Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Mikus, M. S.; Kolmert, J.; Andersson, L. I.; Ostling, J.; Knowles, R. G.; Gomez, C.; Ericsson, M.; Thorngren, J. -O.; Khoonsari, P. E.; Dahlen, B.; Kupczyk, M.; De Meulder, B.; Auffray, C.; Bakke, P. S.; Beghe', Bianca; Bel, E. H.; Caruso, M.; Chanez, P.; Chawes, B.; Fowler, S. J.; Gaga, M.; Geiser, T.; Gjomarkaj, M.; Horvath, I.; Howarth, P. H.; Johnston, S. L.; Joos, G.; Krug, N.; Montuschi, P.; Musial, J.; Nizankowska-Mogilnicka, E.; Olsson, H. K.; Papi, A.; Rabe, K. F.; Sandstrom, T.; Shaw, D. E.; Siafakas, N. M.; Uhlen, M.; Riley, J. H.; Bates, S.; Middelveld, R. J. M.; Wheelock, C. E.; Chung, K. F.; Adcock, I. M.; Sterk, P. J.; Djukanovic, R.; Nilsson, P.; Dahlen, S. -E.; James, A.; Ahmed, H.; Balgoma, D.; Bansal, A. T.; Baribaud, F.; Bigler, J.; Billing, B.; Bisgaard, H.; Boedigheimer, M. J.; Bonnelykke, K.; Brandsma, J.; Brinkman, P.; Bucchioni, E.; Burg, D.; Bush, A.; Chaiboonchoe, A.; Checa, T.; Compton, C. H.; Corfield, J.; Cunoosamy, D.; D'Amico, A.; Emma, R.; Erpenbeck, V. J.; Erzen, D.; Fichtner, K.; Fitch, N.; Fleming, L. J.; Formaggio, E.; Frey, U.; Gahlemann, M.; Goss, V.; Guo, Y. -K.; Hashimoto, S.; Haughney, J.; Hedlin, G.; Hekking, P. -P. W.; Higenbottam, T.; Hohlfeld, J. M.; Holweg, C. T. J.; Knox, A. J.; Konradsen, J.; Lazarinis, N.; Lefaudeux, D.; Li, T.; Loza, M. J.; Lutter, R.; Manta, A.; Masefield, S.; Matthews, J. G.; Mazein, A.; Meiser, A.; Miralpeix, M.; Mores, N.; Murray, C. S.; Myles, D.; Naz, S.; Nordlund, B.; Pahus, L.; Pandis, I.; Pavlidis, S.; Postle, A.; Powel, P.; Rao, N.; Reinke, S.; Roberts, A.; Roberts, G.; Rowe, A.; Schofield, J. P. R.; Seibold, W.; Selby, A.; Sigmund, R.; Singer, F.; Sjodin, M.; Skipp, P. J.; Sousa, A. R.; Sun, K.; Thornton, B.; Uddin, M.; Van Aalderen, W. M.; Van Geest, M.; Vestbo, J.; Vissing, N. H.; Wagener, A. H.; Wagers, S. S.; Weiszhart, Z.; Wheelock, C. E.; Wheelock, A.; Wilson, S. J.; Yasinska, V.; Brusselle, G. G.; Campbell, D. A.; Contoli, M.; Damm, K.; De Rudder, I.; Delin, I.; Devautour, C.; Duplaga, M.; Eduards, M.; Ek, A.; Ekstrom, T.; Figiel, E.; Gaber, F.; Gauw, S.; Gawlewicz-Mroczka, A.; Gerding, D.; Haque, S.; Hewitt, L.; Hiemstra, P. S.; Holgate, S. T.; Holloway, J.; Kania, A.; Kanniess, F.; Karlsson, O.; Kips, J. C.; Kumlin, M.; Lantz, A. -S.; Lazarinis, N.; Magnussen, H.; Mallia, P.; Martling, I.; Meziane, L.; Oikonomidou, E.; Olsson, M.; Pace, E.; Papadopouli, E.; Papadopoulos, N.; Plataki, M.; Profita, M.; Reinius, L. E.; Richter, K.; Robinson, D. S.; Romagnoli, M.; Samara, K.; Schelfhout, V.; Skedinger, M.; Stamataki, E.; Ten Brinke, A.; Vachier, I.; Wallen-Nielsen, E.; Van Veen, I.; Weersink, E.; Wilson, S. J.; Yasinska, V.; Zervas, E.; Ziolkowska-Graca, B.

doi:10.1183/13993003.00142-2021

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation / Mikus, M.S., Kolmert, J., Andersson, L.I., Ostling, J., Knowles, R.G., Gomez, C., Ericsson, M., Thorngren, J.-O., Khoonsari, P.E., Dahlen, B., Kupczyk, M., De Meulder, B., Auffray, C., Bakke, P.S., Beghe', B., Bel, E.H., Caruso, M., Chanez, P., Chawes, B., Fowler, S.J., et al.. - In: EUROPEAN RESPIRATORY JOURNAL. - ISSN 0903-1936. - 59:2(2022), pp. N/A-N/A. [10.1183/13993003.00142-2021]

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Mikus M. S.;Kolmert J.;Andersson L. I.;Ostling J.;Knowles R. G.;Gomez C.;Ericsson M.;Thorngren J. -O.;Khoonsari P. E.;Dahlen B.;Kupczyk M.;de Meulder B.;Auffray C.;Bakke P. S.;Beghe Bianca;Bel E. H.;Caruso M.;Chanez P.;Chawes B.;Fowler S. J.;Gaga M.;Geiser T.;Gjomarkaj M.;Horvath I.;Howarth P. H.;Johnston S. L.;Joos G.;Krug N.;Montuschi P.;Musial J.;Nizankowska-Mogilnicka E.;Olsson H. K.;Papi A.;Rabe K. F.;Sandstrom T.;Shaw D. E.;Siafakas N. M.;Uhlen M.;Riley J. H.;Bates S.;Middelveld R. J. M.;Wheelock C. E.;Chung K. F.;Adcock I. M.;Sterk P. J.;Djukanovic R.;Nilsson P.;Dahlen S. -E.;James A.;Ahmed H.;Balgoma D.;Bansal A. T.;Baribaud F.;Bigler J.;Billing B.;Bisgaard H.;Boedigheimer M. J.;Bonnelykke K.;Brandsma J.;Brinkman P.;Bucchioni E.;Burg D.;Bush A.;Chaiboonchoe A.;Checa T.;Compton C. H.;Corfield J.;Cunoosamy D.;D'Amico A.;Emma R.;Erpenbeck V. J.;Erzen D.;Fichtner K.;Fitch N.;Fleming L. J.;Formaggio E.;Frey U.;Gahlemann M.;Goss V.;Guo Y. -K.;Hashimoto S.;Haughney J.;Hedlin G.;Hekking P. -P. W.;Higenbottam T.;Hohlfeld J. M.;Holweg C. T. J.;Knox A. J.;Konradsen J.;Lazarinis N.;Lefaudeux D.;Li T.;Loza M. J.;Lutter R.;Manta A.;Masefield S.;Matthews J. G.;Mazein A.;Meiser A.;Miralpeix M.;Mores N.;Murray C. S.;Myles D.;Naz S.;Nordlund B.;Pahus L.;Pandis I.;Pavlidis S.;Postle A.;Powel P.;Rao N.;Reinke S.;Roberts A.;Roberts G.;Rowe A.;Schofield J. P. R.;Seibold W.;Selby A.;Sigmund R.;Singer F.;Sjodin M.;Skipp P. J.;Sousa A. R.;Sun K.;Thornton B.;Uddin M.;van Aalderen W. M.;van Geest M.;Vestbo J.;Vissing N. H.;Wagener A. H.;Wagers S. S.;Weiszhart Z.;Wheelock C. E.;Wheelock A.;Wilson S. J.;Yasinska V.;Brusselle G. G.;Campbell D. A.;Contoli M.;Damm K.;de Rudder I.;Delin I.;Devautour C.;Duplaga M.;Eduards M.;Ek A.;Ekstrom T.;Figiel E.;Gaber F.;Gauw S.;Gawlewicz-Mroczka A.;Gerding D.;Haque S.;Hewitt L.;Hiemstra P. S.;Holgate S. T.;Holloway J.;Kania A.;Kanniess F.;Karlsson O.;Kips J. C.;Kumlin M.;Lantz A. -S.;Lazarinis N.;Magnussen H.;Mallia P.;Martling I.;Meziane L.;Oikonomidou E.;Olsson M.;Pace E.;Papadopouli E.;Papadopoulos N.;Plataki M.;Profita M.;Reinius L. E.;Richter K.;Robinson D. S.;Romagnoli M.;Samara K.;Schelfhout V.;Skedinger M.;Stamataki E.;ten Brinke A.;Vachier I.;Wallen-Nielsen E.;van Veen I.;Weersink E.;Wilson S. J.;Yasinska V.;Zervas E.;Ziolkowska-Graca B.

2022

Abstract

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

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	Anno di pubblicazione
	
				2022
			
	Rivista
	
				EUROPEAN RESPIRATORY JOURNAL
			
	N° del Volume
	
				59
			
	Fascicolo
	
				2
			
	Pagina iniziale
	
				N/A
			
	Pagina finale
	
				N/A
			
	Codice DOI
	
				https://dx.doi.org/10.1183/13993003.00142-2021
			
	Codice WoS
	
				WOS:000798166900005
			
	Codice Scopus
	
				2-s2.0-85124850563
			
	Codice PubMed
	
				34737220
			
	Citazione
	
				Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation / Mikus, M.S., Kolmert, J., Andersson, L.I., Ostling, J., Knowles, R.G., Gomez, C., Ericsson, M., Thorngren, J.-O., Khoonsari, P.E., Dahlen, B., Kupczyk, M., De Meulder, B., Auffray, C., Bakke, P.S., Beghe', B., Bel, E.H., Caruso, M., Chanez, P., Chawes, B., Fowler, S.J., et al.. - In: EUROPEAN RESPIRATORY JOURNAL. - ISSN 0903-1936. - 59:2(2022), pp. N/A-N/A. [10.1183/13993003.00142-2021]
			
	Tutti gli autori
	
						Mikus, M. S.; Kolmert, J.; Andersson, L. I.; Ostling, J.; Knowles, R. G.; Gomez, C.; Ericsson, M.; Thorngren, J. -O.; Khoonsari, P. E.; Dahlen, B.; Ku...espandi
						
	Tipologia
	
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