TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma.
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Genentech Inc., South San Francisco, CA 94080, USA.
David F
DF
Choy
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kevin M
KM
Hart
Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Lee A
LA
Borthwick
Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE3 9QP, UK.
Aarti
A
Shikotra
Genentech Inc., South San Francisco, CA 94080, USA.
Deepti R
DR
Nagarkar
Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE3 9QP, UK.
Salman
S
Siddiqui
Genentech Inc., South San Francisco, CA 94080, USA.
Guiquan
G
Jia
Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE3 9QP, UK.
Chandra M
CM
Ohri
Genentech Inc., South San Francisco, CA 94080, USA. Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.
Emma
E
Doran
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kevin M
KM
Vannella
Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.
Claire A
CA
Butler
Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE3 9QP, UK.
Beverley
B
Hargadon
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Joshua C
JC
Sciurba
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Richard L
RL
Gieseck
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Robert W
RW
Thompson
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sandra
S
White
Genentech Inc., South San Francisco, CA 94080, USA.
Alexander R
AR
Abbas
Genentech Inc., South San Francisco, CA 94080, USA.
Janet
J
Jackman
Genentech Inc., South San Francisco, CA 94080, USA.
Lawren C
LC
Wu
Genentech Inc., South San Francisco, CA 94080, USA.
Jackson G
JG
Egen
Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.
Liam G
LG
Heaney
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Thirumalai R
TR
Ramalingam
Genentech Inc., South San Francisco, CA 94080, USA. arron.joseph@gene.com.
Joseph R
JR
Arron
Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Thomas A
TA
Wynn
Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE3 9QP, UK.
Peter
P
Bradding
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D058504:Th17 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*
D018793:Interleukin-13; D020381:Interleukin-17