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. 2016 Jan;186(1):78-86.
doi: 10.1016/j.ajpath.2015.09.014. Epub 2015 Nov 18.

Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome

David K Meyerholz  1 , Allyn M Lambertz  1 , Paul B McCray Jr  2
Affiliations

Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome

David K Meyerholz et al. Am J Pathol. 2016 Jan.

Abstract

Dipeptidyl peptidase 4 (DPP4, CD26), a type II transmembrane ectopeptidase, is the receptor for the Middle Eastern respiratory syndrome coronavirus (MERS-CoV). MERS emerged in 2012 and has a high mortality associated with severe lung disease. A lack of autopsy studies from MERS fatalities has hindered understanding of MERS-CoV pathogenesis. We investigated the spatial and cellular localization of DPP4 to evaluate an association MERS clinical disease. DPP4 was rarely detected in the surface epithelium from nasal cavity to conducting airways with a slightly increased incidence in distal airways. DPP4 was also found in a subset of mononuclear leukocytes and in serous cells of submucosal glands. In the parenchyma, DPP4 was found principally in type I and II cells and alveolar macrophages and was also detected in vascular endothelium (eg, lymphatics) and pleural mesothelia. Patients with chronic lung disease, such as chronic obstructive pulmonary disease and cystic fibrosis, exhibited increased DPP4 immunostaining in alveolar epithelia (type I and II cells) and alveolar macrophages with similar trends in reactive mesothelia. This finding suggests that preexisting pulmonary disease could increase MERS-CoV receptor abundance and predispose individuals to MERS morbidity and mortality, which is consistent with current clinical observations. We speculate that the preferential spatial localization of DPP4 in alveolar regions may explain why MERS is characterized by lower respiratory tract disease.

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Figures

Figure 1
Figure 1
Dipeptidyl peptidase 4 (DPP4) immunostaining in nasal mucosa. A: Surface epithelial cells lack DPP4 immunostaining but scattered mononuclear cells in the subepithelial connective tissue have cytoplasmic staining (arrows). B: In contrast, the apical surface of serous cells (arrows) in submucosal glands commonly have robust DPP4 immunostaining. Original magnification, ×400 (A and B).
Figure 2
Figure 2
Dipeptidyl peptidase 4 (DPP4) immunostaining in airways. A: In the trachea, DPP4 is observed in scattered mononuclear cells (arrows and inset) within the epithelium and in the subepithelial connective tissue, and DPP4 is sometimes seen in the apical cytoplasm of goblet cells (arrowheads). B: Submucosal glands have apical to cytoplasmic immunostaining in serous cells (arrows), but mucous cells (asterisks) lack immunostaining. Gland lumens also stain positive (arrowheads). C: In bronchus, apical staining is seen in scattered to solitary nonciliated cells (arrowheads), and apical immunostaining is seen in uncommon submucosal gland ducts (arrows). D and E: Bronchioles have robust solitary apical immunostaining in scattered to solitary nonciliated cells (D, inset) or less commonly apical border of ciliated cells including cilia (E, inset). F: Cytoplasmic staining is also uncommonly seen in select nonciliated cells that appear to be undergoing extrusion from the epithelial surface (F, insets). Original magnification: ×600 (A and D–F); ×2100 (A, inset); ×400 (B); ×200 (C); ×100 (D–F); ×225 (D–F, insets).
Figure 3
Figure 3
Dipeptidyl peptidase 4 immunostaining in lung. A: Immunostaining is detected in alveolar macrophages (red arrows) and in type II cells (black arrows). B–D: Vascular lining cells have multifocal immunostaining (arrows, B and D). C: A pulmonary vein with preferential immunostaining on vessel valves. D: Pulmonary lymph node with abundant immunostaining of the vascular cells in the medullary sinus (arrows). Original magnifications: ×600 (A); ×400 (B); ×200 (C); ×100 (D).
Figure 4
Figure 4
Differential dipeptidyl peptidase 4 (DPP4) immunostaining in relatively healthy (top) and remodeled (bottom) regions of the same cystic fibrosis lung. A and C: DPP4 is detected in the visceral pleura (arrow, inset, A) and has more intense staining in remodeled areas with plump reactive mesothelial cells (arrows, inset, C). B and D: Weak to moderate immunostaining is common in alveolar macrophages (arrows, B) in nominally affected lung. However, in areas of remodeling, activated alveolar macrophages (macrophages with larger, foamier cytoplasm and sometimes multinucleate cells) have more robust immunostaining (arrows, D). Original magnification: ×600 (A–D); ×1500 (A and C, insets).
Figure 5
Figure 5
Dipeptidyl peptidase 4 (DPP4) immunostaining increases in activated alveolar macrophages near sites of disease (eg, remodeling). A semiquantitative scoring was used to compare group 1 (healthy) and group 2 (diseased) tissues. Data are expressed as means ± SD. ∗P < 0.05, paired t-test.
Figure 6
Figure 6
Alveoli of a control (A) and chronic obstructive pulmonary disease (COPD) lung (B and C). A: Dipeptidyl peptidase 4 (DPP4) immunostaining is detected in scattered alveolar type II cells (arrows) in control lungs. B: DPP4 immunostaining increases in intensity in type II cells (arrows) and also in type I cells along septal walls (arrowhead). C: Inflammation in a COPD lung airway. Note the immunostaining in macrophages (arrowheads) but absence of immunostaining in neutrophils (arrows). D and E: Assessment of sex differences in DPP4 expression in healthy (group 1) and diseased (group 2) tissues. No significant sex-related differences in DPP4 expression are found in alveolar type II cells or alveolar macrophages. Data are expressed as means ± SD (D and E). Original magnification: ×600 (A and B); ×400 (C).
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