Figure Legends
Figure 1: Treatment based on molecular biomarkers for endotypes
in asthma. Asthma can be subdivided into type 2 (high) and non-type 2
(or type 2 low) endotypes based on their underlying inflammatory
pathways. For type 2 high asthma, potential biomarkers could be serum
specific IgE (sIgE), fractional exhaled nitric oxide (FeNO) and blood or
sputum eosinophils, and in some more specialized centres periostin.
Moreover, type 2 cytokines (IL-4, IL-5 and IL-13) and innate
(epithelial) cytokines (IL-25, IL-33 and TSLP) can also be important
biomarkers. The options to treat with biologicals emphasizing biomarkers
of Type 2 high endotype have entered the market: IgE (Omalizumab), IL-5
(Mepolizumab, Reslizumab, Benralizumab) and IL-4/IL-13 (Dupilumab). In
contrast, the diagnosis of type 2 low asthma is difficult to establish
as generally based on increased sputum neutrophils or pauci-granulocytic
with normal levels of other type 2 markers, and non-type 2 cytokines
(IL-8 or IL-17). There are still some associated indicators including
obesity, smoking habits and psychological aspects. Therefore,
therapeutic strategies for patients with type 2 low asthma could be
macrolides and bronchial thermoplasty.
Figure 2: Microbiome Biomarkers in Asthma. Alterations in the
gut and airway microbiota during childhood have been associated with
asthma risk. The higher relative abundance of Veillonella andPrevotella and a switch from aCorynebacterium and Dolosigranulum cluster to aMoraxella cluster in the upper-airways were associated with a
higher risk of severe asthma exacerbation in children with asthma. The
lower relative abundance of genera including Lachnospira ,Veillonella , Faecalibacterium , Rothia ,Bifidobacterium and Akkermansia in the gut during early
life have been associated with the development of asthma. The increases
in relative abundance of Gemmiger, Escherichia, Candidaand Rhodotorula within the gut were also associated with the
subsequent development of asthma.
Figure 3: Immune cells and mediators as biomarkers in allergic
rhinitis (AR). AR is associated with abnormalities in epithelial
barrier function which is caused by exposure to exogenous proteases from
allergens bacteria and viruses. These changes in epithelial barrier
could contribute to the allergen absorption and disruption of epithelial
tight junction. Activated dendritic cells (DCs) present allergen
peptides to naive T cells and drive them to differentiate into Th2 cells
and also allergen specific Th2A cells. Damaged epithelial cells release
a high level of alarmin (TSLP, IL-25, and IL-33), which activate the
group 2 innate lymphoid cells (ILC2s) as well as pathogenic memory T
helper (Th) 2 cells. All these cells produce large amounts of
proinflammatory mediators including IL-4, IL-5, IL-9, and IL-13.
Besides, IL-4 and IL-13 are involved in IgE class-switch in B cells. IgE
binding to mast cells can trigger the release of mast cell-associated
mediators, such as prostaglandin D2 and leukotrienes, which could also
activate the function of ILC2. PGD2 signaling could be a promising
biomarker, as it can also activate eosinophils and basophils. Moreover,
CD203c expression on basophils exhibits a time-of-day-dependent
variation, which could partly be responsible for temporal symptomatic
variations in AR. IgG4 increased during allergen immunotherapy (AIT) is
purported to be a blocking antibody by competing for allergen binding
with IgE bound to Fcε receptors on mast cells and basophils.cysLT,
Leukotrienes; PGD2, prostaglandin D2.
Figure 4: Biomarkers of viral infections in the exacerbation of
AR. After the epithelial cells are infected with viruses, the
replicating virus can cause cell lysis and direct damage to the
epithelium which causes deficiency in the production of antiviral
interferon (IFN)-β and IFN-λ1. Together with the allergen induced
cytokines IL-25, IL-33 and TSLP, ILC2s are activated and produce more
type 2 cytokines. Subepithelial plasmacytoid dendritic cells (pDCs)
recognize virus antigens and present them to CD4+ T
cells and CD8+ T cells through MHC class Ⅱ or Ⅰ, and
drive them towards a more type 2 centric response. Excessive release of
chemokines and cytokines can be triggered by infections such as
respiratory-syncytial virus (RSV). Together with type 2 cytokines, they
could further promote the function of type 2 macrophages, a small
fraction of IL-4-secreting NK cells, IL-4-secreting NK-T cells,
neutrophils, eosinophils and mast cells, and augment type 2 responses in
chronically inflamed airways. With the production of perforin and
granzymes, CD8+ T cells can show cytotoxicity to
virus-infected epithelial cells and induce apoptosis. The viral RNA is
released and detected by airway smooth muscle cells and stimulates the
production of prostaglandins (PGs) in an autocrine manner.
Figure 5: Biomarkers in food allergy diagnosis and treatment
outcomes prediction. Conventional clinical approaches to diagnose food
allergy include family history, skin integrity and the oral food
challenge. Nowadays, expanded approaches focusing on genetic risk
factors, allergen-specific and non-specific humoral and cellular
biomarkers were explored. Genome, epigenome and mRNA linked to
epithelial integrity and barrier (dys)function are linked to the
development of food allergy. The measurement of IgE and IgG4 binding to
linear or conformational epitopes could be more powerful to diagnose
food allergy than conventional approaches. The soluble high-affinity IgE
receptor (FcεRI) may also act as a biomarker for IgE mediated
pathologies in a less allergen independent way. Moreover,
allergen-specific Th2A cells and memory B cells have been discovered as
new cellular biomarkers. Functional tests that simulate allergen
exposure in vitro or ex vivo like the basophil activation test
(BAT) and mast cell activation test (MAT) offer the possibility to
assess allergen induced IgE crosslinking.
Figure 6: Mechanisms of immune-mediated reactions to drugs.These reactions encompass immediate reactions (mediated by IgE), and
non-immediate reactions (mediated by T cells). In immediate reactions,
drug-induced polarization of Th2 cells from Th0 cells, promote B cells
to produce specific IgE (sIgE). These sIgE bind to the FcεRI receptor on
mast cells. In subsequent drug contacts, the simultaneous recognition by
at least two sIgE initiates the degranulation and release of mediators.
Non-immediate reactions are generally characterized by a Th1 response
with the increased secretion of IFN-γ from Th1 cells and granulysin from
NK cells.
Figure 7: Mechanisms of cross-reactive hypersensitivity
reactions to NSAIDs. NSAIDs induce reactions relying on their COX-1
inhibitory activity, i.e. activation of mast cells and other
immune cells without involvement of adaptive immunity. During
NSAID-exacerbated respiratory disease (NERD), the administration of
NSAIDs permits strong 5-lipoxygenase (5LOX) activation and further
generation of leukotriene E4 (LTE4). LTE4 induce the release of IL-33
and TSLP, and consequent mast-cell activation, with bronchoconstriction
occurring as a result of the direct effects of leukotriene C4 (LTC4),
prostaglandin D2 (PGD2), and other mast cell-derived products. PGD2
recruits effector cells such as Th2 cells, group 2 innate cells (ILC2s),
basophils and eosinophils to the airway. Consistently, in
NSAIDs-exacerbated cutaneous disease (NECD) and NSAIDs-induced
urticarial-angioedema (NIUA), increased PGD2 can act on the skin
epidermis. In addition, cross‐reactive hypersensitivity to NSAIDs may
involve additional sources of inflammatory mediators, such as
eosinophils and platelets. ILC2: innate lymphoid cells 2; LTE4/C4:
leukotriene E4/C4; NSAID: Non-steroidal anti-inflammatory drugs; PGD2:
prostaglandin D2; TSLP: thymic stromal lymphopoietin; 5LOX:
5-lipooxygenase.
Figure 8: Current view on mechanism and biomarkers in use to
monitor AIT. A. Scheme of immune modulation by AIT, where low dose,
repeated exposure to allergen is thought to occur with limited to no
inflammation. As a result, Th skewing is balanced towards Th1 and Treg,
which subsequently modify the B-cell response. Especially the production
of IL-10 is thought to drive IgG4 class switching. Thus, local and
systemic memory is rebalanced, both in the T-cell and the B-cell
compartment, and there is a strong increase in allergen-specific IgG4
antibodies. Upon allergen challenge, IgG4 and potentially other soluble
factors are thought to inhibit IgE-mediated degranulation of target
cells, i.e. desensitization. Together with the loss of Th2 skewing, this
underlies the observed clinical tolerance. B. Laboratory
biomarkers utilized in diagnostics and clinical trials for AIT (adapted
from 230). Abbreviations: IgE-FAB, IgE-facilitated
allergen binding; IgE-BF, IgE-blocking factor; BHR, basophil histamine
release; DAO, diamine oxidase; Treg, regulatory T cell; Breg, regulatory
B-cell; DC, dendritic cell. Figure reproduced from228.