of lung and skin fibrosis identified a common upregulation of MZB1, the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG, and negatively with diffusing capacity of the lung for carbon monoxide (DLCO).CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1+ plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis (IPF).

AB - RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets.OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across endstage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis.METHODS: We collected samples of ILD tissue (n=45) and healthy donor controls (n=10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n=6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging.MEASUREMENTS AND MAIN RESULTS: We determined the abundance of >7900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteome comparison of lung and skin fibrosis identified a common upregulation of MZB1, the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG, and negatively with diffusing capacity of the lung for carbon monoxide (DLCO).CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1+ plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis (IPF).

KW - Journal Article

U2 - 10.1164/rccm.201611-2263OC

DO - 10.1164/rccm.201611-2263OC

M3 - Journal article

C2 - 28654764

VL - 196

SP - 1298

EP - 1310

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 10

ER -