Page 21 - Škrgat, Sabina, ed. 2022. Severe Asthma - Basic and Clinical Views. Koper: University of Primorska Press. Severe Asthma Forum, 1
P. 21
racterization for the design of clinical tri- Innate Lymphoid Cells 21
als and the development of new biologic ther-
apies13. It is 12 years since the discovery of innate endotypes and immune cells in severe asthma
lymphoid cells (ILCs)3. ILCs reside at bar-
Immune Cells Drivers of Severe Asthma rier surfaces and regulate tissue homeosta-
sis, immunity, and disease pathology. Cy-
Eosinophils tokine-producing ILCs are divided into 3
groups, group 1 ILCs (ILC1s), group 2 ILCs
Eosinophils have been widely considered to (ILC2s), and group 3 ILC3 (ILC3s), based
play a prominent role in the pathogenesis of on their functional similarities to the main
T2-high asthma and have pleiotropic effects groups of adaptive T helper (Th) cells. ILC1s
on various inflammatory cells. Eosinophils are the innate equivalents of Th1 cells and
are implicated in several pathologic processes produce IFN-γ and TNF-α. ILC2s are the
including epithelial damage, smooth muscle innate equivalents of adaptive Th2 cells. On
hypertrophy, neural plasticity, and impaired activation, they secrete type 2 cytokines in-
tissue repair processes, promoting chronic cluding Il-4, IL-5 IL-9, and IL-13. They also
airway remodelling and airflow obstruction. produce amphiregulin and IL-10. ILC3s are
Additionally, blood eosinophilia or an in- the innate equivalents of Th17 cells. ILC3s
creased number of eosinophils in blood posi- produce IL-17A/F and IL-22.
tively correlated with increased disease sever-
ity, worse disease control, and increased risk Recent data suggest that ILC2s might be
of severe exacerbations. Eosinophilia results highly important in the pathogenesis of asth-
from the stimulation of eosinophil produc- ma3. They respond rapidly to allergen expo-
tion from hematopoietic stem and progeni- sure and environmental insults in mucosal
tor cells. The differentiation and survival of organs, producing type 2 cytokines. It was
eosinophils involve signalling by IL-3, IL-5, shown that epithelium-derived cytokines IL-
and GM-CSF. Of these three cytokines, IL-5 25, IL-33, and TSLP activate ILC2s result-
plays the most critical role, which is very im- ing in eosinophilia, mucus hypersecretion,
portant from a therapeutic view as a target. and remodelling of mucosal tissues. Increased
Tissue recruitment involves the activation of ILC2s have been reported in blood and BAL
their surface integrins in response to chem- from patients with asthma as compared with
otactic factors including eotaxins and lipid healthy controls, and in blood and induced
mediators. Once infiltrated, eosinophils may sputum of patients with severe asthma in
undergo activation. Upon stimulation and comparison with mild asthma. The number
activation, eosinophils release a myriad of of circulating ILC2s correlated with eosino-
signature mediators, chemokines, cytokines phil counts in induced sputum and blood and
and growth factors including ECP, eosino- ILC2s frequencies were also increased in in-
phil-derived neurotoxin (EDN), EPX, MBP, duced sputum of pediatric patients with se-
IL-5, IL-13, eotaxin, CysLT, and transform- vere asthma. Regarding the activation sta-
ing growth factor (TGF)-β1. Among these tus of circulating ILC2s subjects with severe
factors are several key actors of T2 immuni- asthma or uncontrolled asthma had increased
ty and tissue remodelling, most notably IL-4, numbers of IL-5+ and IL-13+ ILC2s cells.
IL-13, and TGF-β1. Furthermore, CysTL is a Besides IL-25, IL-33, and TSLP cytokines
potent bronchoconstrictor that acts in syner- eicosanoids likely play a critical role in pro-
gy with IL-33 and further drives the self-am- moting migration and activation of ILC2s in
plifying loop that characterizes T2 inflam- asthma. Involvement of ILC2s was also ob-
mation13,20. served with viral triggers of asthma besides
allergens, both in respiratory syncytial virus
infection in mice and e xperimental r hinovirus
als and the development of new biologic ther-
apies13. It is 12 years since the discovery of innate endotypes and immune cells in severe asthma
lymphoid cells (ILCs)3. ILCs reside at bar-
Immune Cells Drivers of Severe Asthma rier surfaces and regulate tissue homeosta-
sis, immunity, and disease pathology. Cy-
Eosinophils tokine-producing ILCs are divided into 3
groups, group 1 ILCs (ILC1s), group 2 ILCs
Eosinophils have been widely considered to (ILC2s), and group 3 ILC3 (ILC3s), based
play a prominent role in the pathogenesis of on their functional similarities to the main
T2-high asthma and have pleiotropic effects groups of adaptive T helper (Th) cells. ILC1s
on various inflammatory cells. Eosinophils are the innate equivalents of Th1 cells and
are implicated in several pathologic processes produce IFN-γ and TNF-α. ILC2s are the
including epithelial damage, smooth muscle innate equivalents of adaptive Th2 cells. On
hypertrophy, neural plasticity, and impaired activation, they secrete type 2 cytokines in-
tissue repair processes, promoting chronic cluding Il-4, IL-5 IL-9, and IL-13. They also
airway remodelling and airflow obstruction. produce amphiregulin and IL-10. ILC3s are
Additionally, blood eosinophilia or an in- the innate equivalents of Th17 cells. ILC3s
creased number of eosinophils in blood posi- produce IL-17A/F and IL-22.
tively correlated with increased disease sever-
ity, worse disease control, and increased risk Recent data suggest that ILC2s might be
of severe exacerbations. Eosinophilia results highly important in the pathogenesis of asth-
from the stimulation of eosinophil produc- ma3. They respond rapidly to allergen expo-
tion from hematopoietic stem and progeni- sure and environmental insults in mucosal
tor cells. The differentiation and survival of organs, producing type 2 cytokines. It was
eosinophils involve signalling by IL-3, IL-5, shown that epithelium-derived cytokines IL-
and GM-CSF. Of these three cytokines, IL-5 25, IL-33, and TSLP activate ILC2s result-
plays the most critical role, which is very im- ing in eosinophilia, mucus hypersecretion,
portant from a therapeutic view as a target. and remodelling of mucosal tissues. Increased
Tissue recruitment involves the activation of ILC2s have been reported in blood and BAL
their surface integrins in response to chem- from patients with asthma as compared with
otactic factors including eotaxins and lipid healthy controls, and in blood and induced
mediators. Once infiltrated, eosinophils may sputum of patients with severe asthma in
undergo activation. Upon stimulation and comparison with mild asthma. The number
activation, eosinophils release a myriad of of circulating ILC2s correlated with eosino-
signature mediators, chemokines, cytokines phil counts in induced sputum and blood and
and growth factors including ECP, eosino- ILC2s frequencies were also increased in in-
phil-derived neurotoxin (EDN), EPX, MBP, duced sputum of pediatric patients with se-
IL-5, IL-13, eotaxin, CysLT, and transform- vere asthma. Regarding the activation sta-
ing growth factor (TGF)-β1. Among these tus of circulating ILC2s subjects with severe
factors are several key actors of T2 immuni- asthma or uncontrolled asthma had increased
ty and tissue remodelling, most notably IL-4, numbers of IL-5+ and IL-13+ ILC2s cells.
IL-13, and TGF-β1. Furthermore, CysTL is a Besides IL-25, IL-33, and TSLP cytokines
potent bronchoconstrictor that acts in syner- eicosanoids likely play a critical role in pro-
gy with IL-33 and further drives the self-am- moting migration and activation of ILC2s in
plifying loop that characterizes T2 inflam- asthma. Involvement of ILC2s was also ob-
mation13,20. served with viral triggers of asthma besides
allergens, both in respiratory syncytial virus
infection in mice and e xperimental r hinovirus
